N-acetylglucosaminyltransferase V modulates radiosensitivity and migration of small cell lung cancer through epithelial-mesenchymal transition
N-acetylglucosaminyltransferase V modulates radiosensitivity and migration of small cell lung cancer through epithelial-mesenchymal transition
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DOI：
10.1111/febs.13419
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发表时间：
2015-11-01
期刊：
影响因子：
5.4
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
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作者：
Huang, Chunyue;Huang, Miaojuan;Zhang, Jian
n -乙酰氨基葡萄糖转移酶V （Gnt-V）与多种人类癌症的迁移有关。最近我们发现抑制Gnt-V增加了癌细胞的放射敏感性。然而，Gnt-V介导放射敏感性和迁移的机制，特别是在小细胞肺癌（SCLC）中仍不清楚。在我们的研究中，我们使用了两种SCLC细胞系（H1688和H146）来研究Gnt-V是否通过上皮间充质转化（epithelial mesenchymal transition， EMT）调节SCLC细胞的放射敏感性和迁移。结果显示，Gnt-V的表达与SCLC患者的N分期相关。过表达Gnt-V导致辐照后细胞的相对活细胞数和存活比例进一步增加，凋亡率和Bax/Bcl-2比值降低。相比之下，照射抑制Gnt-V导致相对活细胞数和存活比例进一步降低，但凋亡率和Bax/Bcl-2比值升高。表达高水平Gnt-V的细胞增加迁移，而低水平Gnt-V抑制细胞迁移。此外，短暂的ZEB2敲低导致SCLC细胞的放射敏感性增加和迁移受到抑制。此外，Gnt-V与E-cadherin表达呈负相关，而与N-cadherin、vimentin和ZEB2表达呈正相关。最后，一项体内研究表明，上调Gnt-V可使肿瘤生长更快，并促进emt相关标志物（N-cadherin、vimentin和ZEB2）的表达。综上所述，该研究表明，Gnt-V的升高可能通过诱导EMT导致SCLC细胞的放射敏感性和迁移，从而突出了Gnt-V作为预防EMT相关肿瘤放射耐药和迁移的潜在治疗靶点。
N-acetylglucosaminyltransferase V (Gnt-V) has been linked to the migration of various human cancers. Recently we have found that inhibition of Gnt-V increases the radiosensitivity of cancer cells. However, the mechanisms by which Gnt-V mediates radiosensitivity and migration, especially in small cell lung cancer (SCLC) remain unknown. In our study, two SCLC cell lines (H1688 and H146) were used to investigate whether Gnt-V modulated the radiosensitivity and migration of SCLC cells through the epithelial mesenchymal transition (EMT). The results showed that the expression of Gnt-V correlated with the N stage in patients with SCLC. Overexpression of Gnt-V led to a further increase in the relative viable cell number and survival fraction with a decrease in apoptosis rate and Bax/Bcl-2 ratio, when the cells were treated with irradiation. By contrast, knockdown of Gnt-V with irradiation resulted in a further decrease in the relative viable cell number and survival fraction but an increase in apoptosis rate and Bax/Bcl-2 ratio. Cells expressing high levels of Gnt-V increased migration whereas low levels of Gnt-V suppressed cell migration. Besides, the transient knockdown of ZEB2 led to an increase in radiosensitivity and an inhibition in the migration of SCLC cells. Furthermore, Gnt-V was negatively correlated with E-cadherin expression but positively correlated with N-cadherin, vimentin and ZEB2 expression. Finally, an in vivo study revealed that upregulation of Gnt-V caused tumour growth more quickly, as well as the expression of EMT-related markers (N-cadherin, vimentin and ZEB2). Taken together, the study suggested that an elevation of Gnt-V could lead to the radiosensitivity and migration of SCLC cells by inducing EMT, thereby highlighting Gnt-V as a potential therapeutic target for the prevention of EMT-associated tumour radioresistance and migration.