线粒体DNA控制区与结直肠癌相关性研究进展

Progress research on relationship between mitochondrial DNA displacement loop region and colorectal cancer

线粒体作为独立存在于细胞核外唯一具有DNA的代谢性细胞器,在结直肠癌的发生发展过程中起到重要的作用。而结直肠癌与线粒体DNA(mtDNA)的相关性研究亦层出不穷,mtDN控制区(D-loop)作为其转录与复制的起始位点成为该研究领域的热点之一。本文试从D-loop区的突变、多态性、甲基化、微卫星不稳定以及拷贝数改变等方面综述其与结直肠癌相关性研究进展。目前的研究证明肿瘤D-loop区突变的存在与不良预后相关,且可作为Ⅲ期结直肠癌患者术后辅助化疗效应的预测因子。高变区段1(HV1)中核苷酸16290T的次要单倍型和核苷酸16298T的频繁单倍型与结直肠癌的高生存率相关,其中16290位点的多态性被认定可作为结直肠癌预后的独立预测因子。该区域的去甲基化可能参与到mtDNA拷贝数和NADH脱氢酶亚单位2(ND-2)表达的调节,且其微卫星不稳定(mtMSI)与基于氟尿嘧啶的辅助化疗的耐药性及不良预后相关。D-loop区作为mtDNA的重要转录起始区域,深入而全面的研究势必有助于我们了解其在结直肠癌的发病以及进展过程中的作用,并进一步为临床的诊断、治疗提供指导。

Mitochondria,as the only metabolic organelles which exist independently of the cell nucleus with DNA,play an important role in the development and progression of colorectal cancer.There are many researches about the relationship between colorectal cancer and mitochondrial DNA(mtDNA)emerge in endlessly.As the starting site of transcription and replication,displacement loop region(D-loop)region becomes one of the hot spots among these researches.In this paper,we reviewed the progress research about the correlation between mutations,polymorphisms,methylation,microsatellite instability and copy number changes of D-loop region and colorectal cancer.Some studies have shown that the presence of tumor D-loop mutations are associated with poor prognosis and can be used as a predictor of postoperative adjuvant chemotherapy in patients with stage Ⅲ colorectal cancer.The frequent haplotypes of secondary haplotypes of nucleotide 16290T and the frequent haplotypes of nucleotide 16298T in hypervariable region 1(HV1)are associated with the high survival rates of colorectal cancer,and the polymorphism at position 16290 is identified as independent predictors of colorectal cancer prognosis.The demethylation of the D-loop region may be involved in the regulation of mtDNA copy number and nicotinamide adenine dinucleotide dehydrogenase subunit 2(ND-2)expression,and its microsatellite instability is associated with drug resistance and poor prognosis of the fluorouracil-based adjuvant chemotherapy.Due to D-loop region as an important transcriptional initiation region of mtDNA,the in-depth and comprehensive study will help us understand its role in the pathogenesis and progression of colorectal cancer,and further provide guidance for clinical diagnosis and treatment.