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Int J Mol Sci. 2019 Jan 28;20(3). pii: E555. doi: 10.3390/ijms20030555.

Novel Gastric Cancer Stem Cell-Related Marker LINGO2 Is Associated with Cancer Cell Phenotype and Patient Outcome.

Author information

1
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea. JUNGHYUNJO83@yuhs.ac.
2
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea. ELLIE0813@yuhs.ac.
3
Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul 03722, Korea. semi2010.park@samsung.com.
4
Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea. semi2010.park@samsung.com.
5
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea. LHS6865@yuhs.ac.
6
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea. MISSKCY90@yuhs.ac.
7
Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea. estherjung@yuhs.ac.
8
Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea. sysong@yuhs.ac.
9
Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea. sysong@yuhs.ac.

Abstract

The expression of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 (LINGO2) has been reported in Parkinson's disease; however, its role in other diseases is unknown. Gastric cancer is the second leading cause of cancer death. Cancer stem cells (CSC) are a subpopulation of cancer cells that contribute to the initiation and invasion of cancer. We identified LINGO2 as a CSC-associated protein in gastric cancers both in vitro and in patient-derived tissues. We studied the effect of LINGO2 on cell motility, stemness, tumorigenicity, and angiogenic capacity using cells sorted based on LINGO2 expression and LINGO2-silenced cells. Tissue microarray analysis showed that LINGO2 expression was significantly elevated in advanced gastric cancers. The overall survival of patients expressing high LINGO2 was significantly shorter than that of patients with low LINGO2. Cells expressing high LINGO2 showed elevated cell motility, angiogenic capacity, and tumorigenicity, while LINGO2 silencing reversed these properties. Silencing LINGO2 reduced kinase B (AKT)/extracellular signal-regulated kinase (ERK)/ERK kinase (MEK) phosphorylation and decreased epithelial-mesenchymal transition (EMT)-associated markers-N-Cadherin and Vimentin and stemness-associated markers- POU class 5 homeobox 1 (OCT4) and Indian hedgehog (IHH), and markedly decreased the CD44⁺ population. These indicate the involvement of LINGO2 in gastric cancer initiation and progression by altering cell motility, stemness, and tumorigenicity, suggesting LINGO2 as a putative target for gastric cancer treatment.

KEYWORDS:

LINGO2; and tissue microarray analysis; angiogenesis; cancer stem cells; epithelial to mesenchymal transition; gastric cancer; tumorigenesis

PMID:
30696080
PMCID:
PMC6387145
DOI:
10.3390/ijms20030555
[Indexed for MEDLINE]
Free PMC Article

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