MUC13在肝内胆管癌生长和转移过程中的作用及其机制研究

Intrahepatic cholangiocarcinoma (iCCA) displays a rapid progression and poor outcome. Currently, there is no effective systemic therapeutic treatment for iCCA. MUC13 has recently been reported as an oncogene in various tumors, but its role in iCCA is still unclear. Our preliminary results showed that MUC13 was overexpressed in iCCA specimens compared with the paired adjacent nonmalignant tissues. MUC13 promoted the growth and invasion of iCCA cells through activation of the PI3K/AKT signaling pathway, and the epidermal growth factor receptor (EGFR) might play a pivotal role in this process. Therefore, we suggest that MUC13 may be an important oncogene of iCCA, and exhibit its function by enhancing the ligand-induced activation of the EGFR, leading to activation of the PI3K/AKT signaling pathway. This project is intended to carry out the following work: (1) Expand the number of clinical samples to further explore the expression of MUC13 and its clinical significance in iCCA; (2) perform in vitro experiments to examine the effects of overexpression or downregulation of MUC13 on the growth and invasion of iCCA; (3) establish animal models to confirm the results of in vitro experiments; (4) investigate the specific mechanism by which MUC13 exhibits its function, by co-immunoprecipitation, immunofluorescence and western blotting techniques. The results will reveal a new mechanism for the growth and metastasis of iCCA, and provide a new target for the diagnosis and treatment of iCCA.

肝内胆管癌进展迅速，预后较差，至今仍缺乏有效的治疗措施。MUC13是新近发现的一种癌基因，我们前期研究发现MUC13在肝内胆管癌组织中过表达，可以通过激活PI3K/AKT通路促进肝内胆管癌细胞的生长和侵袭，且表皮生长因子受体（EGFR）在这一过程中起到重要作用。因此，我们推测：MUC13以癌基因形式参与肝内胆管癌的发生发展，通过增强配体诱导的EGFR活化，进而导致PI3K/AKT通路激活而发挥其作用。本项目拟开展以下工作：一、扩大临床样本容量，明确MUC13在肝内胆管癌中的表达情况和临床意义；二、通过体外实验观察过表达或者下调MUC13对肝内胆管癌细胞生长和侵袭的影响；三、通过建立动物模型进一步验证体外实验的结果。四、通过免疫共沉淀、免疫荧光、免疫印迹等实验探讨MUC13发挥作用的分子机制。研究结果将揭示肝内胆管癌生长和转移的新机制，为肝内胆管癌的诊断和治疗提供新的靶点。

肝内胆管癌是一种起源于肝内胆管上皮细胞的恶性肿瘤，其发病率在世界范围内呈上升趋势。由于肝内胆管癌具有进展迅速、化疗高度耐药以及复发率高等特点，导致其五年生存率极低。因此，迫切需要明确肝内胆管癌发生发展的分子机制。MUC13最近被报道在一些人类恶性肿瘤组织中扮演着癌基因的角色，而其在肝内胆管癌中的确切功能仍有待进一步明确。本项目研究成果表明：（1）MUC13在肝内胆管癌组织中的表达明显高于正常组织，并且其高表达与血管侵袭、淋巴结转移及预后不佳密切相关。（2）体内和体外实验证明MUC13可以通过活化PI3K/AKT/TIMP1/MMP9通路促进肝内胆管癌细胞的生长和转移。（3）MUC13可以与EGFR直接结合而促进EGFR二聚化并抑制其内陷化，最终导致EGFR活化。（4）MUC13是MiR-212-3p的靶基因，MUC13在肝内胆管癌中的高表达要归因于MiR-212-3p在肝内胆管癌中的低表达，并且MiR-212-3p的启动子异常高甲基化是导致其低表达的主要原因。上述结果发表于国际肝脏病学主流杂志《Journal of Hepatology》（影响因子：18.946）上。本项目阐明了MUC13在肝内胆管癌进展过程中的作用及其分子机制，为临床肝内胆管癌靶向基因治疗提供了科学依据。此外，在本项目基金的支持下，本人以第一作者身份发表论文于Oncogenesis（影响因子：5.995），以通讯作者及第三作者身份发表论文于Molecular Therapy-Nucleic Acids（影响因子：5.919），以并列第一作者身份发表论文于CELL DEATH & DISEASE（影响因子：5.638）。