Identification of MAP kinase pathways as therapeutic targets in gallbladder carcinoma using targeted parallel sequencing
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Mengdan Li1,*, Lihong Chen2,*, Yiping Qu1, Fang Sui1, Qi Yang1,3, Meiju Ji3, Bingyin Shi1,3, Mingwei Chen4, Peng Hou1,3
1Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University School of Medicine, Xi’an 710061, P.R. China
2Department of Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, P.R. China
3Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, P.R. China
4Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, P.R. China
*These authors contributed equally to this work
Peng Hou, email: firstname.lastname@example.org
Keywords: gallbladder carcinoma (GBC), targeted massively parallel sequencing, MAP kinase pathways, Wnt/β-catenin pathway, NF-κB pathway
Received: February 22, 2017 Accepted: March 21, 2017 Published: March 31, 2017
The aim of this study was to profile somatic mutation spectrum in gallbladder cancers (GBCs), and determine the role of MAP kinase pathway in GBC by a series of in vitro and in vivo studies. We performed targeted massively parallel sequencing of DNA isolated from GBCs and matched blood from 14 GBC patients to search for mutations in 504 genes commonly altered in human cancers. We identified recurrent mutations enriched in several major signaling pathways including MAP kinase, Wnt/β-catenin and NF-κB pathways. Immunohistochemistry analysis further validated overactivation of MAP kinase and Wnt pathways in a panel of GBC samples. By treating GBC cells with MEK inhibitor trametinib, we found that trametinib not only dramatically inhibited the activity of MAPK/ERK pathway, but also blocked the Wnt/β-catenin signaling through decreasing β-catenin expression or suppressing nucleus translocation of β-catenin. Moreover, trametinib inhibited the proliferation of GBC cell in a dose- and time-dependent manner, induced GBC cell apoptosis, and inhibited GBC cell migration and invasion. Growth of xenograft tumors derived from GBC cell line NOZ in nude mice was also significantly inhibited by trametinib. Our data highlight the critical role of MAP kinase pathways in GBC pathogenesis, and may represent therapeutic targets for this cancer.
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