Gastric Cancer Branch, Division of Translational and Clinical Research I, National Cancer Center Research Institute and Hospital, Jungbalsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea.
PLoS One. 2011;6(9):e25103. doi: 10.1371/journal.pone.0025103. Epub 2011 Sep 22.
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.
已知半乳糖凝集素-3 可调节癌症转移。然而，其潜在机制尚未明确。通过沉默半乳糖凝集素-3 后的 DNA 微阵列研究，我们在此证明半乳糖凝集素-3 在上调蛋白酶激活受体-1（PAR-1）和基质金属蛋白酶-1（MMP-1）的表达中发挥关键作用，从而促进胃癌转移。
方法/主要发现：我们检查了胃癌患者组织中半乳糖凝集素-3、PAR-1 和 MMP-1 的表达水平，还研究了用特定的 siRNA 沉默这些蛋白以及用特定的 lentiviral 构建体过表达它们的效果。我们还采用斑马鱼胚胎模型分析体内胃癌细胞侵袭。这些研究表明：a）沉默半乳糖凝集素-3 可降低 PAR-1 的表达。b）过表达半乳糖凝集素-3 可增加细胞迁移和侵袭，而这种增加可被 PAR-1 沉默逆转，表明半乳糖凝集素-3 通过上调 PAR-1 增加细胞迁移和侵袭。c）半乳糖凝集素-3 直接与 AP-1 转录因子相互作用，该复合物结合到 PAR-1 启动子并驱动 PAR-1 转录。d）半乳糖凝集素-3 还通过增加 MMP-1 的表达来放大 PAR-1 的下游靶点磷酸化斑联蛋白。沉默 MMP-1 可阻断半乳糖凝集素-3 过表达引起的磷酸化斑联蛋白放大和细胞侵袭。e）在斑马鱼胚胎模型中，沉默半乳糖凝集素-3、PAR-1 或 MMP-1 均可显著减少细胞向血管内迁移。f）半乳糖凝集素-3、PAR-1 和 MMP-1 在胃癌患者的恶性组织中高表达且共定位。
结论/意义：半乳糖凝集素-3 通过产生蛋白酶发挥激活细胞表面受体的关键作用，促进胃癌转移。半乳糖凝集素-3 有可能成为预防胃癌转移的有用药理学靶点。
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