Novel role of LLGL2 silencing in autophagy: reversing epithelial-mesenchymal transition in prostate cancer.

IF 4.3 2区 生物学 Q1 BIOLOGY Biological Research Pub Date : 2024-05-08 DOI:10.1186/s40659-024-00499-w
Geum-Lan Hong, Kyung-Hyun Kim, Yae-Ji Kim, Hui-Ju Lee, Sung-Pil Cho, Seung-Yun Han, Seung Woo Yang, Jong-Soo Lee, Shin-Kwang Kang, Jae-Sung Lim, Ju-Young Jung
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Abstract

Purpose: Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo.

Methods: PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model.

Results: In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition.

Conclusion: Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.

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LLGL2沉默在自噬中的新作用:逆转前列腺癌的上皮-间质转化。
目的:前列腺癌(PCa)是一种主要的泌尿系统疾病,与男性严重的发病率和死亡率有关。LLGL2 是哺乳动物 Lgl 的同源物。它是乳腺癌和肝癌的肿瘤抑制因子。然而,LLGL2在PCa中的作用及其内在机制尚未阐明。在此,我们研究了LLGL2在PCa中通过体外和体内自噬调节上皮-间质转化(EMT)的作用:方法:用 siLLGL2 或质粒 LLGL2 转染 PC3 细胞并检测自噬。在自噬调控下,对 PC3 细胞的侵袭、迁移和伤口愈合进行了评估。使用 shLLGL2 异种移植小鼠模型评估肿瘤生长情况:结果:在PCa患者中,LLGL2水平较高,自噬缺陷和EMT增加。我们的研究结果表明,敲除LLGL2可通过上调Vps34和ATG14L诱导自噬通量。LLGL2敲除可通过上调E-cadherin、下调纤连蛋白和α-SMA来抑制EMT。雷帕霉素对自噬的药理激活抑制了EMT,而3-甲基腺嘌呤处理则逆转了这些效应。有趣的是,在shLLGL2异种移植小鼠模型中,肿瘤大小和EMT均有所减小,自噬诱导可改善肿瘤大小和EMT,而自噬抑制则会恶化肿瘤大小和EMT:结论:LLGL2表达缺陷会导致自噬通量上调,从而减轻PCa的EMT。我们的研究结果表明,LLGL2是通过调节自噬缓解PCa的一个新靶点。
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来源期刊
Biological Research
Biological Research 生物-生物学
CiteScore
10.10
自引率
0.00%
发文量
33
审稿时长
>12 weeks
期刊介绍: Biological Research is an open access, peer-reviewed journal that encompasses diverse fields of experimental biology, such as biochemistry, bioinformatics, biotechnology, cell biology, cancer, chemical biology, developmental biology, evolutionary biology, genetics, genomics, immunology, marine biology, microbiology, molecular biology, neuroscience, plant biology, physiology, stem cell research, structural biology and systems biology.
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