title: Low c-Met expression levels are prognostic for and predict the benefits of temozolomide chemotherapy in malignant gliomas.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Li
authors.affiliation: Beijing Neurosurgical Institute, Beijing, 100050, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Yang
authors.affiliation: Beijing Neurosurgical Institute, Beijing, 100050, China.
authors.forename: Yan-Wei
authors.initials: YW
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Chuan-Bao
authors.initials: CB
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, Liao Ning Province, 116000, China.
authors.forename: Kuan-Yu
authors.initials: KY
authors.lastname: Wang
authors.affiliation: Beijing Neurosurgical Institute, Beijing, 100050, China.
authors.forename: Yin-Yan
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Department of Pathology, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yao
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Radiation Therapy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Xiao-Guang
authors.initials: XG
authors.lastname: Qiu
authors.affiliation: Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Li
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health and Family Medicine, Capital Medical University.
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Peng
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
authors.forename: Yong-Zhi
authors.initials: YZ
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.|Beijing Neurosurgical Institute, Beijing, 100050, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D015203:Reproducibility of Results; D000077204:Temozolomide; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D019859:Proto-Oncogene Proteins c-met; D045643:DNA Repair Enzymes; D000077204:Temozolomide