Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy

Human malignant melanoma has poor prognosis because of resistance to apoptosis and therapy. We describe identification of the expression profile of 1,037 mitochondria-focused genes and 84 survival-apoptosis genes in 21 malignant melanoma cell lines and 3 normal melanocyte controls using recently developed hMitChip3 cDNA microarrays. Unsupervised hierarchical clustering analysis of 1,037 informative genes, and 84 survival-apoptosis genes, classified these malignant melanoma cell lines into type A ( n = 12) and type B ( n = 9). Three hundred fifty-five of 1,037 (34.2%) genes displayed significant ( P ≤ 0.030; false discovery rate ≤ 3.68%) differences (±≥2.0-fold) in average expression, with 197 genes higher and 158 genes lower in type A than in type B. Of 84 genes with known survival-apoptosis functions, 38 (45.2%) displayed the significant ( P < 0.001; false discovery rate < 0.15%) difference. Antiapoptotic ( BCL2, BCL2A1, PPARD , and RAF1 ), antioxidant ( MT3, PRDX5, PRDX3, GPX4, GLRX2 , and GSR ), and proapoptotic ( BAD, BNIP1, APAF1, BNIP3L, CASP7, CYCS, CASP1 , and VDAC1 ) genes expressed at higher levels in type A than in type B, whereas the different set of antiapoptotic ( PSEN1, PPP2CA, API5, PPP2R1B, PPP2R1A, and FIS1 ), antioxidant ( HSPD1, GSS, SOD1, ATOX1 , and CAT ), and proapoptotic ( ENDOG, BAK1, CASP2, CASP4, PDCD5, HTRA2, SEPT4, TNFSF10 , and PRODH ) genes expressed at lower levels in type A than in type B. Microarray data were validated by quantitative reverse transcription-PCR. These results showed the presence of two types of malignant melanoma, each with a specific set of dysregulated survival-apoptosis genes, which may prove useful for development of new molecular targets for therapeutic intervention and novel diagnostic biomarkers for treatment and prognosis of malignant melanoma.[Mol Cancer Ther 2009;8(5):OF1–13]