2. Academic Validation
  3. Oncogenic Roles of Laminin Subunit Gamma-2 in Intrahepatic Cholangiocarcinoma via Promoting EGFR Translation

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

  • Adv Sci (Weinh). 2024 Mar 25:e2309010. doi: 10.1002/advs.202309010.
Jianjuan Zhang 1 2 3,  Fubo Ji 1 2 3,  Yaqi Tan 1 2 3,  Lei Zhao 4,  Yongzhi Zhao 1 2 3,  Jiaxin Liu 1 2 3,  Liyuan Shao 2,  Jiong Shi 5,  Meihua Ye 6,  Xianglei He 6,  Jianping Jin 1 2 3,  Bin Zhao 1 2 3,  Jun Huang 1 2 3,  Stephanie Roessler 7,  Xin Zheng 8,  Junfang Ji 1 2 3
Affiliations

Affiliations

  • 1 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.
  • 2 Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing, Zhejiang, 321000, China.
  • 3 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 4 Shandong Cancer Hospital and Institute, Shandong Cancer Hospital of Shandong First Medical University, Jinan, Shandong Province, 250117, China.
  • 5 Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, China.
  • 6 Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang, 310014, China.
  • 7 Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany.
  • 8 Taoharmony Biotech L.L.C., Hangzhou, Zhejiang, 310018, China.
PMID: 38526177 DOI: 10.1002/advs.202309010
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.

Keywords

EGFR; LAMC2; glycosylation; intrahepatic cholangiocarcinoma; protein translation.

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