TSLP基因介导JAK/STAT信号通路调控胃神经内分泌癌发生过程的分子机制研究

Gastric Neuroendocrine Carcinoma (GNEC) is a rare tumor with high heterogeneity, challenging malignancy and unsatisfactory efficacy, which appear most frequently in China. The pathogenic mechanism of GNEC is unclear at present, and the clinical work is faced with great challenges around the world. Our research team have established domestic multi-center database of GNEC patients including clinical information and biological specimens. In our preliminary work, tissue and blood samples of GNEC patients were tested through whole-exome sequencing, we have found the new diver gene thymic stromal lymphopoietin (TSLP) and its closely related JAK/STAT signaling pathway. Moreover, our results have showed that TSLP have associated with the staging and poor prognosis of GNEC patients, and TSLP could increase the proliferation and suppress the apoptosis of tumor cells. We suppose TSLP may participate in the progression of GNEC through JAK/STAT signaling pathways. Therefore, we will enlarge the sample size to verify the correlation between TSLP and clinicalpathological features, clinical prognosis. In addition, the effect of TSLP wild-type and mutated-type on cellular biological function were studied by both in vitro and animal models. We will explore the deeper molecular mechanisms about how TSLP mediate the JAK/STAT signaling pathway to regulate the tumor progression. The purpose of this study is to provide theoretical support for increasing early diagnosis, develop new treatment, and finally improve the overall survival of GNEC patients.

胃神经内分泌癌（GNEC）是一种异质性强、恶性度高、疗效不佳的罕见肿瘤，临床诊治工作带面临着极大挑战，中国属全球高发地区，目前对其致病机制尚无明确报道。本课题组前期已建立国内多中心GNEC临床信息及生物样本资源库，通过高通量全外显子测序筛选出新的候选驱动基因胸腺基质淋巴细胞生成素（TSLP）及密切相关的JAK/STAT信号通路；初步分析显示TSLP与GNEC临床分期和不良预后相关；且影响肿瘤细胞增殖能力和凋亡过程。我们推测TSLP可能通过JAK/STAT信号通路参与GNEC发生发展的过程。因此，本研究拟扩大样本验证TSLP与GNEC临床病理特征和预后相关性；通过体内实验和动物模型明确TSLP野生型和突变型对细胞不同生物学功能的影响及致癌作用；进一步探讨TSLP介导JAK/STAT信号通路调控GNEC进程的分子机制。这将为提高GNEC早诊率、研发治疗新策略、改善患者生存提供新的思路和理论依据。

胃神经内分泌癌这一中国特色的罕见胃部恶性肿瘤的临床病理特征和患者预后，其恶性度高、生存率低给临床诊治工作带来了极大的挑战，从治疗策略上仅仅参照胃腺癌的治疗模式。目前暂无明确关于致病机制、遗传易感性、异质性等方面的研究，而相关治疗策略也仅处于起步阶段，存在很多盲点和未知领域。本研究通过高通量全外显子测序筛选出的驱动基因胸腺基质淋巴细胞生成素（TSLP）及密切相关的JAK/STAT信号通路；大样本临床标本分析显示TSLP与GNEC的临床病理特征和不良预后相关；且促进肿瘤细胞增殖能力和抑制凋亡。通过体内实验和动物模型明确TSLP野生型和突变型对细胞不同生物学功能的影响及致癌作用；进一步探讨TSLP介导JAK/STAT信号通路调控GNEC进程的分子机制，证明TSLP通过JAK/STAT信号通路参与GNEC发生发展过程。本研究为揭示胃神经内分泌癌的分子机制和靶向治疗提供了初步参考依据。