Glypican 1 promotes proliferation and migration in esophagogastric adenocarcinoma via activating AKT/GSK/β-catenin pathway

Akshay Pratap; Anqi Li; Lindsey Westbrook; Anna K Gergen; Sanchayita Mitra; Argudit Chauhan; Linling Cheng; Michael J Weyant; Martin McCarter; Sachin Wani; Robert Alexander Meguid; John D Mitchell; Mitchell Cohen; David Fullerton; Xianzhong Meng

doi:10.21037/jgo-22-240

Glypican 1 promotes proliferation and migration in esophagogastric adenocarcinoma via activating AKT/GSK/β-catenin pathway

J Gastrointest Oncol. 2022 Oct;13(5):2082-2104. doi: 10.21037/jgo-22-240.

Authors

Affiliations

¹ Division of Gastrointestinal Tumor and Endocrine Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
² Division of Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
³ Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴ Department of Biomedical Engineering, University of Colorado, Boulder, CO, USA.
⁵ Division of Thoracic Surgery, Inova Fairfax Hospital, Falls Church, VA, USA.
⁶ Division of Surgical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁷ Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Abstract

Background: Glypican 1 (GPC1) is a heparan sulphate proteoglycan cell membrane protein. It is implicated in driving cancers of the breast, brain, pancreas, and prostate; however, its role in esophagogastric cancer (EGAC) remains unexplored. The aim of the study was to investigate and elucidate the molecular mechanistic of GPC1 in human EGAC.

Methods: Thirty tissue and 120 microarray sections of EGAC were evaluated with Anti-GPC1 immunohistochemistry. Loss and gain of GPC1 function were performed using lentivirus transfection in EGAC cell lines. Mechanistically, AKT/GSK/β-catenin pathway was evaluated using AKT inhibitor MK-2206 and Wnt/β-catenin stimulant LiCl.

Results: GPC1 overexpression was found in 102 cases (68%). Overexpression of GPC1 correlated with lymph node metastasis, poor differentiation and decreased overall survival. Lentivirus mediated GPC1 knockdown resulted in decreased cell proliferation, migration, invasion, and colony formation. Knockdown caused G0/G1 cell cycle arrest, increased apoptosis, and reduced epithelial mesenchymal transition (EMT). GPC1 mediated its effects by activation of AKT/GSK/β-catenin pathway.

Conclusions: This is the first descriptive study to decipher the role of GPC1 in EGAC. Our results suggest that GPC1 regulates cell proliferation and growth and may serve as an attractive oncotarget in EGAC.

Keywords: AKT/GSK/β-catenin signaling; Glypican 1 (GPC1); apoptosis; epithelial mesenchymal transition (EMT); esophagogastric adenocarcinoma (EGAC); lentivirus; proliferation.