SPIN1正反馈调控Hippo-YAP信号通路促胃癌侵袭转移的机制研究

侵袭转移是导致胃癌患者死亡的重要原因。纺锤体蛋白SPIN1表达上调和Hippo通路失调与肿瘤侵袭转移密切相关，但SPIN1在胃癌侵袭转移中的作用及机制尚未见报道。我们前期研究发现：(1)SPIN1在胃癌中表达升高，提示预后不良；(2)干扰SPIN1显著抑制胃癌细胞增殖和侵袭；(3)SPIN1能与YAP/TEAD4结合调控Hippo通路活性，且SPIN1是YAP/TEAD4的潜在靶基因。据此，我们提出SPIN1正反馈调控Hippo-YAP通路促胃癌侵袭转移的科学假说。本项目拟采用细胞实验和裸鼠模型观察SPIN1促胃癌细胞侵袭转移的功能；利用Co-IP、荧光素酶报告基因及ChIP等阐明SPIN1与Hippo-YAP通路交互调控的机制；应用TCGA结合临床标本明确SPIN1的潜在临床意义。本项目将阐明SPIN1正反馈调控Hippo-YAP信号通路促胃癌侵袭转移的新机制，可为胃癌的防治提供新靶点。

Invasion and metastasis are the main causes of deaths in patients with gastric cancer (GC). SPIN1 overexpression and dysregulation of Hippo-YAP pathway play a vital role in cancer cell invasion and metastasis. However, the role of SPIN1 in GC metastasis and its underlying mechanism remains unknown. Our preliminary data showed that SPIN1 was significantly upregulated in GC tissues and cell lines. Increased SPIN1 expression was closely associated with poor prognosis in patients with GC. Moreover, SPIN1 silencing could suppress GC cell proliferation and invasion. Mechanistically, SPIN1 regulated the activity of Hippo pathway via forming a ternary complex with YAP and TEAD4. Interestingly, we found SPIN1 might be a direct target gene of the YAP/TEAD4 complex. Therefore, we hypothesized that SPIN1 promotes GC cell metastasis via a positive feedback loop involving the Hippo-YAP pathway. In our present study, we will confirm the biological functions of SPIN1 in accelerating GC cell invasion and metastasis using in vitro and in vivo assays. Meanwhile, the Co-IP (co-immunoprecipitation), luciferase reporter assay and ChIP (Chromatin immunoprecipitation) will be used to clarify if SPIN1 inactivates Hippo pathway through interacting with YAP and TEAD4, and to validate if SPIN1 is a direct target of Hippo pathway. Finally, we aim to utilize the TCGA data and clinical samples to further investigate the clinical significance of this feedback loop in GC patients. Our study will not only illuminate an emerging mechanism that SPIN1 forms a positive feedback loop with Hippo-YAP pathway to facilitate GC invasion and metastasis, but also provide potential therapeutic strategies for patients with GC.