Bivalent Role of LncRNA-LRAHC during Liver Regeneration and Hepatocellular Carcinoma

Abstract

Background: For hepatocellular carcinoma (HCC) patients, surgical resection is the main treatment modality that offers an opportunity for prolonged survival. Tumor recurrence or metastasis after liver resection limits the long-term survival of HCC patients. However, the mechanism of liver regeneration-induced metastasis and augmented growth of residual HCC following liver resection remains obscure. Methods: HCC tissues and matched non-tumor tissues were collected from 75 patients (for mRNA analysis) at the Eastern Hepatobiliary Surgery Hospital from 2008 to 2013. We evaluated the functions of lncRNA-LRAHC through knockdown and overexpression of this lncRNA using lentivirus infection system in vitro and in vivo. Results: In this study, we identified a long noncoding RNA associated with liver regeneration and hepatocellular carcinoma, termed lncRNA-LRAHC, via a liver regeneration microarray (GSE43687). We discovered that lncRNA-LRAHC accelerated hepatocyte proliferation and inhibited HCC cell migration in vitro and in vivo. Mechanistically, we found that lncRNA-LRAHC interacts with RNA-binding protein HuR and enhances XBP1 to promote proliferation during liver regeneration; it combines with protein CDH2 and represses its expression, further altering normal cytoskeleton structure to suppress HCC metastasis. We also found a human ortholog of lncRNA-hLRAHC and determined it was down-regulated in HCC tissues and correlated with poor survival in HCC patients. Conclusions: These data support a crucial function of lncRNA-LRAHC in promoting liver regeneration and tumor suppression in HCC. This indicates a novel therapeutic approach using lncRNA-LRAHC to enhance liver regeneration in HCC patients who undergo liver resection without the risk of cancer recurrence or metastasis. Funding Statement: This work was supported by Grant 81402325, 81874151 from the National Natural Science Foundation of China, Grant 20184Y0241 from Shanghai Municipal Commission of Health and Family Planning. Grant 2016KJ077 from Young Talents Training Moving Program of Tongji University School. Declaration of Interests: The authors have no conflicts to disclose. Ethics Approval Statement: Animal studies were approved by the institutional animal care and use committee of the Fudan University, Shanghai, China.