Aberrant miR-222-3p expression is closely associated with the clinical characteristics of patients with cancer. For instance, miR-222-3p was found to be overexpressed in papillary thyroid carcinoma (PTC) compared with in normal thyroid and benign cancer tissues (38). Additionally, Di Fazio et al (39) reported that miR-222-3p could be used to distinguish patients with typical and atypical lung carcinoid. Furthermore, miR-222-3p combined with a panel of miRNAs (miR-7-5p and miR-146b-5p) exhibited high sensitivity and specificity for identifying different subtypes of PTC (40). This panel of miRNAs could distinguish non-invasive follicular thyroid neoplasms from papillary-like nuclear features, follicular adenomas and infiltrative follicular variants of PTC (40-42). miR-222-3p was reported to be differentially expressed in some types of cancer, as shown in Table I. For example, miR-222-3p expression is decreased in prostate cancer, while it is increased in other types of cancer, including bladder and breast cancer; however, miR-222-3p expression in ovarian carcinoma remains controversial (Table I).

Recently, Wang et al (23) investigated the functions of the clustered miRNAs hsa-miR-221/222-3p in hepatocellular carcinoma (HCC) using a human miRNA tissue atlas, revealing that these two miRNAs and their target genes had potential prognostic value for HCC, especially miR-222-3p, which functioned as a tumor promotor in hepatic tumorigenesis (23). The oncogenic function of miR-222-3p has also been confirmed in non-alcoholic steatohepatitis (NASH)-associated liver carcinogenesis (43), indicating that miR-222-3p may serve as an indicator for the development of NASH-derived HCC.

In addition, dysregulated miR-222-3p expression was found to be closely associated with tumor stage, invasion and metastasis. In gastric carcinoma, high miR-222-3p expression was positively associated with advanced clinical stage and lymph node metastasis (44), and could predict the survival of patients who were unable to receive chemotherapy after surgery (45). Rinnerthaler et al (46) reported that miR-222-3p expression was associated with the progesterone receptor, and elevated miR-222-3p expression was involved in breast cancer development, tumor spread, proliferation and drug resistance. Moreover, miR-222-3p was found to be highly associated with the tumor stage and lymph node metastasis in estrogen receptor α (ERα)-negative patients with endometrial cancer (EC), and lower miR-222-3p expression was detected in ERα-negative EC with lower grades (P=0.0145) and earlier stages (I vs. II, P=0.05; II vs. III, P=0.0043; I vs. III, P=0.0002) (26). By contrast, miR-222-3p upregulation exhibited a positive association with overall survival in patients with epithelial ovarian cancer (EOC), and its expression level was negatively associated with tumor growth in an EOC mouse model (37).

miR-222-3p serves as a specific biomarker for various types of tumors in body fluids, such as serum, plasma and urine (13,47,48) indicating that miR-222-3p has the potential to be developed into a non-invasive diagnostic biomarker for tumors. High expression levels of circulating miR-222-3p were significantly associated with lymph node metastasis (P=0.009) and clinical stages (P<0.001) in gastric cancer in an analysis of 38 plasma samples (49). Chang et al (50) revealed that miR-222-3p was negatively associated with clinical staging and lymph node metastasis status in plasma samples collected from patients with oral carcinoma, and miR-222-3p may be a useful diagnostic biomarker for the differentiation of oral squamous cell carcinoma and oral leukoplakia plaque. Furthermore, Fredsoe et al (51) developed a three-microRNA ratio model (miR-222-3p*/miR-24-3p/miR-30c-5p), which provided accurate markers in the differential diagnosis of benign prostatic hyperplasia and prostate cancer (PCa). Several studies have found that serum miRNAs could be used to predict the risk of non-muscle invasive bladder cancer, and risk scores were generated according to the combination of the three miRNA ratios (miR-29a-3p/miR-222-3-p, miR-150-5-p/miR-331-3p and miR-409-3-p/miR-433-5-p) (52,53). Similar results were obtained in PTC (38,54). As aforementioned, dysregulated miR-222-3p expression has been observed in numerous types of human cancer, thus providing powerful rationales for its application as a non-invasive diagnostic biomarker.

As well as having a strong potential in the diagnosis of cancer, miR-222-3p also serves an important role in predicting the prognosis of patients with cancer. An increasing number of studies has demonstrated that dysregulated miR-222-3p expression can predict the progression and poor prognosis of patients with cancer, including prostate cancer and papillary thyroid carcinoma (30,31).

Ulivi et al (55) analyzed the expression levels of miRNAs in early non-small cell lung cancer (NSCLC) tissues, lung squamous cell carcinoma tissues and circulating blood. Notably, miR-222-3p was significantly associated with decreased disease-free survival (DFS) and overall survival (55). Wang et al (56) revealed that downregulation of miRNAs (miR-130b-5p, miR-151a-5p, miR-206 and miR-222-3p) was closely associated with a poor prognosis after surgery and that serum miR-222-3p was an independent prognostic factor for a poor DFS time [hazard ratio (HR), 13.19; 95% CI, 1.06-163.59; P=0.045] in patients with breast cancer (56). Additionally, circulating miR-222-3p was significantly associated with the estrogen level of patients with EC, and elevated miR-222-3p expression was positively associated with tumor size, indicating that miR-222-3p may serve as a crucial indicator of prognosis in patients with EC (26).

KRAS and BRAF are poor prognostic indicators used for colorectal cancer (CRC; frequency of mutation in patients: KRAS, 38-44.9%; BRAF, 4.2-5%); KRAS and BRAF mutations were positively associated with a poor prognosis in patients with CRC (57-59). Therefore, more sensitive prognostic biomarkers are required for CRC. A panel of 16 miRNAs (including miR-222-3p) associated with improved 5-year DFS time for stage II and III CRC was identified (57). The signature was identified as an independent prognostic factor for improved 5-year DFS time by multivariate analyses (57). Similar observations were reported in gastric carcinoma (45) and thyroid cancer (54). Additionally, elevated serum miR-222-3p expression may significantly predict a poor probability of 2-year DFS time in patients with glioblastoma (60). Notably, a novel logistic regression model, comprising five urinary miRNAs (miR-151a-5p, miR-204-5p, miR-222-3p, miR-23b-3p and miR-331-3p) and serum prostate-specific antigen (PSA), was established successfully by Fredsoe et al (32) and could predict time to biochemical recurrence in 215 patients with PCa (univariate Cox regression analysis HR, 3.12; P<0.001).

To investigate the prognostic value of miR-222-3p in the survival of patients with various types of cancer, miR-222-3p expression in human cancers was analyzed from The Cancer Genome Atlas database (https://tcga-data.nci.nih.gov/tcga/). The Kaplan-Meier analysis method was used for survival analysis using GraphPad Prism 7.00 (GraphPad Software, Inc.). Log-rank P<0.05 was considered to indicate a statistically significant difference. Considering the mid- and late-stage crossovers, the weighted method of Cramer-von Mises testing was used. The patients were divided into two groups according to the different expression levels of miR-222-3p in each tumor type, either lower or higher than the mean value.

miR-222-3p expression was significantly associated with the survival of patients with breast invasive carcinoma, brain lower grade glioma, clear cell renal carcinomas, glioblastoma multiforme or kidney renal papillary cell carcinoma (Fig. 1A), with high miR-222-3p expression predicting a poorer overall survival compared with low miR-222-3p expression. In 11 other types of cancer (acute myeloblastic leukemia, colon cancer, cutaneous melanoma, esophageal cancer, EC, gastric carcinoma, lung adenocarcinoma, ovarian serous cystadenoma, pancreatic cancer, rectum adenocarcinoma and sarcoma), the expression levels of miR-222-3p were not significantly associated with overall survival (Fig. 1B and C). Although higher miR-222-3p expression seemed to predict longer overall survival in acute myeloblastic leukemia, there was no significant difference between the two groups (P=0.0589; Fig. 1B). Additionally, higher miR-222-3p expression in cervical and prostate cancer predicted a longer overall survival (Fig. 1A). Although these data may be affected by the sample size and stability of the sequencing method in the miR-222-3p quantification, the aforementioned data suggest that miR-222-3p expression may exhibit prognostic value only in certain types of human cancer.

Therapeutic resistance is a major risk factor for a poor prognosis in tumor patients who undergo chemo- and radio-therapy (61,62). A previous study indicated that miR-222-3p increased raloxifene resistance through suppressing ERα expression in EC cells (26). This mechanism is also observed in the resistance to gemcitabine, a nucleoside analogue with activity against NSCLC, with acquired gemcitabine resistance being a major obstacle in NSCLC treatment (63).

Aberrant miR-222-3p expression serves a crucial role in numerous types of human tumors (64), and it is closely associated with certain aspects of cancer biology, including tumorigenesis (65-68). Recently, several reports have indicated that miR-222-3p exhibited an oncogenic function, including in CRC (18) and EC (69). Moreover, miR-222-3p expression drives cancer stem cell renewal in CRC, making it a potential target for therapy (70). Helicobacter pylori infection acts as a trigger in the carcinogenesis of gastric cancer (71), and increasing studies (53,72) suggest that H. pylori affects miRNA expression. Tan et al (53) revealed that miR-222-3p expression was markedly increased in the cancer group [H. pylori (+)] compared with in the normal group [H. pylori (-)]. miR-222-3p associated with H. pylori targets homeodomain-interacting protein kinases 2 (HIPK2) to promote cell proliferation and invasion, and to inhibit apoptosis in gastric cancer (72). Functional experiments demonstrated that miR-222-3p overexpression significantly enhanced the proliferative activity while inhibiting the apoptosis of SGC7901 gastric cancer cells, but miR-222-3p-knockdown exhibited the opposite effects (35). Consistent with this finding, an in vivo experiment revealed that downregulated miR-222-3p expression in AN3CA cells inhibited EC tumor growth in a mouse xenograft model (26). By contrast, Fu et al (37) demonstrated that higher miR-222-3p expression was associated with improved overall survival in patients with EOC, and its level was negatively associated with tumor growth in vivo. Thus, miR-222-3p may govern key processes during the development of various types of cancer.

As a cellular regulator, miR-222-3p affects gene expression via direct binding to complementary sequences in the 3′-UTR of target mRNAs in numerous types of cancer cells (73). miR-222-3p determines the malignancy of cell proliferation or apoptosis in various types of cancer, including breast cancer and colorectal carcinoma (74-76). The global regulatory mechanism of miR-222-3p in determining the fate of cancer cells is shown in Fig. 2.

In addition, it has been reported that overexpression of miR-222-3p induces alteration of the cell cycle (a high ratio of G₁ to S phase) and promotes cell proliferation (26). Conversely, miR-222-3p-knockdown significantly decreases cell proliferation by upregulating cyclin D1 (26). The upregulation of miR-222-3p markedly stimulated cell proliferation and repressed apoptosis by releasing endogenous IL-24 and activating the phosphatidylinositol 3 (PI3K)/AKT signaling pathway in lung cancer (77). Further investigation indicated that activation of the PI3K/AKT signaling pathway directly suppressed high mobility group AT-hook 1 (HMGA1) expression, with the dysregulation of phosphatase and tensin homology deleted on chromosome ten (PTEN) by miR-222-3p (77,78). By contrast, Coarfa et al (17) identified a panel of 12 miRNAs (including miR-222-3p) with a proteomic footprint (using reversed-phase proteomic arrays), and the expression levels of these miRNAs were markedly decreased in metastatic PCa. This miRNA panel significantly decreased cell proliferation and targeted key tumor-associated signaling pathways involving the androgen receptor axis and the Akt/mTOR signaling pathway (17). Additionally, other studies revealed that miR-222-3p expression was decreased upon progression to high-grade PCa (Gleason score 8-10 or PSA level >20 ng/ml; clinical stage, T3a) (79-81). A similar result was obtained in a study of PCa by Tong et al (82). Ottley et al (80) reported that cyclin-dependent kinase inhibitor 1B expression was accompanied by a decrease in miR-93, miR-222-3p and miR-18a expression in activin A-treated prostate cancer LNCaP cells. Furthermore, a previous study observed higher expression levels of miR-222-3p in androgen-independent LNCaP cells than in LNCaP cells, indicating its growth-promoting role in PCa (83). A small molecule inhibitor of murine double minute 2 (MDM2), nutlin-3, selectively disrupted the interaction between MDM2 and p53 (84). Moreover, genome-wide miRNA expression analysis revealed that the expression levels of miR-34a-5p, miR-182-5p, miR-203a, miR-222-3p and miR-432-5p were upregulated following nutlin-3 treatment in a p53-dependent manner (85). Notably, miR-222-3p overexpression promoted apoptosis and suppressed proliferation in neuroblastoma cells (85).

In cancer cells, different types of mutations may mediate amplification or reduction of gene expression and lead to altered protein expression patterns (86). Although miR-222-3p is hypothesized to regulate specific genes, it may not affect some of its predicted genes (26). The function of miR-222-3p mainly affects cell fate-associated signaling pathways.

Aberrant miRNA expression has been reported in metastatic cancers, which universally display an aggressive pathophysiology (20). Consistent with this finding, miR-222-3p has been shown to be essential for the invasion and metastasis of different types of cancer, including osteosarcoma, endometrial carcinoma and prostate cancer (25,26,87) (Fig. 2).

Guo et al (25) revealed that forced miR-222-3p expression decreased the expression levels of tissue inhibitor of metalloproteinases 3 (TIMP3) in osteosarcoma cells. TIMP3 inhibits the transfer of endogenous proteases via regulating matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), which are involved in mediating cancer progression (87). Moreover, transfection of MG-63 and U-2OS cells with miR-222-3p inhibitors significantly increased the migration and invasion of these osteosarcoma cells, suggesting that miR-222-3p may act as a cancer suppressor (25). miR-222-3p is highly expressed in ER-negative EC, and overexpression of miR-222-3p significantly promotes the migration and invasion of EC cells by targeting ERα (27). Tan et al (35) revealed that the protein HIPK2 was decreased in gastric cancer tissues [H. pylori (+) group] compared with in normal gastric tissues. Further analysis indicated that miR-222-3p could enhance the migration of gastric cancer cells by binding to the 3′-UTR of HIPK2 (35). Tricho-rhino-pharyngeal syndrome type 1 (TRPS1)/zinc finger E-box binding homeobox 1 (ZEB1) signaling is positively associated with tumor cell migration and invasion (13). TRPS1 can enhance the expression levels of E-cadherin and vimentin by upregulating miR-222-3p expression (13). Additionally, miR-222-3p targets E-cadherin-mediated ZEB1-induced epithelial-mesenchymal transition (EMT), thereby promoting chordoma progression (13).

The resistance of tumors to various anticancer drugs is an important factor that increases the invasiveness and metastasis of tumor cells (88,89), which depend on escaping apoptosis and increasing drug efflux (24,90). Dysregulated miR-222-3p expression may contribute to drug resistance by regulating gene expression (37), the cell cycle and apoptosis (26,37). Therefore, miR-222-3p is commonly perceived to be responsive to cancer treatment and has been emphasized as a new drug target (91) (Fig. 2).

miR-222-3p induces cisplatin resistance in EOC cells by targeting the 3′-UTR of G protein a inhibiting activity poly-peptide 2 (37). Additionally, several studies (26,34,37) revealed that the upregulation of miR-222-3p expression promoted cell survival in cisplatin-treated ovarian cancer cells. In addition, miR-222-3p increased raloxifene resistance via suppressing ERα expression in EC cells (26). Increased miR-222-3p expression directly targeted the 3'-UTR of claudin-2 mRNA to decrease apoptosis and induce CRC resistance to 5-fluo-rouracil (92). Transfection of miR-222-3p inhibitor into doxycycline (DOX)-resistant colon cancer cells (LoVo/ADR cells) decreased the expression levels of apoptotic proteins, such as poly (ADP-ribose) polymerase (PARP) and caspase 3, and significantly increased the expression levels of typical antiapoptotic proteins (BAX, cleaved PARP and cleaved caspase 3) (24). These results indicate that miR-222-3p may be a promising therapeutic target for overcoming chemotherapy resistance in human cancer.

The tumor microenvironment serves an important role in cancer initiation, progression and metastasis (93). The primary components of the tumor micro-environment are fibroblasts, immune cells, endothelial cells, extracellular matrix and cytokines (94,95). Among them, immune cells serve vital roles in enhancing cancer progression by secreting numerous proinflammatory factors (96). According to previous studies (97-100), miR-222-3p can modulate the function of immune cells, such as natural killer (NK) cells and cancer-associated fibroblasts, and serve an important role in the tumor microenvironment.

Ying et al (97) revealed that upregulated miR-222-3p expression activated the JAK/STAT signaling pathway by inhibiting suppressor of cytokine signaling 3 (SOCS3) expression, thereby decreasing the polarization of ovarian cancer-associated M2-like macrophages. Decreased expression levels of apoptosis-inducing ligand tumor necrosis factor and CD107a associated with liver NK cells impaired degranulation, which may contribute to the persistence of chronic hepatitis C virus (HCV) infection (101). Therefore, chronic HCV infection has different effects on the function of NK cell subsets in intrahepatic and peripheral blood chambers (101). In addition, strong inflammatory signals suppress the degranulation of NK cells, increasing the risk of disease progression in several types of patients (102,103). These results indicate that miR-222-3p may be an important factor that can regulate the NK cell activity involved in HCV-associated HCC.