Xu Min, Zhou Hailang, Zhang Chunli, He Junbo, Wei Hong, Zhou Meng, Lu Ying, Sun Yaocheng, Ding Jerry Wanming, Zeng Jian, Peng Wanxin, Du Fengyi, Gong Aihua
Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, P.R. China.
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, N6A 5C1, Canada.
Int J Oncol. 2016 Dec;49(6):2520-2528. doi: 10.3892/ijo.2016.3744. Epub 2016 Oct 21.
Although a disintegrin and metalloproteinase-17 (ADAM17) overexpression has been demonstrated in numerous human tumors including gastric cancer, its role in gastric cancer development remains to be clarified. In the present study, we identify that ADAM17 activates TGF-β/Smad signaling to promote epithelial-mesenchymal transition (EMT) in gastric cancer cells. We found that ADAM17 promotes proliferation, migration and invasion in gastric carcinoma cells. Subsequently, we revealed that silencing ADAM17 induces the expression of epithelial marker of E-cadherin and downregulates expression of mesenchymal markers including N-cadherin, vimentin and Snail in MGC803 and MKN45 cells, whereas ADAM17 overexpression reverses these changes in BGC823 and HGC27 cells. Furthermore, ADAM17 knockdown significantly inhibits the expression of TGF-β and its downstream signaling molecules p-Smad2 and p-Smad3 in MGC803 and MKN45 cells. Consistently, ADAM17 overexpression reversed these changes in BGC823 and HGC27 cells. These results suggest that ADAM17 promotes epithelial-mesenchymal transition via the TGF-β/Smad pathway. Collectively, the present study demonstrates that ADAM17 plays a critical role in the development of gastric cancer and provides a potential therapeutic target for gastric cancer.
尽管在包括胃癌在内的众多人类肿瘤中已证实去整合素和金属蛋白酶17（ADAM17）过表达，但其在胃癌发生发展中的作用仍有待阐明。在本研究中，我们发现ADAM17激活TGF-β/Smad信号通路以促进胃癌细胞的上皮-间质转化（EMT）。我们发现ADAM17促进胃癌细胞的增殖、迁移和侵袭。随后，我们发现沉默ADAM17可诱导MGC803和MKN45细胞中上皮标志物E-钙黏蛋白的表达，并下调包括N-钙黏蛋白、波形蛋白和Snail在内的间质标志物的表达，而ADAM17过表达则逆转了BGC823和HGC27细胞中的这些变化。此外，ADAM17基因敲低显著抑制MGC803和MKN45细胞中TGF-β及其下游信号分子p-Smad2和p-Smad3的表达。同样，ADAM17过表达逆转了BGC823和HGC27细胞中的这些变化。这些结果表明，ADAM17通过TGF-β/Smad途径促进上皮-间质转化。总体而言，本研究表明ADAM17在胃癌发生发展中起关键作用，并为胃癌提供了一个潜在的治疗靶点。
