Expression of Pla2g2a prevents carcinogenesis in Muc2‐deficient mice

Abstract

Mucins are the principal components of intestinal mucus, a viscous substance that provides protection and lubrication to the epithelial mucosa.(1,2) In the intestinal epithelium of mice and humans, the major secretory mucin is MUC2, which is expressed in the goblet cell population. (3,4) MUC2 is a large, heavily glycosylated, protein (5200 amino acids) that constitutes the major structural component of mucus, thus contributing to barrier functions. The role of MUC2 in intestinal tumorigenesis appears to be complex. Goblet cell depletion and down-regulation of MUC2 expression (5)(6)(7) or MUC2 protein alteration (8) occur in a significant percentage of human non-mucinous colorectal adenocarcinomas.(9) MUC2 is robustly expressed in normal colon tissue (3) and its expression is observed in early stages of adenomagenesis but progressive loss of MUC2 function occurs in the transition to carcinogenesis. (5,(9)(10)(11)(12) In contrast, up-regulation of MUC2 is occasionally observed in mucinous adenocarcinomas that are also characterized by microsatellite instability. (10,(12)(13)(14)(15)(16)(17) In addition, mucins secreted by colon cancer cells may contribute to the metastatic process, (12) and are reported to increase the production of prostaglandin E 2 (PGE 2 ) and cyclooxygenase-2 (COX-2) in macrophages. (18) Velcich and colleagues generated a germline knockout of Muc2 (19) in mice on a C57BL/6J-129/SvOla mixed genetic background that resulted in the absence of recognizable goblet cells along the entire length of the intestine, although the expression of some goblet cell differentiation markers was retained. Muc2 knockout mice developed small intestinal tumors by 6 months of age and eventually adenocarcinomas in the duodenum and rectum. Muc2-/-tumors showed no alterations in the β-catenin pathway; thus Muc2 deficiency likely represents an Apc-independent tumor pathway. Despite the different pathways of tumorigenesis, inactivation of p21 WAF1/CIP1 similarly affects tumor formation in both the Muc2 and mutant Apc mouse models of intestinal carcinogenesis. (20) The secretory phospholipase Pla2g2a is a modulator of tumorigenesis that has been shown to confer resistance to intestinal cancer in the mouse. The Pla2g2a gene is part of the Mom1 (Modifier of Min-1) complex of genes on distal mouse chromosome four that confers resistance to tumorigenesis in the Apc Min/+ mouse. (21,22) Pla2g2a is naturally mutant in three strains of mice (including C57BL/6 J and 129/SvOla) that develop a severe Apc Min/+ phenotype and is wildtype in six strains that demonstrate resistance to intestinal tumorigenesis. (23,24) Genetic evidence for the function of Pla2g2a as a tumor suppressor was demonstrated by the reduction in tumors observed in Apc Min/+ mice carrying a wildtype Pla2g2a transgene derived from the AKR strain.(25) The Pla2g2a transgene resistance phenotype is strongest in the large intestine and like Muc2, Pla2g2a is exclusively expressed by the goblet cell population. (22) Pla2g2a and Muc2 share several common genetic and bio...

Transcriptome profiling of malignant transformed rat hepatic stem-like cells by aflatoxin B1

“…Dusp4 was significantly down-regulated in our study, which was consistent with the expression in HepG2 cells [38]. Genetic evidence for the Pla2g2a protecting against tumorigenesis has been demonstrated [39], and the greatest decreased expression was detected in 0.2 μM (-8-fold).…”

A microarray gene analysis of peripheral whole blood in normal adult male rats after long-term GH gene therapy

“…Pla2g2a, which encodes the Pla2 group II A secreted phospholipase A2, showed an over 40-fold lower expression in whole blood after the injection of rAAV2/1-CMV-GH1 than in the NC controls (p < 0.05). Pla2g2a plays diverse roles in human diseases, including colon cancer, coronary artery disease and inflammation [17][18][19][20][21]. The mRNA expression of Gpr109a showed an over 10-fold increase in rat whole blood samples after the injection of rAAV2/1-CMV-GH1 (p < 0.05).…”

Overexpression of Phospholipase A2Group IIA in Esophageal Squamous Cell Carcinoma and Association with Cyclooxygenase-2 Expression

“…Although the reasons for this difference remain to be elucidated, dysregulation of the PLA2G2A protein might cause carcinogenesis through multiple mechanisms (Jiang et al, 2002;Fijneman et al, 2008;Wang et al, 2013). The pro-tumorigenic (e.g., prostate cancer (Jiang et al, 2002;Graham et al, 2008)) or anti-tumorigenic effects (e.g., gastric cancer (Leung et al, 2002;Ganesan et al, 2008;Xing et al, 2011;) of PLA2G2A appear to be tissue specific, as well as in human intestinal cancer, the role of PLA2G2A remains elusive.…”