TY - JOUR
T1 - Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma
AU - Phan, Liem M.
AU - Fuentes-Mattei, Enrique
AU - Wu, Weixin
AU - Velazquez-Torres, Guermarie
AU - Sircar, Kanishka
AU - Wood, Christopher G.
AU - Hai, Tao
AU - Jimenez, Camilo
AU - Cote, Gilbert J.
AU - Ozsari, Levent
AU - Hofmann, Marie Claude
AU - Zheng, Siyuan
AU - Verhaak, Roeland
AU - Pagliaro, Lance
AU - Cortez, Maria Angelica
AU - Lee, Mong Hong
AU - Yeung, Sai Ching J.
AU - Habra, Mouhammed Amir
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-14-3707
DO - 10.1158/0008-5472.CAN-14-3707
M3 - Article
C2 - 26282167
AN - SCOPUS:84945972932
SN - 0008-5472
VL - 75
SP - 4131
EP - 4142
JO - Cancer Research
JF - Cancer Research
IS - 19
ER -