Overexpression of DDR1 contributes to gastric cancer progression by inhibiting the Hippo pathway
Haiying Han1
Tianqi Shen2
Tingting Zhou2
Yixuan Yang3
Weiyi Toy3
Yin Yin Choo3
Fan Lin2
Yoon Pin Lim4
1.Department of Nursing,School of Medicine,Hangzhou City University,Hangzhou,Zhejiang 310000,China2.Department of Cell Biology,School of Basic Medical Sciences;Institute for Brain Tumors & Key Laboratory of Rare Metabolic Diseases;The Affiliated Cancer Hospital,Nanjing Medical University,Nanjing,Jiangsu 211166,China3.Department of Cancer Biology and Innovation,Guoke Ningbo Life and Health Industry Research Institute,Ningbo,Zhejiang 315000,China4.Department of Cancer Biology and Innovation,Guoke Ningbo Life and Health Industry Research Institute,Ningbo,Zhejiang 315000,China;Department of Biochemistry,Yong Loo Lin School of Medicine,National University of Singapore,Singapore 117545,Singapore;NUS Graduate School of Integrative Sciences and Technology,Singapore 117456,Singapore
摘要：Gastric cancer(GC)is a prevalent and devastating disease with a poor prognosis.The lack of biomarkers for early detection and effective targeted therapeutics for GC patients represents two major challenges.Through isobaric tags for relative and absolute quantitation(iTRAQ)coupled with liquid chromatography-tandem mass spectrometry(LC-MS/MS)phosphoproteomic analysis of 14 GC and gastric epithelial cell lines,we discovered the discoidin domain receptor tyrosine kinase 1(DDR1)as a top potential drug target out of 40 tyrosine kinases detected along with over 1 000 phosphoproteins profiled.The DDR1 protein and mRNA levels were upregulated in GC cells concurrent with DDR1 gene amplification.Immunohistochemistry staining of more than 200 clinical samples revealed that DDR1 was overexpressed in approximately 41％and 48％of the intestinal and diffuse types of GC cases,respectively,compared with only 3.5％in normal tissues.Higher DDR1 expression was associated with poor prognosis.In cellular models,DDR1 overexpression led to accelerated proliferation,invasion,and malignant transformation,putatively via inhibition of the Hippo pathway and consequent activation of YAP-TEAD target gene expression.Notably,DDR1-overexpressing GC cells exhibited high vulnerability to selective DDR1 inhibitors.The present study provides preclinical support for the application of DDR1-selective inhibitors in DDR1-overexpressing GC.
机标关键词：pathwayhippocancercontributesgastricinhibitingoverexpressionprogression
分类号：R735.2(消化系肿瘤)
论文发表日期：2025-09-30
在线出版日期：2025-12-01（本平台首次上网日期，不代表文献的发表时间）
页数：15( 500-514 )
英文信息