1. Introduction

IJO

International Journal of Oncology

1019-6439 1791-2423

D.A. Spandidos

10.3892/ijo.2023.5556

ijo-63-4-05556

Articles

Role of miR-181a-5p in cancer (Review)

Junxin

1234 Shen

Jing

234 Zhao

Yueshui

234 Du

Fukuan

234 Li

Mingxing

234 Wu

234 Chen

234 Wang

Shurong

1 Xiao

Zhangang

234 Wu

Zhigui

134

1Department of Pharmacy, Affiliated Hospital of Southwest Medical University 2Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University 3South Sichuan Institute of Translational Medicine 4Laboratory of Personalised Cell Therapy and Cell Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China

Correspondence to: Professor Zhigui Wu, Department of Pharmacy, Affiliated Hospital of Southwest Medical University, 25 Taiping Road, Luzhou, Sichuan 646000, P.R. China, E-mail: zhiguiwu18@126.com Professor Zhangang Xiao, Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, 1 Xianglin Road, Luzhou, Sichuan 646000, P.R. China, E-mail: xzg555898@hotmail.com

10 2023

03 08 2023

63 4

108

09 02 2023 13 07 2023

2023

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

MicroRNAs (miRNAs) are non-coding RNAs (ncRNAs) that can post-transcriptionally suppress targeted genes. Dysregulated miRNAs are associated with a variety of diseases. MiR-181a-5p is a conserved miRNA with the ability to regulate pathological processes, such as angiogenesis, inflammatory response and obesity. Numerous studies have demonstrated that miR-181a-5p exerts regulatory influence on cancer development and progression, acting as an oncomiR or tumor inhibitor in various cancer types by impacting multiple hallmarks of tumor. Generally, miR-181a-5p binds to target RNA sequences with partial complementarity, resulting in suppression of the targeted genes of miR-181a-5p. However, the precise role of miR-181a-5p in cancer remains incompletely understood. The present review aims to provide a comprehensive summary of recent research on miR-181a-5p, focusing on its involvement in different types of cancer and its potential as a diagnostic and prognostic biomarker, as well as its function in chemoresistance.

miR-181a-5p cancers biomarker chemoresistance

Project of Science and Technology Department of Sichuan Province

2021YJ0445

This work was supported by the Project of Science and Technology Department of Sichuan Province (grant no. 2021YJ0445).

1. Introduction

MicroRNA (miRNAs/miRs) are small non-coding (nc) RNAs with the size of 17-25 nucleotides. The first miRNA was identified in 1993 when a small ncRNA was discovered in Caenorhabditis elegans heterochronic gene lin-4 (1). Subsequently, other small RNAs were found in Caenorhabditis elegans, Drosophila and humans (2-4). Later, researchers realized that small ncRNAs are functional products that have an impact on development outside of translating proteins (5-7). The discovery of miRNAs shed light on post-transcriptional regulation of gene expression. Briefly, miRNA genes are transcribed into primary miRNAs and processed into mature miRNA duplexes by pol-II, Drosha and Dicer. Then, the miRNA duplex is loaded into argonaute protein to form the RNA-induced silencing complex, which navigates the mature miRNA to the 3'UTR of their targeted mRNA through base pairing, resulting in mRNA transcriptional inhibition or mRNA degradation (8). In the past few years, studies on miRNAs have increased, and as of June 2023, 38,589 miRNAs have been annotated in the miRBase miRNA database (https://www.mirbase.org/). Abundant studies have substantiated the intricate association between dysregulated miRNAs and a multitude of diseases, notably carcinogenesis (9,10). These miRNAs are powerful regulators of various cellular processes including cell proliferation, differentiation, development and apoptosis (11,12). As a pivotal constituent of the ncRNA network, miRNAs possess the ability to occupy numerous nodes owing to their capacity to target a considerable number of mRNAs (13). With the development of computational and sequencing technology, researchers can easily predict the target genes of a miRNA through its sequence for target recognition called the 'seed sequence', which is the nucleotides 2-8 of a miRNA (13,14). In recent years, studies have deciphered the biological function of miRNAs extensively, but understanding of the role of miRNAs still requires a tremendous amount of work.

MiR-181a-5p has been extensively studied as a regulatory miRNA with altered expression in various diseases. For instance, studies have revealed that miR-181a-5p alleviates vascular inflammation, atherosclerosis and inflammatory response in monocrotaline-induced pulmonary arterial hypertension (15,16). In addition, it is associated with obesity and insulin resistance (17). Currently, numerous research has identified upregulated or downregulated expression levels of miR-181a-5p in different tumors, highlighting its role in regulating tumorigenesis through post-transcriptional suppression of its targeted genes (18,19). The present review summarizes the recent studies on miR-181a-5p, explain its role in cancer and chemotherapy and outlines its potential as a biomarker.

2. Regulation of miR-181a-5p in cancer

MiR-181a-5p is a conserved miRNA belonging to the miR-181 family, which comprises four mature miRNAs. These mature miRNAs, namely miR-181a, miR-181b, miR-181c and miR-181d, all share the identical 'seed' sequence 'ACAUUCA'. In humans, miR-181a is located in chromosome 1. MiR-181a-5p is a mature single strand of miR-181a with the sequence 'AACAUUCAACGCUGUCGGUGAGU', while miR-181a-3p is a passenger strand (15,20).

Numerous studies have suggested that dysregulation of miR-181a-5p in tumors is regulated the following factors:

Competing endogenous RNAs (ceRNAs). MicroRNAs have the ability to bind to specific sequences on target RNA transcripts called microRNA recognition elements (MREs). Through these MREs, ncRNAs that are upstream mediators of miRNAs, such as lncRNAs and circRNAs, can bind to miRNA and function as a miRNA sponge to inhibit its expression (21,22). Numerous ncRNAs, such as colon cancer-associated transcript 1 (CCAT1) and nuclear enriched abundant transcript 1 (NEAT1), have been demonstrated to be sponges of miR-181a-5p in multiple systems of cancer (23-25).

Transcription factors (TFs). NF-κB is positively correlated with the expression of miR-181a-5p. NF-κB short interfering (si)RNA decreases the expression of miR-181a-5p (26). In addition, STAT1 inhibits the expression of miR-181a-5p by binding to its promoter (27). These results indicate that activation or downregulation of miR-181a-5p is modulated by TFs.

DNA methylation. DNA methylation occurs in the CpG island of the promoter region. It is a crucial mechanism of miRNA downregulation. In colorectal cancer, hypermethylation of CpG islands transcriptionally represses the expression of miR-181a-5p (28).

Other factors. Hypoxia also leads to the dysregulation of miR-181a-5p. However, the effects of hypoxia for miR-181a-5p were reversed in different types of cancer. Moreover, the concrete mechanism has not yet been clarified (29,30).

3. MiR-181a-5p in different types of cancer

The growth of cancer is associated with its malignant cell hallmarks, which include the capabilities for sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing/accessing vasculature, activating invasion and metastasis, reprogramming cellular metabolism and avoiding immune destruction (31). MiR-181a-5p exerts its influence on various tumor properties, including cell proliferation, metasitasis, angiogenesis, epithelial-mesenchymal transition (EMT) and autophagy (Fig. 1). It is important to note that the expression of miR-181a-5p is specific to certain tissues and it can simultaneously target multiple genes, potentially playing dual roles. The function of miR-181a-5p is not reliant on a specific target, but rather on the collective impact of its targets, which may encompass both tumor suppressor genes and oncogenes (32). The present study summarizes the existing studies on miR-181a-5p in different tumors and has described them in various systems. The summary of results is provided in (Table I).

Tumors of the digestive system Colorectal cancer

Colorectal cancer (CRC) is the third most common cancer worldwide and also the most frequent tumor of the digestive tract. The high migratory and invasive properties of CRC cells promote the progression of CRC and lead to poor prognosis of patients with CRC (33).

MiR-181a-5p inhibits proliferation and induces apoptosis

In CRC, results indicate that miR-181a-5p suppresses tumor growth by regulating the Wnt/β-catenin signaling pathway. It has been observed to inhibit cell proliferation, 5-FU sensitivity and promote apoptosis (34,35). The inhibitory effect of miR-181a-5p has also been confirmed in microsatellite-instable CRC, where its expression of miR-181a-5p is reduced and miR-181a-5p directly binds to the 3'UTR of pleomorphic adenoma gene 1 (PLAG1) (28). Another well-established target of miR-181a-5p is p53. Upregulation of miR-181a-5p promotes apoptosis by modulating Bax and Bcl-2 (24). In addition, a previous study revealed that lncRNA-ANRIL can sponge miR-181a-5p, inhibiting apoptosis and radiosensitivity in colon cancer cells (36).

MiR-181a-5p inhibits migration and invasion

The lncRNA-SNHG6 has been identified to be positively correlated with tumor progression and distant metastasis (37). MiR-181a-5p is the direct target of both SNHG6 and E2F5. By inhibiting E2F5, miR-181a-5p induces G₀/G₁ arrest and suppresses CRC cell migration and invasion (38). Additionally, a study revealed that miR-181a-5p reverses the effects of circRNA-NSUN2 on promoting cell proliferation and migration by binding to the 3'UTR of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) (39).

MiR-181a-5p promotes CRC growth and metastasis

MiR-181a-5p have been demonstrated to be associated with liver metastasis of CRC. This may be attributed to the enrichment of miR-181a-5p in extracellular vesicles of CRC, which alters the tumor environment (TME) (40). MiR-181a-5p promotes motility, invasion and tumor growth by directly targeting Wnt inhibitory factor 1 (WIF-1). Notably, it participates in the regulation of EMT, which is considered a crucial process in cancer metastasis (41). MiR-181a-5p also promotes metastasis and cell proliferation in CRC by inhibiting PTEN, a tumor suppressor gene (42). Multiple studies have showed that miR-181a-5p binds to the 3'UTR of PTEN mRNA, leading to reduced PTEN expression and subsequent activation of the phosphorylated (p)-AKT pathway (27,43). In these cases, the expression of miR-181a-5p is upregulated by IL-1β/NF-kb signaling (26), while STAT1 acts as an inhibitor of miR-181a-5p (27). Furthermore, miR-181a-5p induces metabolic shifts in CRC, favoring glycolysis over oxidative pathways and resulting in increased lactic acid release (43). Finally, angiogenesis is an important feature for tumor growth and metastasis. The pro-angiogenic ability of miR-181a-5p has been demonstrated, and it inhibits the expression of SRC kinase signaling inhibitor 1 (SRCIN1) and reversion-inducing cysteine-rich protein with Kazal motifs (RECK) to promote angiogenesis (Fig. 2) (44,45).

Gastric cancer

Gastric cancer (GC) is a major health burden worldwide. It is the second cause of cancer-related mortalities after lung cancer (46).

MiR-181a-5p promotes GC cell proliferation

A previous study has reported an elevation of miR-181a-5p in GC tissues, which is corelated with tumor progression (47). Meanwhile, TGF-β level is decreased in GC tissues compared with normal tissues. Experimental results indicate that miR-181a-5p directly interacts with TGF-β, thereby facilitating tumor cell proliferation in vivo and in vitro (48). The Ras association domain family (RASSF) is a crucial contributor in the formation of tumors. Another study has demonstrated that miR-181a-5p promotes GC cell proliferation and G₁/S transition, and suppresses apoptosis by inhibiting RASSF1A (49). MiR-181a-5p also inhibits ATP4B and tyrosine-protein phosphatase megakaryocyte 2 to promote GC tumor growth (50,51).

MiR-181a-5p promotes GC metastasis

MiR-181a-5p modulates the RASSF6/MAPK pathway, promoting proliferation, migration, invasion, metastasis and inducing EMT in GC (52). The role of miR-181a-5p in promoting metastasis in GC is further confirmed by evidence showing that it inhibits caprin-1 to promote cell proliferation, invasion and migration, while reducing apoptosis in vitro and in vivo (53).

MiR-181a-5p inhibits GC growth and metastasis

MiR-181a-5p has been reported to negatively regulate autophagy of cisplatin resistant cells. MiR-181a-5p increases sensitivity of drug-resistant cells to cisplatin and the tumor volume of nude mice. In this context, ATG5 is a potential target of miR-181a-5p (54). Lin et al also revealed that miR-181a-5p blocks GC cell proliferation, migration and invasion (55). Oncogenic factor, Prox1, was considered to be a downstream target of miR-181a-5p (55). In gastric adenocarcinoma, miR-181a-5p has been indicated to inhibit cell proliferation and increase apoptosis by modulating the AKT pathway (Fig. 2) (56).

Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for 75-85% of all types of liver cancer, which caused ~830,000 mortalities worldwide as of 2020 (46). Several experimental results indicate that miR-181a-5p may plays its role as a tumor inhibitor in HCC (Fig. 2).

MiR-181a-5p suppresses HCC metastasis

MiR-181a-5p inhibits c-Met to promote branching-morphogenesis and invasion of HCC cells (18). Additionally, it induces glucose metabolism reprogramming, which is associated with the progression and early lung metastasis of HCC. Mechanistically, miR-181a-5p reduces the expression of mitochondrially encoded (mt)-Cytochrome B and mt-Cytochrome C oxidase subunit 2 proteins, thus decreasing the electron transport chain (ETC). This reduction in ETC activity results in an increase in hexokinase 2 (HK2) and glucose transporter 1, enhancing glucose uptake, lactic acid release and LDH activity (57).

MiR-181a-5p inhibits HCC growth

Early growth response factor1 (Egr1) plays a crucial role in cancer progression by activating the TGF-β/Smad pathway. Evidence has demonstrated that miR-181a-5p inhibits Egr1 by binding to its 3'UTR, resulting in tumor proliferation suppression in HCC (58). Assays have showed that miR-181a-5p inhibits HCC cell autophagy by targeting ATG7, which is positively correlated with autophagy (59).

However, a previous report suggested that lncRNA-XIST increases the cancer suppressor gene PTEN through the inhibition of miR-181a-5p. Restored miR-181a-5p expression promotes the HCC cell proliferation and invasion (60).

Esophageal adenocarcinoma

MiR-181a-5p inhibits cisplatin resistance in esophageal adenocarcinoma. In comparison with constructed cisplatin-resistant EAC cells, the miR-181a-5p expression is significantly higher in normal EAC cells. Furthermore, miR-181a-5p exhibits stronger cisplatin-induced inhibition of proliferation and promotion of apoptosis. In addition, CBLB, which is involved in ubiquitination to aggravate cisplatin resistance, is identified as a direct target of miR-181a-5p (Fig. 2) (61).

Pancreatic cancer

Pancreatic cancer (PC) is the most malignant tumor of the digestive system, which is extremely aggressive (62). Although early findings have revealed that miR-181a-5p, which indirectly inhibits the PTEN and MAP2K4, enhances the invasion capability of PC (63), another report after 8 years revealed that miR-181a-5p inhibits PC by targeting high mobility group box 1 (HMGB1). It inhibits PC cell proliferation, invasion, migration and resistance of gemcitabine, while reducing the expression of miR-181a-5p attenuates these effects. In addition, lncRNA-ANRIL decreases HMGB1 by sponging miR-181a-5p to activate cell autophagy (Fig. 2) (64).

Respiratory system tumors Non-small cell lung cancer (NSCLC)

Lung cancer is the most commonly diagnosed cancer in the world and is characterized by a high rate of metastasis and delayed diagnosis (65). NSCLC accounts for 80-85% of all types of lung cancer (66). The following studies indicate that miR-181a-5p is a tumor inhibitor in NSCLC. It can inhibit tumor growth and metastasis by targeting multiple pro-tumorigenic factors. MiR-181a-5p targets the recognized oncogene Kras by binding to its 3'UTR, thereby slowing cell proliferation and migration (67). It has also been found to target CDK1 and E2F7, which regulate the cell cycle and promote tumor proliferation (68,69). Additionally, miR-181a-5p has been demonstrated to target HMGB2 to inhibit NSCLC cell migration and invasion (25). It is worth mentioning that NF-κB has been indicated to promote miR-181a-5p expression in colorectal cancer (26). However, a report has demonstrated that IL-17 inhibits miR-181a-5p by activating NF-κB (70). Furthermore, vascular cell adhesion molecule 1 has been demonstrated to be a direct target of miR-181a-5p. This laterally proves that miR-181a-5p can reduce vascular oxygen supply (70). In these cases, lncRNA NEAT1 and SNHG7 have been demonstrated to be up-stream regulators of miR-181a-5p as a miRNA sponge (25,69,71). Notably, miR-181a-5p can alleviate immunosuppression and anti-PD-1 resistance of NSCLC, providing a novel strategy for enhancing the efficacy of immunotherapy (72).

Laryngeal cancer

MiR-181a-5p has a tumor suppressor property in laryngeal cancer. Myc target protein 1 (MYCT1) is known to regulate cell apoptosis (73). Recently, Wang et al revealed that MYCT1 collaborates with MYC-associated protein X to enhance the promoter of miR-181a-5p, which binds to the 3'UTR of nucleophosmin 1 (NPM1), thus inhibiting laryngeal cancerous cell viability, colony formation and promoting apoptosis (74). Another study has demonstrated that miR-181a-5p inhibits EMT of laryngeal cancer by targeting Snai2 (75).

Cancer of the reproductive system Breast cancer (BC)

BC is one of the leading causes of mortality among women worldwide (76).

MiR-181a-5p promotes tumor growth of BC

Exosome-derived miR-181a-5p is upregulated in BC. By targeting PIAS3, it promotes the expansion of early-stage myeloid-derived suppressor cells, which in turn exacerbate cell proliferation, induce tumor growth and evade immune destruction (19). In addition, miR-181a-5p increases the level of p-AKT by co-targeting PH-domain leucine-rich repeat-containing protein phosphatase 2 and Inositol polyphosphate 4-phosphatase type II phosphatases in luminal breast cancer, resulting in cell proliferation and S phase entry (77). TGF-β has been demonstrated to upregulate the expression of miR-181a-5p through mediation of its transcription. Increased miR-181a-5p reduces apoptosis and sensitivity to anoikis (78).

MiR-181a-5p promotes BC cell migration and invasion

It has been reported that lncRNA-SOX2 is downregulated and correlates with poor survival of BC. A tumorigenesis experiment conducted on nude mice has demonstrated that SOX2 suppresses tumor development and metastasis by sponging miR-181a-5p. In this case, miR-181a-5p promotes BC metastasis by inhibiting Tumor suppressor candidate 3 (79). MiR-181a-5p also targets the NDRG2 to reduce activation of PTEN, thus facilitating proliferation, invasion and glycolysis of BC (80).

MiR-181a-5p is an inhibitor of BC

MiR-181a-5p is upregulated in TNBC tissues and cells. This may be associated with the suppressive effect of ER-β, which modulates the expression of miRNA to inhibit TNBC. Upregulation of miR-181a-5p is an auxiliary mechanism of ER-β-induced cholesterol biosynthesis inhibition (81). In addition, miR-181a-5p has been revealed to be positively correlated with Bax and Caspase-9, which promote cell apoptosis (82,83). Functional experiment has revealed that miR-181a-5p inhibits cell proliferation, migration and invasion by targeting oncogenes Kruppel-like factor (KLF) 6, KLF15 and progesterone receptor membrane component 1 (Fig. 3) (84).

Cervical cancer (CC)

CC is the fourth leading cause of cancer-associated mortality among women, accounting for >2.6 million deaths worldwide every year (46,85).

MiR-181a-5p promotes CC cell proliferation and inhibits apoptosis

MiR-181a-5p expression is elevated in CC tissues. It negatively targets INPP5A to promote CC cell proliferation and invasion while inhibiting apoptosis (86). MiR-181a-5p also post-transcriptionally inhibits PTEN in CC. Inhibition of miR-181a-5p can impede cell cycle progression by increasing P21, P27, Bax and decreasing Bcl-2 (87). Moreover, miR-181a-5p is upregulated in human CC specimens and cell lines that are not responsive to radiation therapy. It suppresses radiation-induced apoptosis and G₂/M cell cycle arrest by inhibiting protein kinase C delta type (PRKCD) (88).

MiR-181a-5p inhibits CC cell proliferation

A study revealed that miR-181a-5p is aberrantly reduced in CC and inhibits proliferation and resistance of oxaliplatin. In this case, GRP78 is identified as the direct target of miR-181a-5p (89).

MiR-181a-5p inhibits CC metastasis

MiR-181a-5p has direct binding sites with TGFβ1, promoting the expression of TGFβ1 to inhibit CC proliferation, migration and invasion (90). Another group showed that miR-181a-5p inhibits invasion, migration and EMT of CC (91). LncRNA-CCAT1 is located on chromosome 8q24, where human papillomavirus integration usually occurs (92). Overexpression of CCAT1 promotes CC cell proliferation and invasion. MiR-181a-5p is identified as a downstream target of CCAT1and decreases the expression of MMP14. CCAT1 indirectly upregulates the MMP14 by suppressing miR-181a-5p to promote CC progression (Fig. 3) (23).

Endometrial carcinoma (EC)

EC is one of the most common malignancies in women and a leading cause of cancer-associated mortalities worldwide (93).

MiR-181a-5p is a tumor inhibitor in EC

A preliminary experiment revealed that the PTEN is decreased and miR-181a-5p is increased in non-obese patients with EC, suggesting that PTEN is negatively correlated with miR-181a-5p (94). More focused work revealed that miR-181a-5p inhibits EC cell proliferation and migration, while miR-181a-5p inhibitor can neutralize these effects (95). Accumulation of HK2 in EC promotes EMT and glycolysis. MiR-181a-5p is an inhibitor of HK2. An experiment has confirmed that DLEU2 interacts with enhancer of zeste homolog 2 to silence miR-181a-5p, thus inducing EMT and glycolysis (96) (Fig. 3).

Ovarian cancer

Ovarian cancer is a common tumor of the gynecological malignancy. Clinical data has demonstrated that miR-181a-5p is increased in advanced epithelial ovarian cancer and promotes tumor development (97). In an in vivo and vitro experiment, miR-181a-5p has been further indicated to promote cell proliferation, migration, invasion and EMT. SMAD family member 7 (Smd7), an inhibitor of TGF, has been identified as a direct target of miR-181a-5p (97). In high-grade serous ovarian cancer, miR-181a-5p increases stem-cell frequency and resistance of cisplatin by activating the Wnt/β-catenin signaling pathway. This activation is achieved by directly targeting Secreted frizzled-related protein 4 (SFRP4), an inhibitor of the Wnt/β-catenin pathway (Fig. 3) (98).

Prostate cancer (PCa)

PCa is the second most frequently diagnosed cancer and the sixth leading cause of cancer-associated mortality among men worldwide (99).

MiR-181a-5p may promotes EMT and tumor growth in PCa (<xref rid="f3-ijo-63-4-05556" ref-type="fig">Fig. 3</xref>)

The inhibitory effect of miR-181a-5p on PTEN has been observed in PCa. In this context, miR-181a-5p enhances cell proliferation, migration and invasion (100). To the best of our knowledge, two studies have investigated the effect of miR-181a-5p on EMT. The results revealed that miR-181a-5p promotes EMT with high E-cadherin expression by inhibiting the EMT negative regulator, KLF17. Notably, lymphoid enhancer-binding factor 1 and migration and invasion-inhibitory protein have been identified to downregulate the expression of miR-181a-5p in PCa (101,102).

Tumors of the urinary system Bladder cancer (BCa)

To the best of our knowledge, there is only one report focused on the role of miR-181a-5p in BCa. MiR-181a-5p is a tumor inhibitor in BCa. A group demonstrated that expression of circRNA-0068871 is increased, while miR-181a-5p is expressed at a low level in BCa. circRNA-0068871 intensifies cell proliferation, migration and suppressed apoptosis in vivo and vitro. Mechanistically, circRNA-0068871 acts as a sponge for miR-181a-5p, which directly targets EGFR3, indicating that miR-181a-5p is a tumor inhibitor in BCa (103).

Renal cancer

A preliminary experiment indicated that miR-181a-5p may play a role as an oncomiR in renal cancer. Compared with normal tissues and cells, miR-181a-5p is upregulated in both renal cancer tissues and cell lines. In vitro, miR-181a-5p inhibits apoptosis and promotes proliferation, invasion and migration of 786-O and ACHN cell lines (104). In addition, miR-181a-5p has been identified to be associated with tumor size and TNM stages in clear cell renal cell carcinoma. MiR-181a-5p directly binds to KLF6, which induces apoptosis, promoting renal cancer progression and metastasis (105).

Cancer of the endocrine system Thyroid cancer (TC)

According to 2020 statistics, TC is the most common endocrine cancer. Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, accounting for ~85% of thyroid cancer worldwide (106). The following experiments suggest that miR-181a-5p promotes the progression of TC by modulating multiple target genes. In vivo and vitro, a group demonstrated that miR-181a-5p inhibits papillary demethylase and lysine-specific demethylase 5C (KDM5C) to induce cell proliferation and migration, thus promoting the tumor growth (107). In addition, it is widely acknowledged that angiogenesis is a key factor in PTC recurrence and metastasis. By inhibiting MIL3, exosomal miR-181a-5p promotes tumor angiogenesis and growth. In this case, it decreases DACT2 and increases VEGF and YAP (29). Other reports further validated that miR-181a-5p promotes metastasis of PTC. MiR-181a-5p promotes cell proliferation, invasion and EMT to aggravate PCT metastasis, while its downstream target KLF15 and suppressor of cytokine signaling 4 can counteract these effects (108,109). In addition, miR-181a-5p reduces the efficacy of radioactive iodine treatment by suppressing sodium iodide symporter (NIS), which is a potent iodine transporter. A report has indicated that miR-181a-5p directly inhibits sodium/iodide cotransporter (SLC5A5) to regulate NIS (110).

Salivary adenoid cystic carcinoma

To the best of our knowledge, one study explored the role of miR-181a-5p in salivary adenoid cystic carcinoma (SACC) with lung metastasis. Compared with SACC-83 cells (cells from patients with SACC), Ju et al revealed that miR-181a-5p is decreased in SACC-LM cells (SACC patients with lung metastasis). Furthermore, miR-181a-5p is sponged by circRNA-001982, resulting in stronger ability of migration and invasion (111).

Cancer of the circulatory system Leukemia

Leukemia, the most common circulatory system tumor, with >470,000 new cases worldwide in 2020 (46). It can be divided into myeloid leukemia and lymphocyte leukemia according to the pathological cells. Targeting miRNAs associated with leukemia may be an effective approach to treat leukemia. MiR-181a-5p has been identified to be associated with acute myeloid leukemia (AML). Clinical data has demonstrated that miR-181a-5p is decreased in children with AML, along with a decrease in TGF-β and an increase in Smad7 (112). However, there is a conflicting study that suggests miR-181a-5p promotes AML cell proliferation and G₁/S transition by targeting ataxia telangiectasia mutated (113). In addition, miR-181a-5p has also been found to promote the progression of acute lymphoblastic leukemia (ALL) and lymphocyte leukemia by inhibiting WIF1 and STAT3 (114,115). However, another study revealed that miR-181a-5p has an inhibitory effect on myelogenous leukemia. MiR-181a-5p directly binds to the 3'UTR of Ra1A, thus inhibiting proliferation and promoting G₂ cell cycle arrest and apoptosis (116).

Myeloma

Multiple myeloma (MM) is the second most common hematologic tumor with 176,404 new cases worldwide in 2020 (46). MM is a hematological tumor characterized by abnormal proliferation of plasma cells. MiR-181a-5p appears to be a potential therapeutic target for MM. In vitro experiments, miR-181a-5p is associated with lower CDK2, Cyclin E1 and Bcl2 and higher p21, Bax and caspase 3 to regulate proliferation and apoptosis of MM cells by inhibiting the Hippo/YAP axis (117). In addition, miR-181a-5p induces cell cycle to G₀/G₁ phase arrest, and directly targets homeobox transcription factor A1 (HOXA1), which has been demonstrated to promote cell growth and tumor progression (118). These findings suggest that miR-181a-5p plays a suppressive role in MM.

Lymphoma

Lymphoma is a malignant tumor originating in the lymphatic hematopoietic system. Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of non-Hodgkin lymphoma, accounting for 31% in Europe and the USA (119). Common standard treatments cure only about half of patients. MiR-181a-5p suppresses the proliferation and survival of DLBCL, and it modulates NF-kB by directly targeting NF-kB regulatory factors caspase recruitment domain-containing protein 11, encoding nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor-α, p50, p65 and c-Rel. Study using xenograft models revealed that miR-181a-5p prevents tumor growth rate and prolongs the animal survival in NF-kB-dependent DLBCL (120).

Cancer of the nervous system Glioma

Glioma is a highly malignant tumor in the central nervous system, which develops rapidly and is prone to metastasis from early stage (121). The clinical data reveal a decrease in miR-181a-5p in glioma tissues and cell lines. It has been determined that circRNA 0076248 acts as an upstream regulator of miR-181a-5p, indirectly increasing the expression of Sirtuin 1 (SIRT1) (122). Overexpression of miR-181a-5p inhibits cell proliferation, invasion and sensitizes cells to Temozolomide (TMZ) (122). An investigation has also demonstrated that miR-181a-5p acts as a suppressive regulator of glioblastoma multiform (GBM), the most malignant glioma (123). In a study involving patients with GBM treated with carmustine, miR-181a-5p has been shown to enhance G₁ cell cycle arrest and apoptosis by regulating caspase-9, Bcl-2 and SIRT1. Mechanistically, miR-181a-5p inhibits the PI3K/AKT signaling pathway to promote GBM cell apoptosis and carmustine sensitivity (124). MiR-181a-5p also decreases glioblastoma stem-like cells formation and Osteopontin production of GBM, thus inhibiting the tumor development and progression (125,126). In addition, miR-181a-5p has been demonstrated to increase the permeability of the blood-tumor barrier (BTB), thereby improving the delivery of therapeutic drugs (127). However, a study conducted by Liao and coworkers demonstrated that increased expression of miR-181a-5p promotes cell proliferation and TMZ sensitivity through the regulation of the PTEN/AKT signaling pathway (128).

Neuroblastoma and medulloblastoma (MB)

Neuroblastoma is the most frequent extracranial solid tumor in infants worldwide, with 25-50 cases per million individuals. More than 50% of patients already have distant metastases by the time they are diagnosed (129). In a study, researchers attributed the oncogenic role of miR-181a-5p to inhibit ABI1 mRNA. In vitro experiments, it promotes cell proliferation, migration and invasion. Furthermore, a nude mice xenograft model provided further evidence that consolidates the pro-tumorigenic effect of miR-181a-5p (130). MB is an aggressive cerebral tumor, divided into four molecular subtypes: i) WNT; ii) SHH; iii) 3 group; and iv) 4 group. Among them, 3 group has the worst prognosis and the majority of patients have metastasized at the time of diagnosis (131). A previous report provides novel treatment strategies for 3 group-MB. Experimental evidence indicates that miR-181a-5p expression is increased in 3 group-MB cells compared with SHH-MB cells. SHH-MB cells treated with 3 group-MB exosomal miR-181a-5p demonstrate increased aggressiveness and mobility. The tumor-promoting effects of exosomal miR-181a-5p are attributed to activation of the RAS/MAPK signaling pathway (132).

Skin cancer Melanoma

Melanoma is an aggressive cancer of the skin. MiR-181a-5p promotes melanoma cell proliferation and invasion, suggesting that miR-181a-5p has a role of tumor inhibitor. Then, miR-181a-5p is found to directly bind to the 3'UTR of Plexin C1 and is sponged by lncRNA-CASC2 (133). However, another study provided evidence that miR-181a-5p reduces the expression of Bcl2 and induces apoptosis of melanoma stem cells (134).

Cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cuSCC) is the second most commonly diagnosed malignant cancer of the skin after melanoma, accounting for 20% of skin cancer worldwide (135). Two reports came to opposite conclusions on the role of miR-181a-5p in CSCC. In normal epidermal keratinocytes (HaCaT), a group uncovered that expression of miR-181a-5p increases in cuSCC tissues and inhibits apoptosis of UV induced HaCaT cells. In addition, miR-181a-5p suppresses TGF R3 to increase the expression of TGF, which promotes multiple tumorigenic functions (136). The other study demonstrated that miR-181a-5p blocks the Kras/MAPK pathway to slow SCC13 cell proliferation (137). Notably, the two reports treated the cells in different ways and utilized different cell lines for in vitro experiments.

Cancer of the motor system

Osteosarcoma (OS) is a common malignant tumor in adolescents and children (138).

MiR-181a-5p is involved in the progression and metastasis of OS

In OS, miR-181a-5p has been observed to target RASSF6 to promote cell proliferation and invasion. TUSC7 and CASC2 were established as upstream regulators of miR-181a-5p (139,140). Chondrosarcoma is a primary osteosarcoma in which mortality is usually due to lung metastasis. The expression of miR-181a-5p is upregulated significantly in chondrosarcoma (141). By regulating VEGF and G-protein signaling 16, miR-181a-5p has been shown to promote angiogenesis, which is critical for the progression and metastasis of OS (22,142).

4. MiR-181a-5p as a biomarker

With the development of technology, miR-181a-5p can be accurately and conveniently quantitatively detected (143), which makes it a potential biomarker. The following studies showed the potential of using miR-181a-5p as one of the biomarkers for diagnosis, prognosis and assessment of chemotherapy response. These studies are summarized in Table II.

Biomarkers for diagnosis

Although tissue biopsies remain the gold standard for cancer diagnosis, there is evidence that miR-181a-5p can be used as a biomarker for early diagnosis. For example, serum miR-181a-5p level is decreased in patients with BC compared with normal subjects, and the sensitivity of miR-181a-5p level in early diagnosis of BC is higher compared with that of conventional tumor markers CA153 and carcinoembryonic antigen (144). Another study found that plasma exosomal miR-181a-5p is significantly increased in patients with CRC, suggesting that it has the potential as a marker for diagnosing CRC (145). In addition, miR-181a-5p can also be used to determine the subtype or stage of a certain cancer. Researchers found that compared with controls, patients with early esophageal cancer have significantly lower level of miR-181a-5p, which can be used as a novel biomarker for early diagnosis of esophageal cancer (146). In endometrial carcinoma (EC), it is identified to be increased in type I EC and type II EC, while the increase in type II EC was significantly higher compared with that in type I (147). In addition, miR-181a-5p level is elevated in the tissues of Chinese males with lung squamous cell carcinoma (148).

Biomarker for prognosis

Numerous studies have found that the level of miR-181a-5p may predict the risk of progression and survival of multiple types of cancer. In the majority of reports, increased miR-181a-5p in tumor tissue or serum is correlated with poor outcome and shorter overall survival (149-152). For example, in pediatric acute lymphoblastic leukemia, miR-181a-5p increases the risk of central nervous system of leukemia. The expression of miR-181a-5p provides a novel marker for the course of pediatric ALL. In addition, its expression in bone marrow and peripheral blood samples is significantly decreased to the 33rd day of treatment (153). But in NSCLC (154,155) and AML (156), miR-181a-5p is positively associated with an improved prognosis. Moreover, extracellular vesicle-delivered miR-181a-5p may indicate the risk of tumor metastasis. For example, miR-181a-5p is significantly upregulated in patients with bone metastatic prostate cancer (157), while in rectal cancer with lymph node metastasis, it is decreased (158).

Overall, miR-181a-5p may be an effective tool for predicting cancer prognosis. However, more studies are warranted to provide evidence for clinical application.

Biomarker for response to therapy

The level of miR-181a-5p expression can predict the treatment response of patients with cancer, which can improve the reference for the selection of clinical treatment strategy. For example, EGFR-tyrosine kinase inhibitors (TKIs), such as gefitinib, are the first-line treatment of advanced NSCLC in the presence of allergenic mutations. Circulating miR-181a-5p was quantified in plasma samples of 39 patients with advanced EGFR-mutated NSCLC treated with EGFR-TKIs, and the results showed that patients with partial/complete response (PR/CR) had higher baseline miR-181-5p compared with patients with stable/progressive disease (SD/PD) (159). This trend is similar in patients with colorectal cancer treated with EGFR-TKI. A low level of miR-181a-5p indicates poor progression-free survival (PFS) (160). Uniformly, the level of miR-181a-5p is positively associated with the outcomes of anti-tumor treatment, such as EOX (epirubicin/capecitabine/oxaliplatin) regimen, bortezomib, sorafenib or stem cell transplantation. In these cases, serum miR-181a-5p in PR patients may be significantly higher than that in PD patients (161-164). However, in advanced unresectable epithelial ovarian cancer, patients with higher miR-181a-5p expression have shorter overall survival and PFS accompanied by elevated smad2. Combined analysis of p-smad2 and miR-181a-5p may potentially identify those patients with ovarian cancer with a lower chance of responding to platinum-based neoadjuvant chemotherapy (165).

5. MiR-181a-5p in chemotherapy

Chemotherapy is one of the main therapeutic methods used against cancer, and the response of patients with cancer to chemotherapy is influenced by various factors, such as PTEN and the Wnt/β-catenin pathway (166,167). Numerous genes have been identified as being involved in chemotherapy. Therefore, miRNA can impact cancer chemotherapy by binding to chemotherapy-related targets (168,169). Recent research has focused on the role of miR-181a-5p in chemotherapy. These findings provide a foundation for the clinical use of miR-181a-5p mimics or inhibitors to enhance the sensitivity of chemotherapeutics. In this section, the present study discusses the interaction between miR-181a-5p and platinum, as well as other chemotherapeutic agents (Table III).

Platinum

Platinum drugs, such as cisplatin, carboplatin and oxaliplatin, are one of the most commonly used drugs in chemotherapy and are often used in combination with other chemotherapeutic drugs (170). A recent study has shown that miR-181a-5p can enhance the sensitivity of platinum drugs by targeting some oncogenes in certain types of cancer. It has been observed that in cisplatin resistant cells, the level of miR-181a-5p is reduced. Conversely, CUGBP Elav-like family member 1, which is inhibited by miR-181a-5p, increases in cisplatin resistant cells in lung squamous cell carcinoma and as an oncogene. MiR-181a-5p can decrease the IC₅₀ of cells and effectually recover the cisplatin resistance (171).

Vitamin D receptor (VDR) is a nuclear receptor that regulates autophagy (172). In BC cell lines HS578T, miR-181a-5p induces autophagy to promote apoptosis and inhibit proliferation by suppressing VDR, thus increasing the sensitivity of cisplatin (173). Similarly, other studies have also demonstrated that miR-181a-5p can induce apoptosis and promote the sensitivity of cisplatin in NSCLC (174), GC (175) and esophageal cancer (61). In additon, these in vitro results were confirmed in vivo. In a mouse xenograft model, miR-181a-5p expression in tumors increased significantly in the group treated with Xiaoji decoction (XJD) combined with cisplatin comparing with the mice treated with XJD alone. In this case, transcription factor SP1, which promotes tumor progress, is a target of miR-181a-5p. Upregulation of miR-181a-5p inhibits SP1 to increase the sensitivity to cisplatin and reduce the tumor size and weight (176). In cervical cancer, miR-181a-5p indirectly binds to glucose related protein GRP78, which promotes tumor progression and resistance to oxaliplatin, thus attenuating oxaliplatin resistance in drug-resistant cells and mouse model (89). Notably, another study revealed that miR-181a-5p/SFRP4 axis activates the Wnt/β-catenin pathway to reduce cisplatin sensitivity in ovarian cancer (98). These findings suggests that the effect of miR-181a-5p on the same drugs may be different in different types of cancer.

Overall, the studies indicated that miR-181a-5p can increase the sensitivity to platinum except in ovarian cancer. Using miR-181a-5p mimics to increase the miR-181a-5p expression may be a potential strategy for platinum resistance patients.

Other chemotherapeutic agents

MiR-181a-5p showed different effects on various chemotherapeutic agents. For example, it inhibits resistance of gemcitabine (64) and Ara-c (177), but promotes gefitinib resistance (178). Wnt/β-catenin pathway promotes resistance to 5-FU in colorectal cancer. MiR-181a-5p has been identified as an inhibitor of Wnt and PLAG1, and increases the 5-FU sensitivity of colorectal cancer cells (28,34). In melanoma, miR-181a-5p decreases in BRAF inhibitor (dabrafenib) resistant patients. MiR-181a-5p mimics inhibit mitochondrial transcription factor A and reverses dabrafenib resistance (179). In addition, promoting sensitivity of chemotherapy by using miR-181a-5p has been applied in a rat-seeded retinoblastoma model, which demonstrated that using lipid nanoparticles to co-deliver miR-181a-5p and melphalan can enhance the efficacy while reducing cytotoxic side effects by inhibiting BCL-2, MAPK1 and promoting Bax (180). In addition, Carmustine and TMZ are alkylating agents for glioma, and miR-181a-5p can promote sensitivity of carmustine (124); however, results of the effect of miR-181a-5p on TMZ was opposite in two independent studies (122,128).

6. Controversies

The present study elucidates the role of miR-181a-5p in cancers of different systems. These studies helped to understand the effects of miR-181a-5p on tumor progression, chemotherapy and revealed that it has the potential to be a biomarker. However, as a kind of miRNAs, miR-181a-5p is environment-dependent. Since miR-181a-5p can simultaneously bind to multiple targets (possibly oncogenes or tumor suppressor genes), and these targets express differently in different types of cancer, scientists often get conflicting results in the study of miR-181a-5p. Due to this uncertainty, it is difficult to actually put miR-181a-5p into clinical use. More research and clinical trials are needed to provide a further understanding of miR-181a-5p.

7. Conclusions

The present review summarizes some interesting studies on miR-181a-5p for its role in different systems of cancer. The dysregulation of miR-181a-5p has been implicated in various types of cancer and functions as an oncomiR or tumor inhibitor. Mechanistically, miR-181a-5p targets multiple mRNAs to regulate intricate and diverse signaling pathways. Additionally, numerous factors, such as ncRNAs and TFs, serve as upstream regulators that modulate the expression of miR-181a-5p. MiR-181a-5p is capable of mediating cellular processes, such as proliferation, apoptosis, autophagy, angiogenesis and the regulation of tumor growth in xenograft models. It can also either promote or suppress the cell migration, invasion, EMT and tumor metastasis. In addition, miR-181a-5p shows promise as a potential biomarker and target to increase the sensitivity for chemotherapy. These findings may provide implications for oncological research and treatment strategies of cancer.

Availability of data and materials

Not applicable.

Authors' contributions

JL wrote the major parts of the manuscript and prepared the figures and tables. JS and YZ revised the manuscript. FD, ML, XW and YC prepared the manuscript. SW and ZX oversaw the process and wrote the manuscript. ZW conceptualized the study and oversaw the process. Data authentication is not applicable. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

Authors declare that they have no competing interests.

Acknowledgments

Not applicable.

References 1

Lee

Feinbaum

Ambros

The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14

Cell758438541993

10.1016/0092-8674(93)90529-Y

8252621

Lagos-Quintana

Rauhut

Lendeckel

Tuschl

Identification of novel genes coding for small expressed RNAs

Science2948538582001

10.1126/science.1064921

11679670

Lau

Lim

Weinstein

Bartel

An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans

Science2948588622001

10.1126/science.1065062

11679671

Lee

Ambros

An extensive class of small RNAs in Caenorhabditis elegans

Science2948628642001

10.1126/science.1065329

11679672

Cable

Heard

Hirose

Prasanth

Chen

Henninger

Quinodoz

Spector

Diermeier

Porman

Noncoding RNAs: Biology and applications-a keystone symposia report

Ann N Y Acad Sci15061181412021

10.1111/nyas.14713

34791665

9808899

Bejerano

Pheasant

Makunin

Stephen

Kent

Mattick

Haussler

Ultraconserved elements in the human genome

Science304132113252004

10.1126/science.1098119

15131266

Reinhart

Slack

Basson

Pasquinelli

Bettinger

Rougvie

Horvitz

Ruvkun

The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans

Nature4039019062000

10.1038/35002607

10706289

Hill

Tran

miRNA interplay: Mechanisms and consequences in cancer

Dis Model Mech14dmm0476622021

10.1242/dmm.047662

33973623

8077553

Rivera-Barahona

Pérez

Richard

Desviat

Role of miRNAs in human disease and inborn errors of metabolism

J Inherit Metab Dis404714802017

10.1007/s10545-017-0018-6

28229250

Rupaimoole

Slack

MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases

Nat Rev Drug Discov162032222017

10.1038/nrd.2016.246

28209991

Jeffries

Zhou

Hsu

Deng

miRNA-223 at the crossroads of inflammation and cancer

Cancer Lett4511361412019

10.1016/j.canlet.2019.02.051

30878527

6441621

Zhang

Liao

Tang

MicroRNA-34 family: A potential tumor suppressor and therapeutic candidate in cancer

J Exp Clin Cancer Res38532019

10.1186/s13046-019-1059-5

30717802

6360685

Bartel

MicroRNAs: Target recognition and regulatory functions

Cell1362152332009

10.1016/j.cell.2009.01.002

19167326

3794896

Rani

Sengar

Biogenesis and mechanisms of microRNA-mediated gene regulation

Biotechnol Bioeng1196856922022

10.1002/bit.28029

34979040

Yuan

Zhang

Lei

Zhang

Guo

Hong

MicroRNA-181a-5p and microRNA-181a-3p cooperatively restrict vascular inflammation and atherosclerosis

Cell Death Dis103652019

10.1038/s41419-019-1599-9

31064980

6504957

Zhao

Guo

Sun

Zhang

Wang

miR-181a/b-5p ameliorates inflammatory response in monocrotaline-induced pulmonary arterial hypertension by targeting endocan

J Cell Physiol235442244332020

10.1002/jcp.29318

Lozano-Bartolomé

Llauradó

Portero-Otin

Altuna-Coy

Rojo-Martínez

Vendrell

Jorba

Rodríguez-Gallego

Chacón

Altered expression of miR-181a-5p and miR-23a-3p Is associated with obesity and TNFα-induced insulin resistance

J Clin Endocrinol Metab103144714582018

10.1210/jc.2017-01909

Korhan

Erdal

Atabey

MiR-181a-5p is downregulated in hepatocellular carcinoma and suppresses motility, invasion and branching-morphogenesis by directly targeting c-Met

Biochem Biophys Res Commun450130413122014

10.1016/j.bbrc.2014.06.142

25058462

Jiang

Zhang

Liu

Guo

Cancer exosome-derived miR-9 and miR-181a promote the development of early-stage MDSCs via interfering with SOCS3 and PIAS3 respectively in breast cancer

Oncogene39468146942020

10.1038/s41388-020-1322-4

32398867

Yang

Wan

Zhang

Yang

Miao

Zhong

Zhao

Evolution of the mir-181 microRNA family

Comput Biol Med5282872014

10.1016/j.compbiomed.2014.06.004

25016292

Smillie

Sirey

Ponting

Complexities of post-transcriptional regulation and the modeling of ceRNA crosstalk

Crit Rev Biochem Mol Biol532312452018

10.1080/10409238.2018.1447542

29569941

5935048

Salmena

Poliseno

Tay

Kats

Pandolfi

A ceRNA hypothesis: The Rosetta Stone of a hidden RNA language?

Cell1463533582011

10.1016/j.cell.2011.07.014

21802130

3235919

Shen

Wang

Xiong

Ren

Gao

Ding

Zhu

Wang

Long non-coding RNA CCAT1 promotes cervical cancer cell proliferation and invasion by regulating the miR-181a-5p/MMP14 axis

Cell Cycle18111011212019

10.1080/15384101.2019.1609829

31084453

6592243

Shang

Wang

Chen

Sun

Long non-coding RNA CCAT1 promotes colorectal cancer progression by regulating miR-181a-5p expression

Aging (Albany NY)12830183202020

10.18632/aging.103139

32380476

7244037

Yang

Xia

Fan

Yang

Long noncoding RNA NEAT1 promotes proliferation and invasion via targeting miR-181a-5p in non-small cell lung cancer

Oncol Res262892962018

10.3727/096504017X15009404458675

Hai Ping

Feng Bo

Nan Hui

Hong

IL-1β/NF-kb signaling promotes colorectal cancer cell growth through miR-181a/PTEN axis

Arch Biochem Biophys60420262016

10.1016/j.abb.2016.06.001

27264420

Zhang

Tan

Pei

STAT1 inhibits MiR-181a expression to suppress colorectal cancer cell proliferation through PTEN/Akt

J Cell Biochem118343534432017

10.1002/jcb.26000

28322462

Shi

Nie

Guo

Mei

Han

DNA methylation-mediated repression of miR-181a/135a/302c expression promotes the microsatellite-unstable colorectal cancer development and 5-FU resistance via targeting PLAG1

J Genet Genomics452052142018

10.1016/j.jgg.2018.04.003

29735329

Wang

Cen

Yang

Liu

Zhao

miR-181a, delivered by hypoxic PTC-secreted exosomes, inhibits DACT2 by downregulating MLL3, leading to YAP-VEGF-mediated angiogenesis

Mol Ther Nucleic Acids246106212021

10.1016/j.omtn.2021.02.027

8054101

Sun

Wei

Chen

Terek

MicroRNA regulates vascular endothelial growth factor expression in chondrosarcoma cells

Clin Orthop Relat Res4739079132015

10.1007/s11999-014-3842-0

4317450

Hanahan

Hallmarks of cancer: New dimensions

Cancer Discov1231462022

10.1158/2159-8290.CD-21-1059

35022204

Svoronos

Engelman

Slack

OncomiR or tumor suppressor? The duplicity of MicroRNAs in cancer

Cancer Res76366636702016

10.1158/0008-5472.CAN-16-0359

27325641

4930690

Siegel

Miller

Jemal

Cancer statistics, 2020

CA Cancer J Clin707302020

10.3322/caac.21590

Han

Zhang

Jia

Bai

The lncRNA CRNDE promotes colorectal cancer cell proliferation and chemoresistance via miR-181a-5p-mediated regulation of Wnt/β-catenin signaling

Mol Cancer1692017

10.1186/s12943-017-0583-1

Shan

Pan

Tian

Liu

Sun

Xue

Han

The lncRNA ZEB1-AS1 sponges miR-181a-5p to promote colorectal cancer cell proliferation by regulating Wnt/β-catenin signaling

Cell Cycle17124512542018

10.1080/15384101.2018.1471317

6110576

Sun

Shen

Zhang

LncRNA ANRIL negatively regulated chitooligosaccharide-induced radiosensitivity in colon cancer cells by sponging miR-181a-5p

Adv Clin Exp Med3055652021

10.17219/acem/128370

33529508

Chang

Yuan

Guo

Xiao

Dong

Liu

Upregulation of SNHG6 regulates ZEB1 expression by competitively binding miR-101-3p and interacting with UPF1 in hepatocellular carcinoma

Cancer Lett3831831942016

10.1016/j.canlet.2016.09.034

27702662

Sun

Leng

Yang

Long noncoding RNA SNHG6 functions as a competing endogenous RNA by sponging miR-181a-5p to regulate E2F5 expression in colorectal cancer

Cancer Manag Res116116242019

10.2147/CMAR.S182719

30666158

6331078

Chi

Liu

Shi

Zhang

Xiong

Zeng

Dong

circNSUN2 promotes the malignant biological behavior of colorectal cancer cells via the miR-181a-5p/ROCK2 axis

Oncol Rep461422021

10.3892/or.2021.8093

8165598

Zhao

Zheng

Wei

Zhang

Cai

Highly-metastatic colorectal cancer cell released miR-181a-5p-rich extracellular vesicles promote liver metastasis by activating hepatic stellate cells and remodelling the tumour microenvironment

J Extracell Vesicles11e121862022

10.1002/jev2.12186

35041299

8765330

Chen

Zhan

Yao

Zhang

Yan

MicroRNA-181a promotes tumor growth and liver metastasis in colorectal cancer by targeting the tumor suppressor WIF-1

Mol Cancer13862014

10.1186/1476-4598-13-86

24755295

4021214

Wang

Sun

Han

Expression and mechanism of microRNA-181A on incidence and survival in late liver metastases of colorectal cancer

Oncol Rep35140314082016

10.3892/or.2016.4546

Wei

Cui

Mei

Liu

Zhang

miR-181a mediates metabolic shift in colon cancer cells via the PTEN/AKT pathway

FEBS Lett588177317792014

10.1016/j.febslet.2014.03.037

24685694

Sun

Wang

You

Feng

Kong

Zhang

Liu

Jiao

MicroRNA-181a promotes angiogenesis in colorectal cancer by targeting SRCIN1 to promote the SRC/VEGF signaling pathway

Cell Death Dis94382018

10.1038/s41419-018-0490-4

29739921

5941226

Zhang

Wang

Liu

Wang

The BAP31/miR-181a-5p/RECK axis promotes angiogenesis in colorectal cancer via fibroblast activation

Front Oncol1310569032023

10.3389/fonc.2023.1056903

9989165

Sung

Ferlay

Siegel

Laversanne

Soerjomataram

Jemal

Bray

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

CA Cancer J Clin712092492021

10.3322/caac.21660

33538338

Chen

Shen

Wang

Huang

Zhou

Hsa-miR-181a-5p expression and effects on cell proliferation in gastric cancer

Asian Pac J Cancer Prev14387138752013

10.7314/APJCP.2013.14.6.3871

Zhang

Deng

Sun

Ning

Fan

Wang

Zhang

Zhou

MiR-181a, a new regulator of TGF-β signaling, can promote cell migration and proliferation in gastric cancer

Invest New Drugs379239342019

10.1007/s10637-018-0695-5

Sun

Wang

Wei

Gao

Zheng

MicroRNA-181a promotes cell proliferation and inhibits apoptosis in gastric cancer by targeting RASSF1A

Oncol Rep40195919702018

6111568

Ding

Tian

Wang

Teng

Hong

Hypermethylated long noncoding RNA MEG3 promotes the progression of gastric cancer

Aging (Albany NY)11813981552019

10.18632/aging.102309

Liu

Sun

Hong

Liu

Fen

Yin

Wang

Chen

Guan

MEG2 is regulated by miR-181a-5p and functions as a tumour suppressor gene to suppress the proliferation and migration of gastric cancer cells

Mol Cancer161332017

10.1186/s12943-017-0695-7

28747184

5530520

Zhang

Jiang

Weng

Zhou

Huang

Tang

Liu

Cui

miR-181a-5p promotes the progression of gastric cancer via RASSF6-mediated MAPK signalling activation

Cancer Lett38911222017

10.1016/j.canlet.2016.12.033

Chen

Sun

Wang

Ding

Liu

Zhang

Miao

Liu

Zhou

MicroRNA-181a functions as an oncogene in gastric cancer by targeting caprin-1

Front Pharmacol915652019

10.3389/fphar.2018.01565

6335395

Zhao

Nie

Wang

Lin

MiR-181a suppresses autophagy and sensitizes gastric cancer cells to cisplatin

Gene5768288332016

10.1016/j.gene.2015.11.013

Lin

Yan

Liu

Qian

Shen

Lin

Mao

MicroRNA-181a inhibits tumor proliferation, invasiveness, and metastasis and is downregulated in gastric cancer

Oncol Res2275842015

10.3727/096504014X14024160459203

25706394

7838452

Luo

Pang

Yin

Cui

Fang

Xue

MALAT1 promotes gastric adenocarcinoma through the MALAT1/miR-181a-5p/AKT3 axis

Open Biol91900952019

10.1098/rsob.190095

31480991

6769293

Zhuang

Chen

Shao

Cao

Zhou

Xie

Shi

Mitochondrial miR-181a-5p promotes glucose metabolism reprogramming in liver cancer by regulating the electron transport chain

Carcinogenesis419729832020

10.1093/carcin/bgz174

Zheng

Bao

Liao

MicroRNA-181a-5p suppresses cell proliferation by targeting Egr1 and inhibiting Egr1/TGF-β/Smad pathway in hepatocellular carcinoma

Int J Biochem Cell Biol1061071162019

10.1016/j.biocel.2018.11.011

Guo

Peng

Jin

Liu

LncRNA CCAT1 promotes autophagy via regulating ATG7 by sponging miR-181 in hepatocellular carcinoma

J Cell Biochem12017975179832019

10.1002/jcb.29064

Chang

Chen

Wang

Sun

Long non-coding RNA XIST regulates PTEN expression by sponging miR-181a and promotes hepatocellular carcinoma progression

BMC Cancer172482017

10.1186/s12885-017-3216-6

28388883

5383949

Yang

Wang

Cong

Zhang

Shen

Zhang

Han

miRNA-181a-5p enhances the sensitivity of cells to cisplatin in esophageal adenocarcinoma by targeting CBLB

Cancer Manag Res12498149902020

10.2147/CMAR.S251264

32612385

7323973

Ilic

Epidemiology of pancreatic cancer

World J Gastroenterol22969497052016

10.3748/wjg.v22.i44.9694

27956793

5124974

Liu

Wang

Zheng

Jiang

LPS induced miR-181a promotes pancreatic cancer cell migration via targeting PTEN and MAP2K4

Dig Dis Sci59145214602014

10.1007/s10620-014-3049-y

24532253

Wang

Zhou

Yin

lncRNA ANRIL aggravates the chemoresistance of pancreatic cancer cells to gemcitabine by targeting inhibition of miR-181a and targeting HMGB1-induced autophagy

Aging (Albany NY)1319272192812021

10.18632/aging.203251

Harðardottir

Jonsson

Gunnarsson

Hilmarsdottir

Asmundsson

Gudmundsdottir

Saevarsdottir

Hansdottir

Hannesson

Gudbjartsson

Advances in lung cancer diagnosis and treatment-a review

Laeknabladid10817292022In Icelandic

Duma

Santana-Davila

Molina

Non-small cell lung cancer: Epidemiology, screening, diagnosis, and treatment

Mayo Clin Proc94162316402019

10.1016/j.mayocp.2019.01.013

31378236

Qiu

Wang

Zhang

Yuan

Wei

Zhao

Lou

MiR-181a-5p inhibits cell proliferation and migration by targeting Kras in non-small cell lung cancer A549 cells

Acta Biochim Biophys Sin (Shanghai)476306382015

10.1093/abbs/gmv054

Shi

Zhou

Chen

Zheng

Fang

MiR-181a inhibits non-small cell lung cancer cell proliferation by targeting CDK1

Cancer Biomark205395462017

10.3233/CBM-170350

28946554

Wang

Zhang

Wang

SNHG7 contributes to the progression of non-small-cell lung cancer via the SNHG7/miR-181a-5p/E2F7 axis

Cancer Manag Res12321132222020

10.2147/CMAR.S240964

32440218

7213887

Cao

Zhao

Wang

Qiao

Qin

Wang

MicroRNA-181a-5p impedes IL-17-induced nonsmall cell lung cancer proliferation and migration through targeting VCAM-1

Cell Physiol Biochem423463562017

10.1159/000477389

Liu

Long noncoding RNA SNHG7 accelerates proliferation, migration and invasion of non-small cell lung cancer cells by suppressing miR-181a-5p through AKT/mTOR signaling pathway

Cancer Manag Res12830383122020

10.2147/CMAR.S258487

7494385

Zhang

Gao

Long

Zhang

Yang

Zhu

Pei

Qiu

Chen

The circular RNA circHMGB2 drives immunosuppression and anti-PD-1 resistance in lung adenocarcinomas and squamous cell carcinomas via the miR-181a-5p/CARM1 axis

Mol Cancer211102022

10.1186/s12943-022-01586-w

35525959

9077876

Chen

Quan

Zhang

Overexpression of MYCT1 inhibits proliferation and induces apoptosis in human acute myeloid leukemia HL-60 and KG-1a cells in vitro and in vivo

Front Pharmacol910452018

10.3389/fphar.2018.01045

6157318

Wang

Tong

Zhang

Sun

Yan

MYCT1 represses apoptosis of laryngeal cancerous cells through the MAX/miR-181a/NPM1 pathway

FEBS J286389239082019

10.1111/febs.14942

31152622

Hao

Zhang

Guo

Guan

Long non-coding RNA ANRIL promotes proliferation, clonogenicity, invasion and migration of laryngeal squamous cell carcinoma by regulating miR-181a/Snai2 axis

Regen Ther112822892019

10.1016/j.reth.2019.07.007

6813643

Wilkinson

Gathani

Understanding breast cancer as a global health concern

Br J Radiol95202110332022

10.1259/bjr.20211033

8822551

Strotbek

Schmid

Sánchez-González

Boerries

Busch

Olayioye

miR-181 elevates Akt signaling by co-targeting PHLPP2 and INPP4B phosphatases in luminal breast cancer

Int J Cancer140231023202017

10.1002/ijc.30661

28224609

Taylor

Sossey-Alaoui

Thompson

Danielpour

Schiemann

TGF-β upregulates miR-181a expression to promote breast cancer metastasis

J Clin Invest1231501632013

10.1172/JCI64946

Liu

Xie

Gao

Zhang

Xiao

Huang

Lin

SOX2 regulates multiple malignant processes of breast cancer development through the SOX2/miR-181a-5p, miR-30e-5p/TUSC3 axis

Mol Cancer16622017

10.1186/s12943-017-0632-9

28288641

5348847

Zhai

Zhao

Zhu

Pan

MiR-181a-5p facilitates proliferation, invasion, and glycolysis of breast cancer through NDRG2-mediated activation of PTEN/AKT pathway

Bioengineered1383952022

10.1080/21655979.2021.2006974

8805873

Alexandrova

Lamberti

Saggese

Pecoraro

Memoli

Cappa

Ravo

Iorio

Tarallo

Rizzo

Small non-coding RNA profiling identifies miR-181a-5p as a mediator of estrogen receptor beta-induced inhibition of cholesterol biosynthesis in triple-negative breast cancer

Cells98742020

10.3390/cells9040874

32260128

7226848

Wang

Yang

Jia

Croteau

Ruan

Hardy

Micro-RNA-181a suppresses progestin-promoted breast cancer cell growth

Maturitas11460662018

10.1016/j.maturitas.2018.06.004

29907248

Cai

Wang

Houda

Yang

Wang

Mueck

Croteau

Ruan

Hardy

MicroRNA-181a suppresses norethisterone-promoted tumorigenesis of breast epithelial MCF10A cells through the PGRMC1/EGFR-PI3K/Akt/mTOR signaling pathway

Transl Oncol141010682021

10.1016/j.tranon.2021.101068

Liu

Cheng

Xia

LncRNA LUCAT1/miR-181a-5p axis promotes proliferation and invasion of breast cancer via targeting KLF6 and KLF15

BMC Mol Cell Biol21692020

10.1186/s12860-020-00310-0

32998707

7525994

Tsu

Jerónimo

Saving the world's women from cervical cancer

N Engl J Med374250925112016

10.1056/NEJMp1604113

27355529

Yang

Zhai

Yang

Lou

miR-181a-5p promotes proliferation and invasion and inhibits apoptosis of cervical cancer cells via regulating inositol polyphosphate-5-phosphatase A (INPP5A)

Oncol Res267037122018

10.3727/096504017X14982569377511

Zhu

Song

Inhibition of microRNA-181a may suppress proliferation and invasion and promote apoptosis of cervical cancer cells through the PTEN/Akt/FOXO1 pathway

J Physiol Biochem727217322016

10.1007/s13105-016-0511-7

27534652

Liang

Yang

Huang

Han

Huang

Zhao

Zha

MiR-181a confers resistance of cervical cancer to radiation therapy through targeting the pro-apoptotic PRKCD gene

Oncogene32301930272013

10.1038/onc.2012.323

Luo

Qiu

miR-181a inhibits cervical cancer development via downregulating GRP78

Oncol Res25134113482017

10.3727/096504017X14867268787969

Zhu

Zhang

Jiang

Cui

Dang

Interference of the long noncoding RNA CDKN2B-AS1 upregulates miR-181a-5p/TGFβI axis to restrain the metastasis and promote apoptosis and senescence of cervical cancer cells

Cancer Med8172117302019

10.1002/cam4.2040

30884187

6488111

Zhang

Liu

Song

Yao

SP1-induced up-regulation of lncRNA LUCAT1 promotes proliferation, migration and invasion of cervical cancer by sponging miR-181a

Artif Cells Nanomed Biotechnol475555642019

10.1080/21691401.2019.1575840

Zhu

Wang

Jia

Zeng

Ding

Wang

Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism

Nat Genet471581632015

10.1038/ng.3178

25581428

Felix

Scott McMeekin

Mutch

Walker

Creasman

Cohn

Ali

Moore

Downs

Ioffe

Associations between etiologic factors and mortality after endometrial cancer diagnosis: The NRG oncology/gynecologic oncology group 210 trial

Gynecol Oncol13970762015

10.1016/j.ygyno.2015.08.022

26341710

4587355

Geletina

Kobelev

Babayants

Feng

Pustylnyak

Gulyaeva

PTEN negative correlates with miR-181a in tumour tissues of non-obese endometrial cancer patients

Gene65520242018

10.1016/j.gene.2018.02.051

29477866

Jiang

Gao

Sun

Liu

Han

LncRNA CCAT1 negatively regulates miR-181a-5p to promote endometrial carcinoma cell proliferation and migration

Exp Ther Med17425942662019

30988798

6447908

Dong

Xiong

Konno

Ihira

Kobayashi

Yue

Watari

Long non-coding RNA DLEU2 drives EMT and glycolysis in endometrial cancer through HK2 by competitively binding with miR-455 and by modulating the EZH2/miR-181a pathway

J Exp Clin Cancer Res402162021

10.1186/s13046-021-02018-1

34174908

8235565

Parikh

Lee

Joseph

Marchini

Baccarini

Kolev

Romualdi

Fruscio

Shah

Wang

microRNA-181a has a critical role in ovarian cancer progression through the regulation of the epithelial-mesenchymal transition

Nat Commun529772014

10.1038/ncomms3977

Belur Nagaraj

Knarr

Sekhar

Connor

Joseph

Kovalenko

Fleming

Surti

Nurmemmedov

Beltrame

The miR-181a-SFRP4 axis regulates Wnt activation to drive stemness and platinum resistance in ovarian cancer

Cancer Res81204420552021

10.1158/0008-5472.CAN-20-2041

33574092

8137569

Zhou

Check

Lortet-Tieulent

Laversanne

Jemal

Ferlay

Bray

Cook

Devesa

Prostate cancer incidence in 43 populations worldwide: An analysis of time trends overall and by age group

Int J Cancer138138814002016

10.1002/ijc.29894

4712103

100

Ding

Yuan

Chen

Shen

Chen

Huang

Muscleblind-like 1 antisense RNA 1 inhibits cell proliferation, invasion, and migration of prostate cancer by sponging miR-181a-5p and regulating PTEN/PI3K/AKT/mTOR signaling

Bioengineered128038142021

10.1080/21655979.2021.1890383

101

Liang

Wei

Daniels

Zhong

Wang

Sfanos

Melamed

Zhao

Lee

LEF1 targeting EMT in prostate cancer invasion is mediated by miR-181a

Am J Cancer Res5112411322015

4449440

102

Yan

Xia

Yan

Zhang

Wang

Yao

Shen

MIIP inhibits EMT and cell invasion in prostate cancer through miR-181a/b-5p-KLF17 axis

Am J Cancer Res106306472020

32195032

7061746

103

Mao

Huang

Wang

Zhang

Liu

Luo

Yao

Fan

Geng

Circular RNA hsa_circ_0068871 regulates FGFR3 expression and activates STAT3 by targeting miR-181a-5p to promote bladder cancer progression

J Exp Clin Cancer Res381692019

10.1186/s13046-019-1136-9

30999937

6472097

104

Lai

Zhao

Quan

Chen

Guan

Lai

microRNA-181a-5p functions as an oncogene in renal cell carcinoma

Mol Med Rep17851085172018

29693121

105

Lei

Zhang

Gao

Fan

Chen

Xie

Chen

Up-regulation of miR-181a in clear cell renal cell carcinoma is associated with lower KLF6 expression, enhanced cell proliferation, accelerated cell cycle transition, and diminished apoptosis

Urol Oncol3693.e2393.e372018

10.1016/j.urolonc.2017.09.019

106

Coca-Pelaz

Shah

Hernandez-Prera

Ghossein

Rodrigo

Hartl

Olsen

Shaha

Zafereo

Suarez

Papillary thyroid cancer-aggressive variants and impact on management: A narrative review

Adv Ther37311231282020

10.1007/s12325-020-01391-1

7467416

107

Wang

Yang

Cen

Zhao

microRNA-181a promotes the oncogene S100A2 and enhances papillary thyroid carcinoma growth by mediating the expression of histone demethylase KDM5C

J Endocrinol Invest4517282022

10.1007/s40618-021-01606-4

108

Sun

Liu

Shi

Wang

Chi

MiR-181a promotes cell proliferation and migration through targeting KLF15 in papillary thyroid cancer

Clin Transl Oncol2466752022

10.1007/s12094-021-02670-1

109

Chen

Lin

lncRNA ZNF674-AS1 inhibits the migration, invasion and epithelial-mesenchymal transition of thyroid cancer cells by modulating the miR-181a/SOCS4 axis

Mol Cell Endocrinol5441115512022

10.1016/j.mce.2021.111551

34990740

110

Gierlikowski

Broniarek

Cheda

Rogulski

Kotlarek-Łysakowska

MiR-181a-5p regulates NIS expression in papillary thyroid carcinoma

Int J Mol Sci2260672021

10.3390/ijms22116067

34199867

8200107

111

Huang

Guo

Han

Zhao

Long

The circular RNAs differential expression profiles in the metastasis of salivary adenoid cystic carcinoma cells

Mol Cell Biochem476126912822021

10.1007/s11010-020-03989-z

112

Nabhan

Louka

Khairy

Tash

Ali-Labib

El-Habashy

MicroRNA-181a and its target Smad 7 as potential biomarkers for tracking child acute lymphoblastic leukemia

Gene6282532582017

10.1016/j.gene.2017.07.052

28732737

113

Liu

Liao

Peng

Luo

Jiang

miR-181a promotes G1/S transition and cell proliferation in pediatric acute myeloid leukemia by targeting ATM

J Cancer Res Clin Oncol14277872016

10.1007/s00432-015-1995-1

114

Lyu

Yun

Huang

Deng

Wang

Chen

Xiao

miR-181a-5p, an inducer of Wnt-signaling, facilitates cell proliferation in acute lymphoblastic leukemia

Oncol Rep37146914762017

10.3892/or.2017.5425

115

Assmann

JLJC

Leon

Stavast

van den Bogaerdt

Schilperoord-Vermeulen

Sandberg

Bellido

Erkeland

Feith

Loughran

JrLangerak

miR-181a is a novel player in the STAT3-mediated survival network of TCRαβ+ CD8+ T large granular lymphocyte leukemia

Leukemia369839932022

10.1038/s41375-021-01480-2

116

Fei

Zhu

Luo

miR-181a post-transcriptionally downregulates oncogenic RalA and contributes to growth inhibition and apoptosis in chronic myelogenous leukemia (CML)

PLoS One7e328342012

10.1371/journal.pone.0032834

22442671

3307705

117

Sun

Jiang

Jia

Zou

Wang

LncRNA MALAT1/miR-181a-5p affects the proliferation and adhesion of myeloma cells via regulation of Hippo-YAP signaling pathway

Cell Cycle18250925232019

10.1080/15384101.2019.1652034

31397203

6738907

118

Chen

Wang

Zhao

Long non-coding RNA CCAT1 promotes multiple myeloma progression by acting as a molecular sponge of miR-181a-5p to modulate HOXA1 expression

Cell Cycle173193292018

10.1080/15384101.2017.1407893

5914888

119

Martelli

Ferreri

Agostinelli

Di Rocco

Pfreundschuh

Pileri

Diffuse large B-cell lymphoma

Crit Rev Oncol Hematol871461712013

10.1016/j.critrevonc.2012.12.009

120

Kozloski

Jiang

Bhatt

Ruiz

Vega

Shaknovich

Melnick

Lossos

miR-181a negatively regulates NF-κB signaling and affects activated B-cell-like diffuse large B-cell lymphoma pathogenesis

Blood127285628662016

10.1182/blood-2015-11-680462

26941399

121

Bao

Wang

Fang

Shan

Wang

Jiang

Intratumor heterogeneity, microenvironment, and mechanisms of drug resistance in glioma recurrence and evolution

Front Med155515612021

10.1007/s11684-020-0760-2

33893983

122

Lei

Huang

Zhou

Zhao

Thapa

Cai

Deng

Circular RNA hsa_circ_0076248 promotes oncogenesis of glioma by sponging miR-181a to modulate SIRT1 expression

J Cell Biochem120669867082019

10.1002/jcb.27966

123

Hanif

Muzaffar

Perveen

Malhi

Simjee

Glioblastoma multiforme: A review of its epidemiology and pathogenesis through clinical presentation and treatment

Asian Pac J Cancer Prev18392017

28239999

5563115

124

Rezaei

Hejazi

Mansoori

Mohammadi

Amini

Mosafer

Rezaei

Mokhtarzadeh

Baradaran

microRNA-181a mediates the chemo-sensitivity of glioblastoma to carmustine and regulates cell proliferation, migration, and apoptosis

Eur J Pharmacol8881734832020

10.1016/j.ejphar.2020.173483

32810491

125

Huang

Zhao

Weng

Sui

Liu

Upregulation of miR-181a suppresses the formation of glioblastoma stem cells by targeting the Notch2 oncogene and correlates with good prognosis in patients with glioblastoma multiforme

Biochem Biophys Res Commun486112911362017

10.1016/j.bbrc.2017.04.008

126

Marisetty

Wei

Kong

Ott

Fang

Sabbagh

Heimberger

MiR-181 family modulates osteopontin in glioblastoma multiforme

Cancers (Basel)1238132020

10.3390/cancers12123813

33348707

7765845

127

Yao

Wang

Liu

Zhao

Xue

MiR-181a regulates blood-tumor barrier permeability by targeting Krüppel-like factor 6

J Cereb Blood Flow Metab34182618362014

10.1038/jcbfm.2014.152

25182666

4269760

128

Liao

Shen

Zhao

Liu

Guo

Peng

Cheng

LncRNA CASC2 interacts with miR-181a to modulate glioma growth and resistance to TMZ through PTEN pathway

J Cell Biochem118188918992017

10.1002/jcb.25910

129

Matthay

Maris

Schleiermacher

Nakagawara

Mackall

Diller

Weiss

Neuroblastoma

Nat Rev Dis Primers2160782016

10.1038/nrdp.2016.78

130

Liu

Peng

Liao

Luo

Cai

Zhang

Luo

Jiang

MiR-181a/b induce the growth, invasion, and metastasis of neuroblastoma cells through targeting ABI1

Mol Carcinog57123712502018

10.1002/mc.22839

131

Orr

Pathology, diagnostics, and classification of medulloblastoma

Brain Pathol306646782020

10.1111/bpa.12837

32239782

7317787

132

Zhu

Liu

Zheng

Yang

Zhang

Chang

Aggressive medulloblastoma-derived exosomal miRNAs promote in vitro invasion and migration of tumor cells via Ras/MAPK pathway

J Neuropathol Exp Neurol797347452020

10.1093/jnen/nlaa041

32417918

133

Wang

Zhou

Dan

Jiang

Long non-coding RNA CASC2 inhibits tumorigenesis via the miR-181a/PLXNC1 axis in melanoma

Acta Biochim Biophys Sin (Shanghai)502632722018

10.1093/abbs/gmx148

29514220

134

Zhang

Wan

Zhang

LncRNA LHFPL3-AS1 contributes to tumorigenesis of melanoma stem cells via the miR-181a-5p/BCL2 pathway

Cell Death Dis119502020

10.1038/s41419-020-03141-1

33149126

7643105

135

Waldman

Schmults

Cutaneous squamous cell carcinoma

Hematol Oncol Clin North Am331122019

10.1016/j.hoc.2018.08.001

136

Chitsazzadeh

Nguyen

de Mingo Pulido

Bittencourt

Adelmann

Ortiz Rivera

Nguyen

Guerra

Davis

miR-181a promotes multiple protumorigenic functions by targeting TGFβR3

J Invest Dermatol14219561965.e22022

10.1016/j.jid.2021.09.040

137

Neu

Dziunycz

Dzung

Lefort

Falke

Denzler

Freiberger

Iotzova-Weiss

Kuzmanov

Levesque

miR-181a decelerates proliferation in cutaneous squamous cell carcinoma by targeting the proto-oncogene KRAS

PLoS One12e01850282017

10.1371/journal.pone.0185028

28931048

5607211

138

Mirabello

Troisi

Savage

Osteosarcoma incidence and survival rates from 1973 to 2004: Data from the surveillance, epidemiology, and end results program

Cancer115153115432009

10.1002/cncr.24121

19197972

2813207

139

Hao

Wang

Cheng

Nie

Downregulation of lncRNA CASC2 facilitates osteosarcoma growth and invasion through miR-181a

Cell Prolif51e124092018

10.1111/cpr.12409

140

Zhao

Liu

Cui

Wang

Sun

Xue

Cui

Yang

Bai

lncRNA TUSC7 inhibits osteosarcoma progression through the miR-181a/RASSF6 axis

Int J Mol Med475835942021

10.3892/ijmm.2020.4825

7797460

141

Mutlu

Kirkbes

Eroglu

Kabukcuoglu

Duymus

ISık

Ulasli

The expression of miR-181a-5p and miR-371b-5p in chondrosarcoma

Eur Rev Med Pharmacol Sci19238423882015

26214773

142

Sun

Charbonneau

Wei

Chen

Terek

miR-181a targets RGS16 to promote chondrosarcoma growth, angiogenesis, and metastasis

Mol Cancer Res13134713572015

10.1158/1541-7786.MCR-14-0697

4573256

143

PTB

Clark

LTT

MicroRNA-based diagnosis and therapy

Int J Mol Sci2371672022

10.3390/ijms23137167

35806173

9266664

144

Guo

Zhang

Decreased serum miR-181a is a potential new tool for breast cancer screening

Int J Mol Med306806862012

10.3892/ijmm.2012.1021

22692639

145

Zhang

Zhu

Shan

Zhou

Wang

Zhang

Tao

Cheng

Chen

A panel of seven-miRNA signature in plasma as potential biomarker for colorectal cancer diagnosis

Gene6872462542019

10.1016/j.gene.2018.11.055

146

Lin

Chen

Lin

Fang

Wang

Wei

Teng

Zhang

Potential miRNA biomarkers for the diagnosis and prognosis of esophageal cancer detected by a novel absolute quantitative RT-qPCR method

Sci Rep10200652020

10.1038/s41598-020-77119-6

7676265

147

Zeng

Zhou

Hsa-microRNA-181a is a regulator of a number of cancer genes and a biomarker for endometrial carcinoma in patients: A bioinformatic and clinical study and the therapeutic implication

Drug Des Devel Ther9110311752015

25733820

4342183

148

Shan

Zhang

Zhou

Wang

Zhang

Shu

Zhu

Wen

Liu

Identification of four plasma microRNAs as potential biomarkers in the diagnosis of male lung squamous cell carcinoma patients in China

Cancer Med7237023812018

10.1002/cam4.1490

6010830

149

Nishimura

Handa

Yamamoto

Tanaka

Shibata

Mimori

Takemasa

Mizushima

Ikeda

Sekimoto

microRNA-181a is associated with poor prognosis of colorectal cancer

Oncol Rep28222122262012

10.3892/or.2012.2059

150

Panoutsopoulou

Avgeris

Magkou

Mavridis

Dreyer

Dorn

Obermayr

Reinthaller

Michaelidou

Mahner

miR-181a overexpression predicts the poor treatment response and early-progression of serous ovarian cancer patients

Int J Cancer147356035732020

10.1002/ijc.33182

32621752

151

Papadimitriou

Papanota

Adamopoulos

Pilala

Liacos

Malandrakis

Mavrianou-Koutsoukou

Patseas

Eleutherakis-Papaiakovou

Gavriatopoulou

miRNA-seq and clinical evaluation in multiple myeloma

miR-181a overexpression predicts short-term disease progression and poor post-treatment outcome

Br J Cancer12679902022

10.1038/s41416-021-01602-8

152

Meijer

Garajová

Caparello

Le Large

TYS

Frampton

Vasile

Funel

Kazemier

Giovannetti

Plasma miR-181a-5p downregulation predicts response and improved survival after FOLFIRINOX in pancreatic ductal adenocarcinoma

Ann Surg271113711472020

10.1097/SLA.0000000000003084

153

Egyed

Kutszegi

Sági

Gézsi

Rzepiel

Visnovitz

Lőrincz

Müller

Zombori

Szalai

MicroRNA-181a as novel liquid biopsy marker of central nervous system involvement in pediatric acute lymphoblastic leukemia

J Transl Med182502020

10.1186/s12967-020-02415-8

7310470

154

Xue

Zhang

Rui

Liu

Yin

Serum miR-1228-3p and miR-181a-5p as noninvasive biomarkers for non-small cell lung cancer diagnosis and prognosis

Biomed Res Int202096018762020

10.1155/2020/9601876

32724822

7364230

155

Gao

Cao

Shen

Pan

Shu

Deregulated expression of miR-21, miR-143 and miR-181a in non small cell lung cancer is related to clinicopathologic characteristics or patient prognosis

Biomed Pharmacother643994082010

10.1016/j.biopha.2010.01.018

156

Schwind

Maharry

Radmacher

Mrózek

Holland

Margeson

Whitman

Hickey

Becker

Metzeler

Prognostic significance of expression of a single microRNA, miR-181a, in cytogenetically normal acute myeloid leukemia: A cancer and leukemia group B study

J Clin Oncol28525752642010

10.1200/JCO.2010.29.2953

21079133

3018359

157

Wang

Fang

Dong

Wang

Gao

Xue

Discovery of extracellular vesicles derived miR-181a-5p in patient's serum as an indicator for bone-metastatic prostate cancer

Theranostics118788922021

10.7150/thno.49186

33391510

7738844

158

Bjørnetrø

Redalen

Meltzer

Thusyanthan

Samiappan

Jegerschöld

Handeland

Ree

An experimental strategy unveiling exosomal microRNAs 486-5p, 181a-5p and 30d-5p from hypoxic tumour cells as circulating indicators of high-risk rectal cancer

J Extracell Vesicles815672192019

10.1080/20013078.2019.1567219

30728923

6352936

159

Leonetti

Capula

Minari

Mazzaschi

Gregori

El Hassouni

Papini

Bordi

Verzè

Avan

Dynamic evaluation of circulating miRNA profile in EGFR-mutated NSCLC patients treated with EGFR-TKIs

Cells1015202021

10.3390/cells10061520

8235748

160

Pichler

Winter

Ress

Bauernhofer

Gerger

Kiesslich

Lax

Samonigg

Hoefler

miR-181a is associated with poor clinical outcome in patients with colorectal cancer treated with EGFR inhibitor

J Clin Pathol671982032014

10.1136/jclinpath-2013-201904

161

Robak

Dróżdż

Jarych

Mikulski

Węgłowska

Siemieniuk-Ryś

Misiewicz

Stawiski

Fendler

Szemraj

The value of serum MicroRNA expression signature in predicting refractoriness to bortezomib-based therapy in multiple myeloma patients

Cancers (Basel)1225692020

10.3390/cancers12092569

32916955

7565855

162

Nishida

Arizumi

Hagiwara

Ida

Sakurai

Kudo

MicroRNAs for the prediction of early response to sorafenib treatment in human hepatocellular carcinoma

Liver Cancer61131252017

10.1159/000449475

28275578

5340220

163

Seipel

Messerli

Wiedemann

Bacher

Pabst

MN1, FOXP1 and hsa-miR-181a-5p as prognostic markers in acute myeloid leukemia patients treated with intensive induction chemotherapy and autologous stem cell transplantation

Leuk Res891062962020

10.1016/j.leukres.2020.106296

164

Danza

Silvestris

Simone

Signorile

Saragoni

Brunetti

Monti

Mazzotta

De Summa

Mangia

Tommasi

Role of miR-27a, miR-181a and miR-20b in gastric cancer hypoxia-induced chemoresistance

Cancer Biol Ther174004062016

10.1080/15384047.2016.1139244

26793992

4910913

165

Petrillo

Zannoni

Beltrame

Martinelli

DiFeo

Paracchini

Craparotta

Mannarino

Vizzielli

Scambia

Identification of high-grade serous ovarian cancer miRNA species associated with survival and drug response in patients receiving neoadjuvant chemotherapy: A retrospective longitudinal analysis using matched tumor biopsies

Ann Oncol276256342016

10.1093/annonc/mdw007

26782955

166

Shi

Zhu

Huang

Zhuo

Wang

Chen

Zhang

Cancer-associated fibroblast-derived exosomal microRNA-20a suppresses the PTEN/PI3K-AKT pathway to promote the progression and chemoresistance of non-small cell lung cancer

Clin Transl Med12e9892022

10.1002/ctm2.989

35857905

9299573

167

Novoa Díaz

Martín

Gentili

Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway: Providing understanding of the complex mechanisms of chemoresistance

World J Gastroenterol28302730462022

10.3748/wjg.v28.i26.3027

168

Kousar

Ahmad

Abduh

Kanwal

Shah

Naseer

Anjum

miRNAs in regulation of tumor microenvironment, chemotherapy resistance, immunotherapy modulation and miRNA therapeutics in cancer

Int J Mol Sci23138222022

10.3390/ijms232213822

36430305

9699074

169

Shah

Ferrajoli

Sood

Lopez-Berestein

Calin

microRNA therapeutics in cancer-an emerging concept

EBioMedicine1234422016

10.1016/j.ebiom.2016.09.017

27720213

5078622

170

Zhang

Gao

Yao

Platinum-based drugs for cancer therapy and anti-tumor strategies

Theranostics12211521322022

10.7150/thno.69424

171

Zhao

Wang

Zhu

Zhang

DLX6-AS1 activated by H3K4me1 enhanced secondary cisplatin resistance of lung squamous cell carcinoma through modulating miR-181a-5p/miR-382-5p/CELF1 axis

Sci Rep11210142021

10.1038/s41598-021-99555-8

8546124

172

Sun

VDR/vitamin D receptor regulates autophagic activity through ATG16L1

Autophagy12105710582016

10.1080/15548627.2015.1072670

173

Lin

Chen

Sun

Wang

Zhao

Upregulation of microRNA-181a-5p increases the sensitivity of HS578T breast cancer cells to cisplatin by inducing vitamin D receptor-mediated cell autophagy

Oncol Lett212472021

10.3892/ol.2021.12508

33664811

7882884

174

Galluzzi

Morselli

Vitale

Kepp

Senovilla

Criollo

Servant

Paccard

Hupé

Robert

miR-181a and miR-630 regulate cisplatin-induced cancer cell death

Cancer Res70179318032010

10.1158/0008-5472.CAN-09-3112

20145152

175

Lou

Yuan

Wang

Zhang

Effects of lncRNA ANRIL-knockdown on the proliferation, apoptosis and cell cycle of gastric cancer cells

Oncol Lett226212021

10.3892/ol.2021.12882

34267814

8258619

176

Tang

Shi

Liu

Chai

Tang

Hann

The regulation and interaction of PVT1 and miR181a-5p contributes to the repression of SP1 expression by the combination of XJD decoction and cisplatin in human lung cancer cells

Biomed Pharmacother1211096322020

10.1016/j.biopha.2019.109632

177

Bai

Cao

Deng

Zhou

Wang

miR-181a sensitizes resistant leukaemia HL-60/Ara-C cells to Ara-C by inducing apoptosis

J Cancer Res Clin Oncol1385956022012

10.1007/s00432-011-1137-3

178

Ping

Gao

Fan

Deng

MiR-181a contributes gefitinib resistance in non-small cell lung cancer cells by targeting GAS7

Biochem Biophys Res Commun495248224892018

10.1016/j.bbrc.2017.12.096

179

Barbato

Iuliano

Volpe

D'Alterio

Brillante

Massa

De Cegli

Carrella

Salati

Russo

Integrated genomics identifies miR-181/TFAM pathway as a critical driver of drug resistance in melanoma

Int J Mol Sci2218012021

10.3390/ijms22041801

33670365

7918089

180

Tabatabaei

Derbali

Yang

Superstein

Hamel

Chain

Hardy

Co-delivery of miR-181a and melphalan by lipid nanoparticles for treatment of seeded retinoblastoma

J Control Release2981771852019

10.1016/j.jconrel.2019.02.014

30776396

Figure 1

MiR-181a-5p inhibits target mRNA by binding to its 3'UTR and regulates multiple harmarks of tumor cells. In addition, miR-181a-5p is modulated by multiple factors, such as ncRNAs, transcription factors, DNA methylation and hypoxia. EMT, epithelial-mesenchymal transition; ORF, Open Reading Frame; AGO, argonaute; lncRNA, long non-coding RNA; circRNA, circular RNA; miR, microRNA; UTR, untranslated region.

Figure 2

Role of miR-181a-5p in different tumors of the digestive system. Targets confirmed in the same report are connected with arrows with same colors and the factors producing different effects are separated by dotted lines (→, promote; -|, inhibit). miR, microRNA; CCAT1, colon cancer-associated transcript 1; Egr-1; c-Met; ATG, autophagy-related gene; ROCK2, Rho-associated coiled-coil-containing protein kinase 2; PLAG1, pleomorphic adenoma gene 1; E2F5, E2f transcription factor family member 5; SRCIN1, SRC kinase signaling inhibitor 1; WIF-1, Wnt inhibitory factor-1; ZEB1-AS1, zinc-finger E homeobox-binding1 antisense1; circ, circular RNA; NSUN2, NOP2/Sun domain family, member 2; CRNDE, Colorectal Neoplasia Differentially Expressed; SNHG6, small nucleolar RNA host gene 6; ANRIL, Antisense non-coding RNA in the INK4 locus; CCAT1, colon cancer associated transcript 1; HMGB1, high-mobility group box 1 protein; prox1, Prospero-related homeodomain transcription factor1; MEG3, maternally expressed gene 3; RASSF, Ras association domain family; MALAT1, metastasis associated lung adenocarcinoma transcript 1; CBLB, second member of the E3 ubiquitin ligase CBL family; XIST, X-inactive specific transcript; PTEN, Phosphatase and Tensin Homolog deleted on Chromosome 10.

Figure 3

Role of miR-181a-5p in different tumors of reproductive system. Targets confirmed in the same report are connected with arrows with the same colors, and the factors producing different effects are separated by dotted lines (→, promote; -|, inhibit). miR, microRNA; KLF, Kruppel-like factors; PGRMC1, progesterone (P4) receptor membrane component 1; PHLPP2, PH domain leucine-rich repeat-containing protein phosphatase 2; INPP4B, Inositol polyphosphate 4-phosphatase type II; PIAS, protein inhibitor of activated STAT; TUSC3, tumor suppressor candidate 3; NDRG2, N-myc downstream-regulated gene 2; SOX2, sex-determining region Y-box 2; LUCAT1, lung cancer-related transcript 1; GRP78, Glucose-Regulated Protein 78; PRKCD, Protein kinase C delta; INPP5A, Inositol Polyphosphate-5-Phosphatase A; DLEU2, deleted in lymphocytic leukemia 2; SFRP4, Secreted Frizzled Receptor Protein 4; LEF1, Lymphoid enhancer factor; MMP, membrane-type matrix metalloproteinase; MBNL1-AS1, Muscle blind-like-proteins antisense 1.

Table I

Role of miR-181a-5p in different types of cancer.

Tumor type	Upstream regulator	Target	Mechanism	Role	(Refs.)
Colorectal cancer	-	WIF-1	Promotes tumor growth and liver and EMT metastasis	oncomiR	(41)
	-	PTEN	Triggers metabolic shift	oncomiR	(43)
	-	PTEN	Promotes liver metastasis	oncomiR	(42)
	NF-κB	PTEN	Promotes tumor growth	oncomiR	(26)
	STAT1	PTEN	Promotes tumor growth	oncomiR	(27)
	-	SRCIN1	Promotes angiogenesis	oncomiR	(44)
	BAP31	RECK	Promotes angiogenesis	oncomiR	(45)
	CRNDE	Wnt/β-catenin	Inhibits tumor development and promotes the sensitivity to 5-FU	inhibitor	(34)
	-	PLAG1	Inhibits tumor development	inhibitor	(28)
	ZEB1-AS1	Wnt/β-catenin/	Suppresses tumor growth and promotes the sensitivity to 5-FU	inhibitor	(35)
	SNHG6	E2F5	Inhibits cell migration, invasion and induces G₀/G₁ arrest	inhibitor	(38)
	CCAT1	P53	Induce cell apoptosis	inhibitor	(24)
	CircNSUN2	ROCK2	Inhibits tumor growth	inhibitor	(39)
	ANRIL	-	Increase tumor apoptosis and radio resistance	inhibitor	(36)
Gastric cancer	-	MEG2	Promotes tumor growth	oncomiR	(51)
	-	TGF-β	promotes cell proliferation	oncomiR	(48)
	-	RASSF1A	promotes cell proliferation, G₁/S transition	oncomiR	(49)
	-	RASSF6	Promotes tumor metastasis and EMT	oncomiR	(52)
	-	caprin-1	Promotes cell migration and invasion	oncomiR	(53)
	MEG3	ATP4B	Promotes tumor growth	oncomiR	(50)
	-	ATG5	Inhibits autophagy and cisplatin resistance	inhibitor	(54)
	-	Prox1	Inhibits tumor growth and metastasis	inhibitor	(55)
	MALAT1	AKT	Inhibits tumor growth	inhibitor	(56)
Hepatocellular carcinoma	XIST	PTEN	Enhances cell proliferation and invasion	oncomiR	(60)
	-	c-Met	Diminishes branching-morphogenesis	inhibitor	(18)
	-	Egr1	Suppresses tumor proliferation	inhibitor	(58)
	CCAT1	ATG7	Inhibits autophagy	inhibitor	(59)
Esophageal adenocarcinoma	-	CBLB	Enhance the sensitivity of cisplatin	inhibitor	(61)
Pancreatic cancer	ANRIL	HMGB1	Inhibit tumor growth and gemcitabine resistance	inhibitor	(64)
	-	PTEN and MAP2K4	Promotes cells invasion	oncomiR	(63)
Non-small cell lung cancer	-	Kras	Inhibits cell proliferation and migration	inhibitor	(67)
	-	CDK1	Inhibits tumor growth	inhibitor	(68)
	-	VCAM-1	Inhibits tumor growth	inhibitor	(70)
	NEAT1	HMGB2	Inhibits cell migration and invasion	inhibitor	(25)
	SNHG7	E2F7	Suppresses tumor growth and metastasis	inhibitor	(69)
Laryngeal cancerous	MYCAT1	NPM1	Inhibits tumor growth	inhibitor	(74)
	ANRIL	Snai2	Inhibits EMT	inhibitor	(75)
Bladder cancer	circ0068871	-	Inhibits cell proliferation and migration	inhibitor	(103)
Renal cancer	-	KLF6	Promotes tumor growth and EMT	oncomiR	(105)
Thyroid cancer	ZNF674-AS1	SOCS4	Aggravates tumor growth, metastasis and EMT	oncomiR	(109)
	-	KDM5C	Promote tumor growth	oncomiR	(107)
	-	SLC5A5	Decrease efficacy of radioiodine treatment	oncomiR	(110)
	-	MIL3	Promotes angiogenesis	oncomiR	(29)
	-	KLF15	Promote tumor growth	oncomiR	(108)
Salivary adenoid cystic carcinoma	circ001982	-	Inhibits cell migration and invasion	inhibitor	(111)
Chondrosarcoma	-	RGS16	Promote tumor growth, metastasis and angiogenesis	oncomiR	(142)
	-	VEGF	Increases expression of VEGF	oncomiR	(30)
Osteosarcoma	CASC2	RASSF6	Promotes cell proliferation and invasion	oncomiR	(139)
	TUSC7	RASSF6	Promotes cell proliferation and invasion	oncomiR	(140)
Breast cancer	TGF-β	-	Promotes anoikis resistance	oncomiR	(78)
	SOX2	TUSC3	Promotes tumor metastasis	oncomiR	(79)
	-	PHLPP2 and INPP4B	Promotes S-phase entry and proliferation	oncomiR	(77)
	-	PIAS3	Promotes tumor growth	oncomiR	(19)
	-	NDRG2	Facilitates metastasis and glycolysis	oncomiR	(80)
	-	PGRMC1	Inhibits tumor growth	inhibitor	(82, 83)
	ERβ	-	Blocks cholesterol biosynthesis	inhibitor	(81)
	LUCAT1	KLF6 and KLF15	Inhibits cell proliferation and invasion	inhibitor	(84)
Cervical cancer	-	PRKCD	Inhibit irradiation-induced apoptosis and decreases G₂/M block	oncomiR	(88)
	-	PTEN	Promotes tumor growth	oncomiR	(87)
	-	INPP5A	Promotes tumor growth	oncomiR	(86)
	-	GRP78	Inhibits tumor growth and oxaliplatin resistance	inhibitor	(89)
	CDKN2B-AS1	TGFβ1	Inhibits tumor metastasis	inhibitor	(90)
	LUCAT1	-	Inhibits tumor growth and EMT	inhibitor	(91)
	CCAT1	MMP14	Inhibits cell proliferation and invasion	inhibitor	(23)
Endometrial carcinoma	CCAT1	-	Inhibits tumor growth	inhibitor	(95)
	DLEU2	-	Inhibits EMT and glycolysis	inhibitor	(96)
Ovarian cancer	-	Smad7	Promotes tumor growth and EMT	oncomiR	(97)
	-	SFRP4	Promotes stem cell frequency and platinum resistance	oncomiR	(98)
Prostate cancer	LEF1	-	Promotes tumor growth and EMT	oncomiR	(101)
	MIIP	KLF17	Promotes EMT	oncomiR	(102)
	MBNL1-AS1	PTEN	Promotes tumor growth	oncomiR	(100)
Melanoma	CASC2	PLXNC1	Promotes tumor growth	oncomiR	(133)
	LEFPL3-AS1	-	Induces apoptosis of melanoma stem cells	inhibitor	(134)
Cutaneous squamous cell carcinoma	-	TGF R3	Promotes tumor development	oncomiR	(136)
	-	Kras	Decelerates proliferation	inhibitor	(137)
Glioma	CASC2	PTEN	Promotes tumor growth and TMZ resistance	oncomiR	(128)
	circ0076248	SIRT1	Inhibits tumor growth and TMZ resistance	inhibitor	(122)
	-	KLF6	Increases permeability of BTB	inhibitor	(127)
	-	OPN	Decreases tumor progression and OPN production	inhibitor	(126)
	-	-	Inhibits tumor growth and camustine resistance	inhibitor	(124)
	-	Notch2	Suppresses the formation of glioblastoma stem cell	inhibitor	(125)
Neuroblastoma	-	ABI1	Induces tumor growth and metastasis	oncomiR	(130)
Medulloblastoma	-	Ras	Promotes cell invasion and migration	oncomiR	(132)
Leukemia	-	ATM	Promotes proliferation and G₁/S transition	oncomiR	(113)
	-	RalA	Suppresses tumor growth	inhibitor	(116)
	-	W1F1	Promotes tumor growth	oncomiR	(114)
	-	STAT3	Inhibits the sensitivity to FAS-mediated apoptosis	inhibitor	(115)
Myeloma	CCAT1	HOXA1	Inhibits tumor growth	inhibitor	(118)
	MALAT1	Hippo-YAP	Inhibits tumor growth	inhibitor	(117)
Lymphoma	-	NF-κB	Inhibits cell proliferation and survival	inhibitor	(120)

OPN, Osteopotin.

Table II

MiR-181a-5p as a biomarker.

Tumor	Expression	Indication	(Refs.)
Breast cancer	Down	Early diagnosis of breast cancer.	(144,160)
Colorectal cancer	Up	Diagnosis of colorectal cancer.	(143,149)
		Lower prognosis and survival outcome.
	Down	Low expression reflects poor PFS of colorectal cancer treated with EGFR-TKIs.	(143)
Endometrial carcinoma	Down	Significantly high in type II endometrial carcinoma.	(147)
Non-small cell lung cancer	Up	Diagnosis of Chinese male lung squamous cell carcinoma.	(148,159)
		High expression has an improved outcome with EGFR-TKIs.
	Down	Shorter overall survival and poor prognosis.	(154,155)
Prostate cancer	Up	Significantly high in bone metastatic prostate cancer patients.	(157)
Acute lymphoblastic leukemia	Up	Upregulated miR-181a-5p predicts higher risk of central nervous system.	(154)
Acute myeloid leukemia	NA	Significantly higher in better prognosis patients.	(156,163)
		Positively associates with outcome treated with intensive induction chemotherapy.
Rectal cancer	Down	Lymph node metastasis and N-positive disease.	(159)
Multiple myeloma	Up	Short progression and poorer prognosis.	(151)
	Down	Bortezomib resistance.	(161)
Pancreatic cancer	NA	Lower in non-progressive stagy.	(145)
Hepatocellular carcinoma	NA	Low expression implicates poor outcome afte treating with sorafenib.	(162)
Gastric cancer	Down	Downregulation of miR-181a-5p is associated with progressive disease treated with EOX regimen.	(164)
Ovarian cancer	NA	High expression reflects shorter overall survival and progression-free survival.	(150,165)
Esophageal cancer	Down	Diagnosis of esophageal cancer.	(146)

NA, not available.

Table III

Impact of miR-181a-5p on chemotherapy.

Chemotherapy Drug	Cancer	Role	Target	(Refs.)
Platinum	NSCLC	Promotes the sensitivity of cisplatin	CELF1, and SP1	(171,176)
	Breast cancer	increases the sensitivity of cisplatin	Vitamin D receptor	(173)
	Gastric cancer	Promotes the sensitivity of DDP	cyclinG1	(175)
	Esophageal cancer	increases the sensitivity of cisplatin	CBLB	(61)
	Cervical cancer	Promotes the sensitivity of oxaliplatin	GRP78	(89)
	Ovarian cancer	Inhibits the sensitivity of cisplatin	SFRP44	(98)
Dabrafinib	Melanoma	Reverses dabrafinib resistance	TFAM	(189)
5-FU	Colorectal cancer	Increases 5-FU sensitivity	Wnt/β-catenin, PLAG1	(28,34)
Melphalan	Seeded retinoblastoma	Enhances the efficacy of melphalan	BCL-2, MAPK1 and Bax	(180)
Carmustine	Glioma	Promotes sensitivity of Carmustine	/	(124)
Gemcitabine	Pancreatic cancer	Suppresses chemoresistance to	HMGB-1 gemcitabine	(64)
Ara-c	Leukemia	Inhibits Ara-c resistance	/	(177)
Gefitinib	Non-small cell lung cancer	Promotes gefitinib resistance	GAS7	(178)