LRH-1 drives hepatocellular carcinoma partially through induction of c-myc and cyclin E1, and suppression of p21

Abstract

Lijia Xiao,1,2,* Yuliang Wang,3,* Weicheng Liang,3 Liping Liu,4 Nannan Pan,1 Huimin Deng,1 Luqian Li,1 Chang Zou,5 Franky Leung Chan,3 Yiwen Zhou1 1Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, China; 2Department of Clinical Laboratory, Nanshan Affiliated Hospital of Guangdong Medical University, Shenzhen, China; 3School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; 4Department of Hepatobiliary and Pancreatic Surgery, The Second Clinical Medical College (Shenzhen People’s Hospital), Jinan University, Shenzhen, China; 5Clinical Medicine Research Center, Shenzhen Public Service Platform of Precision Medicine and Molecular Diagnosis on Tumor, The Second Clinical Medical College (Shenzhen People’s Hospital), Jinan University, Shenzhen, China *These authors contributed equally to this work Background: To explore potential therapeutic target is one of the areas of great interest in both clinical and basic hepatocellular carcinoma (HCC) studies. Nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) is proved to play a positive role in several cancers including breast cancer, pancreatic cancer and intestinal cancer in recent years. However, the exact role of LRH-1 in the development and progression of HCC is not fully elucidated. Methods: The LRH-1 expression level in HCC clinical samples was examined by immunohistochemistry (IHC). Stable LRH-1-suppressed HepG2 clones (HepG2LRH-1/-) were generated by transcription activator-like effector nucleases (TALENs) and both in vitro and in vivo experiments were conducted. Results: We confirmed that LRH-1 showed an increased expression pattern in HCC clinical samples. Our in vitro and in vivo results indicated that suppression of LRH-1 in HepG2 significantly attenuated its proliferation rate and tumorigenic capacity. Gene expression microarray analysis indicated that LRH-1mostly regulated gene expression involved in cell cycle. In addition, our gain-of-function experiments indicated that ectopic expression of LRH-1 dramatically induced the mRNA and protein levels of c-myc and cyclin E1, while attenuating the expression of p21. Conclusion: Our results suggest that LRH-1 might be a potential therapeutic target for clinical HCC treatment. Keywords: LRH-1, HCC, c-myc, p21, cyclin E1

Keywords

• LRH-1；HCC；c-myc；p21；cyclinE1