Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, Georgia.
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas.
Mol Cancer Res. 2021 Sep;19(9):1486-1497. doi: 10.1158/1541-7786.MCR-20-0780. Epub 2021 Jun 7.
DNA damage, induced by either chemical carcinogens or environmental pollutants, plays an important role in the initiation of colorectal cancer. DNA repair processes, however, are involved in both protecting against cancer formation, and also contributing to cancer development, by ensuring genomic integrity and promoting the efficient DNA repair in tumor cells, respectively. Although DNA repair pathways have been well exploited in the treatment of breast and ovarian cancers, the role of DNA repair processes and their therapeutic efficacy in colorectal cancer is yet to be appreciably explored. To understand the role of DNA repair, especially homologous recombination (HR), in chemical carcinogen-induced colorectal cancer growth, we unraveled the role of RAD51AP1 (RAD51-associated protein 1), a protein involved in HR, in genotoxic carcinogen (azoxymethane, AOM)-induced colorectal cancer. Although AOM treatment alone significantly increased expression, the combination of AOM and dextran sulfate sodium (DSS) treatment dramatically increased by several folds. RAD51AP1 expression is found in mouse colonic crypt and proliferating cells. expression is significantly increased in majority of human colorectal cancer tissues, including BRAF/KRAS mutant colorectal cancer, and associated with reduced treatment response and poor prognosis. -deficient mice were protected against AOM/DSS-induced colorectal cancer. These observations were recapitulated in a genetically engineered mouse model of colorectal cancer ( ). Furthermore, chemotherapy-resistant colorectal cancer is associated with increased RAD51AP1 expression. This phenomenon is associated with reduced cell proliferation and colorectal cancer stem cell (CRCSC) self-renewal. Overall, our studies provide evidence that RAD51AP1 could be a novel diagnostic marker for colorectal cancer and a potential therapeutic target for colorectal cancer prevention and treatment. IMPLICATIONS: This study provides first evidence that RAD51AP1 plays a critical role in colorectal cancer growth and drug resistance by regulating CRCSC self-renewal.
DNA 损伤，无论是由化学致癌物还是环境污染物引起的，在结直肠癌的发生中都起着重要作用。然而，DNA 修复过程既参与了癌症的形成，又通过确保基因组的完整性和促进肿瘤细胞中有效 DNA 修复，分别有助于癌症的发展。尽管 DNA 修复途径已在乳腺癌和卵巢癌的治疗中得到充分利用，但 DNA 修复过程及其在结直肠癌中的治疗效果尚未得到充分探索。为了了解 DNA 修复，特别是同源重组（HR）在化学致癌物诱导的结直肠癌生长中的作用，我们揭示了参与 HR 的 RAD51AP1（RAD51 相关蛋白 1）在遗传毒性致癌物（氧化偶氮甲烷，AOM）诱导的结直肠癌中的作用。尽管单独使用 AOM 治疗显著增加了 表达，但 AOM 和葡聚糖硫酸钠（DSS）联合治疗则将其增加了数倍。RAD51AP1 表达存在于小鼠结肠隐窝和增殖细胞中。在大多数人类结直肠癌组织中，包括 BRAF/KRAS 突变型结直肠癌， 表达均显著增加，并与治疗反应降低和预后不良相关。RAD51AP1 缺陷小鼠对 AOM/DSS 诱导的结直肠癌具有保护作用。这些观察结果在结直肠癌的基因工程小鼠模型（）中得到了重现。此外，化疗耐药性结直肠癌与 RAD51AP1 表达增加相关。这种现象与细胞增殖减少和结直肠癌症干细胞（CRCSC）自我更新减少有关。总体而言，我们的研究提供了证据表明 RAD51AP1 可能是结直肠癌的新型诊断标志物，也是结直肠癌预防和治疗的潜在治疗靶点。意义：这项研究首次提供了证据，表明 RAD51AP1 通过调节 CRCSC 自我更新在结直肠癌的生长和耐药中发挥关键作用。
