Expression of LRIG1, a Negative Regulator of EGFR, Is Dynamically Altered during Different Stages of Gastric Carcinogenesis

Abstract

Leucine-rich repeats and immunoglobulin-like domains (LRIG)-1 is a transmembrane protein that antagonizes epidermal growth factor receptor signaling in epithelial tissues. LRIG1 is down-regulated in various epithelial cancers, including bladder, breast, and colorectal cancer, suggesting that it functions as a tumor suppressor. However, its role in gastric carcinogenesis is not well understood. Here, we investigated the changes in LRIG1 expression during the stages of gastric cancer. We used a DMP-777 einduced spasmolytic polypeptide-expressing metaplasia mouse model and a tissue array of human gastric cancer lesions. The effects of LRIG1 knockdown were also assessed using the human gastric cancer cell line SNU638 in a xenograft model. LRIG1 expression varied over the course of gastric carcinogenesis, increasing in spasmolytic polypeptide-expressing metaplasia lesions but disappearing in intestinal metaplasia and cancer lesions, and the increase was concurrent with the up-regulation of epidermal growth factor receptor. In addition, LRIG1 knockdown promoted the tumorigenic potential in vitro, which was manifested as increased proliferation, invasiveness, and migration as well as increased tumor size in vivo in the xenograft model. Furthermore, LRIG1 expression was determined to be a positive prognostic biomarker for the survival of gastric cancer patients. Collectively, our findings indicate that LRIG1 expression is closely related wto gastric carcinogenesis and may play a vital role as a tumor suppressor through the modulation of epidermal growth factor receptor activity. (Am J Pathol 2018, 188: 2912e2923; https://doi.org/10.1016/j.ajpath.2018.08.006) Gastric cancer (GC), one of the most common cancers, 1 occurs via structural changes and metaplasia of the gastric mucosa. 2 Chronic Helicobacter pylori infection, a major cause of the disease, induces prominent inflammation and loss of parietal cells (or oxyntic atrophy), 3 which precedes gastric preneoplasia as it plays an important role in gastric mucosa dedifferentiation. 3,4 In humans, oxyntic atrophy can progress to two types of metaplasia: spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM). 4 SPEM displays morphologic characteristics similar to those of the deep antral glands or Brunner glands, but gastrin-producing cells are not observed in

Targeted mobilization of Lrig1 + gastric epithelial stem cell populations by a carcinogenic Helicobacter pylori type IV secretion system

“…Conversely, little is known about the function of Lrig1 in the stomach and specifically its role in gastric cancer. Recently, LRIG1 expression was linked to survival in patients with gastric cancer, with higher LRIG1 expression levels in gastric tumors associated with a decreased risk of disease relapse (26). In a metaplastic mouse model, the number of Lrig1 + cells were increased in metaplastic regions of the fundus, and furthermore, these cells were found to be proliferative (26).…”

“…Recently, LRIG1 expression was linked to survival in patients with gastric cancer, with higher LRIG1 expression levels in gastric tumors associated with a decreased risk of disease relapse (26). In a metaplastic mouse model, the number of Lrig1 + cells were increased in metaplastic regions of the fundus, and furthermore, these cells were found to be proliferative (26). In the normal mouse stomach, Lrig1 is present in the isthmus of both antral and corpus glands where stem cells reside, suggesting a role for Lrig1 in proliferation (18).…”

Stem Cell-Related Prognostic Signature for Lung Adenocarcinoma

“…LRIG1, a transmembrane protein, has a tumor suppressive effect, and its expression is downregulated in a variety of cancers. It can antagonize epidermal growth factor receptor signaling in epithelial tissues and inhibit cell invasion, migration, VM (angiogenesis simulation) by regulating EGFR / ERK-mediated EMT (epithelial-mesenchymal transition) [43,44]. PABPC1 can combine with adenylate-rich sequences in mRNA under the action of high a nity, which plays an important role in post-transcriptional regulation of genes and is also involved in many metabolic pathways of mRNA, including adenylate polymerization/adenylation, mRNA transport, mRNA translation, microRNA degradation related regulation [45].…”

Epigenetic loss of heterozygosity of Apc and an inflammation-associated mutational signature detected in Lrig1+/−-driven murine colonic adenomas

“…Leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1) is a transmembrane feedback regulator of growth factor receptor tyrosine kinases that is expressed in the Lgr5 + stem cell population present at the base of colonic crypts [14][15][16][17]. Lrig1 acts as a tumor-suppressor gene in several contexts [18][19][20][21][22][23]. The Lrig1-CreERT2/+;Apcfl/+ inducible mouse model of colonic adenoma is based on the conditional Crerecombinase-driven loss of a single copy of Apc under the control of the Lrig1 promoter [24,25].…”