PGK1对乳腺癌紫杉醇化疗敏感性的影响及其机制的研究

PGK1 is a glycolytic enzyme in the glycolytic pathway. PGK1 has been recently documented in various malignancies. The applicant's previous study found that: PGK1 mRNA and protein expression were significantly increased in breast cancer tissues compared with that in normal breast tissues. High levels of PGK1 expression were associated with worse overall survival. Furthermore, patients who underwent paclitaxel chemotherapy with high levels PGK1 expression had shorter overall survival than did those with low levels of PGK1 expression. Silencing PGK1 expression enhanced the sensitivity and apoptosis rate to paclitaxel treastment. Pursuant to which the group proposed assumptions: the expression of PGK1 could reduce the sensitivity to paclitaxel treatment and cause poor survival of breast cancer patients, and upregulation of PGK1 activated the Wnt/β-Catenin pathway to influence the sensitivity to paclitaxel treatment. This project intends to carry out the following work: using the blood of neoadjuvant patients to analysis the correlation of PGK1 expression with sensitivity to paclitaxel treatment. in vivo and in vitro experiments were carried out to clearify how PGK1 influence sensitivity to paclitaxel treatment. Validation of target genes expression in Wnt/β-Catenin pathway was use to analysis the mechanism of PGK1 to paclitaxel treatment.

PGK1是糖酵解途径中的一种关键酶，一系列研究表明PGK1在多种恶性肿瘤中均起到了重要的作用。申请人的前期研究发现：在乳腺癌中PGK1的mRNA和蛋白表达水平明显高于良性乳腺组织。PGK1高表达的乳腺癌患者的总生存要明显差于PGK1低表达的患者。术后进行紫杉醇化疗的患者，PGK1高表达的生存时间，要明显短于PGK1低表达的患者。抑制PGK1的表达能增加细胞对紫杉醇化疗的敏感性和细胞的凋亡水平。据此本课题组提出假设：PGK1通过降低患者对紫杉醇药物敏感性引起患者不良预后。PGK1表达能够通过Wnt/β-Catenin信号通路影响紫杉醇化疗的敏感性。本课题组拟进行如下工作：在新辅助化疗患者血液中，检测PGK1的表达与紫杉醇化疗敏感性的关系。通过细胞和动物水平的研究评估PGK1对紫杉醇化疗敏感性的影响。检测Wnt/β-Catenin通路中靶基因的表达，进一步研究PGK1对药物敏感性影响的机制。

我们前期的研究发现，在应用紫杉醇化疗的乳腺癌患者中， PGK1的表达与患者的预后存在一定的相关性。然而，它对紫杉醇化疗敏感性影响的分子机制尚不清楚。三阴性乳腺癌是已知的高侵袭性的乳腺癌类型，它的复发转移风险相对高。由于缺乏有效的治疗方案，紫杉醇为主的化疗仍是三阴性乳腺癌患者的主要选择。因此，我们在当前研究中分析了PGK1在应用紫杉醇化疗的三阴性乳腺癌患者中的具体作用及其机制。我们观察到，沉默PGK1增加了三阴性乳腺癌细胞的凋亡水平，从而增加了对紫杉醇药物的敏感性。应用RNA测序，分析PGK1沉默的细胞系与对照细胞系间差异表达基因及差异基因富集的信号通路。在三阴性乳腺癌中，PGK1的沉默增加紫杉醇的化疗敏感性是通过XAF1介导的。此外，我们还发现下调XAF1可以降低紫杉醇诱导的PGK1沉默的三阴性细胞的凋亡水平。因此我们的结果证实PGK1可能是治疗三阴性乳腺癌的潜在生物标记物，抑制PGK1的表达可能成为一种增加三阴性乳腺癌对紫杉醇化疗敏感性的新的治疗策略。