Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma

Liem M. Phan, Enrique Fuentes-Mattei, Weixin Wu, Guermarie Velazquez-Torres, Kanishka Sircar, Christopher G. Wood, Tao Hai, Camilo Jimenez, Gilbert J. Cote, Levent Ozsari, Marie Claude Hofmann, Siyuan Zheng, Roeland Verhaak, Lance Pagliaro, Maria Angelica Cortez, Mong Hong Lee, Sai Ching J. Yeung, Mouhammed Amir Habra

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in adrenocortical carcinoma has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of adrenocortical carcinoma. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human adrenocortical carcinoma samples was positively associated with cancer-related biologic processes, including proliferation and angiogenesis, and negatively correlatedwith apoptosis. Accordingly, treatment of adrenocortical carcinoma cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA-mediated knockdown or pharmacologic inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer.

Original languageEnglish (US)
Pages (from-to)4131-4142
Number of pages12
JournalCancer Research
Volume75
Issue number19
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phan, L. M., Fuentes-Mattei, E., Wu, W., Velazquez-Torres, G., Sircar, K., Wood, C. G., Hai, T., Jimenez, C., Cote, G. J., Ozsari, L., Hofmann, M. C., Zheng, S., Verhaak, R., Pagliaro, L., Cortez, M. A., Lee, M. H., Yeung, S. C. J., & Habra, M. A. (2015). Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma. Cancer Research, 75(19), 4131-4142. https://doi.org/10.1158/0008-5472.CAN-14-3707