Carcinogenesis Advance Access published online on March 28, 2008
Carcinogenesis, doi:10.1093/carcin/bgn086
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Role of ING4 in human melanoma cell migration, invasion, and patient survival
1 Department of Dermatology and Skin Science
2 Department of Pathology, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
* To whom correspondence should be addressed: Email: gangli{at}interchange.ubc.ca
ING4 has been reported as a tumor suppressor and shown to diminish colony-forming efficiency, induce p53-dependent apoptosis and arrest cell cycle at G2/M phase. In this study, we investigated the role of ING4 in human melanoma pathogenesis. Using the tissue microarray technology, we found that ING4 expression is significantly decreased in malignant melanoma compared with dysplastic nevi (P < 0.0001, 
2 test) and reduced ING4 staining is associated with melanoma thickness, ulceration (P = 0.034 and 0.002, respectively, 2 test), as well as poor overall and disease-specific 5-year survival in primary melanoma patients (P = 0.0002 and 0.001, respectively, 2 test). Cox regression analysis revealed that reduced ING4 staining is an independent factor for the poor prognosis of patients with primary melanomas. Furthermore, we found that overexpression of ING4 suppressed cell migration by 63% and inhibited RhoA activity and Rock-mediated formation of stress fiber in melanoma cells. Moreover, our data showed that overexpression of ING4 inhibited melanoma cell invasion by 43% compared with the control (P = 0.006, t-test) and ING4-overexpressing melanoma cells showed significantly reduced activity of matrix metalloproteinase-2 (MMP-2) and MMP-9. Taken together, this study highlights the importance of ING4 in melanoma pathogenesis and ING4 may serve as a promising prognostic marker and a potential therapeutic target for human melanoma.
Key Words: ING4 • melanoma • cell migration • cell invasion • prognosis
Received February 7, 2008; revised March 23, 2008; accepted March 23, 2008.
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