TGF-β/SPOP负反馈环路在肿瘤转移中的调控作用及分子机制研究

Tumor metastasis is the leading cause of death. So, It is important to explore the mechanism of tumor metastasis. Based on the construction of E3 ubiquitin ligase CRISPR/Cas9 library, we found that SPOP inhibited tumor metastasis through the in vivo metastasis model screen. Using bioinformatics methods, we find that the SPOP mRNA level significantly decreased in a variety of malignant tumors. Studies have shown that SPOP plays an important role in tumorigenesis, but the role of tumor metastasis and its regulatory mechanism is not clear. Further study indicated that activation of TGF-β signaling pathways enhanced the binding of Smad3 to the SPOP promoter region, and then inhibited the expression of SPOP. Furthermore, knockout of SPOP resulted in the activation the TGF-β signaling pathway. These results suggested that SPOP and TGF-β signaling pathway formed negative feedback loop and regulated the tumor metastasis. Based on this, we will mainly study the function of SPOP in the progression and metastasis of cancer, clarify the mechanism of TGF-β/SPOP negative feedback loop, and finally reveal the mechanism of TGF-β/SPOP negative feedback loop in the regulation of cancer metastasis. Our study will provide new theoretical basis for accurate targeted treatment of tumor metastasis.

肿瘤的远处转移是造成患者死亡的主要原因，探究其调控机制对肿瘤的治疗具有重要的意义。申请人前期通过在体转移模型筛选发现，E3泛素连接酶SPOP可抑制肿瘤转移；通过TCGA数据库分析发现，SPOP转录水平在多种恶性肿瘤中明显下调。SPOP在肿瘤发生中起着重要的作用，然而其在肿瘤转移中的作用与其调控机制尚不清楚。我们经过进一步的机制研究发现，激活TGF-β信号通路能增强Smad3与SPOP启动子区的结合能力，抑制SPOP的表达；敲除SPOP可负反馈激活TGF-β信号通路。基于以上结论，我们提出假说：TGF-β/SPOP形成负反馈环路调控肿瘤的转移。本项目拟在分子、细胞和动物水平，重点探讨SPOP在恶性肿瘤转移中的功能，详细阐明TGF-β/SPOP负反馈环路的具体机制，最终揭示TGF-β/SPOP负反馈环路在肿瘤转移中的调控作用及分子机制，为精准靶向治疗肿瘤转移提供理论依据。

肿瘤的远处转移是造成患者死亡的主要原因，探究其调控机制对肿瘤的治疗具有重要的意 义。在本项目中，我们通过在体转移模型筛选发现，E3泛素连接酶SPOP可抑制肿瘤转移；通过TCGA数据库分析发现，SPOP转录水平在多种恶性肿瘤中明显下调。SPOP在肿瘤发生中起着重要的作用 ，然而其在肿瘤转移中的作用与其调控机制尚不清楚。我们经过进一步的机制研究发现，激活TGF-β信号通路能增强Smad3与SPOP启动子区的结合能力，抑制SPOP的表达；敲除SPOP可负反馈激活TGF-β信号通路。基于以上结论，我们提出假：TGF-β/SPOP形成负反馈环路调控肿瘤的转移。本项目在分子、细胞和动物水平，重点探讨SPOP在恶性肿瘤转移中的功能，详细阐明了TGF-β/SPOP负反馈环路的具体机制，最终揭示TGF-β/SPOP负反馈环路在肿瘤转移中的调控作用及分子机制，为精准靶向治疗肿瘤转移提供理论依据。