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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 13/2021

01-12-2021 | Metastasis | Translational Research

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

Authors: Yue-Ju Li, PhD, Cheng-Ning Yang, PhD, Mark Yen-Ping Kuo, PhD, Wei-Ting Lai, PhD, Tai-Sheng Wu, PhD, Been-Ren Lin, MD, PhD

Published in: Annals of Surgical Oncology | Issue 13/2021

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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 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.

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 MSI-high CRC.
Appendix
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Metadata
Title
ATMIN Suppresses Metastasis by Altering the WNT-Signaling Pathway via PARP1 in MSI-High Colorectal Cancer
Authors
Yue-Ju Li, PhD
Cheng-Ning Yang, PhD
Mark Yen-Ping Kuo, PhD
Wei-Ting Lai, PhD
Tai-Sheng Wu, PhD
Been-Ren Lin, MD, PhD
Publication date
01-12-2021
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 13/2021
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-021-10322-5

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