Cysteine-Rich 61 (CCN1) Enhances Chemotactic Migration, Transendothelial Cell Migration, and Intravasation by Concomitantly Up-Regulating Chemokine Receptor 1 and 2

Abstract

Cysteine-rich 61 (Cyr61; CCN1) plays an important role in tumor development and progression in many kinds of human malignancies. Here, we further show the enforced expression of the Cyr61 gene or treatment with recombinant Cyr61 protein enhanced expression of chemokine receptors CXCR1 and CXCR2 in gastric cancer AGS cells. Attenuation of Cyr61 levels in MKN-45 cells by transfecting with antisense Cyr61 significantly reduced the level of CXCR1 and CXCR2. It is suggested that Cyr61 tightly regulates the downstream genes CXCR1 and CXCR2 in gastric cancer cells. Supportively, reverse transcription -PCR and immunohistochemical analysis of human gastric adenocarcinoma showed that there was a high correlation between the expression level of Cyr61 and CXCR1/CXCR2. The up-regulated functionality of CXCR1 andCXCR2 in Cyr61-overexpressing AGS cells could facilitate their chemotactic migration toward interleukin-8, a physiologic ligand of CXCR1 and CXCR2. In addition, the Cyr61-mediated up-regulation of CXCR1/CXCR2 also contributed to transendothelial migration, as well as intravasation in a chick embryo model. Pharmacologic and genetic approaches revealed that phosphoinositide 3-kinase (PI3K)/Akt, but not extracellular signal-regulated kinase 1/2 or p38, signaling pathway is requisite for the up-regulation of CXCR1/CXCR2 mRNA and protein induced by Cyr61. Function-neutralizing antibody to integrin AvB3, but not A 2 B 1 , effectively abolished Cyr61-elicited Src activation and the subsequent PI3K/ Akt pathway. Antagonists toward integrin AvB3, Src kinase, and PI3K/Akt not only suppressed CXCR1/ CXCR2 elevation but also blocked chemotactic migration induced by Cyr61. In conclusion, we suggest that Cyr61 promotes interleukin-8 -dependent chemotaxis, transendothelial migration, and intravasation by induction of CXCR1/CXCR2 through integrin AvB3/Src/PI3K/Akt -dependent pathway.

Cyr61 increases migration and MMP-13 expression via αvβ3 integrin, FAK, ERK and AP-1-dependent pathway in human chondrosarcoma cells

“…Cyr61-directed chondrosarcoma cells migration through avb3 integrin Cyr61 has been reported to stimulate directional migration and invasion of human cancer cells (25,26). We first examined whether Cyr61 express in human chondrosarcoma cells.…”

“…The contrasting expression of Cyr61 in different types of cancer suggests that Cyr61 may exert a sophisticated function depending on cellular context. Previous studies have shown that Cyr61 modulates cell migration and invasion in human cancer cells (25,26). Cyr61-mediated migration may involve activation of integrin receptors (25).…”

A global genomic view of MIF knockdown-mediated cell cycle arrest

“…95,96 The recent study indicates that Cyr61 could promote chemotactic migration, transendothelial cell migration and intravasation by concomitantly upregulating chemokine receptor 1 and 2(CXCR1/CXCR2) through integrin α v β 3 /Src/PI3K/Akt-dependent pathway. 97 In the MIF knockdown cells, Cyr61 expression has been significantly downregulated in both mRNA level and protein levels, which would lead to inhibition of Cyr61-dependent signaling pathway. It suggests Cyr61 is the important MIF-responsive gene which might contribute to MIF-mediated cell proliferation, proinflammation, angiogenesis and even tumorogenesis.…”

Knockdown of cysteine-rich 61 inhibits proliferation, migration, and invasiveness of prostate carcinoma PC-3 cells

“…Binding of Cyr61 to integrin a v b 3 in decidual natural killer cells is shown to induce the expression of vascular endothelial growth factor C, which is modulated by PI3-kinase and its downstream effector Akt . Additionally, Cyr61-expressing cells were reported to exhibit stronger potency in transendothelial migration and intravasation in human gastric adenocarcinoma cell lines through integrin a v b 3 /PI3-kinase/Akt-dependent pathway (Lin et al 2007). We have also found that downregulation of integrin-b 3 is induced by Cyr61 silencing.…”