Galectin-3 facilitates cell motility in gastric cancer by up-regulating protease-activated receptor-1 (PAR-1) and matrix metalloproteinase-1 (MMP-1).

Abstract

BACKGROUND:

Galectin-3 is known to regulate cancer metastasis. However, the underlying mechanism has not been defined. Through the DNA microarray studies after galectin-3 silencing, we demonstrated here that galectin-3 plays a key role in up-regulating the expressions of protease-activated receptor-1 (PAR-1) and matrix metalloproteinase-1 (MMP-1) PAR-1 thereby promoting gastric cancer metastasis.

METHODOLOGY/PRINCIPAL FINDINGS:

We examined the expression levels of Galectin-3, PAR-1, and MMP-1 in gastric cancer patient tissues and also the effects of silencing these proteins with specific siRNAs and of over-expressing them using specific lenti-viral constructs. We also employed zebrafish embryo model for analysis of in vivo gastric cancer cell invasion. These studies demonstrated that: a) galectin-3 silencing decreases the expression of PAR-1. b) galectin-3 over-expression increases cell migration and invasion and this increase can be reversed by PAR-1 silencing, indicating that galectin-3 increases cell migration and invasion via PAR-1 up-regulation. c) galectin-3 directly interacts with AP-1 transcriptional factor, and this complex binds to PAR-1 promoter and drives PAR-1 transcription. d) galectin-3 also amplifies phospho-paxillin, a PAR-1 downstream target, by increasing MMP-1 expression. MMP-1 silencing blocks phospho-paxillin amplification and cell invasion caused by galectin-3 over-expression. e) Silencing of either galectin-3, PAR-1 or MMP-1 significantly reduced cell migration into the vessels in zebrafish embryo model. f) Galectin-3, PAR-1, and MMP-1 are highly expressed and co-localized in malignant tissues from gastric cancer patients.

CONCLUSIONS/SIGNIFICANCE:

Galectin-3 plays the key role of activating cell surface receptor through production of protease and boosts gastric cancer metastasis. Galectin-3 has the potential to serve as a useful pharmacological target for prevention of gastric cancer metastasis.

• Authors: Seok-Jun Kim, Ji-Young Shin, Kang-Duck Lee, Young-Ki Bae, Il-Ju Choi, Seok Hee Park, Kyung-Hee Chun
• Journal: PloS one (PLoS One) Vol. 6 Issue 9 Pg. e25103 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21966428 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Galectin 3
• Receptor, PAR-1
• Matrix Metalloproteinase 1

Topics

• Animals
• Blotting, Western
• Cell Line, Tumor
• Cell Movement (genetics, physiology)
• Chromatin Immunoprecipitation
• Galectin 3 (genetics, metabolism)
• Genetic Vectors (genetics)
• Humans
• Immunohistochemistry
• Immunoprecipitation
• In Vitro Techniques
• Lentivirus (genetics)
• Matrix Metalloproteinase 1 (genetics, metabolism)
• Oligonucleotide Array Sequence Analysis
• Receptor, PAR-1 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Stomach Neoplasms (genetics, metabolism)
• Zebrafish