Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis

Abstract

Background & Aims Early reports suggested androgen/androgen receptor (AR) signals promote hepatocarcinogenesis. However, all antiandrogen clinical trials failed in advanced hepatocellular carcinoma (HCC) without reasonable explanations. We have examined AR functions in HCC cancer metastasis in this study. Methods We examined hepatic AR roles in HCC metastasis by comparing liver hepatocyte AR knockout and wildtype in carcinogen-induced HCC mouse model. We examined tumor histology, cancer metastatic risks, and cancer survival in vivo, as well as cell anoikis and migration using primary hepatic tumor culture in vitro. We also examined therapeutic potentials of AR expression combined with molecular targeting agent, Sorafenib, in HCC metastasis mouse model. Results We found a novel cancer phenotype in which mice lacking hepatic AR developed more undifferentiated tumors and larger tumor size at later metastatic stage. These mice also died earlier with increased lung metastasis, suggesting hepatic-AR may play dual yet opposite roles to promote HCC initiation but suppress HCC metastasis. Mechanistic dissection found that hepatic AR could enhance anoikis and suppress migration of HCC cells via suppression of p38 phosphorylation/activation and the NFκB-MMP9 pathway, respectively. In addition, the in vivo pre-clinical trials concluded that a combination therapy of increased AR expression and reduced multiple-kinase inhibitor (Sorafenib) exhibited better therapeutic efficacy. Conclusions Our study demonstrated that AR could orchestrate intrahepatic signalling hierarchies and cellular behavior, consequently affect HCC progression. Results from combination therapy shed a light on developing new therapeutic paradigm for battling HCC at later metastatic stage.

Androgen receptor in hepatocarcinogenesis: Recent developments and perspectives

“…By contrast, Ma et al (22) established that AR overexpression was only present in tumors with a size of <3 cm (22). In addition, these authors identified a low expression of AR in severe HCC lesions (22). These results appear to be in agreement with those of Zhu et al (26), who demonstrated that the expression of AR was higher in peritumoral tissues compared with tumor tissues (26).…”

“…In previous studies that also analyzed control tissues, a higher AR expression was evident in tumoral tissues compared with peritumoral tissues, revealing that the disruption in AR homeostasis was associated with the incidence of HCC (15,18). Overexpression of AR in HCC cells may lead to the dysregulation of several molecules associated with cellular proliferation, tumor growth and/or metastasis (21,22,25). Findings from clinical HCC specimens revealed that an elevation in the levels of microRNA (miR)-216a and cell cycle-related kinase (CCRK) was positively correlated with an increase in the AR protein level, and that the overexpression of miR-216a and CCRK was associated with poor patient prognoses (18,25).…”

“…Findings from clinical HCC specimens revealed that an elevation in the levels of microRNA (miR)-216a and cell cycle-related kinase (CCRK) was positively correlated with an increase in the AR protein level, and that the overexpression of miR-216a and CCRK was associated with poor patient prognoses (18,25). By contrast, Ma et al (22) established that AR overexpression was only present in tumors with a size of <3 cm (22). In addition, these authors identified a low expression of AR in severe HCC lesions (22).…”

“…These molecules are associated with cellular proliferation, tumor growth and/or metastasis. Notably, studies on transgenic mouse models have demonstrated that AR may play a negative role in HCC metastasis (22). The aforementioned findings indicate that AR exhibits marked oncogenic properties in HCC initiation and development in the early stages of the disease, but functions as a suppressor of metastasis in late-stage HCC.…”

“…By contrast, the suppression of AR by small interfering RNA has been identified to induce cell cycle arrest at the G 1 phase and inhibit HCC cell growth (18). In addition, previous data have indicated that the AR is able to modulate the expression and activity of a number of molecules within HCC cells (18,21,22). These molecules are associated with cellular proliferation, tumor growth and/or metastasis.…”