MiR-503 inhibits hepatocellular carcinoma cell growth via inhibition of insulin-like growth factor 1 receptor Yao Xiao,1 Qinggang Tian,2 Jiantai He,1 Ming Huang,1 Chao Yang,1 Liansheng Gong1 1Department of Hepatobiliary and Pancreatic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 2Department of General Surgery, The Fourth Affiliated Hospital of Baotou Medical College, Baotou, Inner Mongolia, People’s Republic of China MicroRNAs (miRs) have been demonstrated to play key roles in the development and progression of hepatocellular carcinoma (HCC). However, the regulatory mechanism of miR-503 in HCC has not been fully uncovered. In this study, we found that miR-503 was significantly downregulated in HCC tissues compared to nontumorous liver tissues. Moreover, lower miR-503 levels were associated with the malignant progression of HCC, and the expression of miR-503 was also decreased in several common HCC cell lines compared to normal human liver cell line THLE-3. Overexpression of miR-503 inhibited proliferation but induced apoptosis of LM3 and HepG2 cells. Bioinformatical analysis and luciferase reporter assay further identified insulin-like growth factor 1 receptor (IGF-1R) as a novel target of miR-503 in 293T cells. Moreover, overexpression of miR-503 led to a significant decrease in the protein levels of IGF-1R, while knockdown of miR-503 enhanced its protein levels in LM3 and HepG2 cells. Besides, overexpression of IGF-1R reversed the effects of miR-503-mediated HCC cell proliferation and apoptosis, indicating that IGF-1R acts as a downstream effector of miR-503 in HCC cells. Furthermore, IGF-1R was found to be significantly upregulated in HCC tissues compared to nontumorous liver tissues. In addition, the mRNA levels of IGF-1R were inversely correlated to the miR-503 levels in the HCC tissues. Thus, we demonstrate that miR-503 inhibits the proliferation and induces the apoptosis of HCC cells, partly at least, by directly targeting IGF-1R, and suggest that IGF-1R may serve as a promising target for the treatment of HCC. Keywords: hepatocellular carcinoma, microRNA-503, insulin-like growth factor 1 receptor, proliferation, apoptosis

We performed an updated meta-analysis and systematic review to explore the associations between polymorphisms in genes of IL-12 signaling pathway and hepatocellular carcinoma (HCC) risk. Diverse databases were retrieved to identify entire available studies, and odds ratios (ORs) correspondence with 95% confidence intervals (CIs) were performed to assess their associations. Finally, 6 polymorphisms in five genes of the IL-12 signaling pathway were extracted from 39 case-control studies, 26 publications. We identified that STAT4-rs7574865 polymorphism was significantly associated with an increased risk of HCC in allelic contrast, dominant, homozygote and recessive models. However, we failed to uncover any significant association between other polymorphisms in genes of IL-12 signaling pathway and HCC risk, including IL18-rs1946518 and -rs187238, IFN-γ-rs2430561, IL12A-rs568408, IL12B-rs3212227 and STAT4-rs7574865. When the subgroup analysis was conducted based on Hardy-Weinberg Equilibrium (HWE) status, we identified that IFN-γ-rs2430561 polymorphism was significantly associated with an increased risk of HCC in homozygote and recessive models of these studies whose control groups were conformed to HWE. To sum up, our study suggests that STAT4-rs7574865 is a risk factor for HCC. Further well-designed large sample size studies are warranted to shed new light on these findings.

Liver cancer is one of the most lethal malignant tumors in the world, and surgical resection is the main treatment for liver cancer. Liver failure due to insufficient residual liver volume is a fatal complication after hepatectomy. How to effectively increase the residual liver volume after hepatectomy and improve the safety of hepatectomy has always been a problem to be solved in liver surgery. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) effectively reduces the occurrence of liver failure due to insufficient residual liver volume after hepatectomy, thereby increasing the probability of radical resection by inducing rapid proliferation of residual liver tissue. However, the molecular mechanism of residual liver tissue regeneration after primary ALPPS (combined liver partition and portal vein ligation) remains unclear. Here, we found that lots of circular RNAs (circRNAs) are upregulated after ALPPS in pig liver cells; then, we identified the orthologous circRNA in humans and pigs to detect their function in liver regeneration. The results showed that loss of circ-0067724 and circ-0016213 could suppress liver cell proliferation. Together, these findings suggest that circ-0067724 and circ-0016213 play an important role in liver cell proliferation, and this may help us to find new strategies to promote liver regeneration.