The melanoma differentiation associated gene mda-7 suppresses cancer cell growth
The melanoma differentiation associated gene mda-7 suppresses cancer cell growth
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DOI：
10.1073/pnas.93.17.9160
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发表时间：
1996-08-20
影响因子：
11.1
通讯作者：
Fisher, PB
中科院分区：
文献类型：
--
作者：
Jiang, HP;Su, ZZ;Fisher, PB
癌症是一种以生长控制缺陷为特征的疾病，肿瘤细胞经常表现出异常的细胞分化模式。重组人成纤维细胞干扰素和抗白血病剂mezerein的结合纠正了培养的人黑色素瘤细胞中导致不可逆生长停滞和终末分化的这些异常。减法杂交鉴定出黑色素瘤分化相关基因（mda-7）在生长受阻和终末分化的人类黑色素瘤细胞中表达升高，当mda-7转染到不同来源和多种遗传缺陷的人类肿瘤细胞时，集落形成减少。相比之下，在正常细胞（包括人乳腺上皮细胞、人皮肤成纤维细胞和大鼠胚胎成纤维细胞）的瞬时转染试验中，mda-7对生长和集落形成的影响在数量上低于癌细胞。表达mda-7升高的肿瘤细胞表现出单层生长抑制和锚定独立性，用表达反义mda-7的重组5型腺病毒感染可消除mda-7对体外生长和转化表型的抑制。mda-7在不表达或不含视网膜母细胞瘤（RE）和p53基因缺陷的癌细胞中抑制生长的能力表明，在介导mda-7诱导的生长抑制过程中，缺乏这些关键的肿瘤抑制元件的参与。mda-7与先前描述的生长抑制基因缺乏蛋白同源性，以及该基因对正常细胞和癌细胞的差异作用表明，mda-7可能代表了一类具有抗肿瘤活性的新型肿瘤生长抑制基因。
Cancer is a disease characterized by defects in growth control, and tumor cells often display abnormal patterns of cellular differentiation. The combination of recombinant human fibroblast interferon and the antileukemic agent mezerein corrects these abnormalities in cultured human melanoma cells resulting in irreversible growth arrest and terminal differentiation. Subtraction hybridization identifies a melanoma differentiation associated gene (mda-7) with elevated expression in growth arrested and terminally differentiated human melanoma cells, Colony formation decreases when mda-7 is transfected into human tumor cells of diverse origin and with multiple genetic defects. In contrast, the effects of mda-7 on growth and colony formation in transient transfection assays with normal cells, including human mammary epithelial, human skin fibroblast, and rat embryo fibroblast, is quantitatively less than that found with cancer cells. Tumor cells expressing elevated mda-7 display suppression in monolayer growth and anchorage independence, Infection with a recombinant type 5 adenovirus expressing antisense mda-7 eliminates mda-7 suppression of the in vitro growth and transformed phenotype, The ability of mda-7 to suppress growth in cancer cells not expressing or containing defects in both the retinoblastoma (RE) and p53 genes indicates a lack of involvement of these critical tumor suppressor elements in mediating mda-7-induced growth inhibition, The lack of protein homology of mda-7 with previously described growth suppressing genes and the differential effect of this gene on normal versus cancer cells suggests that mda-7 may represent a new class of cancer growth suppressing genes with antitumor activity.