CircHIPK3 sponges miR‐558 to suppress heparanase expression in bladder cancer cells

Correction to: EMBO Reports (2017) 18(9): 1646–1659. DOI: 10.15252/embr.201643581 ¦ Published online 9 August 2017The authors contacted the journal after being alerted to issues in the figures. The authors state that while preparing the figures, images were mislabelled leading to partial duplications in two figure panels. The authors requested to withdraw the affected panels and to replace them with correct representative images that had been generated at the time of the original experimentation. The panels listed below are therefore withdrawn and replaced. The related source data are published with this note.Figure 4DThe transwell assay image for UMUC3 cells showing invasion behaviour upon miR‐558 mimic treatment (“miR‐558”) had been incorrect. An image showing the invasion behaviour of UMUC3 cells upon depletion of circHIPK3 (“si‐circHIPK3#1”) showing the same cells as depicted in Fig 2H was erroneously used. A representative image of the correct data is now displayed in the paper.Figure 4EThe transwell assay image for UMUC3 cells showing migration behaviour upon treatment with an miR‐588 anti‐miR (“anti‐miR‐558”) had been incorrect. An image showing the migration behaviour of UMUC3 cells upon circHIPK3 overexpression (“circHIPK3”) showing the same cells as those depicted in Fig 2D was erroneously used. A representative image of the correct data is now displayed in the paper.Figure 5CThe Western blot image showing the β‐actin loading control for T24T cells had been incorrect. A representative image of the correct data is now displayed in the paper.Figure 5FThe image for UMUC3 cells showing tube formation upon treatment with a control mimic and overexpression of circHIPK3 “mimicNC+circHIPK3” had been incorrect. A representative image of the correct data is now displayed in the paper.The figure issues described above are herewith corrected. The authors state that the errors do not affect the results or conclusions of the study and apologize for any confusion these errors may have caused. Figure 4D. Original. Figure 4D. Corrected. Figure 4E. Original. Figure 4E. Corrected. Figure 5C. Original. Figure 5C. Corrected. Figure 5F. Original. Figure 5F. Corrected.      

A SNP of miR‐146a is involved in bladder cancer relapse by affecting the function of bladder cancer stem cells via the miR‐146a signallings

MiR‐146a‐5p in urine samples was recently reported to be possibly used as a prognostic marker for bladder cancer (BC). Interestingly, YAP1 and COX2 were both demonstrated to function as stem cell regulators in BC. Therefore, in this study, we aimed to establish the molecular mechanism underlying the role of miR‐146a, YAP1 and COX2 in BC relapse. We also studied the possibility of using the C > G genotype of miR‐146a rs2910164 SNP as an indicator of BC relapse. A total of 170 BC patients were assigned into different groups based on their genotypes of rs2910164 SNP. Kaplan‐Meier survival curves were plotted to compare the recurrence‐free rate among these groups. Real‐time PCR, Western Blot, bioinformatic analysis, luciferase assay and IHC assay were conducted to study the role of rs2910164 SNP in the progression of BC. Accordingly, GC/CC‐genotyped patients presented a higher risk of recurrence when compared with GG‐genotyped patients, while the expression of BC regulators was influenced by the presence of rs2910164. COX2 mRNA and YAP1 mRNA were, respectively, validated as direct target genes of miR‐146a, and the expression of YAP1 and COX2 mRNA/protein was both suppressed by miR‐146a precursors. The expression of ALDH1A1 mRNA/protein was inhibited upon the down‐regulation of YAP1, while the expression of let7 and SOX2 mRNA/protein was inhibited upon the down‐regulation of COX2. In conclusion, two signalling pathways, miR‐146a/YAP1/ALDH1A1 and miR‐146a/COX2/PGE2/let7/SOX2, were modulated by miR‐146a. As an SNP regulating the expression of miR‐146a, the rs2910164 G > C SNP could be utilized as a biomarker for BC relapse.     

miR‐1‐3p and miR‐206 sensitizes HGF‐induced gefitinib‐resistant human lung cancer cells through inhibition of c‐Met signalling and EMT

Hepatocyte growth factor (HGF) overexpression is an important mechanism in acquired epidermal growth factor receptor (EGFR) kinase inhibitor gefitinib resistance in lung cancers with EGFR activating mutations. MiR‐1‐3p and miR‐206 act as suppressors in lung cancer proliferation and metastasis. However, whether miR‐1‐3p and miR‐206 can overcome HGF‐induced gefitinib resistance in EGFR mutant lung cancer is not clear. In this study, we showed that miR‐1‐3p and miR‐206 restored the sensitivities of lung cancer cells PC‐9 and HCC‐827 to gefitinib in present of HGF. For the mechanisms, we demonstrated that both miR‐1‐3p and miR‐206 directly target HGF receptor c‐Met in lung cancer. Knockdown of c‐Met mimicked the effects of miR‐1‐3p and miR‐206 transfections Meanwhile, c‐Met overexpression attenuated the effects of miR‐1‐3p and miR‐206 in HGF‐induced gefitinib resistance of lung cancers. Furthermore, we showed that miR‐1‐3p and miR‐206 inhibited c‐Met downstream Akt and Erk pathway and blocked HGF‐induced epithelial‐mesenchymal transition (EMT). Finally, we demonstrated that miR‐1‐3p and miR‐206 can increase gefitinib sensitivity in xenograft mouse models in vivo. Our study for the first time indicated the new function of miR‐1‐3p and miR‐206 in overcoming HGF‐induced gefitinib resistance in EGFR mutant lung cancer cell.     

Aryl hydrocarbon‐estrogen alpha receptor‐dependent expression of miR‐206, miR‐27b,and miR‐133a suppress cell proliferation and migration in MCF‐7 cells

The underlying functions of miR‐206, miR‐133a, miR‐27b, and miR‐21, and their link to the estrogen receptor alpha (ERα) and aryl hydrocarbon receptor (AhR) signaling pathways remain largely unexplored. In this study, we detect the expression of miR‐206, miR‐133a, miR‐27b, and miR‐21 in MCF‐7 through quantificational real‐time polymerase chain reaction assay along with the activation/inhibition of ERα and AhR receptors. Aside from this, cell proliferation and migration as well as AhR‐dependent CYP1A1 enzyme activity were measured. Here, we found that the forced increased expression of miR‐206, miR‐133a, and miR‐27b were closely associated with the suppression of MCF‐7 cell proliferation and migration. The anti‐proliferative‐metastatic effect of miR‐206, miR‐133a, and miR‐27b was probably mediated by targeting the ERα and AhR signaling pathways. Considered together, our study indicated that the overexpression of miR‐206, miR‐133a, and miR‐27b might be potential biomarkers for prognosis and therapeutic strategies in breast cancer.     

miR‐96 regulates migration and invasion of bladder cancer through epithelial‐mesenchymal transition in response to transforming growth factor‐β1

Bladder cancer (BC) is one of the most frequent urological malignancies, and its molecular mechanism still remains unclear. Recent studies have revealed that MicroRNA (miRNAs) acted as oncogenes or tumor suppressors in a variety of cancers. MiRNA‐96 has been reported to play a significant role in the development and progression of many cancers. In the current study, we found that transforming growth factor (TGF)‐β1 played a significant role in the progression that miR‐96 conducted. And TGF‐β1 could also regulate the expression of FOXQ1, which is the target gene of miR‐96. Furthermore, miR‐96 induced epithelial‐mesenchymal transition in BC cells, which is driven by TGF‐β1. In conclusion, our data revealed that miR‐96 regulates the progression and epithelial‐mesenchymal transition, which is driven by TGF‐β1 in BC cells; it may provide a new thought for the therapy of BC.     

Upregulation of miR‐874‐3p and miR‐874‐5p inhibits epithelial ovarian cancer malignancy via SIK2

Based on miR‐874 expression levels in the GSE47841 microarray, we hypothesized that the mature products of miR‐874, miR‐874‐3p, or miR‐874‐5p, would inhibit epithelial ovarian cancer (EOC) cell proliferation, metastasis, and chemoresistance. We first examined miR‐874‐3p and miR‐874‐5p expression levels in primary EOC tumor tissue samples and found that they were significantly decreased. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) cell proliferation and transwell assays revealed that miR‐874‐3p and miR‐874‐5p significantly inhibit EOC cell proliferation, migration, and invasion. Then, using MTT and soft agar assays of paclitaxel‐treated Caov3 and SKOV3 cells transfected with miR‐874‐3p and miR‐874‐5p, we found that miR‐874‐3p and miR‐874‐5p enhance EOC cell chemosensitivity. We then confirmed that serine/threonine‐protein kinase 2 (SIK2) was a target gene of miR‐874‐3p and miR‐874‐5p. Overall, the results of this study indicate that SIK2 expression can serve as a prognostic biomarker for EOC and that miR‐874‐3p and miR‐874‐5p have the potential to enhance clinical treatment of EOC.     

Long non‐coding RNA SNHG15 promotes CDK14 expression via miR‐486 to accelerate non‐small cell lung cancer cells progression and metastasis

Long non‐coding RNAs (lncRNAs) have been validated to play important role in multiple cancers, including non‐small cell lung cancer (NSCLC). In present study, our team investigate the biologic role of SNHG15 in the NSCLC tumorigenesis. LncRNA SNHG15 was significantly upregulated in NSCLC tissue samples and cells, and its overexpression was associated with poor prognosis of NSCLC patients. In vitro, loss‐of‐functional cellular experiments showed that SNHG15 silencing significantly inhibited the proliferation, promoted the apoptosis, and induced the cycle arrest at G0//G1 phase. In vivo, xenograft assay showed that SNHG15 silencing suppressed tumor growth of NSCLC cells. Besides, SNHG15 silencing decreased CDK14 protein expression both in vivo and vitro. Bioinformatics tools and luciferase reporter assay confirmed that miR‐486 both targeted the 3′‐UTR of SNHG15 and CDK14 and was negatively correlated with their expression levels. In summary, our study conclude that the ectopic overexpression of SNHG15 contribute to the NSCLC tumorigenesis by regulating CDK14 protein via sponging miR‐486, providing a novel insight for NSCLC pathogenesis and potential therapeutic strategy for NSCLC patients.