Cell polarity protein Lgl2 is lost or aberrantly localized in gastric dysplasia and adenocarcinoma: an immunohistochemical study

Abstract

The diagnosis of gastric epithelial dysplasia, a precursor lesion of gastric adenocarcinoma, is hindered by interobserver variability and by its resemblance to regenerative changes. Loss of cell polarity, a histological feature of gastric epithelial dysplasia, may be difficult to ascertain, especially in the setting of inflammation or injury. A biomarker of cell polarity could be useful in diagnosis of dysplasia, but has not been reported. The Lethal giant larvae (lgl) gene controls apical-basal polarity of epithelial cells in Drosophila, and has properties of a tumor-suppressor gene. Two homologs, lgl1 and lgl2, are present in mammals and lgl2 mRNA is highly expressed in the stomach. The goal of our study was to test the hypothesis that Lgl2 protein expression and/or localization are disrupted in gastric epithelial dysplasia and adenocarcinoma. Routinely processed pathology specimens including 94 benign mucosae of digestive organs, in addition to 36 reactive gastropathy, 57 gastric epithelial dysplasia, and 77 gastric adenocarcinomas, were immunostained for Lgl2 protein. All normal, reactive, and chronically inflamed gastric epithelia showed basolateral Lgl2 staining. Normal esophageal, duodenal, colonic, biliary, and pancreatic duct mucosae, as well as gastric intestinal metaplasia, did not express Lgl2. All but one case each of gastric epithelial dysplasia and adenocarcinoma showed either complete loss of anti-Lgl2 immunoreactivity or diffuse, mostly weak, cytoplasmic staining. Complete loss of immunoreactivity was significantly more often observed in diffuse-type than in intestinal-type adenocarcinomas (79 vs 48%, respectively). Our data suggest that Lgl2 expression is either aberrantly localized or lost in gastric epithelial dysplasia and adenocarcinoma, whereas it is maintained in reactive gastric mucosa. We propose that Lgl2 may be a potential marker to rule out gastric epithelial dysplasia and adenocarcinoma in diagnostic specimens. However, the consistently negative anti-Lgl2 immunoreactivity seen in intestinal metaplasia does not allow differentiation of dysplasia from intestinal metaplasia with reactive change.

SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia

“…Deregulation of Scribble complex members (SCRIB, DLG1, and LLGL2) has been correlated to a number of human epithelial cancers (11)(12)(13)(14), although somatic mutations remain to be identified. Human colorectal, breast, and endometrial cancers display mislocalized and deregulated SCRIB expression (14)(15)(16)(17)(18), suggesting that SCRIB may be crucial for the homeostatic maintenance of several epithelial tissues.…”

Localization, Not Important in All Tumor-Suppressing Properties: A Lesson Learnt from Scribble

“…Numerous cell polarity proteins, including PKCλ/ι and members of the Scribble complex, Scribble, Discs Large and Lethal Giant Larvae have all been identified as being mislocalized in various cancer types [Nakagawa et al, 2004;Eder et al, 2005;Gardiol et al, 2006;Zhan et al, 2008;Lisovsky et al, 2009;Huang and Muthuswamy, 2010;Pearson et al, 2011;Martin-Belmonte and Perez-Moreno, 2012]. Scribble in particular has been identified as mislocalized in several cancer types, including breast, prostate, cervical and colon cancer [Nakagawa et al, 2004;Gardiol et al, 2006;Zhan et al, 2008;Pearson et al, 2011].…”

Genetic risk for myocardial infarction in Japanese individuals with or without chronic kidney disease

“…Lethal giant larvae homolog 2 (LLGL2) is involved in epithelial cell polarity, asymmetric cell division, and hemidesmosome formation through the association with submembranous actin cytoskeleton of the basolateral cell domain (31,32). Collagen, type XIII, ·1 (COL13A1) is a constituent of type XIII collagen.…”