3673

ITGA2

integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor);ITGA2;integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor)

CD49 antigen-like family member B|VLA2 receptor, alpha-2 subunit|collagen receptor|human platelet alloantigen system 5|integrin alpha-2|platelet antigen Br|platelet glycoprotein GPIa|platelet membrane glycoprotein Ia|very late activation protein 2 recepto

5q11.2

protein-coding

Integrins regulate cell-cell and cell-matrix adhesion and thereby play critical roles in tumor progression and metastasis. Although work in preclinical models suggests that beta1 integrins may stimulate metastasis of a number of cancers, expression of the beta1 subunit alone has not been shown to be a useful prognostic indicator in human cancer patients. Here we have demonstrated that the alpha2beta1 integrin suppresses metastasis in a clinically relevant spontaneous mouse model of breast cancer. These data are consistent with previous studies indicating high expression of alpha2beta1 integrin in normal breast epithelium and loss of alpha2beta1 in poorly differentiated breast cancer. They are also consistent with our systematic analysis of microarray databases of human breast and prostate cancer, which revealed that decreased expression of the gene encoding alpha2 integrin, but not genes encoding alpha1, alpha3, or beta1 integrin, was predictive of metastatic dissemination and decreased survival. The predictive value of alpha2 expression persisted within both good-risk and poor-risk cohorts defined by estrogen receptor and lymph node status. Thus, the alpha2beta1 integrin functionally inhibits breast tumor metastasis, and alpha2 expression may serve as an important biomarker of metastatic potential and patient survival.

BACKGROUND: Although integrins have been implicated in the progression of breast cancer, the exact mechanism whereby they exert this regulation is clearly not understood. To understand the role of integrins in breast cancer, we examined the expression levels of several integrins in mouse breast cancer cell lines by flow cytometry and the data were validated by Western and RT-PCR analysis. The importance of integrins in cell migration and cell invasion was examined by in vitro assays. Further the effect of integrins on metastasis was investigated by in vivo experimental metastasis assays using mouse models. RESULTS: Integrin alpha5 subunit is highly expressed in the nonmetastatic cell line 67NR and is significantly low in the highly invasive cell line 4T1. In contrast, expression levels of integrin alpha6 subunit are high in 4T1 cells and low in 67NR cells. In vitro data indicated that overexpression of alpha5 subunit and knockdown of alpha6 integrin subunit inhibited cell proliferation, migration, and invasion. Our in vivo findings indicated that overexpression of integrin alpha5 subunit and knockdown of alpha6 subunit decreased the pulmonary metastasis property of 4T1 cells. Our data also indicated that overexpression of alpha 5 integrin subunit and suppression of alpha6 integrin subunit inhibited cells entering into S phase by up-regulating p27, which results in downregulation of cyclinE/CDK2 complexes, This suggests that these integrins regulate cell growth through their effects on cell-cycle-regulated proteins. We also found that modulation of these integrins upregulates E2F, which may induce the expression of chk1 to regulate cdc25A/cyclin E/CDK2/Rb in a feedback loop mechanism. CONCLUSION: This study indicates that Integrin alpha5 subunit functions as a potential metastasis suppressor, while alpha6 subunit functions as a metastasis promoter. The modulation of integrins reduces cdc25 A, another possible mechanism for downregulation of CDK2. Taken together we demonstrate a link between integrins and the chk1-cdc25-cyclin E/CDK2-Rb pathway.

Osteosarcoma, the most common primary bone tumor in children and young adolescents, is characterized by local invasion and distant metastasis. But the detailed mechanisms of osteosarcoma metastasis are not well known. In the present study, we found that betaig-h3 promotes metastatic potential of human osteosarcoma cells in vitro and in vivo. Furthermore, betaig-h3 co-localized with integrin alpha2beta1 in osteosarcoma cells. But betaig-h3 did not change integrin alpha2beta1 expression in Saos-2 cells. Interaction of betaig-h3 with integrin alpha2beta1 mediates metastasis of human osteosarcoma cells. The second FAS1 domain of betaig-h3 but not the first FAS1 domain, the third FAS1 domain or the fourth FAS1 domain mediates human osteosarcoma cells metastasis, which is the alpha2beta1 integrin-interacting domain. We further demonstrated that PI3K/AKT signaling pathway is involved in betaig-h3-induced human osteosarcoma cells metastasis process. Together, these results reveal betaig-h3 enhances the metastasis potentials of human osteosarcoma cells via integrin alpha2beta1-mediated PI3K/AKT signal pathways. The discovery of betaig-h3-mediated pathway helps us to understand the mechanism of human osteosarcoma metastasis and provides evidence for the possibility that betaig-h3 can be a potential therapeutic target for osteosarcoma treatment.

Men who die of prostate cancer (PCa) do so because of systemic metastases, the most frequent of which are within the skeleton. Recent data suggest that the colonization of the skeleton is mediated in part by collagen type I, the most abundant protein within the bone. We have shown that enhanced collagen I binding through increased expression of integrin alpha2beta1 stimulated in vitro invasion and promoted the growth of PCa cells within the bone. Accordingly, we sought to determine whether alpha2beta1 integrin is a potential mediator of skeletal metastasis. To examine whether alpha2beta1 integrin mediates PCa metastasis, alpha2 integrin was over-expressed in low-tumorigenic LNCaP PCa cells or selectively knocked-down in highly metastatic LNCaPcol PCa cells. We document that the over-expression of alpha2 cDNA stimulated whereas alpha2 shRNA inhibited the ability of transduced cells to bind to or migrate towards collagen in vitro. Correspondingly, alpha2 integrin knock-down reduced the tumor burden of intra-osseous tumors compared to control-transduced cells. To investigate the clinical significance of alpha2beta1 expression in PCa, alpha2beta1 protein was measured in prostatic tissues and in soft tissue and bone metastases. The data demonstrate that alpha2beta1 protein was elevated in PCa skeletal metastases compared to either PCa primary lesions or soft tissue metastases suggesting that alpha2beta1 contributes to the selective metastasis to the bone. Taken together, these data support that alpha2beta1 integrin is needed for the efficient metastasis of PCa cells to the skeleton.