PHB2 promotes SHIP2 ubiquitination via the E3 ligase NEDD4 to regulate AKT signaling in gastric cancer.
PHB2 promotes SHIP2 ubiquitination via the E3 ligase NEDD4 to regulate AKT signaling in gastric cancer.
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DOI：
10.1186/s13046-023-02937-1
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发表时间：
2024-01-11
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影响因子：
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Prohibitin 2（PHB 2）在各种癌症类型中表现出促进或抑制肿瘤的相反功能。在这项研究中，我们的目的是探讨其功能和潜在的机制，在胃癌（GC）的背景下。采用免疫印迹法和免疫组化法检测胃癌组织和正常胃黏膜组织中PHB 2蛋白的表达水平。使用GEO数据集（GSE 14210和GSE 29272），通过Kaplan-Meier绘图仪分析，检查PHB 2表达水平与患者结局的相关性。PHB 2的生物学作用及其随后的调节机制在体外和体内被阐明。使用MTT细胞活力分析、克隆形成试验和BrdU掺入试验评估GC细胞活力和增殖，同时通过Ki 67的IHC染色测量GC异种移植肿瘤的生长。PHB 2与SHIP 2之间以及SHIP 2与NEDD 4之间的相互作用通过免疫共沉淀、GST下拉试验和缺失定位实验进行了鉴定。采用放线菌酮处理、质粒转染和免疫共沉淀，随后进行蛋白质印迹分析，评估SHIP 2泛素化和降解。我们的分析显示，与邻近的正常组织相比，胃癌组织中的PHB 2表达显著增加。值得注意的是，较高的PHB 2水平与较差的患者结局相关，表明其具有临床意义。在功能上，沉默GC细胞中的PHB 2显著降低了细胞增殖并延缓了GC肿瘤的生长，而过表达PHB 2进一步增强了GC细胞增殖。PHB 2与胃癌细胞质中的含Src同源2的肌醇5-磷酸酶2（SHIP 2）发生物理相互作用，通过其新的E3连接酶NEDD 4降解SHIP 2。随后激活PI 3 K/Akt信号通路，从而促进GC细胞增殖。我们的研究结果强调了PHB 2上调在推动GC进展中的重要性及其与不良患者结局的相关性。了解PHB 2对GC生长的功能影响有助于对GC的分子基础有价值的见解，并可能为开发靶向治疗以改善患者结局铺平道路。在线版本包含补充材料，可通过10.1186/s13046-023-02937-1获得。
Prohibitin 2 (PHB2) exhibits opposite functions of promoting or inhibiting tumour across various cancer types. In this study, we aim to investigate its functions and underlying mechanisms in the context of gastric cancer (GC). PHB2 protein expression levels in GC and normal tissues were examined using western blot and immunohistochemistry. PHB2 expression level associations with patient outcomes were examined through Kaplan–Meier plotter analysis utilizing GEO datasets (GSE14210 and GSE29272). The biological role of PHB2 and its subsequent regulatory mechanisms were elucidated in vitro and in vivo. GC cell viability and proliferation were assessed using MTT cell viability analysis, clonogenic assays, and BrdU incorporation assays, while the growth of GC xenografted tumours was measured via IHC staining of Ki67. The interaction among PHB2 and SHIP2, as well as between SHIP2 and NEDD4, was identified through co-immunoprecipitation, GST pull-down assays, and deletion-mapping experiments. SHIP2 ubiquitination and degradation were assessed using cycloheximide treatment, plasmid transfection and co-immunoprecipitation, followed by western blot analysis. Our analysis revealed a substantial increase in PHB2 expression in GC tissues compared to adjacent normal tissues. Notably, higher PHB2 levels correlated with poorer patient outcomes, suggesting its clinical relevance. Functionally, silencing PHB2 in GC cells significantly reduced cell proliferation and retarded GC tumour growth, whereas overexpression of PHB2 further enhanced GC cell proliferation. Mechanistically, PHB2 physically interacted with Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) in the cytoplasm of GC cells, thus leading to SHIP2 degradation via its novel E3 ligase NEDD4. It subsequently activated the PI3K/Akt signaling pathway and thus promoted GC cell proliferation. Our findings highlight the importance of PHB2 upregulation in driving GC progression and its association with adverse patient outcomes. Understanding the functional impact of PHB2 on GC growth contributes valuable insights into the molecular underpinnings of GC and may pave the way for the development of targeted therapies to improve patient outcomes. The online version contains supplementary material available at 10.1186/s13046-023-02937-1.
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DOI：
10.1016/j.bbrc.2013.12.124
发表时间：
2014-01-24
影响因子：
3.1
作者：
Guan, Xiaoxiang;Liu, Zhensheng;Wang, Luo;Johnson, David G.;Wei, Qingyi
通讯作者：
Wei, Qingyi
DOI：
10.1111/j.1582-4934.2006.tb00404.x
发表时间：
2006-04
影响因子：
5.3
作者：
Mishra S;Murphy LC;Murphy LJ
通讯作者：
Murphy LJ
禁止素2位于核仁中，以调节核糖体RNA转录并促进RD细胞中的细胞增殖。
影响因子：
4.6
作者：
Zhou Z;Ai H;Li K;Yao X;Zhu W;Liu L;Yu C;Song Z;Bao Y;Huang Y;Wu Y;Zheng L;Sun Y;Wang G;Ma K;Sun L;Li Y
通讯作者：
Li Y
DOI：
10.1186/s13046-023-02695-0
发表时间：
2023-05-20
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
通讯作者：
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影响因子：
4.8
作者：
French, Michael E.;Klosowiak, Julian L.;Hunter, Tony
通讯作者：
Hunter, Tony