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Hepatocyte growth factor/cMET pathway activation enhances cancer hallmarks in adrenocortical carcinoma
- Publication Year :
- 2015
-
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 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. Cancer Res; 75(19); 4131–42. ©2015 AACR.
- Subjects :
- Male
Cancer Research
Angiogenesis
Pyridines
Mice
Adrenocortical carcinoma
Mitotane
Anilides
Molecular Targeted Therapy
RNA, Small Interfering
Aged, 80 and over
Neovascularization, Pathologic
Hepatocyte Growth Factor
Middle Aged
Proto-Oncogene Proteins c-met
Neoplasm Proteins
Gene Expression Regulation, Neoplastic
Oncology
Hepatocyte growth factor
Female
RNA Interference
Cell Division
medicine.drug
Signal Transduction
Adenoma
Adult
medicine.medical_specialty
Mice, Nude
Antineoplastic Agents
Biology
Article
Internal medicine
Cell Line, Tumor
medicine
Carcinoma
Animals
Humans
Aged
Cisplatin
Cell growth
Gene Expression Profiling
Cancer
medicine.disease
Xenograft Model Antitumor Assays
Adrenal Cortex Neoplasms
Endocrinology
Drug Resistance, Neoplasm
Cancer research
Transcriptome
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....6095b7d11769bdb975e627dd6757e580