Department of Clinical Biochemistry, L. Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland.
Department of Clinical Biochemistry, L. Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland.
Free Radic Biol Med. 2021 Nov 20;176:257-264. doi: 10.1016/j.freeradbiomed.2021.10.004. Epub 2021 Oct 5.
The MTH1 (NUDT1) gene, because it is frequently upregulated in many types of human cancers, has been considered a general marker of carcinogenesis for over two decades. The MTH1 protein hydrolyzes the oxidized mutagenic DNA precursor, 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP), to the corresponding 5'-monophosphate and inorganic pyrophosphate. This prevents its incorporation into DNA by DNA polymerases and protects cells from the accumulation of 8-oxo-dGTP-induced point mutations. Elevated MTH1 mRNA and protein in many types of human cancer indicate a worse prognosis. However, the enzymatic activity of MTH1 has remained largely uninvestigated in this context. Therefore, we have set out to determine the specific 8-oxo-dGTPase activity of MTH1 in 57 pairs of human colorectal cancers (CRC) and adjacent cancer-free tissues (CFCF). The goal was to ascertain the potential for measuring this enzymatic activity as a way to differentiate cancerous from non-cancerous specimens of the intestine, as well as defining its capabilities as a prognostic value for disease-free survival. We found that 79% of CRC tumors exhibited a higher MTH1 activity than did CFCF, with a significant 1.6-fold increase in overall median value (p < 1E-6). The 8-oxo-dGTPase in both tissues was proportional to the corresponding levels of MTH1 protein, as assayed by Western blotting. Activity higher than the ROC-optimized threshold (AUC = 0.71) indicated cancerous tissue, with a 54% sensitivity and an 83% specificity. Postoperative fate followed for up to 100 months showed that higher 8-oxo-dGTPase, in either the CFCF or the CRC tumor, clearly lowered the probability of a relapse-free survival, although borderline statistical significance (p < 0.05) was crossed only for the CFCF.
MTH1（NUDT1）基因在许多类型的人类癌症中经常过表达，因此被认为是致癌作用的一般标志物已有二十多年了。MTH1 蛋白将氧化的诱变 DNA 前体 8-氧代-7,8-二氢-2'-脱氧鸟苷 5'-三磷酸（8-oxo-dGTP）水解为相应的 5'-单磷酸和无机焦磷酸。这可防止 DNA 聚合酶将其掺入 DNA 中，并防止细胞中积累 8-oxo-dGTP 诱导的点突变。许多类型的人类癌症中升高的 MTH1mRNA 和蛋白预示着预后较差。然而，在这种情况下，MTH1 的酶活性在很大程度上尚未得到研究。因此，我们着手确定 57 对人结直肠癌（CRC）和相邻无癌组织（CFCF）中 MTH1 的特定 8-oxo-dGTP 酶活性。目的是确定测量这种酶活性作为区分癌性和非癌性肠组织的方法的潜力，并定义其作为无病生存预后价值的能力。我们发现，79%的 CRC 肿瘤的 MTH1 活性高于 CFCF，总体中位数值增加了 1.6 倍（p<1E-6）。Western blot 分析表明，两种组织中的 8-oxo-dGTP 酶与相应的 MTH1 蛋白水平成正比。高于 ROC 优化阈值（AUC=0.71）的活性表明为癌组织，其敏感性为 54%，特异性为 83%。术后随访时间长达 100 个月，结果表明，无论是 CFCF 还是 CRC 肿瘤中的较高 8-oxo-dGTP 酶活性，均明显降低了无复发生存的可能性，尽管仅 CFCF 跨越了边界统计学意义（p<0.05）。
