The matrix protein CCN1/CYR61 is required for αVβ5‐mediated cancer cell migration

CYR61 is one of the six proteins of the CCN family of proteins known to play diverse roles in angiogenesis, cellular proliferation, survival, migration and wound healing. However, the specific function of CYR61 in cancer is unclear, and the literature remains controversial. We used quantitative real‐time PCR to establish the expression profile of CYR61 and integrin αVβ5 in three non–small cell lung cancer, five colorectal cancer, one breast cancer and one oesophageal squamous carcinoma cell lines. We showed that the levels of CYR61 were significantly increased in oesophageal squamous carcinoma cell line along with the enhanced levels of αVβ5 integrin. Further, we investigated whether tumour cell–secreted CYR61 can facilitate cell migration by interacting with the αVβ5 integrin. Using tumour cell lines with low, intermediate and high CYR61 expression and their isogenic variants as a cellular model, we determined that integrin αVβ5 expressed on these tumour cells is required for cell migration. Moreover, we showed that the modulation of expression levels of CYR61 in these cancer cells affected their capacity for migration. These results represent an advance to the understanding of the role of CYR61 and αvβ5 integrin as proteins that cooperate to mediate cancer cell migration. Copyright © 2012 John Wiley & Sons, Ltd.

[1]  Chun-Hao Tsai,et al.  CCN3 increases cell motility and MMP‐13 expression in human chondrosarcoma through integrin‐dependent pathway , 2011, Journal of cellular physiology.

[2]  E. Li,et al.  Involvement of Cyr61 in the growth, invasiveness and adhesion of esophageal squamous cell carcinoma cells. , 2011, International journal of molecular medicine.

[3]  D. Mcgregor,et al.  Cyr61/CCN1 signaling is critical for epithelial-mesenchymal transition and stemness and promotes pancreatic carcinogenesis , 2011, Molecular Cancer.

[4]  E. Platz,et al.  Decreased Expression of Cyr61 Is Associated with Prostate Cancer Recurrence after Surgical Treatment , 2010, Clinical Cancer Research.

[5]  S. Strömblad,et al.  Integrin-mediated Cell Attachment Induces a PAK4-dependent Feedback Loop Regulating Cell Adhesion through Modified Integrin αvβ5 Clustering and Turnover , 2010, Molecular biology of the cell.

[6]  Paula Chaves,et al.  Verification and unmasking of widely used human esophageal adenocarcinoma cell lines. , 2010, Journal of the National Cancer Institute.

[7]  L. Lau,et al.  Functions and mechanisms of action of CCN matricellular proteins. , 2009, The international journal of biochemistry & cell biology.

[8]  D. Xie,et al.  Involvement of Cyr61 in growth, migration, and metastasis of prostate cancer cells , 2008, British Journal of Cancer.

[9]  R. Mirimanoff,et al.  CYR61 and alphaVbeta5 integrin cooperate to promote invasion and metastasis of tumors growing in preirradiated stroma. , 2008, Cancer research.

[10]  E. Cohen-Jonathan-Moyal,et al.  αvβ3 and αvβ5 integrins control glioma cell response to ionising radiation through ILK and RhoB , 2008, International journal of cancer.

[11]  E. Montgomery,et al.  Identification of Fn14/TWEAK receptor as a potential therapeutic target in esophageal adenocarcinoma , 2007, International journal of cancer.

[12]  Yan Wang,et al.  Expression of Cyr61, CTGF, and WISP-1 Correlates with Clinical Features of Lung Cancer , 2007, PloS one.

[13]  L. Lau,et al.  Cytotoxicity of TNFα is regulated by integrin‐mediated matrix signaling , 2007, The EMBO journal.

[14]  L. Lau,et al.  INTEGRIN-MEDIATED CCN FUNCTIONS , 2005 .

[15]  N. Planque,et al.  CCN proteins and cancer: two to tango. , 2005, Frontiers in bioscience : a journal and virtual library.

[16]  L. Girard,et al.  Increased expression of Cyr61 (CCN1) identified in peritoneal metastases from human pancreatic cancer. , 2005, Journal of the American College of Surgeons.

[17]  Carl W. Miller,et al.  Cyr61 Suppresses Growth of Human Endometrial Cancer Cells* , 2004, Journal of Biological Chemistry.

[18]  L. Lau,et al.  Identification of a Novel Integrin αvβ3 Binding Site in CCN1 (CYR61) Critical for Pro-angiogenic Activities in Vascular Endothelial Cells* , 2004, Journal of Biological Chemistry.

[19]  Y. Liu,et al.  Targeted Mutagenesis of the Angiogenic Protein CCN1 (CYR61) , 2004, Journal of Biological Chemistry.

[20]  Carl W. Miller,et al.  Cyr61 suppresses the growth of non-small-cell lung cancer cells via the β-catenin–c-myc–p53 pathway , 2004, Oncogene.

[21]  Ming-Tsan Lin,et al.  Cyr61 Expression Confers Resistance to Apoptosis in Breast Cancer MCF-7 Cells by a Mechanism of NF-κB-dependent XIAP Up-Regulation* , 2004, Journal of Biological Chemistry.

[22]  Dong Xie,et al.  Cyr61 Is Overexpressed in Gliomas and Involved in Integrin-Linked Kinase-Mediated Akt and β-Catenin-TCF/Lef Signaling Pathways , 2004, Cancer Research.

[23]  D. Brigstock The CCN family: a new stimulus package. , 2003, The Journal of endocrinology.

[24]  C. Otey Faculty Opinions recommendation of P21-activated kinase 4 interacts with integrin alpha v beta 5 and regulates alpha v beta 5-mediated cell migration. , 2002 .

[25]  H. Iwata,et al.  Role of matrix metalloproteinase‐9 in in vitro invasion of esophageal carcinoma cells , 2002, Journal of surgical oncology.

[26]  S. Strömblad,et al.  p21-activated kinase 4 interacts with integrin αvβ5 and regulates αvβ5-mediated cell migration , 2002, The Journal of cell biology.

[27]  L. Lau,et al.  The Angiogenic Factor Cysteine-Rich 61 (CYR61, CCN1) Supports Vascular Smooth Muscle Cell Adhesion and Stimulates Chemotaxis through Integrin α6β1 and Cell Surface Heparan Sulfate Proteoglycans. , 2002, Endocrinology.

[28]  R. Elashoff,et al.  Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features. , 2001, Cancer research.

[29]  Carl W. Miller,et al.  Cyr61, a Member of CCN Family, Is a Tumor Suppressor in Non-Small Cell Lung Cancer* , 2001, The Journal of Biological Chemistry.

[30]  R. Winneker,et al.  Aberrant expression of Cyr61, a member of the CCN (CTGF/Cyr61/Cef10/NOVH) family, and dysregulation by 17 beta-estradiol and basic fibroblast growth factor in human uterine leiomyomas. , 2001, The Journal of clinical endocrinology and metabolism.

[31]  J. Lakins,et al.  Expression and function of CYR61, an angiogenic factor, in breast cancer cell lines and tumor biopsies. , 2000, Cancer research.

[32]  A. Sonnenberg,et al.  Structure and function of hemidesmosomes: more than simple adhesion complexes. , 1999, The Journal of investigative dermatology.

[33]  T. V. Kolesnikova,et al.  CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[34]  L. Lau,et al.  Adhesion of Human Umbilical Vein Endothelial Cells to the Immediate-Early Gene Product Cyr61 Is Mediated through Integrin αvβ3 * , 1998, The Journal of Biological Chemistry.

[35]  B. Schäfer,et al.  Isolation of genes differentially expressed in human primary myoblasts and embryonal rhabdomyosarcoma , 1996, International journal of cancer.

[36]  P. Bork The modular architecture of a new family of growth regulators related to connective tissue growth factor , 1993, FEBS letters.

[37]  L. Lau,et al.  Identification of a novel integrin alphavbeta3 binding site in CCN1 (CYR61) critical for pro-angiogenic activities in vascular endothelial cells. , 2004, The Journal of biological chemistry.

[38]  L. Lau,et al.  The angiogenic factor cysteine-rich 61 (CYR61, CCN1) supports vascular smooth muscle cell adhesion and stimulates chemotaxis through integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans. , 2002, Endocrinology.

[39]  L. Lau,et al.  CYR61 stimulates human skin fibroblast migration through Integrin alpha vbeta 5 and enhances mitogenesis through integrin alpha vbeta 3, independent of its carboxyl-terminal domain. , 2001, The Journal of biological chemistry.