Opposing control of rhabdomyosarcoma growth and differentiation by myogenin and interleukin 4

Patrizia Nanni, Giordano Nicoletti, Arianna Palladini, Annalisa Astolfi, Paola Rinella, Stefania Croci, Lorena Landuzzi, Giada Monduzzi, Valeria Stivani, Agnese Antognoli, Annalisa Murgo, Marianna Ianzano, Carla De Giovanni, Pier Luigi Lollini

Research output: Contribution to journalArticlepeer-review

Abstract

Rhabdomyosarcoma is a tumor of striated muscle origin that displays defective myogenic differentiation. Terminal myogenesis switches off cell proliferation and migration, hence, the promotion of rhabdomyosarcoma differentiation should antagonize tumor growth and metastasis. Terminal myogenesis is controlled by cell-intrinsic myogenic transcription factors like myogenin and environmental mediators like interleukin 4 (IL-4). We studied whether the expression of myogenin or exposure to IL-4 could promote the myogenesis of poorly differentiating human rhabdomyosarcoma cells RD/12. Forced expression of myogenin amplified myosin expression and the formation of myotube-like elements, inhibited cell migration, and reduced the growth of local tumors and liver metastases in immunodepressed mice. In contrast, exposure to IL-4 promoted cell proliferation and survival, especially at high cell density, inhibited myogenin expression, and myogenesis. Moreover, IL-4 stimulated the directed migration of cells with low myogenin levels, but not of cells with higher (spontaneous or forced) levels. Thus, IL-4, which was known to promote late stages of normal myogenesis, favors growth and migration, and inhibits further differentiation of the myogenic stages attained by rhabdomyosarcoma cells. Strategies to increase myogenin expression and block IL-4 could simultaneously reduce growth and migration, and enhance terminal differentiation of rhabdomyosarcoma, thus contributing to the control of tumor growth and metastatic spread.

Original languageEnglish
Pages (from-to)754-761
Number of pages8
JournalMolecular Cancer Therapeutics
Volume8
Issue number4
DOIs
Publication statusPublished - Apr 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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