Background Sunitinib resistance can be classified into primary and secondary resistance. While accumulating research has indicated several underlying factors contributing to sunitinib resistance, the precise mechanisms in renal cell carcinoma are still unclear. Methods RNA sequencing and m6A sequencing were used to screen for functional genes involved in sunitinib resistance. In vitro and in vivo experiments were carried out and patient samples and clinical information were obtained for clinical analysis. Results We identified a tumor necrosis factor receptor-associated factor, TRAF1, that was significantly increased in sunitinib-resistant cells, resistant cell-derived xenograft (CDX-R) models and clinical patients with sunitinib resistance. Silencing TRAF1 increased sunitinib-induced apoptotic and antiangiogenic effects. Mechanistically, the upregulated level of TRAF1 in sunitinib-resistant cells was derived from increased TRAF1 RNA stability, which was caused by an increased level of N6-methyladenosine (m6A) in a METTL14-dependent manner. Moreover, in vivo adeno-associated virus 9 (AAV9) -mediated transduction of TRAF1 suppressed the sunitinib-induced apoptotic and antiangiogenic effects in the CDX models, whereas knockdown of TRAF1 effectively resensitized the sunitinib-resistant CDXs to sunitinib treatment. Conclusions Overexpression of TRAF1 promotes sunitinib resistance by modulating apoptotic and angiogenic pathways in a METTL14-dependent manner. Targeting TRAF1 and its pathways may be a novel pharmaceutical intervention for sunitinib-treated patients.
Abstract:Objectives: We retrospectively reviewed the urethral stricture cases treated in our tertiary center, and assessed the safety and feasibility of the high-pressure balloon dilation (HPBD) technique for anterior urethral stricture. Methods: From January 2009 to December 2012, a total of 31 patients with anterior urethral strictures underwent HPBD at our center, while another 25 cases were treated by direct vision internal urethrotomy (DVIU). Patient demographics, stricture characteristics, surgical techniques, and operative outcomes were assessed and compared between the two groups. The Kaplan-Meier survival analysis was applied to evaluate the stricture-free rate for the two surgical techniques. Results: The operation time was much shorter for the HPBD procedure than for the DVIU ((13.19±2.68) min vs. (18.44±3.29) min, P<0.01). For the HPBD group, the major postoperative complications as urethral bleeding and urinary tract infection (UTI) were less frequently encountered than those in DVIU (urethral bleeding: 2/31 vs. 8/25, P=0.017; UTI: 1/31 vs. 6/25 P=0.037). The Kaplan-Meier survival analysis showed that there was no significant difference in stricture-free rate at 36 months between the two groups (P=0.21, hazard ratio (HR)=0.65, 95% confidence interval (CI): 0.34 to 1.26). However, there was a significantly higher stricture-free survival in the HPBD group at 12 months (P=0.02, HR=0.35, 95% CI: 0.14 to 0.87), which indicated that the stricture recurrence could be delayed by using the HPBD technique. Conclusions: HPBD was effective and safe and it could be considered as an alternative treatment modality for anterior urethral stricture disease.
Background Circular RNA (circRNA) is a novel class noncoding RNA (ncRNA) that plays a critical role in various cancers, including prostate cancer (PCa). However, the clinical significance, biological function, and molecular mechanisms of circRNAs in prostate cancer remain to be elucidated. Methods A circRNA array was performed to identified the differentially expressed circRNAs. circPDE5A was identified as a novel circRNA which downregulated in clinical samples. Functionally, the in vitro and in vivo assays were applied to explore the role of circPDE5A in PCa metastasis. Mechanistically, the interaction between circPDE5A and WTAP was verified using RNA pulldown followed by mass spectrometry, RNA Immunoprecipitation (RIP) assays. m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq) was then used to identified the downstream target of circPDE5A. Chromatin immunoprecipitation assay (ChIP) and dual-luciferase reporter assay were used to identified transcriptional factor which regulated circPDE5A expression. Results circPDE5A was identified downregulated in PCa tissues compared to adjacent normal tissue and was negatively correlated with gleason score of PCa patients. circPDE5A inhibits PCa cells migration and invasion both in vitro and in vivo. circPDE5A blocks the WTAP-dependent N6-methyladenisine (m6A) methylation of eukaryotic translation initiation factor 3c (EIF3C) mRNA by forming the circPDE5A-WTAP complex, and finally disrupts the translation of EIF3C. Moreover, the circPDE5A-dependent decrease in EIF3C expression inactivates the MAPK pathway and then restrains PCa progression. Conclusions Our findings demonstrate that FOXO4-mediated upregulation of circPDE5A controls PCa metastasis via the circPDE5A-WTAP-EIF3C-MAPK signaling pathway and could serve as a potential therapeutic targer for PCa.
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