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RASAL2 介导增强 YAP1/TIAM1 信号通路促进胰腺导管腺癌的恶性表型。

RASAL2 mediated the enhancement of YAP1/TIAM1 signaling promotes malignant phenotypes of pancreatic ductal adenocarcinoma.

机构信息

Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.

Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.

出版信息

Int J Biol Sci. 2022 Jun 27;18(10):4245-4259. doi: 10.7150/ijbs.72204. eCollection 2022.

DOI:10.7150/ijbs.72204
PMID:35844783
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9274491/
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a high incidence of metastasis and dismal prognosis. As a member of Gas-Gap gene, RASAL2 is involved in the hydrolysis of RAS-GTP to RAS-GDP and abnormal expression in human cancers. Here we firstly described the function of RASAL2 on PDAC to enrich the knowledge of RAS family.We interestingly observed that RASAL2 expression was upregulated in PDAC at both mRNA and protein levels, and high expression of RASAL2 predicted a poor prognosis in PDAC patients. Additionally, RASAL2 promoted malignant behaviors of PDAC in vitro and in vivo. To determine the mechanistic roles of RASAL2 signaling and its potential as a therapeutic target in PDAC, we clarified that RASAL2 could accumulate the TIAM1 expression in different level through inhibiting YAP1 phosphorylation, increased TIAM1 mRNA expression and suppressed ubiquitination of TIAM1 protein. In conclusion, RASAL2 enhances YAP1/TIAM1 signaling and promotes PDAC development and progression.

摘要

胰腺导管腺癌 (PDAC) 的特点是转移发生率高，预后不良。作为 Gas-Gap 基因家族的一员，RASAL2 参与 RAS-GTP 的水解为 RAS-GDP，并且在人类癌症中异常表达。在这里，我们首次描述了 RASAL2 在 PDAC 中的功能，丰富了 RAS 家族的知识。我们有趣地观察到，RASAL2 在 PDAC 中的 mRNA 和蛋白水平均上调，并且 RASAL2 的高表达预示着 PDAC 患者预后不良。此外，RASAL2 促进了 PDAC 的体外和体内恶性行为。为了确定 RASAL2 信号的机制作用及其作为 PDAC 治疗靶点的潜力，我们阐明 RASAL2 可以通过抑制 YAP1 磷酸化在不同水平上积累 TIAM1 表达，增加 TIAM1 mRNA 表达并抑制 TIAM1 蛋白的泛素化。总之，RASAL2 增强了 YAP1/TIAM1 信号，促进了 PDAC 的发展和进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ce/9274491/c23d1e15df57/ijbsv18p4245g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ce/9274491/c23d1e15df57/ijbsv18p4245g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/48ce/9274491/c23d1e15df57/ijbsv18p4245g008.jpg

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本文引用的文献

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Hippo Signaling in Embryogenesis and Development.Hippo 信号通路在胚胎发生和发育中的作用。
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Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma.多学科护理标准和胰腺导管腺癌的最新进展。
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High Tiam1 expression predicts positive lymphatic metastasis and worse survival in patients with malignant solid tumors: a systematic review and meta-analysis.高Tiam1表达预示恶性实体瘤患者发生阳性淋巴转移及较差的生存率：一项系统评价和荟萃分析。
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