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Identification of MAP kinase pathways as therapeutic targets in gallbladder carcinoma using targeted parallel sequencing.

ABSTRACT: 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/?-catenin and NF-?B 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/?-catenin signaling through decreasing ?-catenin expression or suppressing nucleus translocation of ?-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.

SUBMITTER: Li M

PROVIDER: S-EPMC5482657 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Identification of MAP kinase pathways as therapeutic targets in gallbladder carcinoma using targeted parallel sequencing.

Li Mengdan M Chen Lihong L Qu Yiping Y Sui Fang F Yang Qi Q Ji Meiju M Shi Bingyin B Chen Mingwei M Hou Peng P

Oncotarget 20170501 22

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 N ...[more]

PMID: 28422736

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Project description:IntroductionHepatocellular carcinoma (HCC) is an aggressive malignancy with steadily increasing incidence rates worldwide and poor therapeutic outcomes. Studies show that metabolic reprogramming plays a key role in tumor genesis and progression. In this study, we analyzed the metabolic heterogeneity of epithelial cells in the HCC and screened for potential biomarkers.MethodsThe hepatic single-cell RNA sequencing (scRNA-seq) datasets of HCC patients and healthy controls were obtained from the Gene Expression Omnibus (GEO) database. Based on data intergration and measurement of differences among groups, the metabolic epithelial cell subpopulations were identified. The single-cell metabolic pathway was analyzed and the myeloid subpopulations were identified. Cell-cell interaction analysis and single-cell proliferation analysis were performed. The gene expression profiles of HCC patients were obtained from the GSE14520 dataset of GEO and TCGA-LIHC cohort of the UCSC Xena website. Immune analysis was performed. The differentially expressed genes (DEGs) were identified and functionally annotated. Tumor tissues from HCC patients were probed with anti-ALDOA, anti-CD68, anti-CD163, anti-CD4 and anti-FOXP3 antibodies. Results We analyzed the scRNA-seq data from 48 HCC patients and 14 healthy controls. The epithelial cells were significantly enriched in HCC patients compared to the controls (p = 0.011). The epithelial cells from HCC patients were classified into two metabolism-related subpopulations (MRSs) - pertaining to amino acid metabolism (MRS1) and glycolysis (MRS2). Depending on the abundance of these metabolic subpopulations, the HCC patients were also classified into the MRS1 and MRS2 subtype distinct prognoses and immune infiltration. The MRS2 group had significantly worse clinical outcomes and more inflamed tumor microenvironment (TME), as well as a stronger crosstalk between MRS2 cells and immune subpopulations that resulted in an immunosuppressive TME. We also detected high expression levels of ALDOA in the MRS2 cells and HCC tissues. In the clinical cohort, HCC patients with higher ALDOA expression showed greater enrichment of immunosuppressive cells including M2 macrophages and T regulatory cells.DiscussionThe glycolytic subtype of HCC cells with high ALDOA expression is associated with an immunosuppressive TME and predicts worse clinical outcomes, providing new insights into the metabolism and prognosis of HCC.

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Identification of MAP kinase pathways as therapeutic targets in gallbladder carcinoma using targeted parallel sequencing.

Publications

Identification of MAP kinase pathways as therapeutic targets in gallbladder carcinoma using targeted parallel sequencing.

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