Zhong Amy, Chang Melissa, Yu Theresa, Gau Raymond, Riley Daniel J, Chen Yumay, Chen Phang-Lang
Department of Medicine, Division of Endocrinology, University of California at Irvine.
Department of Medicine, Division of Nephrology, University of Texas Health San Antonio.
J Can Res Updates. 2018;7(3):64-74.
Higher cancer rates and more aggressive behavior of certain cancers have been reported in populations with diabetes mellitus. This association has been attributed in part to the excessive reactive oxygen species generated in diabetic conditions and to the resulting oxidative DNA damage. It is not known, however, whether oxidative stress is the only contributing factor to genomic instability in patients with diabetes or whether high glucose directly also affects DNA damage and repair pathways.
Normal renal epithelial cells and renal cell carcinoma cells are more chemo- and radiation resistant when cultured in high concentrations of glucose. In high glucose conditions, the CHK1-mediated DNA damage response is not activated properly. Cells in high glucose also have slower DNA repair rates and accumulate more mutations than cells grown in normal glucose concentrations. Ultimately, these cells develop a transforming phenotype.
In high glucose conditions, defective DNA damage responses most likely contribute to the higher mutation rate in renal epithelial cells, in addition to oxidative DNA damage. The DNA damage and repair are normal enzyme dependent mechanisms requiring euglycemic environments. Aberrant DNA damage response and repair in cells grown in high glucose conditions underscore the importance of maintaining good glycemic control in patients with diabetes mellitus and cancer.
据报道，糖尿病患者群体中某些癌症的发病率较高，且某些癌症的侵袭性更强。这种关联部分归因于糖尿病状态下产生的过量活性氧以及由此导致的氧化性DNA损伤。然而，尚不清楚氧化应激是否是糖尿病患者基因组不稳定的唯一促成因素，或者高血糖是否也直接影响DNA损伤和修复途径。
当在高浓度葡萄糖中培养时，正常肾上皮细胞和肾细胞癌细胞对化疗和放疗更具抗性。在高血糖条件下，CHK1介导的DNA损伤反应未被正确激活。与在正常葡萄糖浓度下生长的细胞相比，高血糖环境中的细胞DNA修复速率更慢，积累的突变更多。最终，这些细胞会形成转化表型。
在高血糖条件下，除了氧化性DNA损伤外，有缺陷的DNA损伤反应很可能导致肾上皮细胞的突变率升高。DNA损伤和修复是正常的酶依赖性机制，需要正常血糖环境。在高血糖条件下生长的细胞中异常的DNA损伤反应和修复突出了糖尿病合并癌症患者维持良好血糖控制的重要性。
