Department of Cancer Biology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA.
School of Biotechnology, International University, Ho Chi Minh City, Vietnam.
Sci Adv. 2023 May 10;9(19):eadd8023. doi: 10.1126/sciadv.add8023.
Despite the high lethality of colorectal cancers (CRCs), only a limited number of genetic risk factors are identified. The mammalian ssDNA-binding protein complex CTC1-STN1-TEN1 protects genome stability, yet its role in tumorigenesis is unknown. Here, we show that attenuated CTC1/STN1 expression is common in CRCs. We generated an inducible STN1 knockout mouse model and found that STN1 deficiency in young adult mice increased CRC incidence, tumor size, and tumor load. CRC tumors exhibited enhanced proliferation, reduced apoptosis, and elevated DNA damage and replication stress. We found that STN1 deficiency down-regulated multiple DNA glycosylases, resulting in defective base excision repair (BER) and accumulation of oxidative damage. Collectively, this study identifies STN1 deficiency as a risk factor for CRC and implicates the previously unknown STN1-BER axis in protecting colon tissues from oxidative damage, therefore providing insights into the CRC tumor-suppressing mechanism.
尽管结直肠癌 (CRC) 的致死率很高，但目前仅鉴定出少数遗传风险因素。哺乳动物单链 DNA 结合蛋白复合物 CTC1-STN1-TEN1 可保护基因组稳定性，但它在肿瘤发生中的作用尚不清楚。在这里，我们表明 CRC 中常见 CTC1/STN1 表达减弱。我们生成了诱导型 STN1 敲除小鼠模型，发现年轻成年小鼠中 STN1 缺失会增加 CRC 的发生率、肿瘤大小和肿瘤负荷。CRC 肿瘤表现出增强的增殖、减少的凋亡以及升高的 DNA 损伤和复制应激。我们发现 STN1 缺失下调了多个 DNA 糖苷酶，导致碱基切除修复 (BER) 缺陷和氧化损伤积累。总之，这项研究确定 STN1 缺失是 CRC 的一个风险因素，并暗示了以前未知的 STN1-BER 轴在保护结肠组织免受氧化损伤方面的作用，从而为 CRC 的肿瘤抑制机制提供了新的见解。
