The miR-367-3p Increases Sorafenib Chemotherapy Efficacy to Suppress Hepatocellular Carcinoma Metastasis through Altering the Androgen Receptor Signals.
The androgen receptor (AR) was found to suppress hepatocellular carcinoma (HCC) metastasis at late stages. Due to this discovery, we searched for some AR enhancers to increase the efficacy of Sorafenib chemotherapy, and identified the microRNA (miR)-367-3p, whose expression is positively correlated with AR expression in advanced HCC, as an HCC metastasis suppressor. Combining miR-367-3p with Sorafenib showed better efficacy to suppress HCC cell invasion in vitro and in vivo. Mechanism dissection revealed that miR-367-3p could increase AR expression via directly targeting the 3'UTR of MDM2 to decrease MDM2 protein expression. The resultant increase of AR expression might then promote the expression of FKBP5 and PHLPP, thus dephosphorylating and inactivating AKT and ERK, to suppress the HCC cell invasion. Interestingly, the suppression of pAKT by miR-367-3p could subsequently attenuate the phosphorylation of AR and MDM2, giving rise to additional enhancement of AR protein expression, effectively forming a positive feedback loop. Together, these results suggest that miR-367-3p may function as an AR enhancer to increase Sorafenib chemotherapy efficacy via altering the MDM2/AR/FKBP5/PHLPP/(pAKT and pERK) signals to better suppress HCC metastasis. Successful development of this newly combined chemotherapy in the future may help us to better suppress the HCC metastasis at late stages.
Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China; George Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
Junjie
J
Xu
Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
Hui
H
Lin
Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
Gonghui
G
Li
George Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
Yin
Y
Sun
Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China.
Jiang
J
Chen
Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China; George Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA.
Liang
L
Shi
Chawnshang Chang Liver Cancer Center, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University, Hangzhou 310016, China. Electronic address: cxjzu@hotmail.com.
Xiujun
X
Cai
George Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA; Sex Hormone Research Center, China Medical University/Hospital, Taichung 404, Taiwan. Electronic address: chang@urmc.rochester.edu.
Chawnshang
C
Chang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009367:Neoplasm Staging; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C568081:MIRN367 microRNA, human; D035683:MicroRNAs; D010671:Phenylurea Compounds; D011944:Receptors, Androgen; D009536:Niacinamide; D000077157:Sorafenib
Androgen receptor; Hepatocellular carcinoma; Metastasis; miR-367-3p
Cancer Cell. 2009 Sep 8;16(3):259-66
19732725
Hepatology. 2012 Sep;56(3):1025-33
22473819
Oncology. 2010 Jul;78 Suppl 1:172-9
20616601
CA Cancer J Clin. 2012 Nov-Dec;62(6):394-9
23070690
Hepatology. 2007 Apr;45(4):938-47
17393520
J Biol Chem. 2009 Nov 13;284(46):32015-27
19726678
J Cell Biol. 2012 Oct 29;199(3):407-12
23109665
Cancer Res. 2008 Aug 15;68(16):6779-88
18701503
Science. 2001 Oct 26;294(5543):858-62
11679671
Int J Oncol. 2013 Feb;42(2):391-402
23229173
N Engl J Med. 2013 May 2;368(18):1685-94
23534542
Nat Rev Cancer. 2016 May;16(5):330-9
27079803
EMBO J. 2002 Aug 1;21(15):4037-48
12145204
BMC Bioinformatics. 2005 Nov 07;6:267
16274478
Aliment Pharmacol Ther. 2010 Aug;32(3):344-55
20497143
Proc Natl Acad Sci U S A. 2012 Apr 3;109 (14 ):5316-21
22431589
N Engl J Med. 2008 Jul 24;359(4):378-90
18650514
Hepatology. 2004 Dec;40(6):1361-9
15565568
Proc Natl Acad Sci U S A. 2001 Jun 19;98 (13):7200-5
11404460
Sci Transl Med. 2010 May 19;2(32):32ra35
20484730
Mol Cell. 2007 Mar 23;25(6):917-31
17386267
Lancet Oncol. 2009 Jan;10(1):25-34
19095497
CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
22237781
FEBS Lett. 2011 Jun 23;585(12):1828-34
21530512
J Hepatol. 2006 Oct;45(4):529-38
16879891
Science. 2010 Jan 8;327(5962):198-201
19965718
Gastroenterology. 2014 May;146(5):1301-12.e1-10
24530606
Hepatology. 2012 Jul;56(1):176-85
22318717
Oncotarget. 2014 Aug 30;5(16):7081-92
25216524
J Hepatol. 1994 Aug;21(2):187-93
7527437
Surg Clin North Am. 2013 Dec;93(6):1423-50
24206860
Trends Endocrinol Metab. 2008 Aug;19(6):223-30
18511290
Mol Cancer Res. 2010 Jun;8(6):844-54
20501646
Cell. 2009 Jun 12;137(6):1005-17
19524505
PLoS One. 2011 Jan 27;6(1):e16435
21298008
Gastroenterology. 2012 Jun;142(7):1431-43
22504185
Biochim Biophys Acta. 2006 Jun;1764(6):1073-9
16725394
J Hepatol. 2011 Dec;55(6):1325-31
21703203
Gastroenterology. 2011 May;140(5):1618-28.e16
21324318
Gastroenterology. 2011 May;140(5):1410-26
21406195
Cancer. 1996 Feb 15;77(4):635-9
8616754
Science. 2012 Apr 13;336(6078):237-40
22499947
J Biol Chem. 2008 Oct 24;283(43):28988-95
18703514
Endocr Relat Cancer. 2014 May 06;21(3):R165-82
24424503
Cell Rep. 2014 Feb 27;6(4):657-69
24508459
CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
21296855
J Biol Chem. 2015 Jan 30;290(5):2759-68
25527506
Nat Methods. 2015 Aug;12(8):697
26226356
Asian Pac J Cancer Prev. 2013;14(12):7367-9
24460304
Oncogene. 2008 Sep 18;27(42):5578-89
18504433
Hepatology. 2008 Mar;47(3):897-907
18176954
Genet Test Mol Biomarkers. 2015 Feb;19(2):69-74
25489984
J Biol Chem. 2002 Nov 1;277(44):41311-7
12177000
Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12182-7
18723679