Key role for activin B in cellular transformation after loss of the von Hippel-Lindau tumor suppressor.
The von Hippel-Lindau tumor suppressor gene (VHL) is mutated in clear cell renal cell carcinomas (RCC), leading to the activation of hypoxia-inducible factor (HIF)-mediated gene transcription. Several VHL/HIF targets, such as glycolysis, angiogenesis, cell growth, and chemotaxis of tumor cells, have been implicated in the transformed phenotype of RCC-regulating properties. Here, we show that VHL suppresses key features of cell transformation through downregulation of the HIF-dependent expression of activin B, a member of the transforming growth factor beta superfamily. Activin B expression is repressed by restoration of VHL in VHL-deficient RCC cells and upregulated by hypoxia. RCC tumor samples show increased expression of activin B compared to that in the normal kidney. VHL increases cell adhesion to the extracellular matrix, promotes cell flattening, and reduces invasiveness. These effects are completely phenocopied by RNA interference-mediated knockdown of activin B and reverted by treatment with recombinant activin B. Finally, knockdown of activin B reduces tumor growth of RCC cells in nude mice. Our data indicate that activin B is a key mediator of VHL/HIF-induced transformation in RCC.
Wacker
Ingrid
I
Nikolaus Fiebiger Center, University Erlangen-Nürnberg, Glückstr. 6, 91054 Erlangen, Germany.
Sachs
Martin
M
Knaup
Karl
K
Wiesener
Michael
M
Weiske
Jörg
J
Huber
Otmar
O
Akçetin
Ziya
Z
Behrens
Jürgen
J
D028341:Activins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048430:Cell Shape; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering; C044147:activin B; D028341:Activins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human