MT1-MMP dependent repression of the tumor suppressor SPRY4 contributes to MT1-MMP driven melanoma cell motility
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Khvaramze Shaverdashvili1, Keman Zhang1, Iman Osman2, Kord Honda3, Rauli Jobava4, Barbara Bedogni1
1From the Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA
2From the Departments of Dermatology, Urology and Medicine, New York University Langone Medical Center, New York, NY, USA
3From the Department of Pathology and Dermatology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
4From the Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
Barbara Bedogni, e-mail: [email protected]
Keywords: cell migration, melanoma, SPRY4, matrix metalloproteinase (MMP)
Received: July 01, 2015 Accepted: August 31, 2015 Published: September 12, 2015
Metastatic melanoma is the deadliest of all skin cancers. Despite progress in diagnostics and treatment of melanoma, the prognosis for metastatic patients remains poor. We previously showed that Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) is one of the drivers of melanoma metastasis. Classically, MT1-MMP regulates a verity of cellular functions including cell-to-cell interaction and cell-to-matrix communication. Recently, MT1-MMP has been found to also modulate gene expression. To specifically assess MT1-MMP dependent gene regulation in melanoma, microarray gene expression analysis was performed in a melanoma cell line whose metastatic properties depend on the activity of MT1-MMP. We identified the tumor suppressor gene SPRY4 as a new transcriptional target of MT1-MMP that is negatively regulated by the protease. Knockdown of MT1-MMP enhances SPRY4 expression at the mRNA and protein level. SPRY4 expression inversely correlates with that of MT1-MMP in melanoma samples and importantly, correlates with melanoma patient survival. SPRY4 modulates MT1-MMP dependent cell migration such that inhibition of SPRY4 rescues cell migration that has been impaired by MT1-MMP knock down. MT1-MMP decreases SPRY4 in part through an MMP2/RAC1 axis we previously show promotes cell motility downstream of MT1-MMP. These results identify the tumor suppressor SPRY4 as a novel molecular effector of MT1-MMP affecting melanoma cell motility.
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