CRC, the second-leading cause of mortality in the United States, is a principal global health issue (1,32). With the revelation of novel molecular and epigenetic mechanisms, lncRNAs, including HOX transcript antisense RNA (33), colon cancer-associated transcript 2 (34), metastasis-associated lung adenocarcinoma transcript 1 (35), carcinoembryonic antigen (36) and LINC00152 (37), have become biological targets for diagnostic, therapeutic and prognostic applications in patients with CRC. However, they all have limitations in the early diagnosis of CRC (38). Therefore, it is vital to identify novel bio-targets associated with CRC tumourigenesis (39).

Through reverse transcription-quantitative polymerase chain reaction analysis, Nissan et al (22) first demonstrated that CCAT1 expression levels in the mucosa of colon adenocarcinoma were significantly higher compared with normal colon tissues. A recent genome-wide association analysis in CRC demonstrated the same result (40). In addition, in the later stages of the disease, CCAT1 is strongly expressed in early stages of tumourigenesis, including tumour-proximal colonic epithelium and adenomatous polyps, which was demonstrated by Alaiyan et al (41) across the colon adenocarcinoma sequence. Elevated CCAT1 expression levels are positively associated with advanced clinical stages, lymphatic metastasis, local invasive depth, vascular invasion, CA19-9, recurrence-free survival (RFS) and overall survival (OS) (30,42–44). Furthermore, CCAT1 expression levels are significantly increased in the peripheral blood of patients with CRC. In particular, at a mild phase, increased CCAT1 combined with increased plasma HOTAIR was able to more powerfully diagnose patients with CRC from a group of healthy controls (22,45). In addition, CCAT1-specific peptide nucleic acid-based molecular beacons have been identified as a diagnostic marker to detect CRC in vitro, ex vivo and in situ (46). However, because of the relatively small number of specimens in this previous study, extensive and multi-centre randomized controlled trials are required.

In vitro, CCAT1 is overexpressed in CRC-derived cells compared with normal colon-derived fibroblasts. Decreased CCAT1 was able to repress proliferation, migration, invasion and EMT, and led to G0/G1 cell-cycle arrest in CRC cell lines (30,42,43).

Previous studies suggested that c-Myc, which is a pivotal transcriptional regulator significantly amplified in various types of cancer, may directly combine with E-box elements in the CCAT1 promoter regions to activate CCAT1 transcription (Fig. 2A) (30,42). Additionally, CCAT1 may serve as an enhancer-templated RNA to predict bromodomain and extraterminal (BET)-mediated c-Myc regulation, and BET inhibition JQ1 sensitivity in CRC, which has been observed in specific previous studies with certain haematological malignancies (47,48).

This data suggests that the oncogene CCAT1 may serve as a novel biomarker for the early diagnosis and prognosis of CRC. In particular, it may be ideal for those patients who are sensitive to BET inhibitor-JQ1 in the treatment of CRC.

LSCC is the second most common head and neck malignancy (resulting in high mortality rates) worldwide (49,50). Despite the progress achieved in the diagnosis and therapy of LSCC in the past few decades, the survival rate has not noticeably increased (51). Therefore, novel molecular targets for LSCC are urgently required.

CCAT1 expression was higher in LSCC compared with matched normal tissues, and it was associated with advanced clinical stage (31,52). Mechanistically, CCAT1 overexpression promotes LSCC cell proliferation and invasion by suppressing let-7 expression and enhancing its target genes Myc and HMGA2, or by enhancing the zinc finger protein, X-linked, by sponging microRNA-218 (Fig. 3) (31,52).

ESCC is developing at the fastest rate among all cancer types in East Asia (53,54). Therefore, a deeper understanding of the molecular basis underlying ESCC is required to improve diagnosis and treatment.

CCAT1 is frequently increased in ESCC, which partly results from H3K27-acetylation activation of promoter (Fig. 2B), and it is an independent prognostic factor for advanced histological grade of patients with ESCC (55). Furthermore, proliferation and migration, in vitro and in vivo, are significantly supressed following knockdown of CCAT1 (55). Zhang et al (55) identified that in the nucleus, CCAT1 has the role of a modular scaffold for polycomb repressive complex 2 and Suppressor Of Variegation 3–9 Homolog 1. This combination modulates the histone methylation of sprouty RTK signalling antagonist 4 (SPRY4) promoter, thereby epigenetically silencing tumour suppressor genes SPRY4 (Fig. 2B). In the cytoplasm, CCAT1 upregulates HOXB13 as a molecular decoy for miR-7, thereby facilitating cell viability and migration (Fig. 3).

GC is one of the most lethal malignancies worldwide (1). The expression of CCAT1 is notably upregulated in GC compared with normal tissue (56,57). Notably, the CCAT1 expression levels in adjacent normal tissues from GC cases were higher compared with a negative control group, and recurrent GC tissues demonstrated the highest expression levels among these groups (57). Furthermore, CCAT1 overexpression is positively associated with metastasis, TNM grade, OS and RFS in patients with GC (58–60).

In vitro, abnormal CCAT1 expression levels promote GC cell proliferation, migration and invasion (58,59). Similar to CRC, c-Myc activates the promoter and increases CCAT1 expression levels by directly binding to E-box elements (58). Zhang et al (56) demonstrated that CCAT1 was involved in the ERK/MAPK signalling pathway to promote the growth of GC (Fig. 2D). Another previous study suggested that CCAT1 may additionally function as ceRNA by sponging miR-490 and free miR-490 target heterogeneous nuclear RNP A1 (hnRNPA1) for tumourigenesis in GC (Fig. 3) (59); the relevance has been verified in breast, colorectal, lung and glioma cancer (61–65).

HCC is the third leading cause of tumour-induced mortality worldwide and accounts for a large proportion of mortalities in China (3,66). Despite recent progress in experimental oncology, patients with HCC continue to have poor long-term prognosis (67). Therefore, it is crucial to identify reliable biomarkers of HCC to develop novel clinical strategies and increase the survival rates of patients with HCC.

CCAT1 expression levels are higher in HCC compared with pair-matched healthy hepatic tissues, particularly in highly metastatic HCC (25,68). Upregulation of CCAT1 has been identified to be positively associated with tumour size, liver cirrhosis, tumour number, vascular invasion, microvascular invasion, capsular formation, Edmondson-Steiner grade and α foetal protein, and it is an independent risk factor for disease-free survival and OS (25,68–70). Additionally, CCAT1 overexpression significantly accelerates HCC cell proliferation, migration and invasion, in vitro (25,68,69).

Similar to CRC and LSCC, CCAT1 activated by c-Myc (70), promotes HCC proliferation and metastasis by functioning as a let-7 sponge to supress its endogenous targets, HMGA2 and c-Myc (25). Furthermore, the CCAT1/miR-200b and CCAT1/miR-490-3p/cyclin-dependent kinase 1 regulatory pathway may additionally promote HCC progression (Fig. 3) (71,72). These findings implicate the potential role of CCAT1 in HCC therapies.

Gallbladder cancer (GBC) is the most common cancer of the biliary tract, and has a particularly high incidence in Chile, Japan and northern India (73). Despite the great efforts made to identify novel molecular abnormalities that contribute to GBC, many remain unknown (74).

CCAT1 is upregulated in GBC and is positively correlated with tumour status, lymph node invasion and advanced TNM stage (75). CCAT1 was able to improve the proliferation, migration and invasion of GBC cells in vitro (75). These effects are dependent on its competitive binding to miR-218-5p, thereby regulating Bmi1 (Fig. 3) (75).

Without typical symptoms and sensitive indicators, the diagnosis of the majority of CCA cases typically occurs at a late stage, with poor prognosis (76). Therefore, identifying more efficient markers and examining the molecular mechanism underlying the carcinogenesis and progression of CCA is urgently required.

It was observed that CCAT1 expression levels are elevated in CCA compared with the adjacent normal controls, and it is positively associated with histological differentiation, lymph node invasion, TNM stage and OS in patients with CCA (77). A previous mechanistic study identified that CCAT1 led to migration, invasion and EMT activation by binding to miR-152 in CCA cells (78).

PC is a lethal digestive system malignancy (1) due to the late detection of the disease and the lack of effective therapies for terminally staged tumours (79); only 25% of patients with metastatic PC have a five-year survival rate (80). Therefore, a comprehensive understanding of the molecular mechanisms underlying PC tumourigenesis is urgently required to identify novel therapeutic targets.

CCAT1 expression levels are notably higher in PC specimens and PC cell lines compared with matched noncancerous controls (81). In addition, the silencing of CCAT1 inhibited proliferation and migration, extending the cell cycle progression and decreasing cyclin D1 expression in PC cells (82). In CRC, GC and HCC, c-Myc was able to activate CCAT1 expression by targeting its promoter at the E-box, thereby contributing to tumourigenesis and metastasis in PC, suggesting that CCAT1 may serve as a potential therapeutic target for PC.

LC is one of the frequent causes of cancer mortality worldwide, resulting in more than one million mortalities annually (83,84). Despite advancements in clinical and experimental oncology, effective diagnostic and prognostic biomarkers and alternative treatment options are still required due to the late diagnosis and quick onset of chemoresistance (85).

Overexpression of CCAT1 is evident in non-small cell lung cancer (NSCLC) and is associated with reduced OS times, advanced disease stage and lymph node involvement (86–88). Knockdown of CCAT1 suppressed the proliferation, migration and invasion, and reversed the EMT of NSCLC cells (88). Furthermore, CCAT1 was able to enhance cisplatin resistance of NSCLC cells through the CCAT1/miR-130a-3p/ sex-determining region Y-box (SOX)4 axis (Fig. 3) (89).

As cigarette smoking is a key risk factor for LC, Lu et al (90) determined that CCAT1 was able to regulate neoplastic activity by epigenetically silencing miR-218 and acting through Bmi1, thereby promoting cell cycle progression in the cigarette smoke extract (CSE)-induced carcinogenesis of human bronchial epithelial (HBE) cells (Fig. 3). In a subsequent study, the authors additionally demonstrated that CCAT1 bound let-7c and subsequently upregulated c-Myc, which was able to promote CSE-transformed HBE cell proliferation and invasion (Fig. 3) (91).

CCAT1 is upregulated in the docetaxel-resistant lung adenocarcinoma (LAD) cell line, and suppression of CCAT1 inhibits cell proliferation, enhances apoptosis, decreases chemoresistance, and reverses the docetaxel-resistant LAD cells-induced EMT phenotype (92). Furthermore, CCAT1 exerted the oncogenic function in LAD cells, partially by competitive sponging (let-7c) to prevent the inhibition of B cell lymphoma-extra-large, thereby resulting in chemoresistance and EMT in docetaxel-resistant LAD cells (Fig. 3).

These results suggested that CCAT1 is a critical oncogene associated with the diagnosis and prognosis of various types of lung cancer, as well as a potential target for strengthening the response to chemotherapeutic drugs in lung cancer.

EOC, characterized by quick disease progression, is a lethal gynaecological cancer (66). CCAT1 upregulation in EOC was associated with the International Federation of Gynaecology and Obstetrics stage, histological grade, lymph node metastasis and poor survival (93). In addition, CCAT1 promotes EOC cell migration, invasion and EMT by sponging miR-152 and miR-130b, which may function as a potential molecular target for EOC (Fig. 3) (93,94).

BC is a prevalent malignancy among women, and it affects approximately one million women worldwide (95). Among patients with BC, high CCAT1 expression levels are significantly associated with differentiation grade and TNM stage compared with other clinicopathological factors (96). Furthermore, reduced CCAT1 may improve breast cancer radiosensitivity by negatively regulating miR-148b expression (Fig. 3) (97). These previous studies provide a crucial basis to identify more effective treatments for breast cancer.

The aberrant upregulation of CCAT1 was detected in human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCC), cervical cancer, endometrial carcinoma, medulloblastoma, acute myeloid leukaemia (AML), osteosarcoma, nasopharyngeal carcinoma (NPC), retinoblastoma (RB), melanoma and glioma cancer (26,98–107) (Tables I and II), and it was associated with clinicopathological features, in addition to clinical outcomes. Furthermore, CCAT1 may serve as an intermediate in HPV16 infection and promote myeloid-derived suppressor cell aggregation in HNSCC (100,108).

Mechanistically, CCAT1 may promote medulloblastoma cell proliferation and metastasis through the MAPK signaling pathway (Fig. 2D), as in GC (101). In addition, CCAT1 inhibits monocytic differentiation and promotes AML cell growth by sequestering tumour suppressive miR-155, thereby upregulating c-Myc (Fig. 3) (102). Additionally, the biological function of osteosarcoma cells was regulated by the CCAT1/miR-148a/phosphatidyl inositol 3-kinase interacting protein 1 signaling pathway (Fig. 3) (103). Wang et al (104) observed that upregulated CCAT1 significantly weakened the sensitivity of paclitaxel in NPC cells through the miR-181a/CPEB2 axis (Fig. 3).

CCAT1 promotes RB and melanoma tumourigenesis and metastasis through negative modulation of miR-218-5p and miR-33a, respectively (Fig. 3) (26,105). Furthermore, CCAT1 was able to promote glioma cell progress by inhibiting miR-410 and miR-181b, which provides novel insight into the proliferation of glioma (Fig. 3) (106,107).