SLC12A5通过与SOX18相互作用调控MMP-7表达影响膀胱癌血管生成及侵袭转移的分子机制

Human SLC12A5 (solute carrier family 12 member 5), a novel of the SLC12 gene family, was found in a study of human neoplastic gene regulation. Our previous studies found that high expression of SLC12A5 associated with poor prognosis of bladder cancer. Silencing of SLC12A5 resulted in down-regulation of MMP-7 expression and inhibition of invasiveness/metastasis in bladder cancer cells (Cell Death Dis, 2017). Preliminary results demonstrated down-regulation of SLC12A5 in bladder cancer cells inhibited the ability of angiogenesis. Furthermore, the effect of SLC12A5 on tumor angiogenesis was significantly recovered by replenishment of MMP-7 expression in SLC12A5-silenced bladder cancer cells. Meanwhile, we found that SLC12A5 protein interacted with SOX18 which serves as a transcription factor of MMP-7, but the potential regulation mechanism is still unclear. Based on these findings, this project will investigate the roles and mechanisms of SLC12A5 interacting with SOX18 in regulating MMP-7 expression in bladder cancer invasiveness/metastasis and angiogenesis by using techniques and methods including molecular cellular biology and experimental zoology. Our study would dissect the underlying mechanism of how SLC12A5 interacts with SOX18 in regulating MMP-7 expression to affect bladder cancer invasiveness/metastasis and angiogenesis, enrich our knowledge of the development and progression of bladder cancer. The finish of this project might provide a potential new target for precision treatment of bladder cancer.

SLC12A5是SLC12家族中可能影响肿瘤发生发展的一个新成员。我们前期研究发现SLC12A5蛋白高表达与膀胱癌预后差相关，沉默SLC12A5能够通过下调MMP-7表达使膀胱癌细胞侵袭转移受抑制。预实验发现下调SLC12A5能够抑制膀胱癌细胞的血管生成能力，而在稳定干扰SLC12A5的细胞中恢复MMP-7的表达后，细胞也恢复了SLC12A5的促血管生成能力，此外，我们还发现SLC12A5和MMP-7的促转录因子SOX18存在蛋白间相互作用，但其分子机制尚不明确。本研究将在此基础上进一步通过分子细胞生物学技术和动物模型等探讨SLC12A5通过与SOX18相互作用调控MMP-7表达的分子机制及其在膀胱癌血管生成及侵袭转移中的意义。对SLC12A5、SOX18及MMP-7在膀胱癌血管生成和侵袭转移中作用和机制的探讨将丰富我们对膀胱癌发生发展的认识，期待为膀胱癌的精准治疗提供潜在新靶点、新思路。

SLC12A5已被发现与多种肿瘤中的发生发展关系密切。本课题组前期研究发现SLC12A5高表达与膀胱癌浸润转移密切相关，但作用机制尚不十分明确。课题组通过预实验发现干扰SLC12A5的表达介导了膀胱癌细胞的侵袭转移并导致细胞中MMP-7表达的下调，而在稳定干扰SLC12A5的细胞中恢复MMP-7的表达后，细胞也恢复了促侵袭转移能力，此外，我们还发现SLC12A5和MMP-7的促转录因子SOX18存在蛋白间相互作用。我们通过分子、细胞、整体水平的研究及临床样本的验证中，发现SLC12A5在膀胱癌中广泛上调，且高表达与膀胱癌差预后显著相关。SLC12A5通过与SOX18相互作用调控MMP-7表达，从而诱导膀胱癌侵袭转移。分析和总结与膀胱癌患者侵袭转移有关的高危的分子指标，为今后临床治疗提供参考。此外，我们还发现，新型纳米材料FeSiNTs载siRNA-SPAG5增强siRNA-SPAG5在血液循环过程中的稳定性；提高siRNA-SPAG5在膀胱癌细胞及组织中的摄取和累积，从而在三种膀胱癌动物模型（裸鼠皮下移植瘤模型、裸鼠尾静脉注射肺转移模型、大鼠原位膀胱癌模型）中抑制肿瘤的发生发展，且无明显毒副反应。我们的研究结果不仅丰富了膀胱癌侵袭转移的调控通路，且为膀胱癌病人的治疗提供新靶点、新思路，具有重要的临床实践指导意义。