Background and Aims Circular RNAs (circRNAs) and extracellular vesicles (EVs) are involved in various malignancies. We aimed to clarify the functions and mechanisms of dysregulated circRNAs in the cells and EVs of cholangiocarcinoma (CCA). Approach and Results CircRNA microarray was used to identify circRNA expression profiles in CCA tissues and bile‐derived EVs (BEVs). CCA‐associated circRNA 1 (circ‐CCAC1) expression was measured by quantitative real‐time PCR. The clinical importance of circ‐CCAC1 was analyzed by receiver operating characteristic curves, Fisher’s exact test, Kaplan–Meier plots, and Cox regression model. The functions of circ‐CCAC1 and exosomal circ‐CCAC1 were explored in CCA cells and human umbilical vein endothelial cells (HUVECs), respectively. Different animal models were used to verify the in vitro results. RNA sequencing, bioinformatics, RNA immunoprecipitation, RNA pulldown, chromatin immunoprecipitation followed by sequencing, and luciferase reporter assays were used to determine the regulatory networks of circ‐CCAC1 in CCA cells and HUVECs. Circ‐CCAC1 levels were increased in cancerous bile‐resident EVs and tissues. The diagnostic and prognostic values of circ‐CCAC1 were identified in patients with CCA. For CCA cells, circ‐CCAC1 increased cell progression by sponging miR‐514a‐5p to up‐regulate Yin Yang 1 (YY1). Meanwhile, YY1 directly bound to the promoter of calcium modulating ligand to activate its transcription. Moreover, circ‐CCAC1 from CCA‐derived EVs was transferred to endothelial monolayer cells, disrupting endothelial barrier integrity and inducing angiogenesis. Mechanistically, circ‐CCAC1 increased cell leakiness by sequestering enhancer of zeste homolog 2 in the cytoplasm, thus elevating SH3 domain‐containing GRB2‐like protein 2 expression to reduce the levels of intercellular junction proteins. In vivo studies further showed that increased circ‐CCAC1 levels in circulating EVs and cells accelerated both CCA tumorigenesis and metastasis. Conclusions Circ‐CCAC1 plays a vital role in CCA tumorigenesis and metastasis and may be an important biomarker/therapeutic target for CCA.

No abstract

Background: The molecular function of pannexin1 (Panx1) in different tumor types has been remained equivocal. Until now, there is no study focused on the function of panx1 in hepatocellular carcinoma (HCC). This study aimed to explore the role of Panx1 in the invasion and metastasis of HCC. Methods: The expressions of Panx1 in 126 cases of HCC were analyzed by immunohistochemistry (IHC). The effects of Panx1 on HCC cell metastasis and invasion were observed by transwell. The expression levels of Panx1 and epithelial-mesenchymal transition (EMT) related proteins in HCC cells and tissues were detected by western blot and IHC. The tumor metastatic abilities were compared between Panx1 knockout mice and nude mice. Results: The higher expression of Panx1 in HCC was positively correlated with tumor lymph node metastasis, TNM (tumor, node, metastasis) classification and poor prognosis (overall survival, hazard ratio [HR] 2.769, 95% confidence interval [95%CI] 1.528-5.017, P=0.001; disease-free survival, HR=2.344, 95%CI 1.473-3.730, P<0.001). Overexpression of Panx1 promoted invasion and migration of HCC cells through modulation of EMT in vitro and in vivo. Conclusions: Our results suggest that the high expression of Panx1 is associated with poor HCC prognosis, providing a new clue for effective intervention for HCC metastasis.

Irisin is a newly discovered exercise-induced cytokine, produced by the proteolytic hydrolysis of fibronectin type III domain-containing protein 5 (FNDC5). Irisin is widely distributed in the human body and is involved in the browning of white adipose tissue, improving insulin resistance, improving cognitive function, and regulating bone metabolism. Recent studies have shown that irisin concentration is elevated in a variety of tumor tissues as compared with that in normal tissues. However, irisin has different effects on the proliferation and apoptosis of tumor cells in breast cancer, lung cancer, and liver cancer through various mechanisms. Irisin plays an important role in the occurrence, development, and metastasis of different tumors, suggesting that irisin can be used as a potential target for tumor diagnosis and treatment. Therefore, studying the expression and function of irisin in tumors may be of great significance for the prevention and treatment of tumors. This article reviews the research progress on the role of irisin in tumors.

Introduction Irisin is a newly identified cytokine that has gained increasing attention because of its potential therapeutic applications in metabolic diseases and human cancers. Recently, accumulating evidence indicates that irisin plays an important role in the development and metastasis of various tumors. The aim of this study was to evaluate the effects and underlying mechanisms of irisin on malignant growth of pancreatic cancer cells. Materials and methods The anti-proliferative effect of irisin was examined using the CCK-8 assay. Irisin-induced apoptosis was determined by the annexin V-FITC/PI staining assay. The effects of irisin on cell migration and invasion were assessed using the scratch-induced wound healing assay and transwell invasion assay, respectively. The expression and phosphorylation of signaling proteins were detected by Western blot analysis. Results Our results showed that irisin inhibited cell proliferation and induced apoptosis of pancreatic cancer cells in a dose-dependent manner. In addition, irisin decreased the migration and invasion of pancreatic cancer cells. Finally, Western blot analysis revealed that irisin downregulated the PI3K/AKT signaling pathway. Conclusion Our findings suggest that irisin is a novel therapeutic agent for pancreatic cancer.

No abstract

Increasing evidence connects gallstone disease (GD) to cardio-cerebrovascular disease (CVD). The aim of the present systematic review and meta-analysis was to determine whether and to what extent an association between GD and CVD existed. PubMed, EMBASE and the Cochrane Library were systemically searched up to March 3rd, 2018. A total of 10 studies (1,272,177 participants; 13,833 records; 5 prospective cohorts and 5 retrospective cohorts) were included. It was demonstrated that GD was associated with an increased risk of incidence [hazard ratio=1.24, 95% (CI) confidence interval: 1.17–1.31] and prevalence (unadjusted odds ratio=1.23, 95% CI: 1.21–1.25) of CVD. In conclusion, the presence of GD was associated with an increased risk of CVD incidence and prevalence. The association may be influenced by age and sex. These findings suggest that individuals identified with cardio-cerebrovascular disease should be evaluated for GD.

Increasing evidence revealed that ten‐eleven translocation 1 (TET1) plays an important role in tumorigenesis and chemoresistance, but its functions in gemcitabine resistance in cholangiocarcinoma (CCA) remain unknown. This study aims to investigate the effect of TET1 on gemcitabine resistance in CCA and the possible effect on P‐glycoprotein (P‐gp) expression encoded by multidrug resistance (MDR) genes. We established two kinds of gemcitabine‐resistant CCA cell lines and confirmed its specific features. The expression of TET1 and P‐gp was evaluated in gemcitabine‐resistant CCA cells and their parental cells at mRNA and protein level by quantitative RT‐PCR and western blot analysis. After transfecting the gemcitabine‐resistant CCA cell lines with TET1 gene or siRNA, the cell viability test was obtained to verify the effect of TET1 on the sensitivity of CCA cells to gemcitabine. And then, the possible effect of TET1 on the expression of P‐gp was examined by western blot analysis. Xenograft tumor experiment was conducted to confirm the association between TET1 and P‐gp expression under gemcitabine chemoresistance. The associations between clinical outcomes of CCA patients with chemotherapy and TET1 expression were analyzed in 82 patients. The results showed that TET1 expression was significantly decreased, and P‐gp expression was increased in gemcitabine‐resistant CCA cells. Additionally, overexpression of TET1 augmented the sensitivity of CCA cells to gemcitabine and induced the decreased expression of P‐gp in gemcitabine‐resistant CCA cells. Furthermore, multivariate Cox regression analysis indicated that TET1 expression and TNM stage were independent risk factors (P < 0.001) for the clinical outcomes of CCA patients with chemotherapy. Additionally, Kaplan‐Meier survival and the log‐rank test showed that decreased expression of TET1 was associated with poorer prognosis of CCA patients with chemotherapy. These findings suggest that TET1 expression reverses gemcitabine resistance in CCA accompanied by a reduction in P‐gp expression. Thus, TET1 may be a promising target to overcome chemoresistance in CCA.