Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis.
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 examined AR functions in HCC cancer metastasis in this study. We examined hepatic AR roles in HCC metastasis by comparing liver hepatocyte AR knockout and wildtype in a 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 the molecular targeting agent sorafenib in an HCC metastasis mouse model. We found a novel cancer phenotype in which mice lacking hepatic AR developed more undifferentiated tumors and larger tumor size at the metastatic stage. These mice also died earlier with increased lung metastasis, suggesting that 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 by way of suppression of p38 phosphorylation/activation and the nuclear factor kappa B (NF-κB)/matrix metallopeptidase 9 (MMP9) pathway, respectively. In addition, the in vivo preclinical trials concluded that a combination therapy of increased AR expression and reduced multiple-kinase inhibitor (sorafenib) exhibited better therapeutic efficacy.


CONCLUSIONS
Our study demonstrates that AR could orchestrate intrahepatic signaling hierarchies and cellular behaviors, consequently affect HCC progression. Results from combination therapy shed light on developing new therapeutic paradigms for battling HCC at later metastatic stages.
Sex Hormone Research Centre and Graduate Institute of Clinical Medical Science, China Medical University/Hospital, Taichung, Taiwan.
Wen-Lung
WL
Ma
Cheng-Lung
CL
Hsu
Chun-Chieh
CC
Yeh
Ming-Heng
MH
Wu
Chiung-Kuei
CK
Huang
Long-Bin
LB
Jeng
Yao-Ching
YC
Hung
Tze-Yi
TY
Lin
Shuyuan
S
Yeh
Chawnshang
C
Chang
D000818:Animals; D023102:Anoikis / Q000187:drug effects* / Q000235:genetics; D001557:Benzenesulfonates / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D011897:Random Allocation; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism*; D000077157:Sorafenib; D014407:Tumor Cells, Cultured
D001557:Benzenesulfonates; D016328:NF-kappa B; D010671:Phenylurea Compounds; D011725:Pyridines; D011944:Receptors, Androgen; D009536:Niacinamide; D000077157:Sorafenib