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Role of tumor suppressor ING4 in human cutaneous melanoma pathogenesis and progression Li, Jun

Abstract

ING4 was identified as a tumor suppressor in 2003 and shown to diminish colony-forming efficiency, induce p53-dependent apoptosis, and arrest cell cycle at G2/M phase. To investigate the role of ING4 in human cutaneous melanoma, we examined ING4 expression using tissue microarray and found that ING4 expression was significantly decreased in malignant melanoma compared with dysplastic nevi and reduced ING4 expression was correlated with melanoma thickness, ulceration and poor 5-year survival of melanoma patients. Multivariate analysis revealed that ING4 expression is an independent prognostic marker in melanoma patients. In melanoma cells, we found that overexpression of ING4 suppressed melanoma cell migration through RhoA-ROCK pathway and cell invasion by inhibiting MMP-2 and MMP-9 activity. We also demonstrated that ING4 inhibits endothelial cell growth and tube formation in vitro through suppressing NF- κB/IL-6 pathway. In vivo model revealed that ING4 inhibited blood vessel formation and recruitment of endothelial cells in matrigel plugs. Strikingly, we found that ING4 is induced by BRMS1. Further experiments showed that BRMS1 expression was significantly decreased in metastatic melanoma compared with primary melanoma or dysplastic nevi, and reduced BRMS1 staining was correlated with AJCC stages and worse 5-year survival of melanoma patients. Moreover, we demonstrated that BRMS1 overexpression inhibited endothelial cell growth and tube formation in vitro through suppressing NF-κB/IL-6 pathway and this BRMS1-mediated IL-6 expression is dependent on NF-κB. In vivo studies indicated that BRMS1 inhibited supportive blood vessel formation in matrigel plugs. Furthermore, we demonstrated that ING4 knockdown abrogated the suppressive effect of BRMS1 on HUVECs growth, while ING4 overexpression inhibited BRMS1 knockdown-induced angiogenesis, indicating BRMS1 as upstream regulator of ING4 in regulating tumor angiogenesis. Finally, we found that the integrate score of six-biomarker system, including ING4, BRMS1 together with other four biomarkers, showed higher variations between melanoma with and without metastasis, and predicted melanoma patients outcome more accurately than individual biomarker. In summary, reduced ING4 expression in melanoma results in deficient suppression of melanoma cell migration and invasion. With BRMS1 as the upstream regulator, ING4 inhibits NF-κB/IL-6 to modulate melanoma angiogenesis. ING4 expression can be a prognostic marker and novel target for human melanoma treatment.

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