Opposing control of rhabdomyosarcoma growth and differentiation by myogenin and interleukin 4.
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.
Section of Cancer Research, Department of Hematology and Oncological Sciences, University of Bologna, Bologna, Italy.
Patrizia
P
Nanni
Giordano
G
Nicoletti
Arianna
A
Palladini
Annalisa
A
Astolfi
Paola
P
Rinella
Stefania
S
Croci
Lorena
L
Landuzzi
Giada
G
Monduzzi
Valeria
V
Stivani
Agnese
A
Antognoli
Annalisa
A
Murgo
Marianna
M
Ianzano
Carla
C
De Giovanni
Pier-Luigi
PL
Lollini
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D024510:Muscle Development; D018008:Myogenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018233:Rhabdomyosarcoma, Embryonal / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D018008:Myogenin; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; D015847:Interleukin-4; D009218:Myosins