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The expression of XAF1 in melanoma and the role of ILK in melanoma invasive behavior

University of British Columbia

The high metastatic potential and the resistance to apoptosis are common features of melanoma that make effective treatment difficult. The design of novel strategies for the treatment of this disease relies on the identification of key regulators of melanoma apoptosis and metastasis. In the current study, we characterized the protein expression of a novel tumor suppressor, XIAP-associated factor 1 (XAF1) in 70 primary melanomas and determined the role of integrin-linked kinase (ILK) in melanoma cell migration and invasion. Our first study shows that XAF1 mRNA expression was weak or undetectable in majority of melanoma cell lines. More importantly, XAF1 expression was significantly reduced in melanoma tissues compared with benign nevi in both nucleus and cytoplasm. Since XAF1 has been shown to inhibit the antiapoptotic activity of XIAP, the loss of XAF1 in melanoma may contribute to the impairment of apoptosis pathway and ultimately the malignant nature of melanoma. In the second study, we have determined the possible role of ILK as a regulator of melanoma progression. Inhibition of the kinase activity of ILK and depletion of endogenous ILK expression both significantly reduced melanoma cell migration. Moreover, melanoma cells stably expressing ILK short hairpin RNA resulted in a marked reduction in colony formation on soft agar and inhibition of invasion through Matrigel. In vivo data from melanoma xenograft indicated that mice inoculated with melanoma cells depleted of ILK expression showed a much slower tumor growth compared with mice inoculated with control melanoma cells. In summary, the loss of XAF1 expression in melanoma biopsies and the inhibition of cell migration and invasion through the inhibition of ILK suggest that both factors may play a prominent role in melanoma apoptosis pathway and invasion, respectively. Further study on the therapeutic value of ILK inhibition and proapoptotic function of XAF1 may help the development of effective therapy against metastatic melanoma.

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2011-02-25

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http://hdl.handle.net/2429/31801

Experimental Medicine

University of British Columbia

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