MP10-02 A NOVEL THERAPEUTIC TARGET SCG2 MIGHT COOPERATE WITH HIF1α IN TKI-RESISTANT RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) I (MP10)1 May 2024MP10-02 A NOVEL THERAPEUTIC TARGET SCG2 MIGHT COOPERATE WITH HIF1α IN TKI-RESISTANT RENAL CELL CARCINOMA Wataru Fukumoto, Hirofumi Yoshino, Saeki Saito, Gang Li, Junya Arima, Ichiro Kawahara, Takashi Sakaguchi, Shuichi Tatarano, and Hideki Enokida Wataru FukumotoWataru Fukumoto , Hirofumi YoshinoHirofumi Yoshino , Saeki SaitoSaeki Saito , Gang LiGang Li , Junya ArimaJunya Arima , Ichiro KawaharaIchiro Kawahara , Takashi SakaguchiTakashi Sakaguchi , Shuichi TataranoShuichi Tatarano , and Hideki EnokidaHideki Enokida View All Author Informationhttps://doi.org/10.1097/01.JU.0001008588.39303.c9.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Renal cell carcinoma (RCC) is well known to be associated with vascular endothelial growth factor (VEGF) signaling. Therefore, VEGF targeting drugs, such as sunitinib, are key reagents for patients with recurrent or distant metastasis. However, intrinsic or acquired resistance to sunitinib have become a major issue for treatment. Then, we focused on the mechanisms of sunitinib resistance in RCC in this study. METHODS: RNA-seq analysis was performed using sunitinib-resistant RCC cells (SUR-Caki1, SUR-ACHN, SUR-A498), established in our laboratory, and selected candidate genes that were associated with angiogenesis. Among them, we analyzed the significance of a candidate gene by using The Cancer Genome Atlas (TCGA) database. Next, we performed functional analyses between SUR-RCC cells and their parent cells. Loss-of-function studies about the candidate gene were also performed in SUR-RCCs and their parental cells. In addition, we explored the mechanism of SCG2 in RCC by tube formation assay and pull-down assay. RESULTS: According to the result of RNA-seq analysis, it was found that secretogranin II (SCG2) was one of the most elevated genes in SUR-RCC cells compared with the parent cells. TCGA database also showed that SCG2 expressions were significantly elevated in RCC cells (n=533) compared to normal cells (n=72), and that SCG2 expressions in the clinical stage T2 and T3 groups were significantly higher than these in the clinical stage T1 and T2 groups. In addition, the survival rate was significantly lower in the SCG2 high expression group (n=156) than in the low group (n=156). In functional analyses, SUR-RCC cells showed more migrate and invasive abilities compared with the parental cells, and SCG2 knockdown significantly suppressed migration, invasion and angiogenesis in SUR-RCC cells. Further analyses by qRT-PCR showed higher expression of HIF1α and VEGF-C in SUR-RCC cells, and SCG2 suppression lead to decrease the expressions of HIF1α, VEGF-A, and VEGF-C. And pull-down assay showed that SCG2 has an interaction with HIF1α. Overexpression of SCG2 was shown to attenuate the tumor suppressive effect of axitinib by loss-of-function assays and tube formation assay, and this may be true for other TKIs as well. CONCLUSIONS: Our findings suggested that SCG2 might be a key molecule which was responsibility for sunitinib resistance. Therefore, our studies may lead to a novel understanding in VHL/HIF/VEGF pathway, and the development of a new therapeutic strategy for sunitinib-resistant RCC. Source of Funding: None © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e137 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Wataru Fukumoto More articles by this author Hirofumi Yoshino More articles by this author Saeki Saito More articles by this author Gang Li More articles by this author Junya Arima More articles by this author Ichiro Kawahara More articles by this author Takashi Sakaguchi More articles by this author Shuichi Tatarano More articles by this author Hideki Enokida More articles by this author Expand All Advertisement PDF downloadLoading ...