PD64-08 LYSOSOMAL PROTEIN TRANSMEMBRANE 5 MEDIATES LUNG-SPECIFIC METASTASIS OF RENAL CANCER BY REGULATING BMP/SMAD1 PATHWAY

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology III (PD64)1 Apr 2020PD64-08 LYSOSOMAL PROTEIN TRANSMEMBRANE 5 MEDIATES LUNG-SPECIFIC METASTASIS OF RENAL CANCER BY REGULATING BMP/SMAD1 PATHWAY Bo Jiang*, Wei Chen, Xiaozhi Zhao, and Hongqian Guo Bo Jiang*Bo Jiang* More articles by this author , Wei ChenWei Chen More articles by this author , Xiaozhi ZhaoXiaozhi Zhao More articles by this author , and Hongqian GuoHongqian Guo More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000981.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Despite progression in cancer control and survival, metastases are still diagnosed in a notable proportion of renal cancer (RCC) patients with a significant tendency to lung. Lung metastasis seriously affects the prognosis of patients and the current clinical drugs fail to achieve satisfactory therapeutic effects. It is urgent to develop new drugs based on the molecular theory of lung metastasis of RCC for better personalized treatment. However, the research on the mechanism of lung-specific metastasis of RCC is still blank. METHODS: Left ventricular injection of luci-labeled murine RCC cells (Renca-Luci) was used to establish the multiple organ metastasis model of RCC, metastases were measured by in vivo imaging system, then metastatic tumor cells in lung and other organs were primarily cultured. After verification, metastatic cells from lung (LuM), brain (BrM) and bone (BoM) along with untreated parental Renca cells were sent for high-throughput RNA-seq analysis. Sphere formation assay and subcutaneous tumor formation assay were conducted to test the stemness of RCC cells. In addition, we further evaluated the effect of lysosomal inhibitor (chloroquine) on the regulation of the BMP/SMAD1 pathway by LAPTM5, and attempted to explore its application prospect of anti-pulmonary metastasis. RESULTS: LuM, BrM, BoM and parental Renca-Luci cells were re-injected into left ventricular of mice, LuM cells showed greater ability to invade the lungs than other cells. LAPTM5 revealed significantly higher mRNA level according to the RNA-seq data and further validated by western-blotting assay at protein level. Overexpression of LAPTM5 in Renca and 786-O cells facilitated the formation of pulmonary metastases in mice, conversely, down-regulation of LAPTM5 in Renca cells significantly reduced lung metastatic lesions. Meanwhile, the ability to invade the brain and bone of Renca-Luci cells was not significantly affected which suggested that LAPTM5 mediates lung-specific metastasis of RCC. BMP/SMAD1 signal suppressed cancer stem cell behavior and was responsible for tumor cell dormancy in the lungs, we provided evidence that LAPTM5 inhibited phosphorylation of smad1 of RCC cells after stimulated with recombinant BMP4 and thereby enhancing the self-renewal capability of RCC cells, the inhibitory effect disappeared after chloroquine treatment. CONCLUSIONS: Our results unraveled that LAPTM5 mediates lung-specific metastasis of RCC by inhibiting BMP/SMAD1 pathway and represents therapeutic targets for RCC. Source of Funding: This work was supported by grants from the National Natural Science Foundation of China (81502203, 81772710), the National Natural Science Foundation of Jiangsu Province (BK20150097), the Project of Invigorating Health Care through Science, Technology and Education Jiangsu Provincial Key Medical Discipline (ZDXKB201601 4), the “Summit of the Six Top Talents” Program of Jiangsu Province (SWYY-084), Postdoctoral Scientific Research Project of China (2017M621729) and the Postdoctoral Research Foundation of Jiangsu Province (1701021B), Nanjing Medical Science and technique Development Foundation (QRX17139). © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1303-e1303 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bo Jiang* More articles by this author Wei Chen More articles by this author Xiaozhi Zhao More articles by this author Hongqian Guo More articles by this author Expand All Advertisement PDF downloadLoading ...