Abstract
Colon cancer‐associated transcript 2 (CCAT2) was originally identified as an oncogenic long non‐coding RNA in colorectal cancer. Since its discovery, the oncogenic role of CCAT2 has been increasingly demonstrated in human cancers. In this connection, CCAT2 upregulation is frequently reported and very often associated with tumour progression and poor clinical outcomes. Functionally, knockdown of CCAT2 could induce cancer cell apoptosis and suppress cell proliferation and invasiveness, suggesting that CCAT2 might be a therapeutic target. The present review summarized current literature concerning the expression and functional role of CCAT2 in human malignancies.
Keywords: cancers, CCAT2, lncRNAs, long non‐coding RNA
1. Introduction
Most of human genomic DNA is transcribed into RNAs that do not further translate into proteins. These transcripts are known as non‐coding RNAs (ncRNAs).1 Long non‐coding RNAs (lncRNAs) are RNAs longer than 200 nucleotides without evident protein‐coding functions. lncRNAs regulate gene expression through various mechanisms, including transcriptional and post‐transcriptional processing as well as chromatin modification.2 Increasing evidence has demonstrated that lncRNAs actively participate in the development of human diseases through regulating the expression of their downstream targets.3, 4 In tumorigenesis, lncRNAs could function as oncogenes or tumour suppressor genes.5, 6, 7, 8 Pertinent to clinical practice, lncRNAs have been reported to serve as diagnostic or prognostic biomarkers or as therapeutic targets in many types of human cancers.9, 10
Colon cancer‐associated transcript 2 (CCAT2) is a 1752 bp lncRNA originally identified as an oncologic lncRNA in colorectal cancer.11 CCAT2 is located on chromosome 8q24.21. The CCAT2 genomic locus harbours the SNP rs6983267, which has been demonstrated to be associated with increased risks for various malignancies. Subsequent studies also demonstrated that CCAT2 expression was upregulated in different types of human cancers, including gastric, breast, lung and oesophageal cancers. In this review, we summarize current evidence regarding the role of CCAT2 in tumorigenesis.
2. CCAT2 deregulation in human cancers
The expression and functions of CCAT2 in different types of malignancies are summarized as Table 1.
Table 1.
CCAT2 expressions in human cancers
| Cancer type | Expression | Role in invasion/metastasis | References |
|---|---|---|---|
| Lung cancer | Increased | Oncogenic | 16, 17 |
| Breast cancer | Increased | Oncogenic | 20, 21 |
| Gastric cancer | Increased | Oncogenic | 22 |
| Oesophageal cancer | Increased | Oncogenic | 24, 25 |
| Hepatocellular cancer | Increased | Oncogenic | 26 |
| Colon cancer | Increased | Oncogenic | 11 |
| Cervical cancer | Increased | Oncogenic | 27, 28 |
| Ovarian cancer | Increased | Oncogenic | 29 |
| Prostate cancer | Increased | Oncogenic | 30 |
| Bladder cancer | Increased | Oncogenic | 32 |
| Glioma | Increased | Oncogenic | 34 |
2.1. CCAT2 in lung cancer
Lung cancer is the leading cause of cancer mortality worldwide, accounting for a quarter of cancer‐related death.12, 13, 14, 15 Lung cancer is further classified into two subgroups, namely small cell (SCLC) and non‐small cell lung cancer (NSCLC). CCAT2 expression was higher in NSCLC tissues as compared with paired adjacent tissues.16 Overexpression of CCAT2 was correlated with lung adenocarcinoma but not squamous cell cancer of NSCLC. Functionally, knockdown of CCAT2 suppressed NSCLC cell proliferation and invasion. As a biomarker, combination of CCAT2 overexpression with carcinoembryonic antigen predicted lymph node metastasis. In SCLC, CCAT2 expression was upregulated in cancer tissues and cell lines.17 CCAT2 expression was also significantly associated with tumour grade and poor prognosis in SCLC patients. Furthermore, silencing CCAT2 effectively inhibited cell proliferation and metastasis in SCLC cell lines. Gong and colleagues18 further showed that CCAT2 rs6983267 polymorphism was significantly associated with lung cancer susceptibility. Genetic polymorphisms of CCAT2 were also strongly correlated with platinum‐based chemotherapy response in lung cancer. Taken together, these data indicated that CCAT2, which is upregulated in lung cancer, functioned as an oncogene in the development and progression of lung cancer, in which it also serves as a predictive factor for prognosis and platinum‐based chemotherapy response.
2.2. CCAT2 in breast cancer
Breast cancer is the most common type of cancer in women worldwide, in which its metastasis remains the leading cause of breast cancer‐related death.13, 19 CCAT2 expression was found to be upregulated in around two third of breast cancer patients.20 While the expression levels of CCAT were the highest in lymph node‐negative breast cancer, a high CCAT2 expression was associated with a poor therapeutic benefit from cyclophosphamide/methotrexate/fluorouracil‐containing adjuvant chemotherapy in patients with lymph node‐positive breast cancer. As an oncogenic lncRNA, enforced expression of CCAT2 increased breast cancer cell migration and reduce chemosensitivity to 5‐fluorouracil. CCAT2 expression was upregulated in breast cancer tissues and cell lines compared with adjacent non‐tumour tissues and normal fibroblast cell line.21 Prognostically, high CCAT2 expression was correlated with poorer prognosis and shorter overall survival rate in breast cancer patients. Knockdown of CCAT2 inhibited tumorigenesis through decreasing cell proliferation and invasion both in vitro and in vivo. CCAT2 knockdown was found to suppress the Wnt/β‐catenin activity, which is implicated in the development of breast cancer.
2.3. CCAT2 in gastric cancer
Globally, gastric cancer ranks the second leading cause of cancer‐related death.12, 13, 14, 15 CCAT2 expression was significantly elevated in gastric cancer tissues compared with adjacent normal gastric tissues.22 The expression level of CCAT2 was also positively correlated with lymph node metastasis and distance metastasis and served as an independent predictive factor for shorter overall survival in gastric cancer patients. These findings indicated that upregulation of CCAT2 was correlated with gastric cancer development and metastasis and might function as a potential prognostic biomarker for stratifying gastric cancer patients with different clinical outcomes.
2.4. CCAT2 in oesophageal squamous cell carcinoma
Oesophageal squamous cell carcinoma (ESCC) is a common digestive cancer in China.23 CCAT2 expression was higher in ESCC tissues as compared with adjacent normal tissues.24 Moreover, higher expression level of CCAT2 was correlated with advanced tumour‐node‐metastasis (TNM) staging, lymph node metastasis, as well as MYC amplification. More importantly, upregulated CCAT2 expression and MYC amplification were associated with shorter overall survival in ESCC patients, suggesting that CCAT2 expression might serve as a prognostic marker in ESCC. Another study also showed that CCAT2 expression was significantly upregulated in ESCC tissues compared with paired adjacent normal oesophageal tissues.25 In additional, no alteration in CpG island methylation was observed in the chromosome region of CCAT2, indicating that DNA methylation might not play a role in regulating CCAT2 expression. More than 95% of CCAT2 transcripts were localized in the nucleus in ESCC cell lines. Interestingly, the expression level of CCAT2 was positively associated with the smoking status. As a diagnostic biomarker, CCAT2 outperformed other conventional serum biomarkers, including AFP, NSE, and CA153.
2.5. CCAT2 in hepatocellular carcinoma
Hepatocellular carcinoma (HCC) exhibits extremely high morbidity and mortality and is among the top 10 malignancies worldwide.12, 14, 15 The expression of CCAT2 was higher in HCC tissues than in the adjacent liver tissue.26 CCAT2 expression was also higher in HCC cell lines than in the normal liver epithelial cells. Enforced expression of CCAT2 markedly increased HCC cell proliferation and migration, and suppressed apoptosis, suggesting an oncogenic role.
2.6. CCAT2 in colorectal cancer
Colorectal cancer is among the most common digestive tract malignancies.12 CCAT2 expression was significantly upregulated in the colorectal cancer tissue as compared with the paired normal mucosae.11 CCAT2 expression was also significantly higher in microsatellite‐stable cancers than in microsatellite‐unstable tumours. Enforced expression of CCAT2 promoted colon cancer cell proliferation and migration in vitro and enhanced tumorigenicity in a mouse xenograft model. Metastatic colorectal cancer showed a higher CCAT2 expression level compared with those without. Importantly, increased CCAT2 expression levels were associated with poorer metastasis‐free survival.
2.7. CCAT2 in cervical cancer
Cervical cancer ranks the second leading cause of death among gynaecological malignancies worldwide, with an estimated 530 000 deaths annually.12, 15 CCAT2 expression was higher in cervical squamous cell cancer tissues as compared with the adjacent non‐tumour tissues.27 High CCAT2 expression was significantly associated with cervical invasion depth, the International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. High CCAT2 expression was also an independent prognostic factor for poor overall survival and progression‐free survival (PFS) rates in cervical squamous cell cancer patients. Another study demonstrated that knockdown of CCAT2 decreased cell proliferation in three human cervical cancer cell lines, namely HeLa, CaSki and SiHa cells.28 In addition, CCAT2 knockdown induced G0/G1 phase cell cycle arrest and apoptosis.
2.8. CCAT2 in ovarian cancer
Ovarian cancer is the leading cause of mortality among gynaecological malignancies.12, 15 CCAT2 expression was significantly higher in ovarian cancer tissues and cell lines as compared with adjacent non‐tumour tissues and normal ovarian epithelial cell line.29 CCAT2 expression levels were also positively correlated with tumour grade, FIGO stage as well as distant metastasis. Higher CCAT2 expression levels also foreshadowed a shorter disease‐free and overall survival in ovarian cancer patients. Moreover, knockdown of CCAT2 significantly suppressed cell proliferation, migration and invasion in ovarian cancer cells.
2.9. CCAT2 in prostate cancer
Prostate cancer is the second leading cause of cancer mortality in men, with one million new cases diagnosed every year.12 CCAT2 expression in prostate cancer tissues and cells was higher than that in adjacent non‐tumour tissues and normal prostate stromal cells.30 High CCAT2 expression levels also predicted a shorter overall and PFS in prostate cancer patients. Besides, CCAT2 knockdown suppressed prostate cancer cell proliferation, invasion, and migration in vitro and inhibited epithelial‐mesenchymal transition by decreasing the expression of N‐cadherin, vimentin, and increasing the expression of E‐cadherin.
2.10. CCAT2 in bladder cancer
Bladder cancer is the most commonly diagnosed male urogenital malignancies.31 The expression level of CCAT2 was higher in bladder cancer tissues and cell lines as compared with adjacent non‐cancer tissues and normal cell line.32 In addition, CCAT2 expression was significantly correlated with poor histological grade and higher TNM stage of bladder cancer. Functional assays demonstrated that CCAT2 knockdown inhibited cell growth and migration while promoted apoptosis in vitro.
2.11. CCAT2 in glioma
Glioma is the most common type of malignancy of the central nervous system with high mortality.33 The expression level of CCAT2 was higher in glioma tissues than in adjacent non‐tumour tissues.34 CCAT2 expression levels were positively correlated with the advanced tumour stage. Furthermore, CCAT2 knockdown suppressed glioma cell proliferation, cell cycle progression and migration through inhibiting Wnt/β‐catenin signal pathway.
3. CCAT2 and cancer metabolism
Redis and colleagues35 found that CCAT2 could regulate cancer metabolism through a complex, allele‐specific mechanism. By binding the cleavage factor I (CFIm) complex with different affinities for the two subunits (CFIm25 and CFIm68), CCAT2 modulated cancer metabolism both in vitro and in vivo. The interaction between CCAT2 and the CFIm complex fine‐tuned the alternative splicing of glutaminase by selecting the poly(A) site in intron 14 of its precursor mRNA, unveiling that lncRNA could modulate the function of its partner RNA‐binding protein.
4. Conclusions and future perspectives
Taken together, CCAT2 is a novel oncogene upregulated in many types of human cancer, including lung, breast, gastric, liver, colon, oesophageal, cervical, ovarian, prostate, bladder and glioma. The stimulatory effects on Wnt/β‐catenin signal pathway, cancer metabolism and epithelial‐mesenchymal transition might underlie its oncogenic action. However, relatively little is known about the mechanism mediating CCAT upregulation in human cancers. A better understanding of its upstream regulation and downstream signalling could therefore provide insights to devise better strategies to target CCAT2. The influences of genetic, epigenetic and environmental factors on CCAT2 also warrant further investigation. Pertinent to clinical practice, CCAT2 overexpression is very often associated with poor clinical outcomes, including patients' survival. Nevertheless, almost all studies did not include an independent cohort for validation. The prognostic and diagnostic performances of CCAT2 against existing markers in different ethnic groups have also not yet been systemically assessed. It is hopeful that multi‐centre studies with larger cohorts of patients will improve the clinical utility of CCAT2 as a biomarker. Identification of small‐molecule inhibitors of CCAT2 through chemical library screening is also necessary to translate findings from basic science into clinical benefits.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (NSFC) (grant number 81401847).
Conflicts of interest
The authors declare no competing financial interests.
Xin Y, Li Z, Zheng H, Chan MTV, Ka Kei Wu W. CCAT2: A novel oncogenic long non‐coding RNA in human cancers. Cell Prolif. 2017;50:e12342 10.1111/cpr.12342
Xin Yu and Zheng Li contributed equally to this work.
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