AEG-1通过上调eIF4E的表达促进胃癌转移的作用机制研究

发布时间：2018-07-10 16:55

本文选题：胃癌 + 肿瘤转移　；参考：《南京医科大学》2017年硕士论文

【摘要】：胃癌是严重威胁人类健康的恶性肿瘤之一,在我国胃癌是第二大高发肿瘤,也是癌症相关死亡中的第二大高发肿瘤。由于胃癌的早期症状多不明显,绝大多数患者就诊时已处于进展期,同时伴有腹膜转移、远处淋巴结转移和远处脏器转移,这是导致胃癌高死亡率的主要原因。有研究表明在胃癌组织中星形胶质细胞上调基因-1(Astrocyte elevated gene-1,AEG-1)表达增加,且与胃癌的进展和转移密切相关。然而,AEG-1调控胃癌转移的机制目前仍未阐明。本课题中,我们研究发现阻抑AEG-1的表达可以抑制胃癌细胞上皮-间质样转化(epithelial-mesenchymal transition,EMT)、迁移和侵袭,同时下调eIF4E的表达。而过表达AEG-1则得到相反的结果。我们也发现过表达eIF4E可以促进胃癌细胞发生EMT,促进细胞迁移和侵袭,并伴有MMP-9和Twist的表达增加,而阻抑eIF4E的表达也得到了相反的结果。我们进一步在过表达AEG-1的前提下阻抑eIF4E的表达,结果发现阻抑eIF4E的表达可以部分消除AEG-1诱导的EMT、细胞迁移、侵袭,以及MMP-9和Twist的表达增加。在阻抑AEG-1表达时过表达eIF4E则得到相反的结果。说明在胃癌中eIF4E参与了AEG-1调节的EMT、细胞迁移和侵袭。最后,在裸鼠异体移植瘤模型中,阻抑AEG-1的表达显著抑制肿瘤生长,下调eIF4E、MMP-9、Twist的表达,在原位移植瘤模型中,阻抑AEG-1的表达显著抑制胃癌的转移。上述研究结果表明,AEG-1通过上调eIF4E的表达,进而诱导MMP-9、Twist的表达增加,促进胃癌的迁移、侵袭和转移。这一发现进一步阐明了 AEG-1在胃癌转移中的作用机制,为胃癌转移的诊断提供了新指标,为治疗提供新思路。
[Abstract]:Gastric cancer is one of the most serious malignant tumors that threaten human health. Gastric cancer is the second most common tumor in China and the second most common cancer related death in China. Because the early symptoms of gastric cancer are not obvious, most of the patients are in advanced stage, accompanied by peritoneal metastasis, distant lymph node metastasis and distant organ metastasis, which is the main cause of high mortality of gastric cancer. Some studies have shown that astrocytes up-regulate the expression of 1 (Astrocyte elevated gene-1AEG-1) in gastric cancer tissues, which is closely related to the progression and metastasis of gastric cancer. However, the mechanism of AEG-1 regulating gastric cancer metastasis has not been clarified. In this study, we found that inhibiting the expression of AEG-1 could inhibit epithelial-mesenchymal transition-like transformation (EMT), migration and invasion, and down-regulate the expression of eIF4E. Overexpression of AEG-1 resulted in the opposite result. We also found that the expression of eIF4E could promote the development of EMTs, migration and invasion of gastric cancer cells, and increase the expression of MMP-9 and Twist, but inhibit the expression of eIF4E. We further inhibited the expression of eIF4E on the premise of overexpression of AEG-1. The results showed that inhibiting the expression of eIF4E could partly eliminate the AEG-1 induced EMTs, cell migration, invasion, and the increase of MMP-9 and Twist expression. Overexpression of eIF4E in the inhibition of AEG-1 expression was found to be the opposite. These results suggest that eIF4E is involved in the regulation of EMT1, cell migration and invasion in gastric cancer. Finally, in nude mice allograft tumor model, the expression of AEG-1 was inhibited significantly, and the expression of EIF4E, MMP-9 / Twist was down-regulated. In orthotopic transplantation, the expression of AEG-1 was inhibited significantly. These results suggest that AEG-1 can up-regulate the expression of eIF4E and induce the increase of MMP-9 / Twist expression, thus promoting the migration, invasion and metastasis of gastric cancer. This finding further elucidates the role of AEG-1 in gastric cancer metastasis, provides a new index for the diagnosis of gastric cancer metastasis, and provides a new idea for treatment.
【学位授予单位】：南京医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R735.2

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