Cell migration is regulated by AGE-RAGE interaction in human oral cancer cells in vitro

Shun-Yao Ko; Hshin-An Ko; Tzong-Ming Shieh; Weng-Cheng Chang; Hong-I Chen; Shu-Shing Chang; I-Hsuan Lin

doi:10.1371/journal.pone.0110542

Cell migration is regulated by AGE-RAGE interaction in human oral cancer cells in vitro

PLoS One. 2014 Oct 16;9(10):e110542. doi: 10.1371/journal.pone.0110542. eCollection 2014.

Authors

Shun-Yao Ko¹, Hshin-An Ko², Tzong-Ming Shieh³, Weng-Cheng Chang⁴, Hong-I Chen¹, Shu-Shing Chang², I-Hsuan Lin⁴

Affiliations

¹ Graduate Institute of Medical Science, College of Health Science, Chang Jung Christian University, Tainan, Taiwan; Innovate Research Center of Medicine, Chang Jung Christian University, Tainan, Taiwan.
² Innovate Research Center of Medicine, Chang Jung Christian University, Tainan, Taiwan.
³ Department of Dental Hygiene, China Medical University, Taichung, Taiwan.
⁴ Graduate Institute of Medical Science, College of Health Science, Chang Jung Christian University, Tainan, Taiwan.

Abstract

Advanced glycation end products (AGEs) are produced in an irreversible non-enzymatic reaction of carbohydrates and proteins. Patients with diabetes mellitus (DM) are known to have elevated AGE levels, which is viewed as a risk factor of diabetes-related complications. In a clinical setting, it has been shown that patients with oral cancer in conjunction with DM have a higher likelihood of cancer metastasis and lower cancer survival rates. AGE-RAGE (a receptor of AGEs) is also correlated with metastasis and angiogenesis. Recent studies have suggested that the malignancy of cancer may be enhanced by glyceraldehyde-derived AGEs; however, the underlying mechanism remains unclear. This study examined the apparently close correlation between AGE-RAGE and the malignancy of SAS oral cancer cell line. In this study, AGEs increased ERK phosphorylation, enhanced cell migration, and promoted the expression of RAGE, MMP2, and MMP9. Using PD98059, RAGE antibody, and RAGE RNAi to block RAGE pathway resulted in the inhibition of ERK phosphorylation. Cell migration, MMP2 and MMP9 expression were also reduced by this treatment. Our findings demonstrate the importance of AGE-RAGE with regard to the malignancy of oral cancer, and help to explain the poor prognosis of DM subjects with oral cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation / drug effects
Cell Proliferation / genetics
Diabetes Complications / genetics*
Diabetes Complications / pathology
Diabetes Mellitus / genetics*
Diabetes Mellitus / pathology
Female
Flavonoids / administration & dosage
Gene Expression Regulation, Neoplastic / drug effects
Glycation End Products, Advanced / genetics*
Humans
Male
Matrix Metalloproteinase 2 / biosynthesis
Matrix Metalloproteinase 9 / biosynthesis
Mouth Neoplasms / complications
Mouth Neoplasms / genetics*
Mouth Neoplasms / pathology
Neoplasm Metastasis
RNA, Small Interfering
Receptor for Advanced Glycation End Products / antagonists & inhibitors
Receptor for Advanced Glycation End Products / genetics*

Substances

AGER protein, human
Flavonoids
Glycation End Products, Advanced
RNA, Small Interfering
Receptor for Advanced Glycation End Products
MMP2 protein, human
Matrix Metalloproteinase 2
MMP9 protein, human
Matrix Metalloproteinase 9
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Grants and funding

This work was supported by grants from the National Science Council, Taiwan (NSC 100-2314-B-309-002-MY3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.