外泌体介导的TCTP蛋白促进胆囊癌侵袭转移的分子机制及其干预研究

Tumor metastasis is the main cause of death in patients with gallbladder carcinoma. Exosomes play an important role in tumor metastasis. The mechanism of exosomes in the metastasis of gallbladder carcinoma remains unclear. In our previous study, TCTP was associated with the metastasis of gallbladder carcinoma and existed in the exosomes of high metastatic potential gallbladder cancer cell. Exosomes rich in TCTP could significantly promoted the invasion and metastasis of low metastatic potential gallbladder carcinoma cells. Some studies have confirmed that Dihydroartemisinin can bind TCTP and promote TCTP degradation. Based on this, we hypothesize that high metastatic potential gallbladder carcinoma cells deliver TCTP to low metastatic potential gallbladder carcinoma cells through exosomes, thereby enhancing the latter's metastatic potential. It is expected to achieve the goal of combating gallbladder cancer metastasis by using Dihydroartemisinin to inhibit TCTP. This project intends to further clarify the molecular mechanisms of high metastatic potential gallbladder carcinoma cell exosomes promoting gallbladder carcinoma invasion and metastasis and tap potential interventions to find effective ways to combat gallbladder cancer metastasis, thus to improve gallbladder cancer patients' prognosis.

肿瘤转移是胆囊癌患者的主要死亡原因，外泌体在肿瘤转移中扮演重要角色，而外泌体在胆囊癌转移中的作用机制尚不清楚。我们前期研究发现TCTP与胆囊癌的转移密切相关，并且发现TCTP存在于高转移潜能胆囊癌细胞外泌体中，富含TCTP的外泌体能显著促进低转移潜能胆囊癌细胞侵袭转移，结合已有的研究证实双青蒿素能结合TCTP并促进其降解。据此我们提出假说：高转移潜能胆囊癌细胞通过外泌体将TCTP传递给低转移潜能胆囊癌细胞，从而增强后者的侵袭转移能力。利用双青蒿素抑制外泌体中TCTP，可望达到抗击胆囊癌转移的目的。本课题拟在深入阐明高转移潜能胆囊癌细胞源性外泌体促进胆囊癌侵袭转移分子机制的基础上，进一步挖掘潜在的干预性手段，寻找抗击胆囊癌转移的有效治疗手段，改善胆囊癌患者的预后。

胆囊癌早期缺乏特异性症状，诊断困难，早期就能通过直接浸润、淋巴转移、血运转移等方式广泛扩散，因此多数患者确诊时已处于晚期。据统计胆囊癌导致的死亡绝大部分是由于肿瘤转移造成的，其中肝转移是胆囊癌最主要的转移部位，深入研究其转移机制，寻求与胆囊癌转移有关的分子靶标及靶向药物成为胆囊癌防治的关键，对提高胆囊癌整体预后意义深远。本课题在总结既往TCTP与胆囊癌侵袭转移相关的研究基础上，深入的研究外泌体在TCTP介导的促胆囊癌细胞侵袭转移过程中的重要作用，进一步发现高转移潜能胆囊癌细胞源性外泌体中富含TCTP蛋白，并能促进低转移潜能胆囊癌细胞侵袭转移，在此基础上进一步利用TCTP的抑制剂-双青蒿素阻断外泌体中TCTP，证实了双青蒿素能显著抑制外泌体TCTP从而抑制胆囊癌细胞体内体外转移能力，为临床建立胆囊癌转移的新阻断剂提供理论依据，因此双青蒿素有望成为治疗胆囊癌转移的新型药物，改善胆囊癌患者的预后。