Transforming growth factor-β-induced lncRNA-Smad7 inhibits apoptosis of mouse breast cancer JygMC(A) cells

Cancer Sci. 2014 Aug;105(8):974-82. doi: 10.1111/cas.12454. Epub 2014 Jul 25.

Abstract

Transforming growth factor (TGF)-β exhibits both pro-apoptotic and anti-apoptotic effects on epithelial cells in a context-dependent manner. The anti-apoptotic function of TGF-β is mediated by several downstream regulatory mechanisms, and has been implicated in the tumor-progressive phenotype of breast cancer cells. We conducted RNA sequencing of mouse mammary gland epithelial (NMuMG) cells and identified a long non-coding RNA, termed lncRNA-Smad7, which has anti-apoptotic functions, as a target of TGF-β. lncRNA-Smad7 was located adjacent to the mouse Smad7 gene, and its expression was induced by TGF-β in all of the mouse mammary gland epithelial cell lines and breast cancer cell lines that we evaluated. Suppression of lncRNA-Smad7 expression cancelled the anti-apoptotic function of TGF-β. In contrast, forced expression of lncRNA-Smad7 rescued apoptosis induced by a TGF-β type I receptor kinase inhibitor in the mouse breast cancer cell line JygMC(A). The anti-apoptotic effect of lncRNA-Smad7 appeared to occur independently of the transcriptional regulation by TGF-β of anti-apoptotic DEC1 and pro-apoptotic Bim proteins. Small interfering RNA for lncRNA-Smad7 did not alter the process of TGF-β-induced epithelial-mesenchymal transition, phosphorylation of Smad2 or expression of the Smad7 gene, suggesting that the contribution of this lncRNA to TGF-β functions may be restricted to apoptosis. Our findings suggest a complex mechanism for regulating the anti-apoptotic and tumor-progressive aspects of TGF-β signaling.

Keywords: Apoptosis; Smad7; breast cancer; long non-coding RNA; transforming growth factor-β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Base Sequence
  • Blotting, Northern
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic / physiology
  • Immunoprecipitation
  • Lymphotoxin-alpha / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Small Interfering
  • Reverse Transcriptase Polymerase Chain Reaction
  • Smad7 Protein / genetics
  • Smad7 Protein / metabolism*

Substances

  • Lymphotoxin-alpha
  • RNA, Long Noncoding
  • RNA, Small Interfering
  • Smad7 Protein
  • Smad7 protein, mouse

Associated data

  • GENBANK/AB904933
  • GENBANK/AB904934
  • GENBANK/CF356854
  • GENBANK/CX230377