LAPTM5调控BMPR1A溶酶体途径降解介导肾癌选择性肺转移的作用和机制研究

肾癌转移频率高，且对肺有显著倾向，是重要临床问题，目前缺乏对肾癌选择性肺转移的机制探讨。本项目前期筛选获得了器官转移倾向的肾癌细胞株，经转录组测序，结合临床芯片数据分析，筛选出溶酶体相关跨膜蛋白5（LAPTM5）可能是介导肾癌选择性肺转移的关键分子。后续研究发现，LAPTM5抑制BMP通路活化，促进BMPR1A转录后水平下调。由此提出假说：LAPTM5可能通过调控BMPR1A溶酶体途径降解阻断肺部来源的抑制性BMP信号，恢复肺部定植肾癌细胞的自我更新能力，促进肾癌选择性肺转移。为验证假说，我们拟，首先证明LAPTM5促进肾癌选择性肺转移的作用；其次明确LAPTM5阻断BMP信号、促进细胞自我更新能力恢复的功能；随后探索LAPTM5调控靶分子溶酶体途径降解的分子机制；最后评估LAPTM5及下游信号在临床肾癌肺转移预测和治疗方面的价值。本研究将首次阐述调控肾癌选择性肺转移的关键分子及作用机制。

Clinically, the lung is the preferred organ for distant metastasis of renal cancer (RCC), which happens very frequently in RCC patients. However, there is a lack of research on how to prevent and treat this; and the mechanism underlying lung-specific metastasis of RCC is still unclear. Transcriptome sequencing of RCC cells with metastasis organotropism, co-analyzed with microarray gene expression data of clinical samples, showed that lysosomal protein transmembrane 5 (LAPTM5) may act as the pivotal molecule mediating lung-specific metastasis of RCC. We also found that LAPTM5 inhibited the activation of BMP pathway and promoted the down-regulation of BMPR1A at post-transcriptional level. Our hypothesis is that LAPTM5 could block lung-derived BMP signal through regulating lysosomal degradation of BMPR1A, thus restore the self-renewal ability of tumor cells colonized in the lung to promote lung-specific metastasis of RCC. To test the hypothesis, firstly, we will demonstrate the role of LAPTM5 in promoting lung-specific metastasis of RCC. Secondly, the effect of LAPTM5 blocking BMP signal and promoting the self-renewal ability recovery of RCC cells will be verified. Subsequently, we will explore the molecular mechanism by which LAPTM5 regulates lysosomal metabolism. Finally, we will evaluate the potential of LAPTM5 and its downstream signals in the prediction and treatment of lung metastasis in RCC. This study will, for the first time, elucidate the key molecules and mechanisms involved in the regulation of lung-specific metastasis in RCC.