Requirement of Stat3 signaling for HGF/SF-Met mediated tumorigenesis.
Hepatocyte Growth Factor/Scatter Factor (HGF/SF) mediates a wide variety of cellular responses by acting through the Met tyrosine kinase receptor. Inappropriate expression of HGF/SF and/or Met has been found in most types of solid tumors and is often associated with poor prognosis. Importantly, constitutional and sporadic activating mutations in Met have been discovered in human papillary renal carcinomas and other cancers, while autocrine and paracrine signaling of this receptor/ligand pair has been shown to contribute to tumorigenesis and metastasis. Numerous downstream signaling molecules have been implicated in HGF/SF-Met mediated tumorigenesis and metastasis. Stat3 is a downstream signaling molecule activated by HGF/SF-Met signaling, and is reported to contribute to cell transformation induced by a diverse set of oncoproteins. Stat3 is constitutively activated in many primary tumors and tumor cell lines, suggesting that signaling by this molecule may be important for cell transformation. To address whether Stat3 is required for HGF/SF-Met mediated tumorigenesis and metastasis, we introduced a dominant-negative form of Stat3, Stat3beta into the human leiomyosarcoma cell line SK-LMS-1. We found that Stat3beta has no effect on the transformed morphology, proliferation, invasion or branching morphogenesis in vitro. By contrast, expression of Stat3beta affected HGF/SF-Met mediated anchorage-independent colony formation and prevented tumorigenic growth in athymic nu/nu mice. Thus, Met signaling through Stat3 provides an essential function for tumorigenic growth, which is manifested in vitro by loss of anchorage-independent growth.
Zhang
Yu-Wen
YW
Laboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, Michigan, MI 49503, USA.
Wang
Ling-Mei
LM
Jove
Richard
R
Vande Woude
George F
GF
D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D009024:Morphogenesis / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D017228:Hepatocyte Growth Factor