HUSCAP logo Hokkaido Univ. logo

Hokkaido University Collection of Scholarly and Academic Papers >
Graduate School of Medicine / Faculty of Medicine >
Peer-reviewed Journal Articles, etc >

Molecular Classification and Tumor Microenvironment Characterization of Gallbladder Cancer by Comprehensive Genomic and Transcriptomic Analysis

This item is licensed under:Creative Commons Attribution 4.0 International

Files in This Item:

The file(s) associated with this item can be obtained from the following URL: https://doi.org/10.3390/cancers13040733


Title: Molecular Classification and Tumor Microenvironment Characterization of Gallbladder Cancer by Comprehensive Genomic and Transcriptomic Analysis
Authors: Ebata, Nobutaka Browse this author
Fujita, Masashi Browse this author
Sasagawa, Shota Browse this author
Maejima, Kazuhiro Browse this author
Okawa, Yuki Browse this author
Hatanaka, Yutaka Browse this author
Mitsuhashi, Tomoko Browse this author
Oosawa-Tatsuguchi, Ayako Browse this author
Tanaka, Hiroko Browse this author
Miyano, Satoru Browse this author
Nakamura, Toru Browse this author
Hirano, Satoshi Browse this author →KAKEN DB
Nakagawa, Hidewaki Browse this author
Keywords: gallbladder cancer
tumor microenvironment
EMT
TGF-β
signaling pathway
Issue Date: Feb-2021
Publisher: MDPI
Journal Title: Cancers
Volume: 13
Issue: 4
Start Page: 733
Publisher DOI: 10.3390/cancers13040733
Abstract: Simple Summary Gallbladder cancer (GBC) is a rare but lethal cancer. Molecular characterization of GBC is insufficient so far, and a comprehensive molecular portrait is warranted to uncover new targets and classify GBC. Clustering analysis of RNA expression revealed two subclasses of 36 GBCs, which reflects the status of the tumor microenvironment (TME) and poor prognosis of GBC, including epithelial-mesenchymal transition (EMT), immune suppression, and the TGF-beta signaling pathway. The knockout of miR125B1 in GBC cell lines decreased its invasion ability and altered the EMT pathway. Mutations of the genes related to the TGF-beta signaling pathway were enriched in the poor-prognosis/TME-rich cluster of GBCs. This comprehensive molecular analysis provides a new classification of GBCs based on the TME activity, which is involved with EMT and immune suppression for poor prognosis of GBC. This information may be useful for GBC prognosis and therapeutic decision-making. Gallbladder cancer (GBC), a rare but lethal disease, is often diagnosed at advanced stages. So far, molecular characterization of GBC is insufficient, and a comprehensive molecular portrait is warranted to uncover new targets and classify GBC. We performed a transcriptome analysis of both coding and non-coding RNAs from 36 GBC fresh-frozen samples. The results were integrated with those of comprehensive mutation profiling based on whole-genome or exome sequencing. The clustering analysis of RNA-seq data facilitated the classification of GBCs into two subclasses, characterized by high or low expression levels of TME (tumor microenvironment) genes. A correlation was observed between gene expression and pathological immunostaining. TME-rich tumors showed significantly poor prognosis and higher recurrence rate than TME-poor tumors. TME-rich tumors showed overexpression of genes involved in epithelial-to-mesenchymal transition (EMT) and inflammation or immune suppression, which was validated by immunostaining. One non-coding RNA, miR125B1, exhibited elevated expression in stroma-rich tumors, and miR125B1 knockout in GBC cell lines decreased its invasion ability and altered the EMT pathway. Mutation profiles revealed TP53 (47%) as the most commonly mutated gene, followed by ELF3 (13%) and ARID1A (11%). Mutations of ARID1A, ERBB3, and the genes related to the TGF-beta signaling pathway were enriched in TME-rich tumors. This comprehensive analysis demonstrated that TME, EMT, and TGF-beta pathway alterations are the main drivers of GBC and provides a new classification of GBCs that may be useful for therapeutic decision-making.
Rights: https://creativecommons.org/licenses/by/4.0/
Type: article
URI: http://hdl.handle.net/2115/81369
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Export metadata:

OAI-PMH ( junii2 , jpcoar_1.0 )

MathJax is now OFF:


 

 - Hokkaido University