Novel gastric cancer stem cell-related marker, LINGO2 enhances migration and invasion in gastric cancer cells associated with epithelial-mesenchymal transition

Abstract

Background: Cancer stem cells (CSCs) are a small subpopulation of cancer cells with the capacity for self-renewal, tumor initiation and drug resistance, similar to normal stem cells. CSCs are suggested to be critical in cancer invasion and metastasis related with the epithelial-mesenchymal transition (EMT). Aim: We investigated the function of the novel gastric CSC-related marker, LINGO2 (leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 precursor) by comparing DNA microarray data for gastric cancer tumor sphere and adherent cells.Methods: DNA microarray results from gastric cancer sphere and adherent cells were analyzed for cancer stem cell-related markers. LINGO2 was upregulated in both sphere-forming gastric cancer cell lines. LINGO2 expression was confirmed by RT-PCR, western blots of gastric cancer cells and immunohistochemistry of a human gastric cancer tissue microarray. To determine LINGO2 functions, gastric cancer sphere cells were sorted by LINGO2 expression into LINGO2-high and LINGO2-low cells. And, we performed targeted knockdown using shRNA in SNU484 gastric cancer cell lines. Results: LINGO2 was expressed in gastric cancer sphere cells and most gastric cancer cell lines. Migration ability increased in cells with LINGO2-high compared to LINGO2-low expression. LINGO2 shRNA-knockdown cells also had decreased migration and invasion in SNU484 gastric cancer cells. Expression of mesenchymal markers N-cadherin, vimentin, and matrix metalloproteinases were significantly inhibited in LINGO2 knockdown cells. LINGO2 knockdown reduced CD44 expression and AKT and MEK/ERK phosphorylation. Clinically, LINGO2 expression correlated positively with lymph node invasion in human gastric cancer tissues.Conclusion: These results suggested that the novel gastric CSC-related marker LINGO2, which is associated with the EMT pathway, enhanced migration and invasion in gastric cancer cells. LINGO2 is a potential therapeutic target for gastric cancer.