title: MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment.
abstract: Although temozolomide (TMZ) is the first-line chemotherapeutic agent for glioblastoma, it is often non-curative due to drug resistance. To overcome the resistance of glioblastoma cells to TMZ, it is imperative to identify prognostic markers for outcome prediction and to develop chemo-sensitizing agents. Here, the gene expression profiles of TMZ-resistant and TMZ-sensitive samples were compared by microarray analysis, and mitogen-activated protein kinase kinase 2 (MEK2) was upregulated specifically in resistant glioma cells but not in sensitive tumor cells or non-tumor tissues. Moreover, a comprehensive analysis of patient data revealed that the increased level of MEK2 expression correlated well with the advancement of glioma grade and worse prognosis in response to TMZ treatment. Furthermore, reducing the level of MEK2 in U251 glioma cell lines or xenografted glioma models through shRNA-mediated gene knockdown inhibited cell proliferation and enhanced the sensitivity of cells toward TMZ treatment. Further analysis of tumor samples from glioma patients by real-time PCR indicated that an increased MEK2 expression level was closely associated with the activation of many drug resistance genes. Finally, these resistance genes were downregulated after MEK2 was silenced in vitro, suggesting that the mechanism of MEK2-induced chemo-resistance could be mediated by the transcriptional activation of these resistance genes. Collectively, our data indicated that the expression level of MEK2 could serve as a prognostic marker for glioma chemotherapy and that MEK2 antagonists can be used as chemo-sensitizers to enhance the treatment efficacy of TMZ.
authors.affiliation: Department of Neurosurgery, Changzheng Hospital, Second Affiliated Hospital of Second Military Medical University, 415 Fengyang Road, Shanghai 200003, P.R.China.
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, School of Medicine, University of Virginia, USA.
authors.forename: Maojin
authors.initials: M
authors.lastname: Yao
authors.affiliation: Department of Hematology, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Bangbao
authors.initials: B
authors.lastname: Tao
authors.affiliation: Department of Neurosurgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Feili
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Wannan Medical College, 22 Wenchang Road Wuhu 241002, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Changzheng Hospital, Second Affiliated Hospital of Second Military Medical University, 415 Fengyang Road, Shanghai 200003, P.R.China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Neurosurgery, Changzheng Hospital, Second Affiliated Hospital of Second Military Medical University, 415 Fengyang Road, Shanghai 200003, P.R.China.
authors.forename: Chenran
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Changzheng Hospital, Second Affiliated Hospital of Second Military Medical University, 415 Fengyang Road, Shanghai 200003, P.R.China.
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Department of Neurosurgery, Changzheng Hospital, Second Affiliated Hospital of Second Military Medical University, 415 Fengyang Road, Shanghai 200003, P.R.China.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Changzheng Hospital, Second Affiliated Hospital of Second Military Medical University, 415 Fengyang Road, Shanghai 200003, P.R.China.
authors.forename: Guohan
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Neurosurgery, Changzheng Hospital, Second Affiliated Hospital of Second Military Medical University, 415 Fengyang Road, Shanghai 200003, P.R.China.
authors.forename: Chun
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, School of Medicine, University of Virginia, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zong
authors.affiliation: Department of Neurosurgery, Changzheng Hospital, Second Affiliated Hospital of Second Military Medical University, 415 Fengyang Road, Shanghai 200003, P.R.China.
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D011379:Prognosis; D000077204:Temozolomide; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D014408:Biomarkers, Tumor; D003606:Dacarbazine; D048370:MAP Kinase Kinase 2; D000077204:Temozolomide