title: Orphan nuclear receptor HNF4G promotes bladder cancer growth and invasion through the regulation of the hyaluronan synthase 2 gene.
abstract: Nuclear receptors (NRs) are a class of transcription factors that are closely involved in the progression of certain types of cancer. We aimed to study the relation between bladder cancer and NRs, with special focus on orphan NRs whose ligands and functions have not been identified. First, we examined the expression levels of 22 genes encoding orphan NRs in clinical bladder cancer and found that hepatocyte nuclear factor 4γ (HNF4G; NR2A2) and NR2F6 were the genes that were upregulated most frequently in cancer tissues compared with their paired normal tissues. Knockdown and overexpression of each of these orphan NRs suppressed and stimulated the growth of bladder cancer cells in vitro, respectively. HNF4G also promoted tumor growth in bladder cancer xenograft models in vivo. Furthermore, HNF4G was both necessary and sufficient for the invasion of bladder cancer cells in vitro. Moreover, using microarray analyses, we identified hyaluronan synthase 2 (HAS2) as one of the genes induced by HNF4G in bladder cancer cells. Transcription was activated by HNF4G in reporter assays using the promoter/enhancer region of the HAS2 gene. The endogenous expression of the HAS2 gene was suppressed by knockdown of HNF4G. In turn, knockdown of HAS2 inhibited the growth and invasion of bladder cancer cells. Taken together, our data suggest that some orphan NRs are involved in bladder cancer progression and that, among them, HNF4G promotes the growth and invasion of bladder cancer, at least in part, via the regulation of the HAS2 gene.
authors.affiliation: Department of Urology, Kyorin University School of Medicine, Mitaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Okegawa
authors.forename: K
authors.initials: K
authors.lastname: Ushio
authors.forename: M
authors.initials: M
authors.lastname: Imai
authors.forename: M
authors.initials: M
authors.lastname: Morimoto
authors.forename: T
authors.initials: T
authors.lastname: Hara
references.citation: J Urol. 2010 Jan;183(1):68-75
references.pmid: 19913255
references.citation: Urol Oncol. 2010 Mar-Apr;28(2):180-8
references.pmid: 19070520
references.citation: Am J Pathol. 2009 Mar;174(3):1027-36
references.pmid: 19218337
references.citation: Urol Oncol. 2012 Sep;30(5):673-9
references.pmid: 20884250
references.citation: Cancer Res. 2008 Jan 15;68(2):483-91
references.pmid: 18199543
references.citation: Cancer. 2010 Jan 15;116(2):340-6
references.pmid: 19908257
references.citation: Mol Pharmacol. 2010 Mar;77(3):396-404
references.pmid: 20023005
references.citation: PLoS One. 2011;6(7):e21667
references.pmid: 21829439
references.citation: Eur Urol. 2006 Jan;49(1):71-5
references.pmid: 16310928
references.citation: Cancer Res. 2008 Feb 15;68(4):1128-35
references.pmid: 18281488
references.citation: Pharmacol Rev. 2006 Dec;58(4):798-836
references.pmid: 17132856
references.citation: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references.pmid: 20610543
references.citation: Cancer Res. 1999 Mar 1;59(5):1141-5
references.pmid: 10070975
references.citation: J Clin Oncol. 2010 Aug 10;28(23):3784-96
references.pmid: 20625130
references.citation: Curr Cancer Drug Targets. 2012 Jan;12(1):14-22
references.pmid: 22111835
references.citation: Leukemia. 2011 Nov;25(11):1687-96
references.pmid: 21637284
references.citation: Endocr Relat Cancer. 2010 Oct 29;17(4):965-75
references.pmid: 20817789
references.citation: Am J Pathol. 2009 Sep;175(3):1235-45
references.pmid: 19644015
references.citation: J Biol Chem. 1999 Aug 27;274(35):25085-92
references.pmid: 10455188
references.citation: Connect Tissue Res. 2008;49(3):215-8
references.pmid: 18661346
references.citation: Urol Oncol. 2010 Jul-Aug;28(4):409-28
references.pmid: 20610279
references.citation: Cancer Res. 2012 Apr 1;72(7):1728-39
references.pmid: 22350413
references.citation: Ann Surg Oncol. 2011 Jun;18(6):1775-81
references.pmid: 21184188
references.citation: Curr Opin Oncol. 2012 May;24(3):272-7
references.pmid: 22327837
references.citation: Arch Med Res. 2006 Jan;37(1):109-16
references.pmid: 16314195
references.citation: Pharmacol Rev. 2006 Dec;58(4):685-704
references.pmid: 17132848
references.citation: Cancer. 2011 Mar 15;117(6):1197-209
references.pmid: 20960509
references.citation: J Urol. 2000 Jan;163(1):348-56
references.pmid: 10604388
references.citation: Cancer Lett. 2011 Oct 28;309(2):137-44
references.pmid: 21696885
references.citation: Cancer Res. 2001 Apr 1;61(7):3176-81
references.pmid: 11306505
references.citation: Carcinogenesis. 2012 Jul;33(7):1384-90
references.pmid: 22523087
references.citation: Eur Urol. 2011 Aug;60(2):279-90
references.pmid: 21592649
references.citation: Curr Opin Pharmacol. 2010 Dec;10(6):698-705
references.pmid: 20833107
references.citation: Mol Biol (Mosk). 2008 Sep-Oct;42(5):786-97
references.pmid: 18988528
references.citation: J Urol. 2011 Mar;185(3):787-94
references.pmid: 21239012
references.citation: Int J Cancer. 2007 Jun 15;120(12):2557-67
references.pmid: 17315194
references.citation: Oncol Rep. 2010 Apr;23(4):1125-32
references.pmid: 20204300
references.citation: Cancer Res. 2004 Jul 1;64(13):4670-6
references.pmid: 15231680