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.
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MDM2 通过调节视网膜母细胞瘤中 HIF-1α 和 pVHL 的表达促进癌细胞存活
DOI：
10.3389/pore.2023.1610801
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发表时间：
2023
影响因子：
2.8
通讯作者：
Chai, Yong
中科院分区：
文献类型：
--
作者：
Zhang, Shouhua;Xu, Hongyan;Li, Weiming;Ji, Jianfeng;Jin, Qifang;Chen, Leifeng;Gan, Qiang;Tao, Qiang;Chai, Yong
缺氧是一种重要的肿瘤特征，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。小鼠双微体2同源物（MDM 2）促进视网膜母细胞瘤（RB）中的癌细胞存活，其潜在机制仍然难以捉摸。本研究探讨了MDM 2在RB中的作用及其与HIF-1α的关系。原代RB组织中MDM 2的表达与HIF-1α的表达呈正相关，与HIF-1α的调节因子von Hippel-Lindau蛋白（pVHL）呈负相关。与此一致的是，在缺氧条件下，MDM 2过表达的RB细胞显示出HIF-1α表达增加和pVHL表达减少，而MDM 2 siRNA敲除或MDM 2特异性抑制剂的细胞显示出相反的效果。进一步免疫沉淀分析显示MDM 2可直接与pVHL相互作用，促进其泛素化和降解，从而导致HIF-1α表达增加。用特异性抑制剂抑制MDM 2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MDM 2通过调节pVHL和HIF-1α的表达来促进RB的存活，并且靶向MDM 2和/或HIF-1α代表了RB治疗的潜在有效方法。
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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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
3.8
作者：
Park KS;Kim JH;Shin HW;Chung KS;Im DS;Lim JH;Jung CR
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Jung CR
影响因子：
16.8
作者：
Nomura K;Klejnot M;Kowalczyk D;Hock AK;Sibbet GJ;Vousden KH;Huang DT
通讯作者：
Huang DT
影响因子：
4.2
作者：
Dimaras H;Corson TW
通讯作者：
Corson TW
影响因子：
11.2
作者：
Jeong, Hoibin;Kim, Sehui;Ahn, G-One
通讯作者：
Ahn, G-One