DataVXAdvanced SciencePaper
journal article·2024-06Open access

Oncogenic Roles of Laminin Subunit Gamma‐2 in Intrahepatic Cholangiocarcinoma via Promoting EGFR Translation

Jianjuan Zhang, Fubo Ji, Yaqi Tan, Lei Zhao, Yongzhi Zhao, Jiaxin Liu, Liyuan Shao, Jiong Shi, Meihua Ye, Xianglei He, Jianping Jin, Bin Zhao, Jun Huang, Stephanie Roessler, Xin Zheng, Junfang Ji

Advanced Science· Volume 11· Issue 21
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Abstract

Abstract Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal biliary epithelial cancer in the liver. Here, Laminin subunit gamma‐2 (LAMC2) with important oncogenic roles in iCCA is discovered. In a total of 231 cholangiocarcinoma patients (82% of iCCA patients) across four independent cohorts, LAMC2 is significantly more abundant in iCCA tumor tissue compared to normal bile duct and non‐tumor liver. Among 26.3% of iCCA patients, LAMC2 gene is amplified, contributing to its over‐expression. Functionally, silencing LAMC2 significantly blocks tumor formation in orthotopic iCCA mouse models. Mechanistically, it promotes EGFR protein translation via interacting with nascent unglycosylated EGFR in the endoplasmic reticulum (ER), resulting in activated EGFR signaling. LAMC2‐mediated EGFR translation also depends on its interaction with the ER chaperone BiP via their C‐terminus. Together LAMC2 and BiP generate a binding “pocket” of nascent EGFR and facilitate EGFR translation. Consistently, LAMC2‐high iCCA patients have poor prognosis in two iCCA cohorts. LAMC2‐high iCCA cells are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs) treatment both in vitro and in vivo. Together, these data demonstrate LAMC2 as an oncogenic player in iCCA by promoting EGFR translation and an indicator to identify iCCA patients who may benefit from available EGFR‐targeted TKIs therapies.
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Research context

OpenAlex topics: Cholangiocarcinoma and Gallbladder Cancer Studies · Peptidase Inhibition and Analysis · Cancer-related molecular mechanisms research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

The MOE Key Laboratory of Biosystems Homeostasis & Protection Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology Life Sciences Institute Zhejiang University Hangzhou Zhejiang 310058 China

Center for Life Sciences Shaoxing Institute Zhejiang University Shaoxing Zhejiang 321000 China

Cancer Center Zhejiang University Hangzhou Zhejiang 310058 China

Shandong Cancer Hospital and Institute Shandong Cancer Hospital of Shandong First Medical University Jinan Shandong Province 250117 China

Department of Pathology Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing Jiangsu Province 210008 China

Zhejiang Provincial People's Hospital Hangzhou Zhejiang 310014 China

Institute of Pathology University Hospital Heidelberg 69120 Heidelberg Germany

Taoharmony Biotech L.L.C. Hangzhou Zhejiang 310018 China

Funding

National Natural Science Foundation of China · National Basic Research Program of China · Fundamental Research Funds for the Central Universities · Deutsche Forschungsgemeinschaft · Deutsche Krebshilfe · Key Technology Research and Development Program of Shandong Province · Key Research and Development Program of Zhejiang Province

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