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

Wen Lung Ma, Cheng Lung Hsu, Chun Chieh Yeh, Ming Heng Wu, Chiung Kuei Huang, Long Bin Jeng, Yao Ching Hung, Tze Yi Lin, Shuyuan Yeh, Chawnshang Chang

Research output: Contribution to journalArticle

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Abstract

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. Conclusion: 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.

Original languageEnglish
Pages (from-to)176-185
Number of pages10
JournalHepatology
Volume56
Issue number1
DOIs
Publication statusPublished - Jul 2012
Externally publishedYes

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Anoikis
Androgen Receptors
Cell Movement
Hepatocellular Carcinoma
Neoplasm Metastasis
Liver
Neoplasms
Therapeutics
Androgen Antagonists
NF-kappa B
Metalloproteases
Liver Neoplasms
Carcinogens
Androgens
Dissection
Hepatocytes
Histology
Phosphotransferases
Phosphorylation

ASJC Scopus subject areas

  • Hepatology

Cite this

Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis. / Ma, Wen Lung; Hsu, Cheng Lung; Yeh, Chun Chieh; Wu, Ming Heng; Huang, Chiung Kuei; Jeng, Long Bin; Hung, Yao Ching; Lin, Tze Yi; Yeh, Shuyuan; Chang, Chawnshang.

In: Hepatology, Vol. 56, No. 1, 07.2012, p. 176-185.

Research output: Contribution to journalArticle

Ma, WL, Hsu, CL, Yeh, CC, Wu, MH, Huang, CK, Jeng, LB, Hung, YC, Lin, TY, Yeh, S & Chang, C 2012, 'Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis', Hepatology, vol. 56, no. 1, pp. 176-185. https://doi.org/10.1002/hep.25644
Ma, Wen Lung ; Hsu, Cheng Lung ; Yeh, Chun Chieh ; Wu, Ming Heng ; Huang, Chiung Kuei ; Jeng, Long Bin ; Hung, Yao Ching ; Lin, Tze Yi ; Yeh, Shuyuan ; Chang, Chawnshang. / Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis. In: Hepatology. 2012 ; Vol. 56, No. 1. pp. 176-185.
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