IL-13/IL-13RA2 signaling promotes colorectal cancer stem cell tumorigenesis by inducing ubiquitinated degradation of p53

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外文摘要：Cancer stem cells(CSCs)are considered tumor-initiating cells and the main drivers of disease progression.Targeting these rare cancer cells,however,remains challenging with respect to therapeutic benefit.Here,we report the up-regulation of IL-13RA2 expression in colorectal cancer(CRC)tissues and spheroid cells.The expression of IL-13RA2 was positively correlated with canonical stemness markers in CRC.We further demonstrated that the level of IL-13 was up-regulated in the serum of CRC patients.Biologically,recombinant IL-13(rIL-13)stimulation promoted the sphere formation,proliferation,and migration of CRC cells in vi-tro and enhanced tumorigenesis in vivo.This phenotype could be reversed by knocking down IL-13RA2.Mechanistically,IL-13 activated autophagy by inducing LC3Ⅰ/LC3Ⅱ transformation in CRC-CSCs,which was crucial for the biological functions of IL-13.We further demonstrated that IL-13RA2 acted as a modular link of the E3 ligase UBE3C and the substrate p53 protein,enhancing the interaction of UBE3C and p53,thereby inducing the K48-linked ubiquitination of p53.In conclusion,the IL-13/IL-13RA2 signaling cascade promotes CRC-CSC self-renewal and tumorigenesis by inducing p53 ubiquitination,adding an important layer to the connection between IL-13 and p53,which can be translated into novel targeted therapies.

外文关键词：

AutophagyColorectal cancer stem cellsIL-13/IL-13RA2 signalingp53Ubiquitinated degradation

作者：

Baoyu He、Jing Liang、Qianqian Qin、Yuqin Zhang、Shuo Shi、Jinghe Cao、Zhixin Zhang、Qingli Bie、Rou Zhao、Li Wei、Baogui Zhang、Bin Zhang

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作者单位：

Department of Laboratory Medicine,Affiliated Hospital of Jining Medical University,Jining Medical University,Jining,Shandong 272000,China

Postdoctoral Mobile Station of Shandong University of Traditional Chinese Medicine,Jinan,Shandong 250355,China

Department of Reproductive Medicine,Affiliated Hospital of Jining Medical University,Jining Medical University,Jining,Shandong 272000,China

Department of Gastrointestinal Surgery,Affiliated Hospital of Jining Medical University,Jining Medical University,Jining,Shandong 272000,China

Institute of Forensic Medicine and Laboratory Medicine,Jining Medical University,Jining,Shandong 272067,China

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基金：

国家自然科学基金国家自然科学基金国家自然科学基金中国博士后科学基金中国博士后科学基金Shandong Postdoctoral innovation project(China)Tai Shan Young Scholar Foundation of Shandong Province,ChinaShandong Provincial Natural Science Foundation(China)Shandong Provincial Natural Science Foundation(China)Shandong Provincial Natural Science Foundation(China)Youth Innovation Science and Technology Support Plan of Shandong Province's colleges and universities(China)Project of Medicine Health and Technology Development Plan of Shandong Province,ChinaProject of Medicine Health and Technology Development Plan of Shandong Province,ChinaMiaopu Research of the Affiliated Hospital of Jining Medical University,Shandong,ChinaMiaopu Research of the Affiliated Hospital of Jining Medical University,Shandong,ChinaPh.D.Research Foundation of the Affiliated Hospital of Jining Medical University,Shandong,ChinaResearch Fund for Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University,Shandon

项目编号：

8217337182273447822730692022M7113202022M711322SDCX-ZG-202201002tsqn201909192ZR2020YQ59ZR2021QH021ZR2021120200992021KJ017202103030586202103030411MP-ZD-2020-005MP-ZD-2021-0012022-BS-003JYHL2022FZD04

出版年：

2024

DOI：

10.1016/j.gendis.2023.01.027

基因与疾病(英文)

ISSN：

年,卷(期)：2024.11(1)

参考文献量44