Center for Molecular Oncology, UConn Health, Farmington, CT 06030-3101, USA.
Center for Molecular Oncology, UConn Health, Farmington, CT 06030-3101, USA.
Stem Cell Reports. 2022 Dec 13;17(12):2661-2673. doi: 10.1016/j.stemcr.2022.10.009. Epub 2022 Nov 10.
Lynch syndrome (LS) is the most common hereditary form of colon cancer, resulting from a germline mutation in a DNA mismatch repair (MMR) gene. Loss of MMR in cells establishes a mutator phenotype, which may underlie its link to cancer. Acquired downstream mutations that provide the cell a selective advantage would contribute to tumorigenesis. It is unclear, however, whether loss of MMR has other consequences that would directly result in a selective advantage. We found that knockout of the MMR gene MSH2 results in an immediate survival advantage in human stem cells grown under standard cell culture conditions. This advantage results, in part, from an MMR-dependent response to oxidative stress. We also found that loss of MMR gives rise to enhanced formation and growth of human colonic organoids. These results suggest that loss of MMR may affect cells in ways beyond just increasing mutation frequency that could influence tumorigenesis.
林奇综合征（LS）是最常见的遗传性结肠癌形式，由 DNA 错配修复（MMR）基因的种系突变引起。细胞中 MMR 的缺失建立了一个突变体表型，这可能是其与癌症相关的基础。获得性下游突变为细胞提供了选择性优势，这将有助于肿瘤发生。然而，目前尚不清楚 MMR 的缺失是否还有其他直接导致选择性优势的后果。我们发现，在标准细胞培养条件下生长的人类干细胞中，MMR 基因 MSH2 的敲除立即产生生存优势。这种优势部分源自对氧化应激的 MMR 依赖性反应。我们还发现，MMR 的缺失导致人类结肠类器官的形成和生长增强。这些结果表明，MMR 的缺失可能会以超出仅仅增加突变频率的方式影响细胞，从而影响肿瘤发生。
