Rovcanin Branislav, Ivanovski Ivan, Djuric Olivera, Nikolic Dimitrije, Petrovic Jelena, Ivanovski Petar
Branislav Rovcanin, Institute for Human Genetics, Faculty of Medicine, University of Belgrade, Belgrade 11000, Serbia.
World J Gastroenterol. 2014 Sep 21;20(35):12522-5. doi: 10.3748/wjg.v20.i35.12522.
Mitotic crossover is a natural mechanism that is a main source of the genetic variability of primitive organisms. In complex organisms such as mammals, it represents an evolutionary rudiment which persisted as one of the numerous DNA repair mechanisms, and results in the production of homozygous allele combinations in all heterozygous genes located on the chromosome arm distal to the crossover. This event is familiar as loss of heterozygosity, which is one of the key mechanisms responsible for the development and progression of almost all cancers. We propose the hypothesis in which mitotic crossover is a principal source of the increased loss of heterozygosity that leads to the initiation and progression of colorectal carcinoma. The hypothesis could be tested by in vitro inhibition of Rad51 protein, orthotopic grafting of human colon cancer tissue into the gut of mice, and treatment with potential inhibitors. After these procedures, the frequency of mitotic crossover would be estimated. The development of selective inhibitors of mitotic crossover could stop further carcinogenesis of colorectal carcinoma, as well as many other neoplastic events. Loss of heterozygosity is an event responsible for carcinogenesis, its reduction by selective inhibitors of mitotic crossover could have a positive effect on cancer chemoprevention, as well as on growth reduction and a cessation in the progression of earlier developed tumors.
有丝分裂交换是一种自然机制，是原始生物遗传变异的主要来源。在诸如哺乳动物等复杂生物中，它代表了一种进化遗迹，作为众多DNA修复机制之一留存下来，并导致位于交换远端的染色体臂上的所有杂合基因产生纯合等位基因组合。这一事件即杂合性缺失，是几乎所有癌症发生和发展的关键机制之一。我们提出一个假说，即有丝分裂交换是导致结直肠癌发生和发展的杂合性增加缺失的主要来源。该假说可通过体外抑制Rad51蛋白、将人结肠癌组织原位移植到小鼠肠道以及用潜在抑制剂进行治疗来验证。经过这些操作后，将估计有丝分裂交换的频率。有丝分裂交换选择性抑制剂的开发可能会阻止结直肠癌以及许多其他肿瘤事件的进一步癌变。杂合性缺失是致癌的一个原因，通过有丝分裂交换选择性抑制剂降低杂合性缺失可能对癌症化学预防以及对早期形成肿瘤的生长抑制和进展停止产生积极影响。
