Instability of a dinucleotide repeat in the 3′‐untranslated region (UTR) of the microsomal prostaglandin E synthase‐1 (mPGES‐1) gene in microsatellite instability‐high (MSI‐H) colorectal carcinoma. Issue 7 (5th March 2015)

• Record Type: Journal Article
• Authors: Cherukuri, Durga Prasad; Deignan, Joshua L.; Das, Kingshuk; Grody, Wayne W.; Herschman, Harvey
• Is Part Of: Molecular oncology. Volume 9:Issue 7(2015:Aug.)
• Page Start: 1252
• Page End: 1258
• Publication Date: 2015-03-05
• Subjects: mPGES-1 -- Dinucleotide repeat -- Microsatellite instability -- Colorectal cancer; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1016/j.molonc.2015.01.009
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : DNA mismatch‐repair gene mutations, with consequent loss of functional protein expression, result in microsatellite instability (MSI). Microsatellite sequences are found in coding regions and in regulatory regions of genes (i.e., 5′‐UTRs and 3′‐UTRs). In addition to being a surrogate marker of defective mismatch repair, deletion or insertion microsatellite sequences can dysregulate gene expression in MSI‐H (microsatellite instability‐high) tumors. The microsomal prostaglandin E synthase‐1 (mPGES‐1) gene product, mPGES‐1, participates in prostaglandin E2 (PGE2) production. Moreover, mPGES‐1 is often overexpressed in human colorectal tumors, and is thought to contribute to progression of these tumors. Here we identified a dinucleotide repeat, (GT)24, in the mPGES‐1 gene 3′ untranslated region (3′‐UTR), and analyzed its mutation frequencies in MSI‐H and microsatellite stable (MSS) tumors. The (GT)24 repeat exhibited instability in all MSI‐H tumors examined (14), but not in any of the MSS tumors (13). In most cases, (GT)24 repeat instability resulted in insertion of additional GT units. We also determined mPGES‐1 mRNA levels in MSI‐H and MSS colorectal cancer cell lines. Three of four previously designated "MSI‐H" cell lines showed higher mPGES‐1 mRNA levels compared to MSS cell lines; correlations between elevated mPGES‐1 mRNA levels and microsatellite (GT)24 repeat characteristics are present for all six cell lines. Our results demonstrate that mPGES‐1 is a target gene of defective mismatch repair in human colorectal cancer, with functional consequence. Highlights: Identified a (GT)24 dinucleotide repeat in the mPGES‐1 gene 3ʹ‐untranslated region. Examined the (GT)24 mutation frequency in MSS and MSI‐H human colorectal tumors. The (GT)24 repeat exhibited instability in all MSI‐H tumors, but not in MSS tumors. mPGES‐1 mRNA levels and GT24 profiles correlate for six MSS and MSH‐1 CRC lines.