The cancer growth suppressing gene mda-7 induces apoptosis selectively in human melanoma cells
The cancer growth suppressing gene mda-7 induces apoptosis selectively in human melanoma cells
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DOI：
10.1038/sj.onc.1205116
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发表时间：
2002-01-24
期刊：
影响因子：
8
通讯作者：
Fisher, PB
中科院分区：
文献类型：
--
作者：
Lebedeva, IV;Su, ZZ;Fisher, PB
人黑色素瘤细胞在用成纤维细胞干扰素（IFN-β）和蛋白激酶C激活剂美泽瑞因（MEZ）的组合治疗后生长不可逆地停滞，失去致瘤潜力并终末分化。应用差减杂交技术克隆了黑色素瘤分化相关基因mda-7。mda-7的表达与黑色素瘤的发生和进展呈负相关，在正常黑色素细胞和痣中表达升高，在放射状生长期、垂直生长期和转移性黑色素瘤中表达逐渐降低。当通过无复制能力的腺病毒（Ad.mda-7）表达时，黑色素瘤的生长，而不是正常的早期传代或永生的人黑色素细胞的生长，被显著抑制，并且细胞经历程序性细胞死亡（凋亡）。用Ad.mda-7感染转移性黑素瘤细胞导致细胞周期的G（2）/M期细胞增加，并且促凋亡（BAX，巴克）与抗凋亡（BCL-2，BCL-XL）蛋白的比率改变。Ad.mda-7感染导致大多数黑素细胞/黑素瘤细胞系中的mda-7 mRNA和细胞内MDA-7蛋白的暂时增加，并且在Ad.mda-7感染黑素细胞和黑素瘤细胞两者后容易检测到MDA-7蛋白的分泌。目前的研究证明了黑素细胞和黑色素瘤细胞对mda-7异位表达的不同反应，并支持mda-7在转移性黑色素瘤基因治疗中的未来应用。
Human melanoma cells growth arrest irreversibly, lose tumorigenic potential and terminally differentiate after treatment with a combination of fibroblast interferon (IFN-beta) and the protein kinase C activator mezerein (MEZ). Applying subtraction hybridization to this model differentiation system permitted cloning of melanoma differentiation associated gene-7, mda-7. Expression of mda-7 inversely correlates with melanoma development and progression, with elevated expression in normal melanocytes and nevi and increasingly reduced expression in radial growth phase, vertical growth phase and metastatic melanoma. When expressed by means of a replication incompetent adenovirus (Ad.mda-7) growth of melanoma, but not normal early passage or immortal human melanocytes, is dramatically suppressed and cells undergo programmed cell death (apoptosis). Infection of metastatic melanoma cells with Ad.mda-7 results in an increase in cells in the G(2)/M phase of the cell cycle and changes in the ratio of pro-apoptotic (BAX, BAK) to anti-apoptotic (BCL-2, BCL-XL) proteins. Ad.mda-7 infection results in a temporal increase in mda-7 mRNA and intracellular MDA-7 protein in most of the melanocyte/melanoma cell lines and secretion of MDA-7 protein is readily detected following Ad.mda-7 infection of both melanocytes and melanoma cells. The present studies document a differential response of melanocytes versus melanoma cells to ectopic expression of mda-7 and support future applications of mda-7 for the gene-based therapy of metastatic melanoma.