胃癌特异分泌蛋白信号肽引导tumstatin的靶向基因治疗

Gastric cancer is one of the commonest malignancies risking human health, and its gene therapy using secretory protein is a hot field. In our previous study, COL4A3, a precursor protein of tumstatin was highly expressed in gastric intestinal metaplasia, compared with gastritis and gastric cancer. COL4A3 expression was positively correlated with tumor size, lymphatic and venous invasion, TNM staging and poor prognosis of cancer. Tumstatin 185-203 showed a significant inhibitory effect on the proliferation of gastric cancer cells. Here, we plan to screen specific secretory protein with signal peptide for intestinal- and diffuse-type cancer by plasmid Escherichia coli ampicillin secretion trap(pCAST) system and explore the effects of specific signal peptide-guided tumstatin secretion on aggressive phenotypes and related molecular mechanisms, including the karyoplasmic ratio, proliferation, cell cycle, apoptosis,differentiation, migration, invasion, lamellipodia and invapodia formation. Finally, the in vivo suppressive role of different signal peptide- guided tumstatin secreting lentivirus in growth and metastasis of gastric cancer cells was determined in nude mice. In the present study, the screening of specific signal peptides will provide a good tool for the gene therapy of secretory protein for the patients with gastric cancer. As a novel target molecule inhibiting proliferation and angiogenesis, tumstatin will improve the survival rate and quality of the patients with gastric cancer to a large-scale degree.

胃癌是是严重威胁人类健康的常见恶性肿瘤之一，其分泌蛋白基因治疗是目前研究热点。本项目组发现肠化生中tumstatin前体COL4A3蛋白表达高于胃癌和胃炎，COL4A3蛋白表达与胃癌肿块大小、淋巴管侵袭、静脉侵袭、TNM分期和不良预后呈正相关，tumstatin 185-203多肽对胃癌细胞增殖有显著抑制作用。本研究拟利用苄青霉素分泌追踪质粒（pCAST）系统筛选肠型和弥漫型胃癌特异信号肽，揭示不同信号肽引导tumstatin分泌对胃癌细胞核质比、增殖、细胞周期、凋亡、分化、迁徙、侵袭、片状和侵袭伪足形成等细胞表型影响及相关分子机制，体内观察信号肽引导tumstatin慢病毒系统对胃癌细胞生长和转移的抑制作用。本研究顺利实施，筛选出胃癌特异的信号肽系统将为胃癌分泌蛋白基因治疗提供便利工具，作为胃癌细胞血管形成和肿瘤增殖抑制剂的新靶点tumstatin将极大提高胃癌患者生存率和生存质量。

胃癌是是严重威胁人类健康的常见恶性肿瘤之一，其分泌蛋白基因治疗是目前研究热点。本项目组发现肠化生中tumstatin前体COL4A3蛋白表达高于胃癌和胃炎，COL4A3蛋白表达与胃癌肿块大小、淋巴管侵袭、静脉侵袭、TNM分期和不良预后呈正相关，tumstatin 185-203多肽对胃癌细胞增殖有显著抑制作用。本研究拟利用苄青霉素分泌追踪质粒（pCAST）系统筛选肠型和弥漫型胃癌特异信号肽，揭示不同信号肽引导tumstatin分泌对胃癌细胞核质比、增殖、细胞周期、凋亡、分化、迁徙、侵袭、片状和侵袭伪足形成等细胞表型影响及相关分子机制，体内观察信号肽引导tumstatin慢病毒系统对胃癌细胞生长和转移的抑制作用。本研究顺利实施，筛选出胃癌特异的信号肽系统将为胃癌分泌蛋白基因治疗提供便利工具，我们研究认为目前其还不能作为胃癌细胞血管形成和肿瘤增殖抑制剂的新靶点tumstatin，但其可以导致胃癌移植瘤肠化，还值得进一步探讨。