Selective Inhibition of HIF1α Expression by ZnSO4 Has Antitumoral Effects in Human Melanoma
Selective Inhibition of HIF1α Expression by ZnSO4 Has Antitumoral Effects in Human Melanoma
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DOI：
10.1007/s12253-018-00573-1
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发表时间：
2020-04-01
影响因子：
2.8
通讯作者：
Timar, Jozsef
中科院分区：
文献类型：
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作者：
Burian, Z.;Ladanyi, A.;Timar, Jozsef
锌作为一种重要的微量金属，是细胞各种分子中普遍存在的成分。研究表明，它可以调节各种癌细胞类型的功能，甚至可以在实验模型中抑制转移形成。在黑色素瘤中，锌会影响黑色素的产生并诱导细胞凋亡。使用人类黑色素瘤细胞系，我们测试了 ZnSO4 对细胞增殖、存活、迁移以及体内实验肝集落形成的影响。我们发现ZnSO4在体外具有抗增殖和促凋亡作用。在 SCID 小鼠中，腹腔注射 ZnSO4 特异性抑制肝集落形成，而不影响原发性肿瘤生长。为了揭示锌在人黑色素瘤中作用的分子机制，我们测试了锌指转录因子的 mRNA 表达，发现与 WT1 相比，对 HIF1 α 具有很强的抑制作用，而 HIF2 α 和 MTF1 表达不受影响。肝转移中 HIF1 α 蛋白的免疫组织化学检测证实，体内 ZnSO4 处理后其核表达降低。这些数据表明，在人类黑色素瘤中，由于 HIF1 α 的选择性下调，锌给药可能具有抗转移作用。
Zinc as an essential trace metal is a ubiquitous component of various molecules of the cell. Studies indicated that it may modulate functions of various cancer cell types, and can even inhibit metastasis formation in experimental models. In melanoma, zinc was shown to affect melanin production and to induce apoptosis. Using human melanoma cell lines, we have tested the effects of ZnSO4 on cell proliferation, survival, migration as well as in vivo on experimental liver colony formation. We have found that ZnSO4 has antiproliferative and proapoptotic effects in vitro. In SCID mice intraperitoneal administration of ZnSO4 specifically inhibited liver colony formation without affecting primary tumor growth. To reveal the molecular mechanisms of action of zinc in human melanoma, we have tested mRNA expression of zinc finger transcription factors and found a strong inhibitory effect on HIF1 alpha, as compared to WT1 whereas HIF2 alpha and MTF1 expression was unaffected. Immunohistochemical detection of HIF1 alpha protein in liver metastases confirmed its decreased nuclear expression after in vivo ZnSO4 treatment. These data indicate that in human melanoma zinc administration may have an antimetastatic effect due to a selective downregulation of HIF1 alpha.