Abstract 1645: DNA-damaging compound 0404 effectively inhibits hepatocellular carcinoma by upregulation of miR-34a and miR-200c expression

Abstract Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and the third most common cause of cancer deaths worldwide. DNA-damaging agents have a long history of use in cancer chemotherapy. Unfortunately, chemotherapeutic treatment strategies against HCC are very ineffective. We have screened of a novel DNA-damaging compounds, 0404, by using time-dependent cellular response (TCRP) based on unique TCRP DNA-damage signature. This new compound could induce apoptosis effectively in hepatocellular carcinoma at nM-degree concentration. Since microRNAs (miRNAs) have been show play critical roles in pathogenesis of HCC, the present study was aimed to investigate the role of miRNAs in the anticancer effects of 0404. We found that, HepG2 cells, which retain wild-type p53, were more sensitive to 0404 treatment than Huh7 cells, which with mutant p53. At IC50 and IC99 concentration, 0404 upregulated the expression of miR-34a and miR-200c, two major miRNA regulated by p53, in a dose- and time-dependent manner in HepG2 cells. Western blot analysis further show that up-regulation of miR-34a decreased SIRT1 expression, leading to an increase in acetylated p53 levels and also an increase in p53 targets such as p21 and PUMA. In addition, up-regulation of miR-200c decreased the expression of EMT-inducing transcription factors ZEB1 and ZEB2, which play key role in tumor invasion and metastasis. Furthermore, miR-34a or miR-200c inhibitors impaired the down-regulation of miR-34a or miR-200c target genes, respectively, by 0404 treatment, and partially impaired the tumor suppression effect of 0404. These results suggest that 0404 may be an attractive agent in chemotherapy for HCC, especially in HCC with wt p53, by regulation of miR-34a and miR-200c. Financial support: This study was supported by the National Natural Science Fund (81272679) and the Major national S&T Projects (2013ZX09041003). Citation Format: Caixia Xia, Yanning Liu, Guohua Lou, Xiao Xu, Long Mao, Min Zheng. DNA-damaging compound 0404 effectively inhibits hepatocellular carcinoma by upregulation of miR-34a and miR-200c expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1645. doi:10.1158/1538-7445.AM2015-1645