title: socs7, a target gene of microRNA-145, regulates interferon-β induction through STAT3 nuclear translocation in bladder cancer cells.
abstract: We recently reported that microRNA (miR)-145 is downregulated and induces apoptosis in human bladder cancer cells. Also, it is suggested that the ectopic expression of miR-145 induces apoptosis with the induction of TRAIL expression in several cancer cells. Here, we demonstrated a novel mechanism of apoptosis induction by miR-145 in bladder cancer cells. Exogenous miR-145 in T24 and NKB1 cells markedly increased the expression levels of interferon (IFN)-β, 2'-5'-oligoadenylate synthetase 1, which lies upstream of 2'-5' oligoadenylates/RNase L system, and TRAIL, and induced apparent caspase-dependent apoptosis that was suppressed by cotreatment with a pan-caspase inhibitor; moreover, these expression levels were reduced by cotreatment with an miR-145 inhibitor. The apoptosis did not depend on Toll-like receptor 3 (TLR3) expression, because TLR3-silencing failed to inhibit IFN-β induction by miR-145. Then, we focused on the suppressor of cytokine signaling 7 (socs7), whose expression level was upregulated in bladder cancer cells compared with its level in normal human urothelial cells, as a putative target gene involved in IFN-β induction by miR-145. Expectedly, exogenous miR-145 decreased the expression level of SOCS7, and socs7-silencing enhanced IFN-β induction by transfection with a TLR3 ligand, polyinosinic acid-polycytidylic acid (PIC). The results of a luciferase reporter assay revealed that miR-145 targeted socs7. In addition, socs7-silencing significantly decreased the level of p-Akt and suppressed the growth of T24 cells. Furthermore, exogenous miR-145 or socs7-silencing promoted nuclear translocation of STAT3. In conclusion, the machinery of IFN-β induction through the regulation of SOCS7 by miR-145 was closely associated with the induction of apoptosis. Moreover, exogenous miR-145 promoted IFN-β induction by targeting socs7, which resulted in the nuclear translocation of STAT3. Additionally, our data indicate that SOCS7 functioned as an oncogene, the finding that revealed a novel mechanism of carcinogenesis in bladder cancer cells.
authors: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, Japan. snoguchi@gifu-u.ac.jp
authors: S
authors: S
authors: Noguchi
authors: N
authors: N
authors: Yamada
authors: M
authors: M
authors: Kumazaki
authors: Y
authors: Y
authors: Yasui
authors: J
authors: J
authors: Iwasaki
authors: S
authors: S
authors: Naito
authors: Y
authors: Y
authors: Akao
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism*; D035683:MicroRNAs / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C108775:SOCS7 protein, human; D050796:STAT3 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D051057:Proto-Oncogene Proteins c-akt; C475085:OAS1 protein, human; D015088:2',5'-Oligoadenylate Synthetase; D020169:Caspases; D011070:Poly I-C
references: Oncogene. 2010 Feb 18;29(7):1073-84
references: 19915607
references: Int J Cancer. 2009 Jul 15;125(2):345-52
references: 19378336
references: J Leukoc Biol. 2001 Jun;69(6):912-20
references: 11404376
references: Proc Natl Acad Sci U S A. 2006 May 30;103(22):8459-64
references: 16714379
references: J Biol Chem. 2005 Apr 8;280(14):13817-23
references: 15677474
references: J Biol Chem. 2004 Jan 9;279(2):1123-31
references: 14570908
references: Clin Cancer Res. 2001 Jun;7(6):1821-31
references: 11410525
references: Cancer Sci. 2007 Dec;98(12):1914-20
references: 17892514
references: BMC Genomics. 2010 Mar 15;11:175
references: 20230625
references: Br J Cancer. 2010 Mar 2;102(5):883-91
references: 20160723
references: Cancer Res. 2004 May 15;64(10):3386-90
references: 15150089
references: Cancer Res. 2005 Feb 1;65(3):939-47
references: 15705894
references: Hum Cell. 1996 Mar;9(1):49-56
references: 9183630
references: Cell Mol Life Sci. 1998 Oct;54(10):1109-21
references: 9817990
references: Nat Rev Immunol. 2006 Aug;6(8):602-12
references: 16868551
references: Stem Cells. 2001;19(5):378-87
references: 11553846
references: DNA Cell Biol. 2007 May;26(5):311-20
references: 17504027
references: Cancer Lett. 2013 Jan 28;328(2):353-61
references: 23104321
references: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3207-12
references: 19202062
references: Br J Cancer. 2010 Jul 13;103(2):256-64
references: 20588276
references: J Vet Med Sci. 2012 Jan;74(1):1-8
references: 21836381
references: Curr Opin Mol Ther. 2007 Jun;9(3):248-57
references: 17608023
references: Cell. 2009 May 15;137(4):647-58
references: 19409607
references: Oncogene. 2008 Mar 13;27(12):1788-93
references: 17891175
references: PLoS One. 2010 Jan 21;5(1):e8836
references: 20098684
references: Cancer Lett. 2011 Aug 28;307(2):211-20
references: 21550168
references: J Biol Chem. 1995 Feb 24;270(8):4133-7
references: 7876164
references: J Exp Med. 1997 Sep 15;186(6):967-72
references: 9294150
references: World J Urol. 2009 Jun;27(3):343-6
references: 19479263
references: Nat Immunol. 2004 Jul;5(7):730-7
references: 15208624
references: Nature. 2006 May 4;441(7089):101-5
references: 16625202
references: Nat Rev Drug Discov. 2007 Dec;6(12):975-90
references: 18049472