Identification of TDP-43 as an oncogene in melanoma and its function during melanoma pathogenesis
Identification of TDP-43 as an oncogene in melanoma and its function during melanoma pathogenesis
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DOI：
10.1080/15384047.2016.1250984
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发表时间：
2017-01
影响因子：
3.6
通讯作者：
Q. Zeng;K. Cao;Rui Liu;Jinhua Huang;K. Xia;Jintian Tang;Xiang Chen;Ming Zhou;H. Xie;Jianda Zhou
中科院分区：
文献类型：
--
作者：
Q. Zeng;K. Cao;Rui Liu;Jinhua Huang;K. Xia;Jintian Tang;Xiang Chen;Ming Zhou;H. Xie;Jianda Zhou
摘要背景：尽管最近的研究已经揭示TAR（trans-activating response region）DNA结合蛋白（TDP-43）作为癌症的潜在治疗靶点，但其作用和与黑色素瘤的临床关联尚未被探索。目的：探讨TDP-43在黑色素瘤发病过程中的作用和功能。方法：首先，探讨TDP-43表达与患者生存期的关系。然后测量TDP-43在黑素瘤组织和不同黑素瘤细胞系中的表达水平。在黑色素瘤细胞中沉默TDP-43表达后，研究了TDP-43对细胞增殖、转移、葡萄糖摄取和葡萄糖转运蛋白水平的影响。最后，在体内测试TDP-43耗尽对黑素瘤细胞致瘤性的影响。结果：TDP-43在黑色素瘤石蜡标本中的表达高于痣组织。TDP-43的高表达水平与患者生存率差相关。通过沉默TDP-43，我们观察到A375和WM 451细胞中的细胞增殖和转移的显著抑制。TDP-43基因敲低可抑制葡萄糖转运蛋白4（GLUT 4）的表达，降低葡萄糖摄取。GLUT 4在黑色素瘤细胞中表达下调可抑制细胞增殖和转移。TDP-43敲低显著减缓了肿瘤生长并降低了体内GLUT 4表达。结论：TDP-43是黑色素瘤中的新癌基因，可能通过调节葡萄糖代谢来调节黑色素瘤的增殖和转移。
ABSTRACT Background: Although recent studies have revealed TAR (trans-activating response region) DNA binding protein (TDP-43) as a potential therapeutic target for cancers, its role and clinical association with melanoma have not been explored. Objective: To identify the role and function of TDP-43 during melanoma pathogenesis. Methods: Firstly, the relationship between TDP-43 expression and patient survival was explored. Then TDP-43 expression level in melanoma tissue and different melanoma cell lines was measured. After silencing TDP-43 expression in melanoma cells, the impacts of TDP-43 on cellular proliferation, metastasis, glucose uptake, and glucose transporters levels were studied. In the end, effect of TDP-43 depletion on tumorigenicity of melanoma cells was tested in vivo. Results: Our results showed that TDP-43 was overexpressed in melanoma paraffin samples compared with that in nevi tissues. The high expression level of TDP-43 was associated with poor patient survival. By silencing TDP-43, we saw significant inhibition of cell proliferation and metastasis in A375 and WM451 cells. TDP-43 knockdown could suppress glucose transporter type-4 (GLUT4) expression and reduce glucose uptake. And downregulation of GLUT4 in melanoma cells induced inhibition of cell proliferation and metastasis. TDP-43 knockdown significantly slowed down tumor growth and decreased GLUT4 expression in vivo. Conclusion: TDP-43 is a novel oncogene in melanoma and regulates melanoma proliferation and metastasis potentially through modulation of glucose metabolism.