转录因子p8调控的内质网自噬在胰腺癌吉西他滨耐药中的机制

Pancreatic carcinoma is one of the most aggressive tumors with poor prognosis and high mortality rate. As the preferred chemotherapy drug in advanced pancreatic carcinoma, gemcitabine can improve patients survival to some extent. In our previous study, autophagy was found increased in gemcitabine resistant pancreatic cancer cells compared to control cells. Meanwhile, levels of reticulophagy markers ATF4 and ATF6 were significantly increased, but not mitophagy marker parkin. We found that transcription factor p8, which regulated reticulophagy was increased in gemcitabine resistant cells. Thus, we suppose that the reticulophagy regulated by p8 is of important significance in gemcitabine resistant pancreatic cancer cells. In this project, we will continue the research in the molecular mechanism of p8 regulated reticulophagy using p8 overexpression or knockdown cell lines, ChIP-Seq and autophagy molecular libraries, et al. The relationship between p8 regulated reticulophagy and gemcitabine chemotherapy curative effect in pancreatic carcinoma was designed using gemcitabine treatment nude mouse model and clinical samples. The intervention technique was found by inhibiting the reticulophagy pathway regulated by p8 in gemcitabine resistant cells. This study aims to clarify the mechanism of p8 regulated reticulophagy, provide important theoretical basis and new adjuvant treatment in gemcitabine resistant pancreatic carcinoma. and also has the very good clinical transformation and application prospect

胰腺癌是一种预后极差的恶性肿瘤，吉西他滨作为首选化疗药物能在一定程度上提高患者的预后。然而部分患者由于获得性耐药导致肿瘤进展，但机制不明。我们发现胰腺癌吉西他滨耐药株中自噬指标LC3B、内质网自噬指标ATF4、ATF6均显著升高，而线粒体自噬指标parkin没有变化。同时内质网自噬调控分子p8在耐药株中明显上升。因此我们推测p8调控的内质网自噬可能在胰腺癌吉西他滨耐药过程中发挥重要作用。本项目拟通过p8过表达及干扰细胞、ChIP-Seq、自噬分子库筛选等技术，获得p8调控内质网自噬的分子机制。结合裸鼠吉西他滨化疗模型和胰腺癌临床信息，明确p8调控的内质网自噬在耐药中的作用。通过对p8及内质网自噬相关分子的抑制，发现耐药过程中的治疗靶点，提出相关的干预技术。本项目对阐明胰腺癌吉西他滨耐药的分子机制及建立胰腺癌辅助治疗新方案具有重要意义，也具有极好的临床转化和应用前景。

胰腺癌是一种预后极差的恶性肿瘤，吉西他滨作为首选化疗药物能在一定程度上提高患者预后。然而部分患者由于获得性耐药导致肿瘤进展，但机制不明。我们研究发现胰腺癌吉西他滨耐药株中自噬指标LC3B、内质网自噬指标ATF4、ATF6均显著升高，而线粒体自噬指标parkin没有变化。同时内质网自噬调控分子p8在耐药株中明显上升。在p8稳定过表达的胰腺癌细胞株中，内质网自噬相关指标增加，并激活p8-p53-PKCα和AMPK通路，在p8敲减的胰腺癌细胞株中则相反。我们还发现漆黄素能抑制胰腺癌细胞增殖，激活AMPK/mTOR通路。漆黄素还能在胰腺癌细胞中上调p8，并通过p53/PKC-α信号传导，诱导内质网应激，调节ATF6、ATF4和PERK。此外，漆黄素还能诱导线粒体自噬，调节Parkin和PINK。本项目研究结果将阐明胰腺癌吉西他滨耐药的分子机制，分析p8在胰腺癌中调节自噬的机制，为建立胰腺癌辅助治疗新方案具有重要意义，也具有极好的临床转化和应用前景。