Abstract 3558: Interrogation of onco-microRNA 125b reveals androgen receptor as a key upstream transcriptional factor that is targetable in female gastric cancer

Abstract

Abstract Background & Aims: Our prior study revealed a miRNA-regulatory network by an integrated analysis of microRNA and mRNA profiling of gastric cancer (GC). It defined a GC microRNA subtype that was associated with poor survival in GC cases. In this study, we further demonstrate that onco-microRNA miR-125b, a key node in this microRNA regulatory network, is upregulated in GC and associated with poor overall survival by interfering in the apoptosis pathway and this pathway can be regulated by androgen receptor (AR). Our study also clarifies the potential clinical utility of the AR antagonist Bicalutamide on GC treatment. Methods: To further investigate the role of AR-miR-125b axis in GC, we conducted both in vitro experiment and clinical study with a cohort of 373 GC samples. The expression of miR-125b and AR was analyzed and compared with patient survival, and its implications were evaluated between genders of GC cases. We explored the tumor suppressive effect of bicalutamide using in vitro assays and in vivo subcutaneous xenotransplanted tumor model of human GC cell lines in nude mice. Results: The markedly up regulated expression of AR-miR-125b axis was validated in 373 GC samples. Univariate and multivariate analyses find that the miR-125b and/or AR were associated with poor prognosis and this trend was more pronounced among female than male cases. Pathway analysis shows that the predicted targets of miR-125b are highly involved in apoptosis/program death pathway. The robust apoptosis genes, BIK and CASP6 are validated as the directed targets of miR-125b. miR-125b can suppress apoptosis and increase cell growth, migration and invasion in GC cell lines. Furthermore, low expression of BIK and CASP6 in GC were associated with poor disease-free survival. There was a notable positive correlation between miR-125b and AR level in GC samples. Chip, EMSA and luciferase-binding assay confirmed that AR can direct regulated miR-125b expression as a transcriptional factor. We examined AR antagonist bicalutamide to inhibit proliferation and increased apoptosis in AR positive gastric cancer cells. The effect of bicalutamide is more apparent in female than in male nude mice. Conclusions: Our findings suggest that miR-125b regulated apoptosis pathway is important to GC progression and that the AR/miR-125 may be an important clinical biomarker for GC survival and possible therapeutic target for GC treatment. Citation Format: Ben Liu, Meng Zhou, Da Yang, Qinghua Wang, Qiang Zhang, Xiangchun Li, Meng Yang, Qiong Wang, Lian Li, Luyang Liu, Hongji Dai, Fengju Song, Hong Zheng, Wei Zhang, Kexin Chen. Interrogation of onco-microRNA 125b reveals androgen receptor as a key upstream transcriptional factor that is targetable in female gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3558.