Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic.
Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, 140 59 Prague, Czech Republic.
Int J Mol Sci. 2022 May 20;23(10):5704. doi: 10.3390/ijms23105704.
Oxidative stress, oxidative DNA damage and resulting mutations play a role in colorectal carcinogenesis. Impaired equilibrium between DNA damage formation, antioxidant status, and DNA repair capacity is responsible for the accumulation of genetic mutations and genomic instability. The lesion-specific DNA glycosylases, e.g., hOGG1 and MUTYH, initiate the repair of oxidative DNA damage. Hereditary syndromes (MUTYH-associated polyposis, NTHL1-associated tumor syndrome) with germline mutations causing a loss-of-function in base excision repair glycosylases, serve as straight forward evidence on the role of oxidative DNA damage and its repair. Altered or inhibited function of above glycosylases result in an accumulation of oxidative DNA damage and contribute to the adenoma-adenocarcinoma transition. Oxidative DNA damage, unless repaired, often gives rise G:C > T:A mutations in tumor suppressor genes and proto-oncogenes with subsequent occurrence of chromosomal copy-neutral loss of heterozygosity. For instance, G>T transversions in position c.34 of a KRAS gene serves as a pre-screening tool for MUTYH-associated polyposis diagnosis. Since sporadic colorectal cancer represents more complex and heterogenous disease, the situation is more complicated. In the present study we focused on the roles of base excision repair glycosylases (hOGG1, MUTYH) in colorectal cancer patients by investigating tumor and adjacent mucosa tissues. Although we found downregulation of both glycosylases and significantly lower expression of hOGG1 in tumor tissues, accompanied with G>T mutations in KRAS gene, oxidative DNA damage and its repair cannot solely explain the onset of sporadic colorectal cancer. In this respect, other factors (especially microenvironment) per se or in combination with oxidative DNA damage warrant further attention. Base excision repair characteristics determined in colorectal cancer tissues and their association with disease prognosis have been discussed as well.
氧化应激、氧化 DNA 损伤及其导致的突变在结直肠癌的发生中起作用。DNA 损伤形成、抗氧化状态和 DNA 修复能力之间的平衡受损，导致遗传突变和基因组不稳定性的积累。特定于损伤的 DNA 糖苷酶，例如 hOGG1 和 MUTYH，启动氧化 DNA 损伤的修复。伴有碱基切除修复糖苷酶功能丧失的遗传综合征（MUTYH 相关息肉病、NTHL1 相关肿瘤综合征），为氧化 DNA 损伤及其修复的作用提供了直接证据。上述糖苷酶的功能改变或抑制导致氧化 DNA 损伤的积累，并有助于腺瘤-腺癌的转化。除非修复，氧化 DNA 损伤通常会导致肿瘤抑制基因和原癌基因中的 G:C>T:A 突变，随后发生染色体拷贝中性杂合性丢失。例如，KRAS 基因位置 c.34 处的 G>T 颠换可作为 MUTYH 相关息肉病诊断的预筛选工具。由于散发性结直肠癌代表更复杂和异质性的疾病，情况更为复杂。在本研究中，我们通过研究肿瘤和相邻粘膜组织，重点研究了碱基切除修复糖苷酶（hOGG1、MUTYH）在结直肠癌患者中的作用。尽管我们发现两种糖苷酶均下调，且 hOGG1 在肿瘤组织中的表达明显降低，同时伴有 KRAS 基因的 G>T 突变，但氧化 DNA 损伤及其修复不能单独解释散发性结直肠癌的发生。在这方面，其他因素（尤其是微环境）本身或与氧化 DNA 损伤结合，值得进一步关注。还讨论了在结直肠癌组织中确定的碱基切除修复特征及其与疾病预后的关系。
