ASO Visual Abstract: ATMIN Suppresses Metastasis by Altering the WNT Signaling Pathway via PARP1 in MSI-High Colorectal Cancer

Abstract

Background. 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). Methods. 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. Results. 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 bcatenin/transcription factor 4 (TCF4) binding affinity in MSI-high tumors, and PARP1 inhibition significantly decreased the number of metastases from ATMIN knockdown cancer cells. Conclusions. 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 MSIhigh CRC. Colorectal carcinoma (CRC), one of the most common cancers worldwide, is responsible for most cancer-related deaths. The 5-year survival rate is only 55% due to the propensity for local invasion and distant metastasis. Currently, CRCs are classified into microsatellite stable (MSS) and microsatellite instability (MSI)-high groups. Approximately 10–20% of CRCs categorized as MSI-high possess defective DNA mismatch repair systems. Frequently, MSI-high tumors present on the right-hand side with poorly differentiated mucinous histologic features with marked lymphocytic infiltration. Interestingly, patients with MSI-high tumors show a more favorable prognostic clinical outcome than those with MSS tumors, but have worse survival in stage 4. More frequently, MSI is found in stage 2 than in stage 3 disease and less frequently discovered in stage 4 CRC. Recently, clinical advances in chemotherapy have prolonged the survival of CRC patients. However, the sensitivity of chemotherapy differs between MSI-high and MSS populations. Findings have shown MSI-high and MSS tumors to have not only different biometrics but also distinct treatment outcomes. Patients with MSS tumors will benefit from 5-fluorouracil, but the same drugs decrease the Supplementary Information The online version contains supplementary material available at https://doi.org/10.1245/s10434021-10322-5. Society of Surgical Oncology 2021 First Received: 29 March 2021 Accepted: 2 June 2021 B.-R. Lin, MD, PhD e-mail: [email protected] Ann Surg Oncol https://doi.org/10.1245/s10434-021-10322-5