Nuclear-encoded cytochrome c oxidase subunit 4 regulates BMI1 expression and determines proliferative capacity of high-grade gliomas.
Nuclear-encoded cytochrome c oxidase subunit 4 regulates BMI1 expression and determines proliferative capacity of high-grade gliomas.
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DOI：
10.18632/oncotarget.3015
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发表时间：
2015-02-28
期刊：
影响因子：
--
通讯作者：
Griguer CE
中科院分区：
文献类型：
--
作者：
Oliva CR;Markert T;Gillespie GY;Griguer CE
核编码细胞色素c氧化酶亚基4 （COX4）是哺乳动物细胞色素c氧化酶的关键调控亚基，最近的研究表明，COX4异构体1 （COX4-1）可能在胶质瘤化疗耐药中发挥作用。Polycomb复合物蛋白BMI1是一种干细胞调控基因，与许多侵袭性癌症（包括胶质瘤）的发病机制有关。本研究试图确定COX4是否调节BMI1并调节肿瘤细胞增殖。利用癌症基因组图谱数据库和多形性胶质母细胞瘤患者的回顾性数据集，我们发现BMI1表达水平与COX4-1表达和总生存率呈正相关。COX4-1通过增加BMI1表达促进细胞生长，而COX4-2即使在过表达BMI1的细胞中也能抑制细胞生长。我们还证明，COX4-1降低线粒体活性氧（ROS）的产生，这是COX4-1介导的BMI1表达和细胞增殖效应所必需的。值得注意的是，携带表达COX4-1的胶质瘤细胞异种移植物的小鼠迅速发展为侵袭性肿瘤，其特征是存在Ki-67， BMI1和COX4-1阳性的多个病变，而携带表达cox4 -2的异种移植物的小鼠则很少发生肿瘤。COX4-1还能促进胶质瘤干细胞样细胞的自我更新，这与BMI1在干细胞生长中的作用一致。综上所述，这些发现确定了一个新的COX4-1线粒体ROS轴，其中COX4异构体的差异表达调节线粒体ROS的产生并控制BMI1的表达。
Nuclear-encoded cytochrome c oxidase subunit 4 (COX4) is a key regulatory subunit of mammalian cytochrome c oxidase, and recent studies have demonstrated that COX4 isoform 1 (COX4-1) could have a role in glioma chemoresistance. The Polycomb complex protein BMI1 is a stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including glioma. This study sought to determine if COX4 regulates BMI1 and modulates tumor cell proliferation. Using The Cancer Genome Atlas database and a retrospective data set from patients with glioblastoma multiforme, we found that BMI1 expression levels positively correlated with COX4-1 expression and overall survival. Whereas COX4-1 promoted cell growth by increasing BMI1 expression, COX4-2 inhibited cell growth even in cells overexpressing BMI1. We also demonstrate that COX4-1 attenuates mitochondrial reactive oxygen species (ROS) production, which is required for COX4-1-mediated effects on BMI1 expression and cell proliferation. Notably, mice bearing COX4-1-expressing glioma cell xenografts quickly developed invasive tumors characterized by the presence of multiple lesions positive for Ki-67, BMI1, and COX4-1, whereas mice bearing COX4-2-expressing xenografts rarely developed tumors by this point. COX4-1 also promoted the self-renewal of glioma stem-like cells, consistent with the reported role of BMI1 in stem cell growth. Taken together, these findings identify a novel COX4-1-mitochondrial ROS axis, in which differential expression of COX4 isoforms regulates mitochondrial ROS production and controls BMI1 expression.
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影响因子：
3.7
作者：
Griguer CE;Oliva CR;Gobin E;Marcorelles P;Benos DJ;Lancaster JR Jr;Gillespie GY
通讯作者：
Gillespie GY
影响因子：
3.5
作者：
Cenci, Tonia;Martini, Maurizio;Larocca, Luigi Maria
通讯作者：
Larocca, Luigi Maria
影响因子：
5.3
作者：
Abdouh, Mohamed;Facchino, Sabrina;Bernier, Gilbert
通讯作者：
Bernier, Gilbert
影响因子：
51.1
作者：
Berger, F;Gay, E;Wion, D
通讯作者：
Wion, D
影响因子：
11.2
作者：
Godlewski, Jakub;Nowicki, Michal O.;Lawler, Sean
通讯作者：
Lawler, Sean