Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
EBioMedicine. 2019 Feb;40:92-105. doi: 10.1016/j.ebiom.2019.01.002. Epub 2019 Jan 20.
Ubiquinol-cytochrome C reductase core protein II (QCR2) is essential for mitochondrial functions, yet, its role in cancer development has remained elusive.
The expression of QCR2 in cancer patients was assessed by immunohistochemistry. The proliferation of cancer cells was assessed by CCK-8 assay, EdU staining and Flow cytometry analysis. The biological function of QCR2 and PHB were determined using western blotting, RT-qPCR, microarray analysis and xenografts. The interactions between proteins and the ubiquitination of p53 were assessed by immunoprecipitation, mass spectrometry analysis and GST pull down. The subcellular location of PHB and QCR2 was assessed by immunoblotting and immunofluorescence.
The expression of QCR2 is upregulated in multiple human tumors. Suppression of QCR2 inhibits cancer cell growth by activating p53 signaling and inducing p21-dependent cell cycle arrest and senescence. QCR2 directly interacts with PHB in the mitochondria. Overexpression of QCR2 inhibits PHB binding to p53 in the nucleus, and facilitates p53 ubiquitination and degradation, consequently leading to tumorigenesis. Also, increased QCR2 and decreased PHB protein levels are well correlated with decreased expression of p21 in cervical cancer tissues.
These results identify a novel role for QCR2, together with PHB, in negative regulation of p53 stability and activity, thus promote cervical carcinogenesis. FUND: "973" Program of China, the National Science-technology Supporting Plan Projects, the National Natural Science Foundation of China, National Science and Technology Major Sub-Project and Technical Innovation Special Project of Hubei Province.
泛醌细胞色素 C 还原酶核心蛋白 2（QCR2）对于线粒体功能至关重要，但它在癌症发展中的作用仍不清楚。
通过免疫组织化学评估癌症患者中 QCR2 的表达。通过 CCK-8 测定、EdU 染色和流式细胞术分析评估癌细胞的增殖。使用 Western blot、RT-qPCR、微阵列分析和异种移植确定 QCR2 和 PHB 的生物学功能。通过免疫沉淀、质谱分析和 GST 下拉评估蛋白质之间的相互作用和 p53 的泛素化。通过免疫印迹和免疫荧光评估 PHB 和 QCR2 的亚细胞定位。
QCR2 在多种人类肿瘤中表达上调。抑制 QCR2 通过激活 p53 信号通路和诱导 p21 依赖性细胞周期停滞和衰老来抑制癌细胞生长。QCR2 在线粒体中与 PHB 直接相互作用。QCR2 的过表达抑制 PHB 在核内与 p53 的结合，并促进 p53 泛素化和降解，从而导致肿瘤发生。此外，宫颈癌组织中 p21 表达降低与 QCR2 水平升高和 PHB 蛋白水平降低密切相关。
这些结果确定了 QCR2 与 PHB 一起在负调控 p53 稳定性和活性方面的新作用，从而促进宫颈癌的发生。资助：中国“973”计划、国家科技支撑计划项目、国家自然科学基金、国家科技重大专项和湖北省技术创新专项项目。
