Background: Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs formed by a covalently closed loop, and increasing evidence has revealed that circRNAs play crucial functions in regulating gene expression. CircSLC8A1 is a circRNA generated from the SLC8A1 gene. Currently, the role and underlying molecular mechanisms of circSLC8A1 in bladder cancer remain unknown. Methods: The differentially expressed circRNAs were identified from RNA-sequencing data, and circSLC8A1 was determined as a new candidate circRNA. qRT-PCR was used to detect the expression of circRNAs, miRNAs and mRNAs in human tissues and cells. RNA pull-down assay and luciferase reporter assay were used to investigate the interactions between the specific circRNA, miRNA and mRNA. The effects of circSLC8A1 on bladder cancer cells were explored by transfecting with plasmids in vitro and in vivo. The expression of PTEN was detected by Western blot. The biological roles were measured by wound healing assay, transwell assay, and CCK-8 assay. Results: In the present study, we found that circSLC8A1 was down-regulated in bladder cancer tissues and cell lines, and circSLC8A1 expression was associated with the pathological stage and histological grade of bladder cancer. Over-expression of circSLC8A1 inhibited cell migration, invasion and proliferation both in vitro and in vivo. Mechanistically, circSLC8A1 could directly interact with miR-130b/miR-494, and subsequently act as a miRNA sponge to regulate the expression of the miR-130b/miR-494 target gene PTEN and downstream signaling pathway, which suppressed the progression of bladder cancer. Conclusions: CircSLC8A1 acts as a tumor suppressor by a novel circSLC8A1/miR-130b, miR-494/PTEN axis, which may provide a potential biomarker and therapeutic target for the management of bladder cancer. Background Bladder cancer is the most common malignancy of the urinary system and is one of the most prevalent malignancies worldwide [1]. In China, the mortality and morbidity of bladder cancer ranked first among all the tumors of urinary system [2]. Bladder cancer can be classified into two types according to the depth of tumor invasion: non-muscle invasive tumor (70~80%) and muscle-invasive tumor (20~30%) [3].For the patients with muscle-invasive bladder cancer, the occurrence of metastasis is more frequent, and the prognosis is poorer [4]. Even in those muscle-invasive bladder cancer patients who receive optimal treatment with surgery and chemotherapy, the 5-year overall survival rate is only 60% due to distant metastasis [5]. Therefore, it is of great clinical significance to clarify the molecular mechanisms that drive the progression of bladder cancer, which will help to develop more effective anticancer therapies. Circular RNA (circRNA) is a novel class of endogenous noncoding RNA molecules generally characterized

Urinary bladder cancer (UBC) patients at muscle invasive stage have poor clinical outcome, due to high propensity for metastasis. Cancer-associated fibroblasts (CAFs), one of the principal constituents of the tumor stroma, play an important role in tumor development. However, it is unclear whether CAFs from UBC induce cell invasion and which signaling pathway is involved. Herein, we found that conditional medium from UBC CAFs (CAF-CM) enhanced the invasion of UBC cells. CAF-CM induced the epithelial-mesenchymal transition (EMT) by regulating expression levels of EMT-associated markers in UBC cells. Higher concentration of TGFβ1 in CAF-CM, comparing with the CM from adjacent normal fibroblast, led to phosphorylation of Smad2 in UBC cells. Additionally, inhibition of TGFβ1 signaling decreased the EMT-associated gene expression, and cancer cell invasion. Interestingly, a long non-coding RNA, ZEB2NAT, was demonstrated to be essential for this TGFβ1-dependent process. ZEB2NAT depletion reversed CAF-CM-induced EMT and invasion of cancer cells, as well as reduced the ZEB2 protein level. Consistently, TGFβ1 mRNA expression is positively correlated with ZEB2NAT transcript and ZEB2 protein levels in human bladder cancer specimens. Our data revealed a novel mechanism that CAFs induces EMT and invasion of human UBC cells through the TGFβ1-ZEB2NAT-ZEB2 axis.

High tumor recurrence is frequently observed in patients with urinary bladder cancers (UBCs), with the need for biomarkers of prognosis and drug response. Chemoresistance and subsequent recurrence of cancers are driven by a subpopulation of tumor initiating cells, namely cancer stem-like cells (CSCs). However, the underlying molecular mechanism in chemotherapy-induced CSCs enrichment remains largely unclear. In this study, we found that during gemcitabine treatment lncRNA-Low Expression in Tumor (lncRNA-LET) was downregulated in chemoresistant UBC, accompanied with the enrichment of CSC population. Knockdown of lncRNA-LET increased UBC cell stemness, whereas forced expression of lncRNA-LET delayed gemcitabine-induced tumor recurrence. Furthermore, lncRNA-LET was directly repressed by gemcitabine treatment-induced overactivation of TGFβ/SMAD signaling through SMAD binding element (SBE) in the lncRNA-LET promoter. Consequently, reduced lncRNA-LET increased the NF90 protein stability, which in turn repressed biogenesis of miR-145 and subsequently resulted in accumulation of CSCs evidenced by the elevated levels of stemness markers HMGA2 and KLF4. Treatment of gemcitabine resistant xenografts with LY2157299, a clinically relevant specific inhibitor of TGFβRI, sensitized them to gemcitabine and significantly reduced tumorigenecity in vivo. Notably, overexpression of TGFβ1, combined with decreased levels of lncRNA-LET and miR-145 predicted poor prognosis in UBC patients. Collectively, we proved that the dysregulated lncRNA-LET/NF90/miR-145 axis by gemcitabine-induced TGFβ1 promotes UBC chemoresistance through enhancing cancer cell stemness. The combined changes in TGFβ1/lncRNA-LET/miR-145 provide novel molecular prognostic markers in UBC outcome. Therefore, targeting this axis could be a promising therapeutic approach in treating UBC patients.

This study suggested that IR was an independent risk factor for spontaneous abortion. Because of the high prevalence of IR in obese or polycystic ovarian syndrome patients, the risk of spontaneous abortion in these patients can be raised. Patients with IR should be advised to improve their insulin sensitivity through lifestyle change or medical intervention before infertility treatment to reduce their risk of spontaneous abortion.

Although overall altruism and inconvenience were the major motivating factor and deterrent for blood, some demographic differences existed in donor attitude toward incentive programs and preference for the method of contact used by blood centers for recruitment purposes.