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 RAD51AP1 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. RAD51AP1 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. Rad51ap1 -deficient mice were protected against AOM/DSS-induced colorectal cancer. These observations were recapitulated in a genetically engineered mouse model of colorectal cancer ( ApcMin/+ ). 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 in vivo evidence that RAD51AP1 plays a critical role in colorectal cancer growth and drug resistance by regulating CRCSC self-renewal.

中文翻译：

---

RAD51AP1 缺失减弱结直肠癌干细胞更新并对化疗敏感

由化学致癌物或环境污染物引起的 DNA 损伤在结直肠癌的发生中起着重要作用。然而，DNA 修复过程通过确保基因组完整性和促进肿瘤细胞中的有效 DNA 修复，既参与防止癌症形成，也有助于癌症发展。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 修复过程的作用及其在结直肠癌中的治疗效果仍有待充分探索。为了了解 DNA 修复，尤其是同源重组 (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 RAD51AP1（RAD51 相关蛋白 1），一种参与 HR 的蛋白质，在遗传毒性致癌物（偶氮甲烷，AOM）诱导的结肠直肠癌中。虽然单独的 AOM 处理显着增加了 RAD51AP1 的表达，但 AOM 和葡聚糖硫酸钠 (DSS) 处理的组合显着增加了几倍。RAD51AP1 表达存在于小鼠结肠隐窝和增殖细胞中。RAD51AP1 表达在大多数人类结直肠癌组织中显着增加，包括 BRAF/KRAS 突变型结直肠癌，并且与治疗反应降低和预后不良有关。Rad51ap1 缺陷小鼠被保护免受 AOM/DSS 诱导的结肠直肠癌。这些观察结果在结直肠癌基因工程小鼠模型 (ApcMin/+) 中得到了概括。此外，耐化疗的结直肠癌与 RAD51AP1 表达增加有关。这种现象与细胞增殖减少和结直肠癌干细胞 (CRCSC) 自我更新有关。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和结直肠癌预防和治疗的潜在治疗靶点。启示：这项研究提供了第一个体内证据，表明 RAD51AP1 通过调节 CRCSC 自我更新在结直肠癌的生长和耐药性中起关键作用。