Purpose: CADM1-AS1 (cell adhesion molecule 1 antisense RNA 1, long non-coding RNA), was firstly characterized in renal clear cell carcinoma, and exhibits a tumor suppressor role. However, its clinical relevance and exact effects in hepatocellular carcinoma (HCC) remain unknown. Therefore, in this study, we aimed to assess the clinical significance and function of CADM1-AS1 in HCC. Methods: We detected CADM1-AS1 expression in liver cancer tissue samples and cell lines, and analyzed the association between CADM1-AS1 expression and clinical parameters in 90 liver cancer patients. Moreover, we conducted gain-of-function and loss-of-function studies in liver cancer cell to explore the biological function and molecular mechanism of CADM1-AS1. Results: CADM1-AS1 expression was reduced in HCC. Clinical data showed that this downregulation was associated with advanced tumor stage, high TNM stage and reduced survival in HCC patients. CADM1-AS1 overexpression inhibited HCC cells proliferation, migration and invasion, while inducing G0/G1 phase arrest. Meanwhile, we revealed that CADM1-AS1 inhibited the phosphorylation of AKT and GSK-3β. Furthermore, our study showed that CADM1-AS1 decreased the cell cycle associated proteins expression of cyclinD, cyclinE, CDK2 CDK4, CDK6, and enhanced the levels of p15, p21 and p27. More importantly, SC79, a specific activator for AKT;, apparently attenuated the effects of CADM1-AS1 on above cell-cycle associated proteins, confirming that CADM1-AS1 inhibited cell cycles through the AKT signaling pathway. And we also found the CADM1-AS1 has antitumor effect in vivo by a xenograft HCC mouse model. In conclusion, the present findings show that the CADM1-AS1 inhibits proliferation of HCC by inhibiting AKT/GSK-3β signaling pathway, then upregulate p15, p21, p27 expression and downregulate cyclin, CDK expression to inhibit the G0/G1 to S phase transition both in vitro and in vivo. Conclusion: CADM1-AS1 functions as a tumor-suppressive lncRNA. This study reveals a molecular pathway involving PTEN/AKT/GSK-3β which regulates HCC cell-cycle progression.
Keywords: AKT/GSK-3β; CADM1-AS1; cell cycle; hepatocellular carcinoma; long non-coding RNA; proliferation.