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HU Shengmin
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0710 生物学
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07 理学
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       肺癌是全世界癌症发病率和死亡率的主要原因,其患者的5年总生存率仅为19%,这可能是由肺癌的高复发转移率和其潜在的复杂的分子病理机制导致的。PCDH7(protocadherin 7)属于钙粘蛋白超家族,在肿瘤转移中发挥作用。因此,我们进一步探讨PCDH7在肺癌转移中作用的可能机制,并寻找潜在的肺癌分子标志物。
       首先整合分析从小鼠前列腺癌骨—肺转移模型的RNA测序数据,以及包括临床信息的肺癌组织的基因芯片数据,选择PCDH7进行研究。在H1299、 H1975和PC9等肺癌细胞中,通过siRNA介导的敲降PCDH7对细胞进行增殖、集落形成、迁移和侵袭等实验,并采用Western blot、qRT-PCR、RNA-seq和Co-Immunoprecipitation等研究PCDH7在肿瘤进展中的潜在机制。结果显示PCDH7在转移瘤动物模型中显著升高;PCDH7在肺腺癌中的表达高于正常肺组织,且PCDH7过表达与患者的不良预后显著相关。体外实验结果表明敲降PCDH7可以抑制肺癌细胞的迁移侵袭、集落形成和增殖的能力,且发现EGFR、ZEB1和β-catenin蛋白表达下降,通过MG132药物的处理后只有β-catenin蛋白恢复原有水平;过表达PCDH7后发现ZEB1蛋白增加,并通过Co-IP实验发现PCDH7与β-catenin、ZEB1存在结合。另外,敲降EGFR后PCDH7表达不受影响,而ZEB1、β-catenin蛋白表达下降。因此,认为过表达PCDH7可结合β-catenin、ZEB1,并通过作用EGFR来维持β-catenin、ZEB1蛋白的稳定性,从而促进肿瘤细胞的转移和增殖;PCDH7可作为肺癌预后预测的分子标记物和潜在的治疗靶点。

Other Abstract

       Lung cancer is the major cause of cancer morbidity and mortality throughout the world. The overall 5-year patient survival is only 19%, which may be due to the higher recurrence and metastasis rate, as well as the underlying complicated molecular pathology. PCDH7 belongs to cadherin superfamily and plays role in cancer metastasis. Here, we further explored PCDH7 expression pattern and the potential mechanism in lung cancer metastasis and looked for potential molecular markers of lung cancer.
        We first intergraded and analyzed RNA-seq data from an animal model of lung cancer to brain metastasis and microarray data from lung cancer tissues in which clinical information is included. Therefore, PCDH7 was selected for further study. CCK-8 and other functional experiments were performed after PCDH7 siRNA-mediated gene knockdown in H1299,H1975 and PC9 lung cancer cells. Western blot, qRT-PCR, RNA-seq, and Co-IP were performed to explore the underlying mechanism of PCDH7 in cancer progression. We found that PCDH7 overexpression was significantly associated with overall poor patient survival. PCDH7 knockdown with siRNAs inhibited tumor cell migration, invasion, colony formation, and proliferation in lung cancer cells. Mechanistically, we found that PCDH7 depletion reduced the expression of EGFR, ZEB1 and β-catenin, and only β-catenin was rescued to the original level by MG132 treatment. What’s more, overexpressing PCDH7 increased the expression of ZEB1 in protein level, and co-IP assay showed that PCDH7 bound to β-catenin and ZEB1. In addition, knocking down EGFR could reduce the expression of these genes except for PCDH7. Therefore, it is suggested that overexpression of PCDH7 can bind β-catenin and ZEB1 and maintain their stability by acting on EGFR, which can promote lung cancer cells metastasis and proliferation. Furthermore, it may be used as a molecular marker for prognostic prediction and potential therapeutic target of lung cancer.

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胡圣敏. PCDH7通过EGFR通路促进肺癌细胞增殖和侵袭[D]. 深圳. 南方科技大学,2022.
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