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• Research Paper Volume 10, Issue 8 pp 1964-1976

  Circ-BPTF promotes bladder cancer progression and recurrence through the miR-31-5p/RAB27A axis

  Relevance score: 6.946507

  Junming Bi, Hongwei Liu, Zijian Cai, Wei Dong, Ning Jiang, Meihua Yang, Jian Huang, Tianxin Lin

  Keywords: circ-BPTF, miR-31-5p, RAB27A, bladder cancer, prognosis

  Published in Aging on August 9, 2018

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  Circ-BPTF (hsa_circ_0000799) is a novel circular RNA derived from BPTF exons. Although BPTF is a well-studied predecessor gene, the characteristics and functions of circ-BPTF have not yet been reported. Here, we show that expression of circ-BPTF is increased in bladder cancer (BCa) tissues and cell lines compared with noncancerous tissues and cell lines. Consistently, BCa patients with higher expression levels of circ-BPTF were found to have higher tumor grades and poorer prognosis. Functionally, knockdown of circ-BPTF inhibited tumor progression in vitro and in vivo. Mechanistically, a target microRNA of circ-BPTF was confirmed to be miR-31-5p, and miR-31-5p mimics partially reversed the effect of circ-BPTF. Furthermore, RAB27A was predicted and shown to be a target of miR-31-5p, and circ-BPTF attenuated the anti-oncogenic effect of miR-31-5p and consequently enhanced RAB27A expression. In summary, our findings reveal that circ-BPTF promotes BCa progression through the miR-31-5p/RAB27A axis, suggesting that circ-BPTF may be a potential target for BCa treatment.

  

  Validation and characteristics of circ-BPTF in BCa cells. (A) Gel electrophoresis analysis of the PCR products of circ-BPTF and linear BPTF. Divergent primers amplified circ-BPTF only in cDNA, whereas, convergent primers produced linear transcript in both cDNA and gDNA. GAPDH was applied as a linear control. (B) Sanger sequencing of circ-BPTF products amplified by PCR. The back-splice junction site was marked by the red arrow. (C) Schematic illustration showed that circ-BPTF was cyclized from exon 21 and exon 27 of BPTF. (D) The circular and linear form of BPTF levels were examined by qPCR after exposure to Actinomycin D in T24 cells. (E) Circ-BPTF and linear BPTF levels were detected by qPCR in T24 cells treated with or without RNase R. (F) qPCR analysis of circ-BPTF and linear BPTF using random or oligo dT (18) primers in the reverse transcription process. (G and H) Circ-BPTF is mainly presented in the cytoplasm of T24 cells verified by nuclear mass separation assay and FISH. (I) Expression of circ-BPTF in BCa cell lines (5637, EJ, UM-UC-3, T24) and normal urothelial cells (SV-HUC-1) was detected by qPCR. Data indicate means ± SEM. **P<0.01, ***P<0.001.

  
  
  

  

  Circ-BPTF expression and its clinical significance in BCa. (A) The result of qPCR showed that circ-BPTF was up-regulated in BCa tissues compared to the adjacent normal tissues (P < 0.001). (B) Kaplan-Meier analysis demonstrated that patients with high circ-BPTF expression had poorer prognosis. Median expression of circ-BPTF in cancerous tissues was used as a cutoff value in survival analysis. (C) Expression of circ-BPTF in muscle invasive bladder cancer (MIBC) patients was notably higher than that in non-muscle invasive bladder cancer (NMIBC) patients (P<0.001). (D) Expression of circ-BPTF was significantly higher in patients with recurrence (P<0.05).

  
  
  

  

  Circ-BPTF promotes progression of BCa cells in vitro. (A, B and C) Effects of circ-BPTF on cell migratory and invasive capabilities were assessed by transwell migration, Matrigel invasion and wound-healing assays. (D-F) MTS and clone-formation assays showed that the proliferative ability was decreased in T24 and UM-UC-3 cells transfected with si-circ-BPTF. Data indicate the means ± SEM. *P<0.05, **P<0.01.

  
  
  

  

  Knocking down circ-BPTF suppresses the growth of BCa cells in vivo. (A) Sh-circ-BPTF suppressed subcutaneous xenograft growth in vivo (n=5) (B) The Gross of subcutaneous xenograft tumors. (C, D) Analysis of tumor weight and volume of xenograft tumors. Data indicate means±SEM, *P<0.05, **P<0.01.

  
  
  

  

  miR-31-5p directly binds to circ-BPTF. (A) Potential binding sites between circ-BPTF and miR-31-5p were predicted by CircInteractome. (B) miR-31-5p could be pulled down by the circ-BPTF probe. (C) FISH showed the co-localization between circ-BPTF and miR-31-5p. (D) Renilla luciferase activity in 293T cells co-transfected with miR-31-5p mimics and circ-BPTF reporter. Data indicate means±SEM. **P<0.01

  
  
  

  

  Overexpression of miR-31-5p attenuates the oncogenic effects of circ-BPTF in BCa cells. (A, B) The migratory ability enhanced by overexpression of circ-BPTF was attenuated after co-transfection with miR-31-5p mimics. (C, D) The proliferative ability enhanced by overexpression of circ-BPTF was also attenuated after co-transfection with miR-31-5p mimics. Data indicate means ± SEM. *P<0.05, **P<0.01.

  
  
  

  

  Circ-BPTF promotes BCa proliferation and migration through themiR-31-5p/RAB27A axis. (A) Schematic of predicted miR-31-5p binding sites in the 3’ UTR of RAB27A, with complementary pairs showed in black and mismatches showed in red. (B) Expression levels of RAB27A were detected following knockdown of circ-BPTF by qPCR. (C) Western blotting analysis of RAB27A in BCa cell lines upon knockdown of circ-BPTF and overexpression of miR-31-5p. GAPDH was used as a loading control. (D) miR31-5p decreases the luciferase activities of the wild-type RAB27A 3’ UTR reporter but not the luciferase activities of the mutant RAB27A 3’ UTR reporter. (E) Rescue experiment was performed to analyze RAB27A at protein level by western blotting. GAPDH was used as a loading control. **P<0.01.