多巴胺受体2在精神分裂症患者肺癌发病中的作用研究

Previous studies found that patients with schizophrenia have significantly lower incidence than the general, but the cause is unknown. The documents and our previous work demonstrated that drugs for schizophrenia induced differentiation of cancer stem cells by dopamine receptor subtype 2 (D2R). Accordingly, in this project we hypothesized that D2 receptor was involved in regulation of maintenance of cancer stem cells and inhibition of D2 receptor contributed to differentiation of cancer stem cells, which resulted in decreased risk of tumor incidence. Firstly, this project was aimed to study the role of D2 receptor in stem maintenance of stem cells of non small cell lung cancer (NSCLCs) cell lines. Subsequently blood samples and fresh tumor tissues were collected from clinic after surgery. After that dopamine level in plasma and D2 receptor expression in tumor tissue were assayed in order to evaluate the correlation of dopamine level and D2 receptor expression with cancer progress. At last, the role of D2 receptor in incidence of lung cancer in patients with schizophrenia was tested in schizophrenia mice in order to verify that the drugs for schizophrenia were the reasons for low incidence of lung cancer patients with schizophrenia. Overall, the study will determine the roles of D2 receptor in regulation of maintenance of cancer stem cells, uncover the contribution of D2 receptor to lung cancer progress in clinic and provide support for dynamic monitor and therapy strategy for lung cancer. Meantime, this study will also state the mechanisms for low incidence of lung cancer patients with schizophrenia.

研究发现精神分裂症病人肿瘤发病率明显低于正常人，但其原因不明。文献及我们前期工作表明抗精神分裂症药能够诱导肿瘤干细胞分化，这一作用与抑制多巴胺受体2（D2R）有关。因此本研究推测D2R参与肿瘤干细胞干性的调控，抑制D2R能诱导肿瘤干细胞分化并可降低肿瘤发生率。本研究以非小细胞肺癌（NSCLCs）为研究对象，首先在细胞水平研究D2R在NSCLCs干细胞干性维持中的作用，进而收集临床NSCLCs病人标本，检验病人血浆多巴胺水平和肿瘤组织D2R水平，以验证多巴胺和D2R在肺癌发展中的作用；最后在精神分裂症动物模型验证D2R与精神分裂症肺癌发病的关系，证明精神分裂症药物是精神分裂症患者肿瘤发生率降低的原因之一。本研究将明确D2R在调控肿瘤干细胞干性中的作用，揭示多巴胺水平与临床肺癌病情发展的关系，为肺癌临床动态监测和治疗策略选择提供实验数据支持，同时也将阐述精神分裂症患者肿瘤发生率低的机制。

临床研究显示住院的精神分裂症患者肺癌发病率低，但原因不明。近年来，有研究报道抗精神分裂症药物能够抑制肿瘤干细胞。本研究假设抗精神分裂症药物通过多巴胺受体2（D2DR）发挥抗肿瘤作用。研究发现D2DR抑制剂thioridazine和fluphenazine明显抑制NCI-H460肿瘤干细胞形成，而D2DR激动剂quinpirole则逆转thioridazine这一抑制作用；降低D2DR受体表达后肿瘤干细胞成球率、克隆形成能力以及细胞增殖活力明显降低，而高表达D2DR则明显促进肿瘤干细胞球的形成、克隆形成以及增殖活力。体内研究显示，异体移植后高表达D2DR组肿瘤生长速度明显更快，成瘤率显著高于低表达组；临床肺癌组织中D1DR表达明显低于正常组织，培养原代肺癌肿瘤干细胞球，D2DR和CD133均表达于肿瘤干细胞表面；精神分裂症药penfluridol,trifluoperazine,pimozide在10uM时对NCI-H460细胞增殖和肿瘤干细胞形成具有抑制作用，而同样浓度下，clozapine, haloperidol,sulpride则没有显示抑制作用。进一步研究发现，对NCI-H460细胞增殖和肿瘤干细胞球形成具有抑制作用的抗精神分裂症药物同时具有钙调蛋白拮抗或钙离子通道阻断作用，提示抗精神分裂症药物通过多巴胺受体影响了细胞内钙离子信号。体内实验结果显示，抗精神分裂症药物thioridazine和pimozide具有延长烟草致癌剂NNK和B@P诱导的肺癌小鼠模型生存时间。以上结果表明，多巴胺受体2参与了肿瘤干细胞更新和增殖，精神分裂症患者服用的抗精神分裂症药物具有抑制肿瘤增殖的作用，可能是精神病人肺癌发病率低的原因之一。