CCAT2 contributes to hepatocellular carcinoma progression via inhibiting miR‐145 maturation to induce MDM2 expression

Abstract

Long noncoding RNA colon cancer-associated transcript 2 (CCAT2) has been recently found to function as an oncogene in hepatocellular carcinoma (HCC).However, the mechanisms of CCAT2 in HCC development remain to be further explored. In the present study, we found that CCAT2 was abnormally upregulated in HCC cells and tissue specimens, exhibiting an inverse correlation with microRNA (miR)-145 expression. Mechanistic investigation showed that CCAT2 selectively blocked miR-145 processing, leading to decreased mature miR-145 presence. Both the in vitro and in vivo effects of CCAT2 knockdown on the proliferation and metastasis of HCC cells were reversed by miR-145 inhibitor, indicating that miR-145 modulation accounts for CCAT2-meditated HCC progression. Furthermore, miR-145 mimic dramatically suppressed HCC cells' proliferation and metastasis, revealing a tumor suppressor role of miR-145 in HCC. Mechanistically, MDM2 was predicted to be a potential target of miR-145. The luciferase and western blot assay demonstrated that miR-145 mimic largely inhibited MDM2 3′-untranslated region luciferase activity and MDM2 expression, followed by the upregulation of p53/p21 expression. Finally, the coexpression of MDM2 in miR-145 mimic-transfected HCC cells was able to largely compromise the inhibitory effects of miR-145 mimic on HCC cells' proliferation and metastasis in vitro and tumor formation in a xenograft model, confirming MDM2 is the critical mediator of miR-145 in HCC. In summary, our findings indicated that CCAT2 selectively blocks the miR-145 maturation process and plays an oncogene in HCC. Furthermore, a novel CCAT2/miR-145/MDM2 axis was revealed in HCC development and might provide a new target in the molecular treatment of HCC.

Exosomes of Mesenchymal Stem Cells as a Proper Vehicle for Transfecting miR-145 into the Breast Cancer Cell Line and Its Effect on Metastasis

“…In line with our findings, a recent study on hepatocellular carcinoma (HCC) showed that in HCC cells with miR-145 overexpression, the expression level of p53 and p21 will enhance in comparison with control cells. p53 and p21 are considered the most critical checkpoints of the Gap1/Synthesis (G1/S) phase, which link with the complex of Cyclin-Dependent Kinase 6 (CDK6)/CyclinD1, interrupt with Cyclin-Dependent Kinases (CDKs), and consequently lead to cell cycle arrest [ 65 ]. Also, since the miR-145 binding sites are fit for the 3′-untranslated region (UTR) of the oncogene mouse double minute 2 (MDM2), it is regarded as a possible miR-145 target.…”

“…Also, since the miR-145 binding sites are fit for the 3′-untranslated region (UTR) of the oncogene mouse double minute 2 (MDM2), it is regarded as a possible miR-145 target. In both HCC cells and tumor tissues, the mRNA level of MDM2 is significantly increased which is inversely associated with miR-145 expression [ 65 ]. Also, it is reported that miR-145 overexpression would decrease the expression level of MDM2 mRNA and protein.…”

The Roles of the Colon Cancer Associated Transcript 2 (CCAT2) Long Non-Coding RNA in Cancer: A Comprehensive Characterization of the Tumorigenic and Molecular Functions

“…The CCAT2/miR-145 regulation axis was also described in HCC progression via modulation of the MDM2 gene [45]. MDM2 is an oncogene previously reported in epithelial cancers, high-grade tumors, being a signature biomarker in multiple soft tissues [114].…”

“…Recent studies have also highlighted CCAT2 as having multiple miRNA regulatory targets (Figure 2, Table 1), acting as one of the main pro-neoplastic drivers in various human cancers [39,[41][42][43]. For example, CCAT2 promotes its neoplastic regulatory functions through extensive ceRNA networks involving multiple tumor suppressor miRNAs, including miR-424, miR-145, miR-23b-5p, and miR-143 [39,42,[44][45][46].…”

The Role of microRNA in Pancreatic Cancer

“…Exosomes play an important role in the tumor microenvironment and mediate the interaction between pancreatic cancer cells (PC) and matrix components, including pancreatic stellate cells (PSC), to regulate the progression of pancreatic cancer [56]. Primary PSC was isolated from PC patients and demonstrated that exosomes derived from PSC can be internalized by PC cells to promote cell proliferation.…”