Abstract B16: NR5A2 as a potential therapeutic target for hepatoblastoma

Abstract

Abstract Hepatoblastoma (HB) is the most common malignant liver tumor in very young children. Because of multidrug resistance and severe side effects of anti-HB drugs during HB chemotherapy, it is urgent and important to develop new effective therapeutic agents with less toxicity for the treatment of pediatric patients with liver cancer. Nuclear Receptor Subfamily 5 Group A Member 2 (NR5A2; LRH-1) has been linked to various types of malignancies, and it is an emerging therapeutic target for many cancers. However the role of NR5A2 in liver cancer remains elusive. In this study, we found that both mRNA and protein expression levels of NR5A2 were significantly higher in HepG2 and HuH6 human HB cell lines and mouse orthotopic HB liver than the normal liver cell and normal liver tissue. Lentiviral-Mediated Short Hairpin RNA (shRNA) knockdown of NR5A2 inhibited HepG2 and HuH6 cell proliferation and colony formation compared with control cells. Furthermore, we found that silencing of NR5A2 induced downregulation of cell cycle gene CCND1 and the regulator gene c-myc. Similar to the effects of shRNA, we found the NR5A2 antagonist treatment also inhibited the proliferation of human HB cell lines (HepG2, HuH6 and HepT1 cells), reduced colony formation and CCND1 and c-Myc expression. Finally, flow cytometry results showed that the NR5A2 antagonist treatment induced a decreased percentage of cells in S phase which resulted in a significant decrease in the rate of cell proliferation and tumorigenicity, and induced an increased number of cells in the G2/M phase, leading to HB cell cycle arrest at G2/M phase. Collectively, our results suggest that NR5A2 play an important role in HB cancer cell proliferation. Interference of NR5A2 by shRNA or the NR5A2 antagonist inhibits HB cell proliferation and colony formation by inhibiting the cell cycle process through downregulation of CCND1 and c-Myc expression. By targeting NR5A2 signaling pathway, NR5A2 antagonist has promising therapeutic potential in the treatment of HB cancer. Note: This abstract was not presented at the conference. Citation Format: Jingling Jin, Roma Patel, Nan Ge Jin, Yan Shi, Wenjing Sun, Jianhua Yang, Jed G. Nuchtern, Sanjeev A. Vasudevan. NR5A2 as a potential therapeutic target for hepatoblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B16.