STMN1在胆囊癌增殖和化疗耐药中的机制研究

胆囊癌（gallbladder cancer，GBC）作为最常见的胆道恶性肿瘤，其恶性程度高，约75%的患者初诊时已失去手术治疗的机会，5年生存率仅为10%。吉西他滨是GBC的一线化疗药物，一旦耐药将直接影响患者预后。我们前期尚未发表的研究工作发现，STMN1是GBC的潜在风险基因，其表达水平与GBC的发生及患者的化疗耐药密切相关。过表达STMN1会影响细胞周期调控蛋白cyclinB1的表达，并促进GBC细胞的增殖和对吉西他滨的化疗耐药。基于此，我们提出科学假设：STMN1通过和cyclinB1相互作用，使cyclinB1磷酸化并被转运入核，进而调控细胞周期，影响GBC的增殖和化疗耐药。本项目拟从分子、细胞、动物模型及临床等多个层次验证此假设。通过本项目，我们期望在揭示胆囊癌发生及化疗耐药机制的基础上，找出可用于临床化疗疗效评估的新的分子标志物，并尝试一种新的吉西他滨联合用药的治疗策略。

Gallbladder cancer (GBC) is the most common biliary tract malignancy. The 5-year survival rate of GBC patients is around 10%, due to a low radical resection rate. Gemcitabine is the first-line chemotherapy drug to treat gallbladder cancer, but its effect is limited with drug resistance. Thus, it is critical to understand the molecular mechanisms behind the development as well as the chemotherapy resistance in GBC. Our previous work found that STMN1 is a GBC risk gene and its overexpression is associated with the prognosis of patients. Overexpression of STMN1 leads to the overexpression of the cell cycle regulatory protein, cyclinB1, and the gemcitabine resistance in GBC cells. Based on these, we hypothesized that: STMN1 directly interacts and phosphorates cyclinB1 to promote its entry into the nucleus to regulate the cell cycle. This eventually leads to the development and chemotherapy resistance in GBC. Through integrated molecular, cellular, mouse model and clinical data, we want to 1) reveal the role of STMN1/cyclinB1 in the development and gemcitabine resistance in GBC; 2) shed the light on the possibility of new molecular biomarkers to evaluate the effect of chemotherapy; and 3) provide a new combination drug strategy to improve the efficacy of gemcitabine.