Hedgehog信号通路配体Shh在肺鳞癌中富集的分子机制及临床防治研究

Hedgehog signaling pathway regulates organ development in embryonic development. In adults, the Hedgehog signaling pathway is generally in the resting state, but its abnormal activation has been linked to several human cancers. Therefore, Hedgehog signaling pathway has now become an important field of cancer prevention and control. In many malignant tumors, lung squamous cell carcinoma that is a subtype of non-small cell lung cancer lacks of effective diagnostic markers and therapeutic targets, so the clinical treatment is unoptimistic. Based on previous research, we found that the Shh of Hedgehog signaling pathway is specificity overexpressed in lung squamous carcinoma, but its molecular mechanism is remains unclear. The project will combine cell biology, molecular biology, bioinformatics, pharmacology studied the molecular mechanism of specificity overexpression of Shh in lung squamous cell carcinoma, to explore the role and mechanism of Shh in regulation incidence of lung squamous cell carcinoma. Further, we analyze Shh content in pleural fluid from patients with lung squamous carcinoma, lung adenocarcinoma, infectious diseases and non-infectious diseases based on established Shh content detection platform, assess Shh that acts as a clinical diagnostic and prognostic marker of lung squamous carcinoma. The project will provide potential new targets for target therapy and a new biomarker of clinical diagnosis and prognosis for lung squamous cell carcinoma, publish 2-3 papers in SCI journals, and apply 1 patent.

Hedgehog信号通路在胚胎发育过程中调节器官发育。在成人体内，该信号通路一般处于静息状态，其异常活化与多种肿瘤的发生发展关系密切，因而，靶向该信号通路成为肿瘤防治的重要领域之一。在众多恶性肿瘤中，非小细胞肺癌中的肺鳞癌亚型由于缺乏有效的诊断标志物和治疗靶标，临床治疗效果差。基于前期研究，我们发现Hedgehog信号通路中Shh配体在肺鳞癌中特异性高表达，但其分子机制仍不明确。本项目将结合生物信息学、细胞生物学、分子生物学、药理学等多种手段研究Shh在肺鳞癌中特异性高表达的分子机制，探索Shh调控肺鳞癌的发病机制。进一步，我们将基于已建立的Shh含量检测平台，检测并分析肺鳞癌、肺腺癌、感染性和非感染性胸水中Shh含量，评估Shh作为肺鳞癌临床诊断和预后判断的标志物。本项目将提供肺鳞癌靶向治疗的潜在新靶点和临床诊断、预后判断的新生物标志物，在SCI杂志发表论文2-3篇，申请专利1项。

Hedgehog信号通路在胚胎发育过程中调节器官发育。在成人体内，该信号通路一般处于静息状态，其异常活化与多种肿瘤的发生发展关系密切，因而，靶向该信号通路成为肿瘤防治的重要领域之一。在众多恶性肿瘤中，非小细胞肺癌中的肺鳞癌亚型由于缺乏有效的诊断标志物和治疗靶标，临床治疗效果差。. 本项目研究发现Shh调节肺鳞癌细胞的迁移和侵袭。Shh在肺腺癌和肺鳞癌组织中高表达。Shh表达量越高，肺鳞癌的分化程度越低，肺鳞癌病人的无病生存期和总生存期越短。而且，肺鳞癌患者胸水中的Shh含量比肺炎和肺腺癌患者高。进一步，探索Shh在肺鳞癌中高表达的分子机制，研究发现转录因子GATA6在肺鳞癌中特异性低表达，其通过转录抑制调控Shh的表达来抑制肺鳞癌细胞的增殖和迁移。. 基于本项目基金资助，我们还发现DNAJC5在肝癌组织中高表达，其与SKP2相互作用，促进SKP2-p27复合物的形成，使p27的降解。DNAJC5通过调控SKP2-p27信号抑制肝癌细胞的生长。另外，我们还发现特异性敲除小鼠血管内皮细胞中的Arl13b能抑制小鼠视网膜血管的发育和颅内注射的神经胶质瘤细胞的生长，且延长小鼠的生存期。Arl13b增强细胞间信号通讯和VEGFR2信号促进血管形成和肿瘤生长。. 本项目将提供肺鳞癌靶向治疗的潜在新靶点和临床诊断、预后判断的新的生物标志物，为肿瘤（肝癌和神经胶质瘤等）的诊疗提供新的靶点。