热疗中Nrf2和HSP70在食管癌凋亡和转移的功能及机制的研究

As a malignant with high incidence in China, esophageal squamous cell carcinoma (ESCC) was always accompanied with distant metastasis at the time of diagnosis. Then, reveal the molecular pathogenesis of apoptosis and metastasis will contribute to the clinical staging, treatment options and prognosis improved of ESCC. Recently, hyperthermia has drew broad attention to cure tumor, promoted the apoptosis of tumor cells by oxidative stress and suppressed metastasis by reducing MMPs.Nrf2 has effect on carcinogenesis and carcinostasis, but it’s role is unknown in hyperthermia. The expression of HSP70 increases in hyperthermia, the relation with Nrf2 is unknown. Previous results related to Nrf2 by our group suggest that Nrf2 plays an important role in the metastasis of ESCC, but the role in hyperthermia needs to be further investigated. The project will do experiments through clinical, cellular, molecular, and animal levels to clear the clincal value and respective functions of Nrf2 and HSP70 in apoptosis and metastasis of ESCC. In clinical levels, we will applicate immunohistochemistry for detection biomarkers significance of Nrf2 and HSP70. In cellular levels, gain/loss-of-function experiments and flow cytometry will contributes to definite the function of Nrf2 and HSP70 in apoptosis and metastasis of ESCC. In molecular levels, RT-PCR and WB techniques will be used to expose differences in the signaling pathway. Last, the function of Nrf2 and HSP70 in vivo will be tested in animal models. In general, the project will lay the foundation for accurate staging and treatment options for ESSC. Moreover, it will provide new therapeutic targets to improve the poor prognosis of patients.

我国是食管鳞癌的高发区，大部分患者确诊时已伴有远处转移。明确食管鳞癌凋亡和转移的分子机制有助于其临床分期、治疗选择和预后改善。目前，热疗治疗肿瘤引起了广泛的关注，通过氧化应激促进肿瘤细胞的凋亡和抑制基质金属蛋白酶阻碍肿瘤的转移。Nrf2具有促癌和抑癌作用，在热疗治疗中的作用不明，而HSP70在热疗治疗过程中合成增加，其与Nrf2调控机制亦不明确。课题组前期有关Nrf2的研究基础提示Nrf2在食管鳞癌的转移中发挥重要作用，但其在热疗中作用有待进一步明确。本项目拟在临床、细胞、分子与动物四个层次，通过免疫组化、流式细胞术，功能获得及缺失实验、动物模型等方法，探讨Nrf2和HSP70在食管鳞癌凋亡和转移中的临床价值和功能，明确两者的信号通路及精确调控机制，以期为食管鳞癌的精确分期、治疗选择奠定基础，为改善患者的不良预后提供新的治疗靶点。

我国是食管鳞癌的高发区，大部分患者确诊时已伴有远处转移。明确食管鳞癌凋亡和转移的分子机制有助于其临床分期、治疗选择和预后改善。热疗治疗肿瘤引起了广泛的关注，热疗可促进食管癌细胞的凋亡，热疗对细胞的迁移和侵袭无显著影响。沉默Nrf2和HSP70的表达，可促进食管癌细胞的凋亡和抑制肿瘤的增长；沉默Nrf2的表达，可抑制细胞的迁移和侵袭，但沉默HSP70的表达，可促进细胞的迁移和侵袭。Nrf2和HSP70无显著的调节作用。Nrf2和HSP70在食管癌的的凋亡，迁移和侵袭中发挥重要作用，但其调节MMP2，MMP9，caspase8和caspase3由于不同条件而不同。沉默Nrf2可抑制食管癌细胞的增长，侵袭和迁移，同时促进细胞的凋亡，可尝试作为一个分子靶点；而沉默HSP70可抑制食管癌细胞的增长和促进凋亡，然而促进细胞的迁移和侵袭，而产生不同细胞行为，HSP70作为分子伴侣，需要更深入的研究其机制。总之，热疗可以促进食管癌细胞的凋亡，热疗可作为食管癌的辅助治疗方式。Nrf2可以作为食管癌治疗的新靶点。