Activation of JAK2/STAT3 signaling by osteopontin promotes tumor growth in human breast cancer cells
Deregulation of signal transducer and activator of transcription (STAT)-3 signaling plays crucial role in oncogenesis of various cancers. However, the molecular mechanism by which osteopontin (OPN), a chemokine-like extracellular matrix-associated protein, regulates STAT3 activation that leads to tumor progression and inhibits apoptosis in breast cancer cells is not well understood. In this study, we for the first time report that OPN upregulates avb3 integrin-mediated Janus kinase 2 (JAK2)
... kinase 2 (JAK2) phosphorylation and STAT3 activation in breast cancer (MDA-MB-468 and MCF-7) cells. Pretreatment of cells with JAK2 inhibitor (AG 490) suppresses OPN-induced STAT3 phosphorylation, its nuclear localization and DNA binding indicating that JAK2 is involved in this process. Transfection of cells with wild-type (wt) STAT3 enhanced whereas mutant STAT3 (STAT3 Y705F) suppressed OPNinduced breast tumor cell migration. Treatment of cells with OPN followed by staurosporine (STS) showed that OPN protects the cells from STS-induced apoptosis. Moreover, transfection of cells with wt STAT3 upregulates whereas STAT3 Y705F downregulates Bcl2 and cyclin D1 expressions in response to OPN. Interestingly, STAT3-overexpressing cells when injected to non-obese diabetic/ severe combined immunodeficiency mice followed by OPN treatment, the mice developed enhanced tumor growth as compared with STAT3 Y705F-injected mice or mice injected with OPN alone. The levels of Bcl2 and cyclin D1 in wt STAT3 tumors were significantly higher than controls. Clinical specimen analysis revealed that increased OPN and pSTAT3 expressions correlate with enhanced breast tumor progression. Thus, targeting OPN and its regulated STAT3 signaling could be a potent therapeutic approach and understanding these mechanisms may form the basis of new therapeutic regimen for the management of breast cancer. Abbreviations: HEPES, N-2-hydroxyethylpiperazine-N#-2-ethanesulfonic acid; JAK2, Janus kinase 2; MMP, matrix metalloproteinase; NOD/SCID, non-obese diabetic/severe combined immunodeficiency; OPN, osteopontin; STAT, signal transducer and activator of transcription; STS, staurosporine; wt, wild-type.