Background There is increasing evidence that circular RNAs (circRNAs) have significant regulatory roles in cancer development and progression; however, the expression patterns and biological functions of circRNAs in renal cell carcinoma (RCC) remain largely elusive. Method Bioinformatics methods were applied to screen for circRNAs differentially expressed in RCC. Analysis of online circRNAs microarray datasets and our own patient cohort indicated that circSDHC (hsa_circ_0015004) had a potential oncogenic role in RCC. Subsequently, circSDHC expression was measured in RCC tissues and cell lines by qPCR assay, and the prognostic value of circSDHC evaluated. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of circSDHC on RCC proliferation and metastasis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between circSDHC, miR-127-3p and its target genes. Results Clinically, high circSDHC expression was correlated with advanced TNM stage and poor survival in patients with RCC. Further, circSDHC promoted tumor cell proliferation and invasion, both in vivo and in vitro. Analysis of the mechanism underlying the effects of circSDHC in RCC demonstrated that it binds competitively to miR-127-3p and prevents its suppression of a downstream gene, CDKN3, and the E2F1 pathway, thereby leading to RCC malignant progression. Furthermore, knockdown of circSDHC caused decreased CDKN3 expression and E2F1 pathway inhibition, which could be rescued by treatment with an miR-127-3p inhibitor. Conclusion Our data indicates, for the first time, an essential role for the circSDHC/miR-127-3p/CDKN3/E2F1 axis in RCC progression. Thus, circSDHC has potential to be a new therapeutic target in patients with RCC.

Background:EIF5A2, eukaryotic translation initiation factor 5A2, is associated with several human cancers. In this study, we investigated the role of EIF5A2 in the metastatic potential of localised invasive bladder cancer (BC) and its underlying molecular mechanisms were explored.Methods:The expression pattern of EIF5A2 in localised invasive BC was determined by immunohistochemistry. In addition, the function of EIF5A2 in BC and its underlying mechanisms were elucidated with a series of in vitro and in vivo assays.Results:Overexpression of EIF5A2 was an independent predictor for poor metastasis-free survival of localised invasive BC patients treated with radical cystectomy. Knockdown of EIF5A2 inhibited BC cell migratory and invasive capacities in vitro and metastatic potential in vivo and reversed epithelial–mesenchymal transition (EMT), whereas overexpression of EIF5A2 promoted BC cells motility and invasiveness in vitro and metastatic potential in vivo and induced EMT. In addition, we found that EIF5A2 might activate TGF-β1 expression to induce EMT and drive aggressiveness in BC cells. EIF5A2 stabilized STAT3 and stimulated nuclear localisation of STAT3, which resulted in increasing enrichment of STAT3 onto TGF-β1 promoter to enhance the transcription of TGF-β1.Conclusions:EIF5A2 overexpression predicts tumour metastatic potential in patients with localised invasive BC treated with radical cystectomy. Furthermore, EIF5A2 elevated TGF-β1 expression through STAT3 to induce EMT and promotes aggressiveness in BC.

Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, can easily invade local tissues and metastasize, and is resistant to currently available treatments. Recent studies profiling microRNA expression in ccRCC have suggested miR-30a-5p may be deregulated in these cancer cells. To determine its role and mechanism of action in ccRCC, miR-30-5p expression levels were quantified and functions were analyzed using in vitro and in vivo experiments and bioinformatics. A decrease in miR-30a-5p expression was frequently noted in ccRCC cells and tissues. Importantly, low miR-30a-5p levels were significantly associated with a poor ccRCC patient prognosis. Stable overexpression of miR-30a-5p in 769-P cells was sufficient to prevent cellular proliferation and invasion in vitro and in vivo. Upon further examination, it was found that miR-30a-5p directly targeted the 3′-UTR of ZEB2 and suppressed ccRCC cell epithelial–mesenchymal transition. In addition, miR-30a-5p may be downregulated by the long non-coding RNA DLEU2. Taken together, these data reveal an important role for miR-30a-5p in the regulation of ccRCC proliferation and invasion, and indicate the potential for miR-30a-5p in applications furthering ccRCC prognostics and therapeutics.

Rab25, an epithelial-specific member of the Rab family of small guanosine triphosphatases, is associated with several human cancers. The goal of this study was to determine its function in bladder cancer (BC). We examined the Rab25 expression pattern in two different cohorts of BC patients treated with radical cystectomy by quantitative PCR, western blotting and immunohistochemical staining. A series of in vitro and in vivo assays were performed to elucidate the function of Rab25 in BC and its underlying mechanisms. Rab25 expression was significantly elevated at both the messenger RNA and protein levels in BCs compared with normal bladder tissues. High Rab25 expression was closely associated with lymph node (LN) metastasis and was an independent predictor for poor disease-free survival in BC patients. Downregulation of Rab25 in BC cells markedly inhibited invasive motility in vitro and metastatic potential in vivo. In addition, downregulation of Rab25 in BC EJ and T24 cells increased the expression levels of epithelial markers (E-cadherin and α-catenin) and decreased the levels of mechamechy markers (vimentin and fibronectin). Simultaneously, downregulation of Rab25 in EJ and T24 cells resulted in the inactivation of downstream phosphorylated protein kinase B (p-Akt), phosphorylated glycogen synthase kinase-β (p-GSK-3β) and snail signaling. This study demonstrates that Rab25 can promote BC metastasis through induction of epithelial-mesenchymal transition process and activation of Akt/GSK-3β/Snail signaling pathway; Rab25 expression level can predict LN metastasis and inferior clinical outcome in BC patients.

BackgroundZEB2 has been reportedly shown to mediate the epithelial-to-mesenchymal transition (EMT) and disease aggressiveness in human tumors. However, the expression status of ZEB2 in renal cell carcinoma (RCC) and ZEB2’s clinicopathologic/prognostic significance are poorly understood.Methodology/Principal FindingsIn this study, tissue microarray, immunohistochemistry (IHC) and western blot analyses were utilized to investigate the ZEB2 expression status in RCC and adjacent renal tissue samples. In our study, samples from 116 RCC patients treated with radical nephrectomy were used as a training set to generate a ZEB2 optimal cut-point for patient outcome by receiver operating characteristic (ROC) analysis. For validation, the correlation of ZEB2 expression with the clinical characteristics and patient outcomes in another set (including 113 patients) was analyzed to validate the obtained cut-point. In the training and validation sets, high expression of ZEB2, defined by ROC analysis, predicted a poorer overall survival and progression-free survival, as evidenced by the univariate and multivariate analyses. In different subsets of overall patients, ZEB2 expression was also a prognostic indicator in patients with stage I/II, stage III/IV, grade 1/2 and grade 3/4 disease (P<0.05). Downregulation of ZEB2 by shRNA decreased the migration and invasion ability of 769-P cells in vitro. Furthermore, high ZEB2 expression was positively correlated with vimentin expression and inversely linked to E-cadherin expression in RCC.Conclusions/SignificanceOur findings provide a basis for the concept that high ZEB2 expression in RCC may be important in the acquisition of an aggressive phenotype. This evidence suggests that ZEB2 overexpression (examined by IHC) is an independent biomarker for the poor prognosis of patients with RCC.