socs7, a target gene of microRNA-145, regulates interferon-β induction through STAT3 nuclear translocation in bladder cancer cells

Cell Death Dis. 2013 Feb 7;4(2):e482. doi: 10.1038/cddis.2013.11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2',5'-Oligoadenylate Synthetase / metabolism
  • Apoptosis / drug effects*
  • Caspases / metabolism
  • Cell Line
  • Cell Nucleus / metabolism
  • Humans
  • Interferon-beta / metabolism*
  • MicroRNAs / pharmacology*
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Poly I-C / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • STAT3 Transcription Factor / metabolism*
  • Suppressor of Cytokine Signaling Proteins / antagonists & inhibitors
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Toll-Like Receptor 3 / antagonists & inhibitors
  • Toll-Like Receptor 3 / genetics
  • Toll-Like Receptor 3 / metabolism
  • Up-Regulation / drug effects
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology


  • MIRN145 microRNA, human
  • MicroRNAs
  • Nuclear Proteins
  • RNA, Small Interfering
  • SOCS7 protein, human
  • STAT3 Transcription Factor
  • Suppressor of Cytokine Signaling Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • Toll-Like Receptor 3
  • Interferon-beta
  • Proto-Oncogene Proteins c-akt
  • OAS1 protein, human
  • 2',5'-Oligoadenylate Synthetase
  • Caspases
  • Poly I-C