LINC00941 promotes pancreatic cancer malignancy by interacting with ANXA2 and suppressing NEDD4L-mediated degradation of ANXA2.
LINC00941 promotes pancreatic cancer malignancy by interacting with ANXA2 and suppressing NEDD4L-mediated degradation of ANXA2.
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LINC00941 通过与 ANXA2 相互作用并抑制 NEDD4L 介导的 ANXA2 降解促进胰腺癌恶性肿瘤
DOI：
10.1038/s41419-022-05172-2
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发表时间：
2022-08-18
影响因子：
9
通讯作者：
Jiang, Jianxin
中科院分区：
文献类型：
--
作者：
Wang, Jie;He, Zhiwei;Liu, Xinyuan;Xu, Jian;Jiang, Xueyi;Quan, Gang;Jiang, Jianxin
最近，长链非编码rna （lncRNA）已被证明可调节胰腺癌（PC）的进展。我们旨在探讨LINC00941在PC中蛋白结合的发病机制。通过PCR分析，我们发现LINC00941在PC组织中过表达，并且在肝转移患者中高于无肝转移患者。此外，LINC00941高表达与预后不良相关。分别采用功能实验和小鼠模型对体外和体内PC细胞的增殖和迁移进行了评价。结果提示，LINC00941过表达可促进PC的增殖和转移。随后，采用RNA拉下、质谱（MS）和RNA结合蛋白免疫沉淀（RIP）鉴定linc00941相互作用蛋白。结果表明，ANXA2是潜在的linc00941相互作用蛋白。LINC00941的核苷酸500-1390可以结合到ANXA2的Annexin 1结构域。linc00941介导的PC恶性表型被ANXA2的缺失逆转。采用免疫共沉淀法（Co-IP）结合质谱法测定LINC00941的潜在相互作用蛋白。结果表明，参与泛素介导的蛋白降解的E3连接酶NEDD4L结合到ANXA2的Annexin 1结构域并促进其降解。机械地，LINC00941作为诱饵结合到ANXA2上，并通过封闭与NEDD4L结合的结构域抑制其降解。最终，LINC00941上调ANXA2，激活FAK/AKT信号，增加PC细胞的增殖和转移。本研究表明，LINC00941通过结合ANXA2并增强其稳定性，促进PC的增殖和转移，从而激活FAK/AKT信号。我们的数据表明，LINC00941可能作为预后和治疗的新靶点。
Recently, long non-coding RNAs (lncRNA) have been proven to regulate pancreatic cancer (PC) progression. We aimed to explore the pathogenesis of LINC00941 in PC regarding protein binding. By using PCR analysis, we found that LINC00941 was overexpressed in PC tissues and was higher in patients with liver metastasis than in patients without liver metastasis. In addition, high LINC00941 expression was associated with a poor prognosis. Functional experiments and mice models were respectively used to evaluate PC cell proliferation and migration in vitro and in vivo. The results suggested that LINC00941 overexpression promoted PC proliferation and metastasis. Subsequently, RNA pull-down, mass spectrometry (MS), and RNA-binding protein immunoprecipitation (RIP) were performed to identify LINC00941-interacting proteins. The results suggested that ANXA2 was the potential LINC00941-interacting protein. Nucleotides 500–1390 of LINC00941 could bind to the Annexin 1 domain of ANXA2. LINC00941-mediated malignant phenotype of PC was reversed by ANXA2 depletion. Co-immunoprecipitation (Co-IP) followed by MS was conducted to determine the potential interacting protein of LINC00941. The results illustrated that NEDD4L, an E3 ligase involved in ubiquitin-mediated protein degradation, bound to the Annexin 1 domain of ANXA2 and promoted its degradation. Mechanically, LINC00941 functioned as a decoy to bind to ANXA2 and suppressed its degradation by enclosing the domain that binds to NEDD4L. Eventually, LINC00941 upregulated ANXA2 and activated FAK/AKT signaling, increasing PC cell proliferation and metastasis. This study indicates that LINC00941 promotes PC proliferation and metastasis by binding ANXA2 and potentiating its stability, leading to the activation of FAK/AKT signaling. Our data demonstrate that LINC00941 may serve as a novel target for prognosis and therapy.
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影响因子：
64.5
作者：
Manning BD;Toker A
通讯作者：
Toker A
影响因子：
10.9
作者：
通讯作者：
--
DOI：
10.1007/s10555-021-09995-x
发表时间：
2021-09
期刊：
Cancer metastasis reviews
影响因子：
--
作者：
Sempere LF;Powell K;Rana J;Brock AA;Schmittgen TD
通讯作者：
Schmittgen TD
影响因子：
4.6
作者：
Ma K;Chen X;Liu W;Yang Y;Chen S;Sun J;Ma C;Wang T;Yang J
通讯作者：
Yang J
影响因子：
28.5
作者：
Reese M;Dhayat SA
通讯作者：
Dhayat SA