Mitochondrial determinants of cancer health disparities.
Mitochondrial determinants of cancer health disparities.
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DOI：
10.1016/j.semcancer.2017.05.001
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发表时间：
2017-12
影响因子：
14.5
通讯作者：
Singh KK
中科院分区：
文献类型：
--
作者：
Choudhury AR;Singh KK
线粒体参与能量的产生、细胞生长和分化、细胞信号传导、细胞周期控制和细胞死亡。迄今为止，癌症差异的线粒体基础尚不清楚。这篇综述的目的是提供一个理解和线粒体决定因素的框架，可能有助于癌症的种族差异不同的人群。线粒体是多功能的，与转化细胞中的代谢改变有关，涉及癌症的起始和进展。由于基于种族的多样性，线粒体基因组（mtDNA）可能是遗传种族差异和肿瘤发生过程中获得性体细胞突变的基础。在非裔美国人中，线粒体DNA中的几种种系、群体特异性单倍型变异以及线粒体DNA的缺失与癌症易感性和癌症差异有关。事实上，线粒体DNA的缺失和线粒体DNA或核基因组（nDNA）编码的线粒体蛋白的突变导致线粒体功能障碍并促进对细胞凋亡、上皮-间充质转化和转移性疾病的抗性，这反过来可以导致与种族差异相关的癌症差异和肿瘤侵袭性。编码线粒体蛋白质组的nDNA（包括mtDNA复制和修复蛋白、miRNA、转录因子、激酶和磷酸酶以及肿瘤抑制因子和癌基因）的表达水平或遗传变异的种族差异可能是非裔美国人和其他种族对高风险和侵袭性癌症易感性的基础。线粒体逆行信号改变核基因的表达谱，以响应功能失调的线粒体是肿瘤发生的机制。在种族人群中，线粒体功能的差异可能会改变线粒体和细胞核之间在表观遗传和遗传水平上的相互作用，这也可能导致癌症健康差异。靶向线粒体决定簇和线粒体逆行信号传导可以为开发用于处理癌症差异的选择性抗癌治疗提供有希望的策略。此外，将线粒体功能恢复到最佳水平的药物应允许对抗癌药物的敏感性，以治疗发生在种族多样性人群中的侵袭性肿瘤，从而有助于减少种族差异。
Mitochondria are involved in the generation of energy, cell growth and differentiation, cellular signaling, cell cycle control, and cell death. To date, the mitochondrial basis of cancer disparities is unknown. The goal of this review is to provide an understanding and a framework of mitochondrial determinants that may contribute to cancer disparities in racially different populations. Mitochondria, which are multi-functional, have been implicated in the initiation and progression of cancers in relation to metabolic alterations in transformed cells. Due to ethnic-based diversity, the mitochondrial genome (mtDNA) could be a basis for inherited racial disparities and for acquired somatic mutations during tumorigenesis. In African Americans, several germline, population-specific haplotype variants in mtDNA as well as depletion of mtDNA have been linked to cancer predisposition and cancer disparities. Indeed, depletion of mtDNA and mutations in mtDNA or nuclear genome (nDNA)-encoded mitochondrial proteins lead to mitochondrial dysfunction and promote resistance to apoptosis, the epithelial-to-mesenchymal transition, and metastatic disease, which in turn can contribute to cancer disparity and tumor aggressiveness related to racial disparities. Ethnic differences at the level of expression or genetic variations in nDNA encoding the mitochondrial proteome, including mitochondria-localized mtDNA replication and repair proteins, miRNA, transcription factors, kinases and phosphatases, and tumor suppressors and oncogenes may underlie susceptibility to high-risk and aggressive cancers found in African Americans and other ethnicities. The mitochondrial retrograde signaling that alters the expression profile of nuclear genes in response to dysfunctional mitochondria is a mechanism for tumorigenesis. In ethnic populations, differences in mitochondrial function may alter the cross talk between mitochondria and the nucleus at epigenetic and genetic levels, which can also contribute to cancer health disparities. Targeting mitochondrial determinants and mitochondrial retrograde signaling could provide a promising strategy for the development of selective anticancer therapy for dealing with cancer disparities. Further, agents that restore mitochondrial function to optimal levels should permit sensitivity to anticancer agents for the treatment of aggressive tumors that occur in racially diverse populations and hence help in reducing racial disparities.
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