MDM2通过调节HIF-1α和pVHL在视网膜母细胞瘤中的表达促进癌细胞存活。

IF 2.3 4区 医学 Q3 ONCOLOGY
Shouhua Zhang, Hongyan Xu, Weiming Li, Jianfeng Ji, Qifang Jin, Leifeng Chen, Qiang Gan, Qiang Tao, Yong Chai
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引用次数: 3

摘要

缺氧是肿瘤的重要特征,而缺氧诱导因子1 (HIF-1)是细胞对缺氧反应的主要调节因子。小鼠双分钟2同源物(MDM2)促进视网膜母细胞瘤(RB)的癌细胞存活,其潜在机制尚不清楚。在本研究中,我们探讨了MDM2在RB中的作用及其与HIF-1α的关系。原代人RB样品的表达分析显示,MDM2的表达与HIF-1α呈正相关,而与HIF-1α的调控因子pVHL呈负相关。与此一致的是,MDM2过表达的RB细胞HIF-1α表达增加,pVHL表达降低,而MDM2 siRNA敲低或MDM2特异性抑制剂的细胞在缺氧条件下表现出相反的作用。进一步的免疫沉淀分析显示MDM2可以直接与pVHL相互作用,促进其泛素化和降解,从而导致HIF-1α升高。用特异性抑制剂抑制MDM2和/或HIF-1α可诱导RB细胞死亡并降低原代RB细胞的干细胞特性。综上所述,我们的研究表明MDM2通过调节pVHL和HIF-1α的表达来促进RB的生存,靶向MDM2和/或HIF-1α是治疗RB的潜在有效途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

MDM2 promotes cancer cell survival through regulating the expression of HIF-1α and pVHL in retinoblastoma.

MDM2 promotes cancer cell survival through regulating the expression of HIF-1α and pVHL in retinoblastoma.

MDM2 promotes cancer cell survival through regulating the expression of HIF-1α and pVHL in retinoblastoma.

MDM2 promotes cancer cell survival through regulating the expression of HIF-1α and pVHL in retinoblastoma.

Hypoxia is an important tumor feature and hypoxia-inducible factor 1 (HIF-1) is a master regulator of cell response to hypoxia. Mouse double minute 2 homolog (MDM2) promotes cancer cell survival in retinoblastoma (RB), with the underlying mechanism remaining elusive. In this study, we investigated the role of MDM2 and its relation to HIF-1α in RB. Expression analysis on primary human RB samples showed that MDM2 expression was positively correlated with that of HIF-1α while negatively correlated with von Hippel-Lindau protein (pVHL), the regulator of HIF-1α. In agreement, RB cells with MDM2 overexpression showed increased expression of HIF-1α and decreased expression of pVHL, while cells with MDM2 siRNA knockdown or MDM2-specific inhibitor showed the opposite effect under hypoxia. Further immuno-precipitation analysis revealed that MDM2 could directly interact with pVHL and promotes its ubiquitination and degradation, which consequently led to the increase of HIF-1α. Inhibition of MDM2 and/or HIF-1α with specific inhibitors induced RB cell death and decreased the stem cell properties of primary RB cells. Taken together, our study has shown that MDM2 promotes RB survival through regulating the expression of pVHL and HIF-1α, and targeting MDM2 and/or HIF-1α represents a potential effective approach for RB treatment.

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来源期刊
CiteScore
6.30
自引率
0.00%
发文量
134
审稿时长
4-8 weeks
期刊介绍: Pathology & Oncology Research (POR) is an interdisciplinary Journal at the interface of pathology and oncology including the preclinical and translational research, diagnostics and therapy. Furthermore, POR is an international forum for the rapid communication of reviews, original research, critical and topical reports with excellence and novelty. Published quarterly, POR is dedicated to keeping scientists informed of developments on the selected biomedical fields bridging the gap between basic research and clinical medicine. It is a special aim for POR to promote pathological and oncological publishing activity of colleagues in the Central and East European region. The journal will be of interest to pathologists, and a broad range of experimental and clinical oncologists, and related experts. POR is supported by an acknowledged international advisory board and the Arányi Fundation for modern pathology.
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