Our Funds at Work

Role of tumor suppressor ING3 in melanoma growth

Gang Li, MD, BC Cancer Agency, Vancouver, BC

Malignant melanoma is a life-threatening skin cancer and its incidence in Caucasian populations has increased faster than any other malignancy during the last 20 years. Patients with metastatic melanoma can only survive for 6–8.5 months on average. The molecular mechanism of melanoma pathogenesis is poorly understood. Recently, we found that the nuclear expression of ING3, a member of ING (inhibitor of growth) proteins, is significantly reduced in malignant melanoma compared to benign nevi. Furthermore, reduced nuclear ING3 expression is closely associated with poor patient survival. We are now investigating the molecular mechanisms of ING3 tumor suppressive functions. We will examine how ING3 is degraded much faster in melanoma cells than melanocytes and whether restoration of ING3 in melanoma cells will inhibit tumor growth and metastasis in vivo. This project will not only provide new insights into the molecular mechanisms of ING3 inhibitory effect in melanoma progression, but also test the efficacy of using ING3 as a molecular target for melanoma therapy.

Peer-Reviewed Publications Supported by the Canadian Dermatology Foundation

1. Campos EI, Martinka M, Mitchell DL, Dai DL, Li G. Mutations of the ING1 tumor suppressor gene detected in human melanoma abrogate nuclear excision repair. Int. J. Oncol. 25:73-80, 2004.
2. Dai DL, Martinka M, Bush JA, Li G. Reduced Apaf-1 expression in human cutaneous melanoma. Br. J. Cancer 91:1089-1095, 2004.
3. Zhou Y, Dai DL, Martinka M, Su M, Zhang Y, Campos EI, Dorocicz I, Tang L, Nelson C, Ho V, Li G. Osteopontin expression correlates with melanoma invasion and promotes cell growth. J. Invest. Dermatol. 124:1044-1052, 2005.
4. Ho CK, Li G. Mutant p53 melanoma cell lines respond differently to CP-31398-induced apoptosis. Br. J. Dermatol. 153: 900-910, 2005.
5. Tang L, Dai D, Su M, Martinka M, Li G, Zhou Y. Aberrant expression of collagen triple helix repeat containing 1 (CTHRC1): Association with melanoma progression and prevalence in human solid cancers. Clin. Cancer Res. 12:3716-3722, 2006.
6. Karst AM, Li G. BH3-only proteins in tumorigenesis and malignant melanoma. Cell. Mol. Life Sci. 64:318-330, 2007.
7. Kuo WH, Wang Y, Wong RPC, Campos EI, Li G. The ING1b protein facilitates accessibility to damaged nucleosomal DNA. Exp. Cell Res. 313:1628-1638, 2007.
8. Wang Y, Dai DL, Martinka M, Li G. Prognostic significance of ING3 subcellular localization in human cutaneous melanoma. Clin. Cancer Res. 13: 4111-4116, 2007.
9. Garate M, Campos EI, Bush JA, Xiao H, Li G. Phosphorylation of the tumor suppressor p33ING1b at Ser126 influences its protein stability and cell proliferation. FASEB J. 21:3705-3716, 2007.
10. Dai DL, Wang Y, Liu M, Martinka M, Li G. Reduced Bim expression in human cutaneous melanomas. J. Invest. Dermatol. 128:403-407, 2008.
11. Wong RPC, Khosravi S, Martinka M, Li G. Mcl-1 expression is overexpressed in dysplastic nevi and melanoma. Oncol. Rep. 19:933-937, 2008.
12. Garate M, Wong R, Campos EI, Wang Y, Li G. NQO1 inhibits the proteasomal degradation of the tumor suppressor p33ING1b. EMBO Rep. 9:576-581, 2008.
13. Li J, Martinka M, Li G. Role of ING4 in human melanoma cell migration, invasion, and patient survival. Carcinogenesis 29:1373-1379, 2008
14. Gao K, Lockwood WW, Li J, Lam W, Li G. Genomic analyses identify gene candidates for acquired irinotecan resistance in melanoma cells. Int. J. Oncol. 32:1343-1349, 2008.
15. Wong RPC, Lin LH, Li G. Tumor suppressor ING1b regulates PCNA monoubiquitination and S phase recovery after UV irradiation. (submitted to Genes & Dev.)
16. Wang Y, Chen G, Garate M, Zhou J, Li G. SCFSkp2-mediated ING3 degradation regulates cell cycle control in melanoma cells. (submitted to Cancer Res)
17. Li J, Wang Y, Wong RPC, Li G. The role of ING tumor suppressors in UV stress response and melanoma progression. (submitted to Curr Drug Targets)

© 2009