Sp1参与调控PUMA介导的蜈蚣提取液对胆囊腺癌治疗作用研究

Gallbladder carcinoma is the most common malignant tumor of the biliary system, and gallbladder adenocarcinoma is the most common pathological type. In our previous study, we have found that centipede extract could induce apoptosis of cholangiocarcinoma cell by up regulation of Bax and down regulation of Bcl-2 pathway. The preliminary data have shown that centipede extract have obvious inhibitory effect on gallbladder adenocarcinoma. We have also found the positive expression of p53 up-regulated modulator of apoptosis (PUMA) in gallbladder adenocarcinoma specimens and cell lines are closely related to the biological behavior and prognosis of gallbladder adenocarcinoma. Many studies have shown that PUMA mediates the apoptosis of tumor cells by interacting with Bax/Bcl-2. In our previous study, we have also found that when the activity of p53 gene is inhibited by PFT-α, the PUMA expression is not significantly down regulated in gallbladder adenocarcinoma which is treated with centipede extract. Other studies have reported that Sp1 is involved in the transcriptional regulation of PUMA. Based on our preliminary results, gallbladder adenocarcinoma is selected as the breakthrough point, this project aims to systematically determine the essential in vitro and in vivo roles for the therapeutic effect of centipede extract on gallbladder adenocarcinoma, and finally identifying the underlying mechanisms responsible for these observations. These novel results obtained from this work would provide important theoretical significance and application value in clinical practice, and definitely benefit the patients with gallbladder adenocarcinoma.

胆囊癌是胆道系统最常见的恶性肿瘤，其病理类型以胆囊腺癌最多见。本课题组前期研究发现蜈蚣提取液可以通过上调Bax及下调Bcl-2途径引起胆管癌细胞凋亡，预实验发现其对胆囊腺癌亦具有明显的抑制作用。p53上调凋亡调控因子(PUMA)在胆囊腺癌临床标本及细胞株中均呈阳性表达，且其与胆囊腺癌的临床生物学行为及预后密切相关。众多研究表明PUMA通过与Bax/Bcl-2的相互作用介导肿瘤细胞凋亡。本课题组研究发现PFT-α抑制p53基因活性并不能显著降低经过蜈蚣提取液处理的胆囊腺癌细胞株中PUMA表达。另有研究报道Sp1参与PUMA的转录表达调控。因此，本课题组选择胆囊腺癌为突破点，将从临床样本、动物模型以及机制研究系统阐明蜈蚣提取液对胆囊腺癌的治疗作用，以及Sp1参与调控PUMA介导蜈蚣提取液治疗胆囊腺癌的具体作用机制，具有重要的理论指导意义和临床应用价值，将为临床上胆囊腺癌的治疗提供一条新的思路。