期刊
CANCER RESEARCH
卷 75, 期 19, 页码 4131-4142出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-3707
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资金
- Run for Rivenes
- Beverlin Fund for Adrenal Cancer Research
- Vietnam Education Foundation
- Rosalie B. Hite Foundation
- U.S. Department of Defense Breast Cancer Research Program [W81XWH-10-0171]
- NCI Training Grant Program in Molecular Genetics [T32-CA009299]
- NIH Loan Repayment Program
- Health Professional Training Grant from the Department of Health of Fujian Province, China
- Xiamen Public Health Bureau of Science and Technology Project [WQK0605, 3502z20077042]
- NIH cancer prevention fellowship (NCI fellowship) [R25T CA57730]
- NIH minority supplement [3-R01CA089266-08S1, 3-R01CA089266-09S1, 3-R01CA089266-10S1]
- Susan G. Komen for the Cure Promise Grant [KG081048]
- NCI [R01-CA089266]
- NIH/NCI [P30CA016672]
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 correlated with 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. (C) 2015 AACR.
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