TRIM37 Mediates Chemoresistance and Maintenance of Stemness in Pancreatic Cancer Cells via Ubiquitination of PTEN and Activation of the AKT-GSK-3β-β-Catenin Signaling Pathway.
TRIM37 Mediates Chemoresistance and Maintenance of Stemness in Pancreatic Cancer Cells via Ubiquitination of PTEN and Activation of the AKT-GSK-3β-β-Catenin Signaling Pathway.
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DOI：
10.3389/fonc.2020.554787
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发表时间：
2020
影响因子：
4.7
通讯作者：
Sun C
中科院分区：
文献类型：
--
作者：
Chen S;He Z;Zhu C;Liu Y;Li L;Deng L;Wang J;Yu C;Sun C
TRIM 37家族成员参与了许多重要的生物学和病理学过程，并且最近已被证明是蛋白质泛素化的重要调节剂和肿瘤发生的贡献者。我们先前表明TRIM 37在胰腺癌（PC）中过表达并促进其增殖和侵袭。进行球体形成、流式细胞术、qRT-PCR、western印迹、集落形成、EdU掺入、小鼠异种移植模型、TUNEL和IHC测定以检测TRIM 37在体外和体内PC的干性和化学抗性中的作用。使用生物信息学分析和双荧光素酶报告基因测定来确定哪些细胞内途径可能介导TRIM 37在PC细胞中的作用。采用免疫荧光（IF）、免疫共沉淀（CO-IP）、蛋白稳定性和泛素化分析等方法研究TRIM 37与PTEN的关系。TRIM 37调节肿瘤抑制剂磷酸酶和张力蛋白同源物（PTEN）的泛素化和降解，其负调节AKT-GSK-3β-β-连环蛋白信号传导途径，从而维持PC细胞的异常活化。TRIM 37的高表达与PTEN的低表达相结合与PC患者的不良生存相关。总的来说，我们的结果表明，抑制TRIM 37-AKT-GSK-3β-β-连环蛋白轴可能是治疗PC的有希望的策略。
The tripartite motif-containing family member TRIM37 is involved in a number of important biological and pathological processes, and it has recently been shown to be an essential regulator of protein ubiquitination and a contributor to tumorigenesis. We previously showed that TRIM37 is overexpressed in and promotes the proliferation and invasion of pancreatic cancer (PC). Sphere formation, flow cytometric, qRT-PCR, western blot, colony formation, EdU incorporation, mouse xenograft model, TUNEL and IHC assays were performed to detect the role of TRIM37 in stemness and chemoresistance of PC in vitro and in vivo. Bioinformatics analysis and dual-luciferase reporter assays were used to determine which intracellular pathways might mediate the effects of TRIM37 in PC cells. Immunofluorescent(IF) staining, co-immunoprecipitation(CO-IP), protein stability and ubiquitination assays were performed to investigate the relationship between TRIM37 and PTEN. TRIM37 modulates the ubiquitination and degradation of the tumor suppressor phosphatase and tensin homolog (PTEN), which negatively regulates the AKT–GSK-3β–β-catenin signaling pathway, thereby sustaining aberrant activation of PC cells. High expression of TRIM37 combined with low expression of PTEN correlates with poor survival of PC patients. Collectively, our results suggest that inhibition of the TRIM37–AKT–GSK-3β–β-catenin axis may be a promising strategy for treatment of PC.
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