PTPRO在Twist介导的 HER2阳性胃癌转移起始中的作用及其分子机制

Gastric cancer carries a poor prognosis that is largely attributable to early and.frequent metastasis, in which epithelial-mesenchymal transition (EMT) is one.essential mechanism that occurs at the initial stage. Our previous study has.demonstrated suppression of the gene for protein tyrosine phosphatase.receptor-type O (PTPRO) involved in esophageal squamous cell carcinoma. The latest.results in our laboratory showed that ① PTPRO protein expression was.significantly decreased in metastatic gastric cancer tissues; ② ectopic.expression of PTPRO in gastric cancer cells inhibited cell malignant invasiveness. Our .biology information analysis showed that ①JAK/STAT3 is the downstream signal pathway of PTPRO and HER2 is one main target gene; ② The expression of HER2 in.GC with metastasis was higher than that in the advanced GC without metastasis..Consequently, we hypothesize that PTPRO is one of the master genes which.regulate EMT and metastasis in gastric cancer. On the basis of our original.preliminary work, we investigate the effect and molecular mechanism of PTPRO on.gastric cancer metastasis by ① testing whether PTPRO is the switch to control.metastasis initiation using in intro cell culture experiments and in vivo.fluorescence imaging technology; ② evaluating PTPRO-regulated HER2/STAT3/Twist.signaling pathway during EMT and metastasis initiation; and ③ examining clinical.specimens and analyzing the potential relationship between PTPRO expression and.gastric cancer metastasis or prognosis. The present study, aiming at the initial.stage of metastasis, is to identify the original molecular mechanism for gastric.cancer metastasis, which might contribute to reveal the regulation of gastric.cancer metastasis as well as offer us new strategies for drug discovery.

转移是我国高发胃癌致死的主要原因，EMT是转移起始阶段的重要机制。团队最新实验显示：①在已有转移的胃癌组织中PTPRO表达显著降低；②PTPRO下调导致Twist表达增多、E-cadherin表达减少；生物信息学与最新文献支持：① JAK/STAT3是PTPRO的下游信号通路，HER2是PTPRO的靶点分子；② HER2在有转移的胃癌组织表达率明显高于无转移晚期胃癌。据此，团队提出假说：PTPRO是HER2阳性胃癌中控制转移起始的重要基因，通过HER2/STAT3/Twist通路调节E-cadherin是其干预EMT和转移的分子机制。为证实假说，团队拟 ①扩大临床标本明确PTPRO表达与HER2阳性胃癌转移的关系；②应用细胞实验与活体成像技术，在体内外明确PTPRO是控制HER2阳性胃癌转移起始的开关；③分子水平证实PTPRO通过HER2/STAT3/Twist信号通路干预EMT和转移起始

针对转移是胃癌致死的关键原因，本团队通过分析5022例宁夏籍胃癌患者，首先明确早期胃腺癌患者1~、3~、5~年生存率分别为96.1%、87.2%、70.1%，进展期则分别为69.8%、46.3%、23.8%；术后淋巴结阴性胃腺癌患者1~、2~、3~年总生存率分别为92.5%、87.1%、80.4%；与之对应的术后淋巴结阳性患者为78.0%、63.9%、52.9%。分子标志物PTPRO、HER2、Twist、VEGF、Ki67均是影响术后淋巴结阳性进展期胃腺癌患者生存的独立危险因素。来自胃癌患者和皮下-胃间接原位移植瘤小鼠组织学水平的结果均支持：在已有转移的胃癌组织中PTPRO表达显著降低;PTPRO下调导致Twist表达增多、E-cadherin表达减少;HER2在有转移的胃癌组织表达率明显高于无转移晚期胃癌。团队在HER2阳性胃癌SGC7901细胞中转染靶向PTPRO的siRNA，RT-PCR与Western Blot显示：PTPRO下调导致Twist表达增多、E-cadherin表达减少，沉默PTPRO后p-STAT3（phospho-Tyr705-STAT3）与p-HER2（phospho-Tyr1221/22-HER2）水平均显著提高。此外，应用JAK/STAT抑制剂AG490或siRNA沉默STAT3均可阻断下调PTPRO对Twist与E-cadherin表达的影响，反向证实PTPRO通过调控STAT3磷酸化干预EMT关键蛋白表达。上述结果支持：在胃癌细胞中，PTPRO表达缺失通过激活HER2/STAT3/Twist信号通路，最终抑制E-cadherin表达并引发EMT和肿瘤转移。团队针对本项目的成果共发表论文12篇，其中SCI收录论文11篇，中文期刊收录1篇；大会交流3篇。获得宁夏科技进步三等奖1项，已培养博士硕士研究生11名。