The androgen receptor as an emerging target in hepatocellular carcinoma

Figures & data

Table 1 Androgen receptor (AR) and liver diseases from different etiologies

Etiology of HCC	Roles of AR	References
HBV	AR-CAG repeats may be associated with an increased risk of HCC	^Citation116
HBV	AR signaling may affect the risk of HBV-related HCC among men	^Citation117
HBV	AR exon 1 CAG repeat length may contribute to HCC predisposition among women	^Citation118,Citation119
HBV	TNR of AR gene in male HCC	^Citation120
HBV	HBx enhances AR-responsive gene expression	^Citation10,Citation11, ^Citation121^–^Citation123
HBV	AR promotes HBV replication	^Citation124^–^Citation126
HBV	CCRK-AR regulates HBV-associated HCC	^Citation127
HCV	HCV core augments AR-signaling	^Citation12
NAFLD	Association between AR, ER stress, and hepatic lipid deposition	^Citation86,Citation128^–^Citation130
Alcohol	AR associated with severity of liver diseases	^Citation56

Abbreviations: HCC, hepatocellular carcinoma; HBV, hepatitis B virus; TNR, trinucleotide repeats; HBx, hepatitis B virus X; AR, androgen-responsive; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; ER, endoplasmic reticulum; CCRK, cell cycle–related kinase.

Figure 1 Ligand-dependent and ligand-independent androgen receptor (AR)-activation in hepatocytes.

Abbreviations: CYP, cytochrome P450; TGF-β1, transforming growth factor β1; LXR, liver-X-receptor; VEGF, vascular endothelial growth factor; CCRK, cell cycle–related kinase; GRP78/Bip, glucose-regulated protein 78 kDa; ARE, androgen-responsive element; ARGs, androgen-responsive genes; MAPK/ERK, mitogen-activated protein kinase/extracellular signal–regulated protein kinase; STAT, signal-transducer and activator of transcription; AKT, v-akt murine thymoma viral oncogene homolog 1; IL-6, interleukin-6; IL-6R, interleukin-6 receptor; GP130, glycoprotein 130; P, phosphorylation.

Table 2 Representative ARGs in the liver

ARGs	Function	References
CYPs	Drug metabolism and alcohol metabolism	^Citation54^–^Citation57,Citation70
TGF-β1	HCC development, hepatic fibrosis, hepatic damage, and hepatic regeneration	^Citation66
LXR	Cholesterol homeostasis	^Citation71
VEGF	HCC development and angiogenesis	^Citation12,Citation49
CCRK	HCC development	^Citation75
GRP78/Bip	ER stress and HCC development	^Citation86,Citation92

Abbreviations: ARG, androgen-responsive gene; CYP, cytochrome P450; ER, endoplasmic reticulum; HCC, hepatocellular carcinoma; TGF-β1, transforming growth factor β1; LXR, liver-X-receptor; VEGF, vascular endothelial growth factor; CCRK, cell cycle–related kinase; GRP78/Bip, glucose-regulated protein 78 kDa.

Table 3 Clinical trials targeting androgen in hepatocellular carcinoma

Drug (dosage)	Randomized study	Number of patients	Eligibility Child-Pugh class	Stage of HCC	Efficacy: mean survival or response	Ref
Leuprorelin, flutamide, and tamoxifen	Yes	192	Child-Pugh Class A/B/C: 112/50/2; cirrhosis, 90%; ascites, 26%; HBV, 3%; HCV, 19%	Okuda’s classification stage I/II/III: 81/107/4	135.5 d (P=0.21)	^Citation108
Tamoxifen (administered until death)	Yes	184	Child-Pugh Class A/B/C: 105/59/5; cirrhosis, 93%; ascites, 31%; HBV, 10%; HCV, 13%	Okuda’s classification stage I/II/III: 93/83/8	176 d	^Citation108
Flutamide for 8 weeks	Phase II	32	Measurable advanced HCC patients; hepatitis-related, 88%	AJCC stage III/IV: 5/27	10 wks; 9 of 22 (41%), stable diseases; 13 (59%), progress diseases	^Citation109
Antiandrogen (Anandron) plus placebo	Yes	58	Unresectable HCC; cirrhosis, 76%; HBV, 25%	N/A	3.6 mo (NS); 1, complete response	^Citation110
LHRH agonist plus placebo	Yes	61	Unresectable HCC; cirrhosis, 85%; HBV, 21%	N/A	2.7 mo (NS); 1, partial response	^Citation110
Antiandrogen plus LHRH agonist	Yes	60	Unresectable HCC; cirrhosis, 82%; HBV, 14%	N/A	3.9 mo (NS); 1, partial response	^Citation110
Placebo plus placebo	Yes	59	Unresectable HCC; cirrhosis, 83%; HBV, 35%	N/A	5.8 mo	^Citation110
Cyproterone acetate	No	25	Cirrhotics with unresectable HCC	N/A	14 wks; 5, excess in 29 wks; 5, response	^Citation111
Ketoconazole	No	8	Unresectable HCC	N/A	6, <8 weeks	^Citation112
D-Tryptophan-6-luteinizing hormone–releasing hormone	No	17	Cirrhotics with HCC	N/A	No response	^Citation113
LHRH-analog triptorelin and tamoxifene	Yes	33	Child-Pugh: 7.7±2.0 (untreated HCC); cirrhosis, 27; HBsAg (+), 69.7%; anti-HDV (+), 15.2%; anti-HCV (+), 12.1%	Okuda stage I/III (%): 27.3/18.2	282 d (P=0.020 vs placebo)	^Citation114
Triptorelin plus flutamide	Yes	23	Child-Pugh: 8.3±1.6 (untreated HCC); cirrhosis, 18; HBsAg (+), 56.5%; anti-HDV (+), 8.7%; anti-HCV (+), 8.7%	Okuda stage I/III (%): 21.7/13.0	112 d (NS vs placebo)	^Citation114
Placebo	Yes	29	Child-Pugh: 8.9±2.1 (untreated HCC); cirrhosis, 25; HBsAg (+), 58.6%; anti-HDV (+), 10.7%; anti-HCV (+), 20.0%	Okuda stage I/III (%): 24.1/17.2	127 d	^Citation114

Abbreviations: AJCC, American Joint Committee on Cancer; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis delta virus; HBsAg, hepatitis B virus surface antigen; LHRH, luteinizing hormone-releasing hormone; HCC, hepatocellular carcinoma; Ref, references; NS, not significant; N/A, not applicable; d, days; wks, weeks; mo, months; vs, versus.

YuMWChengSWLinMWAndrogen-receptor gene CAG repeats, plasma testosterone levels, and risk of hepatitis B-related hepatocellular carcinomaJ Natl Cancer Inst200092242023202811121465

 PubMedGoogle Scholar

YuMWYangYCYangSYHormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a nested case-control study among menJ Natl Cancer Inst200193211644165111698569

 PubMedGoogle Scholar

YuMWYangYCYangSYAndrogen receptor exon 1 CAG repeat length and risk of hepatocellular carcinoma in womenHepatology200236115616312085360

 PubMed Web of Science ®Google Scholar

YehSHChangCFShauWYDominance of functional androgen receptor allele with longer CAG repeat in hepatitis B virus-related female hepatocarcinogenesisCancer Res200262154346435112154039

 PubMed Web of Science ®Google Scholar

YehSHChiuCMChenCLSomatic mutations at the tri-nucleotide repeats of androgen receptor gene in male hepatocellular carcinomaInt J Cancer200712081610161717230529

 PubMed Web of Science ®Google Scholar

ChiuCMYehSHChenPJHepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen levelProc Natl Acad Sci U S A200710482571257817259306

 PubMed Web of Science ®Google Scholar

ZhengYChenWLMaWLChangCOuJHEnhancement of gene transactivation activity of androgen receptor by hepatitis B virus X proteinVirology2007363245446117335866

 PubMed Web of Science ®Google Scholar

ZhuRZhangJSZhuYZHBx-induced androgen receptor expression in HBV-associated hepatocarcinoma is independent of the methylation status of its promoterHistol Histopathol201126233521117024

 PubMed Web of Science ®Google Scholar

YangWJChangCJYehSHHepatitis B virus X protein enhances the transcriptional activity of the androgen receptor through c-Src and glycogen synthase kinase-3beta kinase pathwaysHepatology20094951515152419205031

 PubMed Web of Science ®Google Scholar

WangSHYehSHLinWHWangHYChenDSChenPJIdentification of androgen response elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis BHepatology20095051392140219670412

 PubMed Web of Science ®Google Scholar

TianYKuoCFChenWLOuJHEnhancement of hepatitis B virus replication by androgen and its receptor in miceJ Virol20128641904191022156518

 PubMed Web of Science ®Google Scholar

YuZGaoYQFengHCell cycle-related kinase mediates viral-host signalling to promote hepatitis B virus-associated hepatocarcinogenesisGut201463111793180424440987

 PubMed Web of Science ®Google Scholar

KandaTSteeleRRayRRayRBHepatitis C virus core protein augments androgen receptor-mediated signalingJ Virol20088222110661107218768969

 PubMed Web of Science ®Google Scholar

DaiRYanDLiJActivation of PKR/eIF2α signaling cascade is associated with dihydrotestosterone-induced cell cycle arrest and apoptosis in human liver cellsJ Cell Biochem201211351800180822228470

 PubMed Web of Science ®Google Scholar

HoggKWoodCMcNeillyASDuncanWCThe in utero programming effect of increased maternal androgens and a direct fetal intervention on liver and metabolic function in adult sheepPLoS One201169e2487721935484

 PubMed Web of Science ®Google Scholar

KellyDMNettleshipJEAkhtarSTestosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient miceLife Sci201410929510324953607

 PubMed Web of Science ®Google Scholar

EagonPKElmMSTadicSDNanjiAADownregulation of nuclear sex steroid receptor activity correlates with severity of alcoholic liver injuryAm J Physiol Gastrointest Liver Physiol20012812G342G43911447013

 PubMed Web of Science ®Google Scholar

ShetMSMcPhaulMFisherCWStallingsNREstabrookRWMetabolism of the antiandrogenic drug (Flutamide) by human CYP1A2Drug Metab Dispos19972511129813039351907

 PubMed Web of Science ®Google Scholar

SongCSJungMHKimSCHassanTRoyAKChatterjeeBTissue-specific and androgen-repressible regulation of the rat dehydroepiandrosterone sulfotransferase gene promoterJ Biol Chem19982733421856218669705324

 PubMed Web of Science ®Google Scholar

NorlinMPetterssonHTangWWikvallKAndrogen receptor-mediated regulation of the anti-atherogenic enzyme CYP27A1 involves the JNK/c-jun pathwayArch Biochem Biophys2011506223624121134350

 PubMed Web of Science ®Google Scholar

YoonGKimJYChoiYKWonYSLimIKDirect activation of TGF-beta1 transcription by androgen and androgen receptor complex in Huh7 human hepatoma cells and its tumor in nude miceJ Cell Biochem200697239341116187311

 PubMed Web of Science ®Google Scholar

KrycerJRBrownAJCross-talk between the androgen receptor and the liver X receptor: implications for cholesterol homeostasisJ Biol Chem201128623206372064721489984

 PubMed Web of Science ®Google Scholar

BoltonECSoAYChaivorapolCHaqqCMLiHYamamotoKRCell- and gene-specific regulation of primary target genes by the androgen receptorGenes Dev200721162005201717699749

 PubMed Web of Science ®Google Scholar

FengHChengASTsangDPCell cycle-related kinase is a direct androgen receptor-regulated gene that drives β-catenin/T cell factor-dependent hepatocarcinogenesisJ Clin Invest201112183159317521747169

 PubMed Web of Science ®Google Scholar

JiangXKandaTNakamotoSMiyamuraTWuSYokosukaOInvolvement of androgen receptor and glucose-regulated protein 78 kDa in human hepatocarcinogenesisExp Cell Res2014323232633624583399

 PubMed Web of Science ®Google Scholar

Groupe d’Etude et de Traitement du Carcinome HépatocellulaireRandomized trial of leuprorelin and flutamide in male patients with hepatocellular carcinoma treated with tamoxifenHepatology20044061361136915565568

 PubMed Web of Science ®Google Scholar

ChaoYChanWKHuangYSPhase II study of flutamide in the treatment of hepatocellular carcinomaCancer19967746356398616754

 PubMed Web of Science ®Google Scholar

GrimaldiCBleibergHGayFEvaluation of antiandrogen therapy in unresectable hepatocellular carcinoma: results of a European Organization for Research and Treatment of Cancer multicentric double-blind trialJ Clin Oncol19981624114179469323

 PubMed Web of Science ®Google Scholar

ForbesAWilkinsonMLIqbalMJJohnsonPJWilliamsRResponse to cyproterone acetate treatment in primary hepatocellular carcinoma is related to fall in free 5 alpha-dihydrotestosteroneEur J Cancer Clin Oncol19872311165916642828073

 PubMedGoogle Scholar

GuptaSKorulaJFailure of ketoconazole as anti-androgen therapy in nonresectable primary hepatocellular carcinomaJ Clin Gastroenterol19881066516542466073

 PubMed Web of Science ®Google Scholar

GuéchotJPeigneyNBalletFVaubourdolleMGiboudeauJPouponREffect of D-tryptophan-6-luteinizing hormone-releasing hormone on the tumoral growth and plasma sex steroid levels in cirrhotic patients with hepatocellular carcinomaHepatology19891033463482547704

 PubMed Web of Science ®Google Scholar

ManesisEKGiannoulisGZoumboulisPVafiadouIHadziyannisSJTreatment of hepatocellular carcinoma with combined suppression and inhibition of sex hormones: a randomized, controlled trialHepatology1995216153515427768497

 PubMed Web of Science ®Google Scholar