ArticlePloS one2012
MSH3-deficiency initiates EMAST without oncogenic transformation of human colon epithelial cells.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 54 citations in OpenAlex.
- A novel quantitative trait locus implicatesGenome research · 2023Article
- Olaparib-mediated enhancement of 5-fluorouracil cytotoxicity in mismatch repair deficient colorectal cancer cells.BMC cancer · 2021Article
- Article
- The Human DNA Mismatch Repair Protein MSH3 Contains Nuclear Localization and Export Signals That Enable Nuclear-Cytosolic Shuttling in Response to Inflammation.Molecular and cellular biology · 2020Article
- Hemophagocytic relapsed intramedullary plasmacytoma.International journal of hematology · 2020Article
- Patterns of germline and somatic mutations in 16 genes associated with mismatch repair function or containing tandem repeat sequences.Cancer medicine · 2020Article
- Immunological Features with DNA Microsatellite Alterations in Patients with Colorectal Cancer.Journal of cancer immunology · 2020Article
- Tetranucleotide Microsatellite Mutational Behavior Assessed in Real Time: Implications for Future Microsatellite Panels.Cellular and molecular gastroenterology and hepatology · 2020Article
- Review
- Combined Microsatellite Instability and Elevated Microsatellite Alterations at Selected Tetranucleotide Repeats (EMAST) Might Be a More Promising Immune Biomarker in Colorectal Cancer.The oncologist · 2019Article
- Inflammation-Associated Microsatellite Alterations Caused by MSH3 Dysfunction Are Prevalent in Ulcerative Colitis and Increase With Neoplastic Advancement.Clinical and translational gastroenterology · 2019Article
- Elevated Microsatellite Alterations at Selected Tetranucleotides (EMAST) Is Not Attributed to MSH3 Loss in Stage I-III Colon cancer: An Automated, Digitalized Assessment by Immunohistochemistry of Whole Slides and Hot Spots.Translational oncology · 2019Article
- Genetic and genomic basis of the mismatch repair system involved in Lynch syndrome.International journal of clinical oncology · 2019Review
- Esophageal cancer genetics in South Africa.Clinical and experimental gastroenterology · 2019Review
- p-21 Activated Kinase as a Molecular Target for Chemoprevention in Diabetes.Geriatrics (Basel, Switzerland) · 2018Review
- A new method for discovering EMAST sequences in animal models of cancer.Scientific reports · 2018Article
- Identification of PMN-released mutagenic factors in a co-culture model for colitis-associated cancer.Carcinogenesis · 2018Article
- Inflammation-associated microsatellite alterations: Mechanisms and significance in the prognosis of patients with colorectal cancer.World journal of gastrointestinal oncology · 2018Review
- Article
- Loss of MSH2 and MSH6 due to heterozygous germline defects in MSH3 and MSH6.Familial cancer · 2017Article
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Authors and funding
14 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND/
aimElevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature in certain cases of sporadic colorectal cancer and has been linked to MSH3-deficiency. It is currently controversial whether EMAST is associated with oncogenic properties in humans, specifically as cancer development in Msh3-deficient mice is not enhanced. However, a mutator phenotype is different between species as the genetic positions of repetitive sequences are not conserved. Here we studied the molecular effects of human MSH3-deficiency.
methodsHCT116 and HCT116+chr3 (both MSH3-deficient) and primary human colon epithelial cells (HCEC, MSH3-wildtype) were stably transfected with an EGFP-based reporter plasmid for the detection of frameshift mutations within an [AAAG]17 repeat. MSH3 was silenced by shRNA and changes in protein expression were analyzed by shotgun proteomics. Colony forming assay was used to determine oncogenic transformation and double strand breaks (DSBs) were assessed by Comet assay.
resultsDespite differential MLH1 expression, both HCT116 and HCT116+chr3 cells displayed comparable high mutation rates (about 4×10(-4)) at [AAAG]17 repeats. Silencing of MSH3 in HCECs leads to a remarkable increased frameshift mutations in [AAAG]17 repeats whereas [CA]13 repeats were less affected. Upon MSH3-silencing, significant changes in the expression of 202 proteins were detected. Pathway analysis revealed overexpression of proteins involved in double strand break repair (MRE11 and RAD50), apoptosis, L1 recycling, and repression of proteins involved in metabolism, tRNA aminoacylation, and gene expression. MSH3-silencing did not induce oncogenic transformation and DSBs increased 2-fold.
conclusionsMSH3-deficiency in human colon epithelial cells results in EMAST, formation of DSBs and significant changes of the proteome but lacks oncogenic transformation. Thus, MSH3-deficiency alone is unlikely to drive human colon carcinogenesis.
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