HIF-1α调控SPOP/Gli2信号轴影响胃癌生长、侵袭及转移的分子机制研究

The incidence and mortality rates related to gastric cancer is really high. Recent evidence suggests that aberrant activation of Hh/Gli signaling pathway is associatied with gastric cancer. HIF -1α expresses high in gastric cancer and interacts with E3 ligase SPOP and Hh/Gli signaling pathway.At present,studies reveal that dysfunction of ubiquitin - proteasome system could accelerate tumorgenesis and.metastasis.As a tumor suppressor, SPOP suppressed gastric tumorigenesis through interacting with Gli2 and inhibiting Hh/Gli2 signaling.pathway. But how to participate in the development of gastric cancer is still not clear.Our previous study showed that the immunostaining of SPOP was much less in GC tissues than in paired adjacent tissues. SPOP was negatively correlated with lymph node metastasis, poor histopathologic differentiation and advanced TNM stages.; SPOP inhibited Gli2 expression inside the cytoplasm and promoted the degradation of Gli2 protein,thus inhibiting Hh/Gli2 signaling activity; SPOP inhibited gastric cancer cell proliferation and migration.Why SPOP decresed in gastric cancer? And the relation to the occurrence and development of gastric cancer? Combined with the others’ and our own previous study, this program plans to study on the role of HIF-1α/SPOP/ Gli2 signaling axis in the occurrence and.development of gastric cancer.Combined with the others’ and our own previous study, this program plans to study on the role of HIF-1α/SPOP/ Gli2 signaling axis in the occurrence and development of gastric cancer.To explore the interaction between HIF-1α, SPOP and Hh/Gli signaling pathway from molecular and cellular level.To observe the role and molecular mechanism of HIF-1α/SPOP/ Gli2 axis to the invasion and metastasis of gastric cancer in vitro and in vivo. It may provide an alternative strategy for developing therapeutic agents and targeted therapy of gastric cancer in future.

胃癌发生率与死亡率非常高，Hh/Gli信号通路在胃癌中呈异常活化状态，HIF-1α在胃癌中高表达，并且与E3连接酶SPOP及Hh/Gli信号通路均存在相互作用。但其如何参与胃癌发生发展的机制仍不明确。我们在前期研究中发现：SPOP在胃癌中呈低表达，与淋巴结转移、肿瘤分化及TNM分期相关；SPOP与Gli2相互作用，下调Hh/Gli2信号通路的活性；SPOP降低胃癌细胞的增殖、迁移与克隆形成。但为何胃癌中SPOP表达降低，其与胃癌发生发展的关系如何？结合他人与自身研究基础，本课题将以HIF-1α/SPOP/Gli2信号轴为研究靶标，从分子及细胞水平研究HIF-1α与SPOP及Hh/Gli信号通路的相互作用；体内外实验观察HIF-1α/SPOP/Gli2信号轴调控胃癌侵袭、转移的作用及分子机制，揭示其在胃癌的发病机制及侵袭转移中的作用，以期探寻胃癌诊断与靶向治疗的新策略提供理论依据

胃癌发生率与死亡率非常高，本项目发现：Hh/Gli信号通路在胃癌中呈异常活化状态，HIF-1α在胃癌中高表达，并且与E3连接酶SPOP及Hh/Gli信号通路均存在相互作用。SPOP在胃癌中呈低表达，HIF-1α与SPOP表达呈互相关，并与淋巴结转移、肿瘤分化、TNM分期、预后相关；HIF-1α、SPOP与Gli2相互作用，下调Hh/Gli信号通路的活性; SPOP降低胃癌细胞的增殖、迁移与克隆形成。本项目研究通过体内外实验证实，HIF-1α与SPOP直接结合，并影响Hh/Gli信号通路，从而调控胃癌的增殖与迁移，为胃癌的临床靶向治疗的新策略提供理论依据。