title: 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.
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.
authors: Department of Pharmacology and UCLA Intercampus Medical Genetics Training Program, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors: Durga Prasad
authors: DP
authors: Cherukuri
authors: Departments of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors: Joshua L
authors: JL
authors: Deignan
authors: Departments of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors: Kingshuk
authors: K
authors: Das
authors: Departments of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors: Wayne W
authors: WW
authors: Grody
authors: Department of Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA, USA. Electronic address: hherschman@mednet.ucla.edu.
authors: Harvey
authors: H
authors: Herschman
mesh_terms: D020413:3' Untranslated Regions; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018900:Dinucleotide Repeats; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D053842:Microsatellite Instability; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D012333:RNA, Messenger; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases
keywords: Colorectal cancer; Dinucleotide repeat; Microsatellite instability; mPGES-1