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

查看全文 作　　者：Baoyu [1,2]He;Jing [1]Liang;Qianqian [3]Qin;Yuqin [1]Zhang;Shuo [1]Shi;Jinghe [3]Cao;Zhixin [4]Zhang;Qingli [1,2]Bie;Rou [1]Zhao;Li [1]Wei;Baogui [4]Zhang;Bin [1,2,5]Zhang 高影响力作者 机构地区：[1]Department of Laboratory Medicine,Affiliated Hospital of Jining Medical University,Jining Medical University,Jining,Shandong 272000,China;[2]Postdoctoral Mobile Station of Shandong University of Traditional Chinese Medicine,Jinan,Shandong 250355,China;[3]Department of Reproductive Medicine,Affiliated Hospital of Jining Medical University,Jining Medical University,Jining,Shandong 272000,China;[4]Department of Gastrointestinal Surgery,Affiliated Hospital of Jining Medical University,Jining Medical University,Jining,Shandong 272000,China;[5]Institute of Forensic Medicine and Laboratory Medicine,Jining Medical University,Jining,Shandong 272067,China高影响力机构 出　　处：《Genes & Diseases》索引2024年第11卷第1期,共14页高影响力期刊 基　　金：supported by the National Natural Science Foundation of China(No.82173371,82273447,82273069);the project funded by China Postdoctoral Science Foundation(No.2022M711320,2022M711322);Shandong Postdoctoral innovation project(China)(No.SDCX-ZG202201002);Tai Shan Young Scholar Foundation of Shandong Province,China(No.tsqn201909192);Shandong Provincial Natural Science Foundation(China)(No.ZR2020YQ59,ZR2021QH021,ZR202112020099);Youth Innovation Science and Technology Support Plan of Shandong Province’s colleges and universities(China)(No.2021KJ017);the Project of Medicine Health and Technology Development Plan of Shandong Province,China(No.202103030586 and 202103030411);the Miaopu Research of the Affiliated Hospital of Jining Medical University,Shandong,China(No.MP-ZD-2020-005 and MP-ZD-2021-001);Ph.D.Research Foundation of the Affiliated Hospital of Jining Medical University,Shandong,China(No.2022-BS003);Research Fund for Lin He’s Academician Workstation of New Medicine and Clinical Translation in Jining Medical University,Shandong,China(No.JYHL2022FZD04). 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(rIL13)stimulation promoted the sphere formation,proliferation,and migration of CRC cells in vitro 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. 关 键 词：Autophagy Colorectal cancer stem cells IL-13/IL-13RA2 signaling P53
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