FOXL2-induced follistatin attenuates activin A-stimulated cell proliferation in human granulosa cell tumors

Biochem Biophys Res Commun. 2014 Jan 10;443(2):537-42. doi: 10.1016/j.bbrc.2013.12.010. Epub 2013 Dec 8.

Abstract

Human granulosa cell tumors (GCTs) are rare, and their etiology remains largely unknown. Recently, the FOXL2 402C>G (C134W) mutation was found to be specifically expressed in human adult-type GCTs; however, its function in the development of human GCTs is not fully understood. Activins are members of the transforming growth factor-beta superfamily, which has been shown to stimulate normal granulosa cell proliferation; however, little is known regarding the function of activins in human GCTs. In this study, we examined the effect of activin A on cell proliferation in the human GCT-derived cell line KGN. We show that activin A treatment stimulates KGN cell proliferation. Treatment with the activin type I receptor inhibitor SB431542 blocks activin A-stimulated cell proliferation. In addition, our results show that cyclin D2 is induced by treatment with activin A and is involved in activin A-stimulated cell proliferation. Moreover, the activation of Smad signaling is required for activin A-induced cyclin D2 expression. Finally, we show that the overexpression of the wild-type FOXL2 but not the C134W mutant FOXL2 induced follistatin production. Treatment with exogenous follistatin blocks activin A-stimulated cell proliferation, and the overexpression of wild-type FOXL2 attenuates activin A-stimulated cell proliferation. These results suggest that FOXL2 may act as a tumor suppressor in human adult-type GCTs by inducing follistatin expression, which subsequently inhibits activin-stimulated cell proliferation.

Keywords: Activin; FOXL2; Follistatin; Human granulosa cell tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / metabolism*
  • Cell Proliferation
  • Down-Regulation
  • Follistatin / metabolism*
  • Forkhead Box Protein L2
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Granulosa Cell Tumor
  • Humans

Substances

  • FOXL2 protein, human
  • Follistatin
  • Forkhead Box Protein L2
  • Forkhead Transcription Factors
  • activin A
  • Activins