Low c-Met expression levels are prognostic for and predict the benefits of temozolomide chemotherapy in malignant gliomas

• Published in: Scientific reports Vol. 6; no. 1; p. 21141
• Main Authors: Li, Ming-Yang, Yang, Pei, Liu, Yan-Wei, Zhang, Chuan-Bao, Wang, Kuan-Yu, Wang, Yin-Yan, Yao, Kun, Zhang, Wei, Qiu, Xiao-Guang, Li, Wen-Bin, Peng, Xiao-Xia, Wang, Yong-Zhi, Jiang, Tao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.02.2016; Nature Publishing Group
• Subjects: 38; 38/61; 631/67/1922; 692/308/1892; 82; 82/80; Adolescent; Adult; Age; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating - pharmacology; Antineoplastic Agents, Alkylating - therapeutic use; Brain tumors; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell Movement - genetics; Cell Proliferation - drug effects; Chemotherapy; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Dacarbazine - therapeutic use; Decision making; DNA Methylation; DNA microarrays; DNA Modification Methylases - genetics; DNA Repair Enzymes - genetics; Drug Resistance, Neoplasm - genetics; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Genomes; Glioma; Glioma - drug therapy; Glioma - genetics; Glioma - mortality; Glioma - pathology; Glioma cells; Humanities and Social Sciences; Humans; Immunohistochemistry; Isocitrate Dehydrogenase - genetics; Male; Middle Aged; mRNA; multidisciplinary; Neoplasm Grading; Neoplasm Staging; O6-methylguanine-DNA methyltransferase; Prognosis; Promoter Regions, Genetic; Proportional Hazards Models; Proto-Oncogene Proteins c-met - genetics; Radiation therapy; Reproducibility of Results; Science; Science (multidisciplinary); Temozolomide; Treatment Outcome; Tumor Suppressor Proteins - genetics; Young Adult
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep21141

Aberrant c-Met has been implicated in the development of many cancers. The objective of this study was to identify an unfavorable prognostic marker that might guide decisions regarding clinical treatment strategies for high-grade gliomas. C-Met expression was measured using immunohistochemistry in 783 gliomas, and we further analyzed c-Met mRNA levels using the Agilent Whole Genome mRNA Microarray in 286 frozen samples. In vitro , we performed cell migration and invasion assays. Cell sensitivity to temozolomide (TMZ) chemotherapy was determined using MTT assays. Both mRNA and protein levels of c-Met were significantly associated with tumor grade progression and inversely correlated with overall and progression-free survival in high-grade gliomas (all P  < 0.0001). These findings were nearly consistent at the mRNA level across 3 independent cohorts. Multivariable analysis indicated that c-Met was an independent prognostic marker after adjusting for age, preoperative Karnofsky Performance Status (KPS) score, the extent of resection, radiotherapy, TMZ chemotherapy, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Further analysis in vitro revealed that downregulating the expression of c-Met dramatically inhibited cell migration and invasion capacities, enhanced sensitivity to TMZ chemotherapy in H4 and U87 glioma cells. Our results suggest that c-Met may serve as a potential predictive maker for clinical decision making.