Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
Division of Colorectal Surgery, Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei City, Taiwan.
Ann Surg Oncol. 2021 Dec;28(13):8544-8554. doi: 10.1245/s10434-021-10322-5. Epub 2021 Jun 19.
Constant DNA damage occurs in cells, and the cells are programmed to respond constitutively. This study explored the roles of ataxia-telangiectasia mutated interactor (ATMIN), one of the impaired pathways involving the DNA damage response (DDR) in mismatch repair-deficient [microsatellite instability (MSI)-high] colorectal carcinoma (CRC).
Expression of ATMIN messenger RNA (mRNA) was detected in CRC specimens with microsatellite instability (MSI) characteristics. The effects of ectopic ATMIN expression and ATMIN knockdown on invasion abilities were evaluated in MSI-high cell lines, and liver metastasis ability was investigated in vivo. Protein-protein interactions were assessed by coimmunoprecipitation analyses in vitro.
Decreased ATMIN expression was positively correlated with advanced stage of disease (P < 0.05), lymph node metastases (P < 0.05), and deeper invasion (P < 0.05) in MSI-high tumors. Transient or stable ATMIN knockdown significantly increased cell motility. Moreover, in the high-throughput microarray and gene set enrichment analysis, ATMIN was shown to act on the Wnt-signaling pathway via PARP1. This cascade influences β-catenin/transcription factor 4 (TCF4) binding affinity in MSI-high tumors, and PARP1 inhibition significantly decreased the number of metastases from ATMIN knockdown cancer cells.
The results not only indicated the critical role of ATMIN, but also shed new light on PARP1 inhibitors, providing a basis for further clinical trials of MSI-high CRC.
细胞内会持续发生 DNA 损伤，而细胞会持续进行应答。本研究探索了共济失调毛细血管扩张突变相关蛋白（ATMIN）在错配修复缺陷（微卫星不稳定（MSI）高）结直肠癌（CRC）的 DNA 损伤反应（DDR）相关受损途径中的作用。
检测具有 MSI 特征的 CRC 标本中 ATMIN 信使 RNA（mRNA）的表达。在外源性表达 ATMIN 和敲低 ATMIN 表达的情况下，评估其对 MSI-高细胞系侵袭能力的影响，并在体内研究其肝转移能力。通过体外免疫共沉淀分析评估蛋白质-蛋白质相互作用。
ATMIN 表达降低与 MSI 高肿瘤的疾病晚期（P < 0.05）、淋巴结转移（P < 0.05）和更深的侵袭（P < 0.05）呈正相关。瞬时或稳定敲低 ATMIN 可显著增加细胞迁移能力。此外，在高通量微阵列和基因集富集分析中，ATMIN 被证明通过聚 ADP 核糖聚合酶 1（PARP1）作用于 Wnt 信号通路。该级联反应影响 MSI-高肿瘤中β-连环蛋白/转录因子 4（TCF4）的结合亲和力，PARP1 抑制可显著减少 ATMIN 敲低癌细胞的转移数量。
研究结果不仅表明了 ATMIN 的关键作用，还为 PARP1 抑制剂提供了新的思路，为 MSI-高 CRC 的进一步临床试验提供了依据。
