Circ_0000591 served as endogenous RNA for miR-326 to promote progression of cholangiocarcinoma via the TLR4/MyD88/IL6 axis.

BACKGROUND: Cholangiocarcinoma (CCA) is the second most common liver malignancy with poor prognosis after hepatocellular carcinoma (HCC). Emerging evidences have proved that circular RNAs (circRNAs) are involved in the progression of multiple cancers, while their roles in tumorigenesis of CCA remains largely unclear. In the present study, we found circ_0000591 was upregulated in CCA cells and tissues. The highly expressed circ_0000591 could promote the proliferation, migration, invasion and carcinogenesis of CCA cells in vitro and in vivo. Functionally, circ_0000591 induced the proliferation, migration and invasion of CCA cells through sponging miR-326. Moreover, silencing of circ_0000591 attenuated LPS-induced anti-apoptosis of CCA cells through the TLR4/MyD88/IL6 pathway. In conclusion, this study revealed a novel regulatory mechanism that circ_0000591 contributed to the progression of CCA via miR-326/TLR4/MyD88/IL6 axis. These findings enhanced our knowledge of potential molecular mechanism involved in the malignant progression of CCA.

Worldwide trend in human papillomavirus-attributable cancer incidence rates between 1990 and 2012 and Bayesian projection to 2030.

BACKGROUND: There is a paucity of global comparative trend analyses of all human papillomavirus (HPV)-attributable cancers. In addition, most analyses by international sources only describe past trends; few studies have projected the future trend of HPV-attributable cancers. METHODS: Data were used from the Cancer Incidence in Five Continents (CI5plus) database that contains annual incidence by cancer site, age, and sex, as well as corresponding populations. Age-standardized HPV-attributable cancer incidence rates were calculated and plotted from 1990 through 2012. A Bayesian age-period-cohort model was used to project the HPV-attributable cancer incidence rates of each country up to 2030. RESULTS: A significant but small decreasing trend worldwide in the HPV-attributable cancer incidence rate was observed with an average annual percent change (AAPC) of -0.3 (95% CI, -0.6 to -0.1). Notably, Uganda had a consistently increasing trend of HPV-attributable cancer incidence rate, with an AAPC of 1.7 (95% CI, 0.6-2.9). U-shaped trends were observed in some high-income countries because of a recent increase in oral cavity and oropharyngeal cancers. Most countries experience a decreasing or stable trend in HPV-attributable cancers incidence rates between 1990 and 2030. However, Japan, the United Kingdom, the Netherlands, Italy, Costa Rica, and Uganda will have an increasing trend during the projection period. CONCLUSIONS: Analyses revealed favorable downward trends in HPV-attributable cancer incidence rates in most of the included countries. However, the persistently increasing trend in HPV-attributable cancer incidence rates in Uganda and the recent increase in oral cavity and oropharyngeal cancer incidence rates in some high-income countries may present a new challenge for global HPV-attributable cancer prevention. LAY SUMMARY: Analyses revealed favorable downward trends in human papillomavirus (HPV)-attributable cancer incidence rates in most of the included countries. However, the persistently increasing trend in HPV-attributable cancer incidence rates in Uganda and the recent increase in oral cavity and oropharyngeal cancer incidence rates in some high-income countries may present a new challenge for global HPV-attributable cancer prevention.

Autophagy protects against senescence and apoptosis via the RAS-mitochondria in high-glucose-induced endothelial cells.

BACKGROUNDS: Autophagy is an important process in the pathogenesis of diabetes and plays a critical role in maintaining cellular homeostasis. However, the autophagic response and its mechanism in diabetic vascular endothelium remain unclear. METHODS AND RESULTS: We studied high-glucose-induced renin-angiotensin system (RAS)-mitochondrial damage and its effect on endothelial cells. With regard to therapeutics, we investigated the beneficial effect of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) against high-glucose-induced endothelial responses. High glucose activated RAS, enhanced mitochondrial damage and increased senescence, apoptosis and autophagic-responses in endothelial cells, and these effects were mimicked by using angiotensin II (Ang). The use of an ACEI or ARB, however, inhibited the negative effects of high glucose. Direct mitochondrial injury caused by carbonyl cyanide 3-chlorophenylhydrazone (CCCP) resulted in similar negative effects of high glucose or Ang and abrogated the protective effects of an ACEI or ARB. Additionally, by impairing autophagy, high-glucose-induced senescence and apoptosis were accelerated and the ACEI- or ARB-mediated beneficial effects were abolished. Furthermore, increases in FragEL™ DNA Fragmentation (TUNEL)-positive cells, ß-galactosidase activation and the expression of autophagic biomarkers were revealed in diabetic patients and rats, and the treatment with an ACEI or ARB decreased these responses. CONCLUSIONS: These data suggest that autophagy protects against senescence and apoptosis via RAS-mitochondria in high-glucose-induced endothelial cells.

MicroRNA-503 inhibits the G1/S transition by downregulating cyclin D3 and E2F3 in hepatocellular carcinoma.

BACKGROUND: Increasing evidence indicates that deregulation of microRNAs (miRNAs) is involved in tumorigenesis. Downregulation of microRNA-503 has been observed in various types of diseases, including cancer. However, the biological function of miR-503 in hepatocellular carcinoma (HCC) is still largely unknown. In this study we aimed to elucidate the prognostic implications of miR-503 in HCC and its pathophysiologic role. METHODS: Quantitative reverse transcriptase polymerase chain reaction was used to evaluate miR-503 expression in HCC tissues and cell lines. Western blotting was performed to evaluate the expression of the miR-503 target genes. In vivo and in vitro assays were performed to evaluate the function of miR-503 in HCC. Luciferase reporter assay was employed to validate the miR-503 target genes. RESULTS: miR-503 was frequently downregulated in HCC cell lines and tissues. Low expression levels of miR-503 were associated with enhanced malignant potential such as portal vein tumor thrombi, histologic grade, TNM stage, AFP level and poor prognosis. Multivariate analysis indicated that miR-503 downregulation was significantly associated with worse overall survival of HCC patients. Functional studies showed miR-503 suppressed the proliferation of HCC cells by induction of G1 phase arrest through Rb-E2F signaling pathways, and thus may function as a tumor suppressor. Further investigation characterized two cell cycle-related molecules, cyclin D3 and E2F3, as the direct miR-503 targets. CONCLUSION: Our data highlight an important role for miR-503 in cell cycle regulation and in the molecular etiology of HCC, and implicate the potential application of miR-503 in prognosis prediction and miRNA-based HCC therapy.

Tenofovir Disoproxil Fumarate Is Superior to Entecavir in Reducing Hepatitis B Surface Antigen for Chronic Hepatitis B in China: 2-Year Comprehensive Comparative Result of a Matched Comparative Study.

Aim: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are equally recommended as the first-line antiviral treatments for chronic hepatitis B (CHB) at present. We aimed to compare the long-term efficacy and safety between ETV and TDF therapy in CHB patients who had not received nucleoside analog treatment. Method: In this single-center retrospective study, 414 patients who received ETV (290 patients) or TDF (124 patients) therapy at our center from January 2017 to May 2019 were included. To reduce the imbalance of baseline variables, propensity score matching (PSM) was employed to yield 124 pairs of patients at a ratio of 1:1 based on the treatment regimen. Result: After PSM, the cumulative rate of patients who achieved complete virological response (CVR) was not different by drug therapy at each inspection time (1, 3, 6, 12, 18, and 24 months). Subgroup analysis on HBeAg status and level of HBV DNA demonstrated that evolution of proportion of achieving CVR was not significantly different between groups. Despite the insignificant incidence of HBsAg seroclearance in either group, patients in TDF group achieved higher on-treatment HBsAg decline at each inspection time (1, 3, 6, 9, 12, 18, and 24 months), 0.39, 0.51, 0.61, 0.64, 0.68, 0.76, and 0.91 log IU/mL, respectively; while the corresponding reduction were 0.27, 0.37, 0.40, 0.45, 0.48, 0.55, and 0.66 log IU/mL in ETV group (p < 0.05). In subgroup analysis, we found that the significant difference still existed in patients with high baseline HBsAg level (>3 log IU/mL). Additionally, the proportion of patients who achieved on-treatment HBsAg decline >1 log IU/mL in TDF and ETV group was 33.3 and 17.1% (p < 0.01) at the 12th month, 44.4 and 29.5% (p = 0.03) at the 24th month, respectively. Mean increase in serum creatinine from baseline was 0.10 and 0.08 mg/dL in TDF and ETV group (p = 0.11), with no patient experienced acute kidney injury. Conclusions: TDF has higher potency in reducing HBsAg than ETV in this study. Considering the effect still existed in patients with high HBsAg level (>3 log IU/mL), TDF might be a superior therapeutic regimen combining with its relatively safety.

Circular RNA hsa_circ_0013958 Functions as an Oncogenic Gene Through Modulating miR-532-3p/WEE1 Axis in Hepatocellular Carcinoma.

BACKGROUND: circ0013958 was identified as a biomarker, which can be used for the diagnosis and screening of lung cancer. However, the role of circ0013958 in hepatocellular carcinoma (HCC) remains unclear. METHODS: In our study, quantitative real-time polymerase chain reaction was performed to determine the levels of circ0013958 in HCC tissues and cell lines. EdU, CCK-8, transwell, flow cytometry and tumorigenesis assays were applied to assess the functions of circ0013958 in HCC in vitro and in vivo. Western blot assay was to detect the expression of WEE1. Luciferase reporter assay, bioinformatics analysis and rescue experiments were used to examine the interaction among circ0013958, miR-532-3p and WEE1. RESULTS: It revealed that circ0013958 was significantly up-regulated in HCC, which was positively correlated with poor prognosis of HCC patients. Circ0013958 promoted HCC cell proliferation and invasion, inhibited cell apoptosis in vitro, and promoted tumorigenesis in vivo. Circ0013958 acted as a miR-532-3p sponge to regulate WEE1 expression, thus promoting the progression of HCC. CONCLUSIONS: Circ0013958 promotes HCC progression through miR-532-3p/WEE1 axis. Circ0013958 may serve as a potential diagnostic biomarker and therapeutic target of HCC.

MicroRNA-663b enhances migration and invasion by targeting adenomatous polyposis coli 2 in colorectal carcinoma cells.

Colorectal carcinoma (CRC) is one of the leading causes of cancer-associated mortality worldwide. Dysregulation of microRNA (miR)-663b has been reported in a variety of diseases. However, the specific biological function of miR-663b in CRC requires further investigation. The aim of the present study was to elucidate the role and underlying molecular mechanism of action of miR-663b in CRC. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis and western blot analysis were employed to measure the expression of miR-663b at the RNA and protein level, respectively. Flow cytometry was used to detect cell apoptosis. Cell proliferation, migration and invasion were evaluated by the Cell Counting Kit-8, wound healing and Transwell assays, respectively. A dual-luciferase reporter assay was used to validate the potential target gene of miR-663b. The expression of miR-663b was identified to be markedly upregulated in CRC cells. Ectopic miR-663b expression promoted CRC cell proliferation, migration and invasion, and inhibited apoptosis. The dual-luciferase reporter assay identified adenomatous polyposis coli 2 (APC2) as a direct target of miR-663b in CRC cells. Further investigation indicated that miR-663b was involved in CRC cell invasion through the Wnt/ß-catenin pathway. Therefore, overexpression of miR-663b was able to promote CRC cell proliferation, migration and invasion by regulating the Wnt/ß-catenin pathway through targeting APC2, suggesting that miR-663b may be a useful target for the diagnosis and treatment of CRC.

microRNA-200a is an independent prognostic factor of hepatocellular carcinoma and induces cell cycle arrest by targeting CDK6.

Deregulation of microRNA­200a (miR­200a) has been observed in different types of diseases, including cancers. However, the exact roles of miR­200a in hepatocellular carcinoma (HCC) are still largely unknown. We aimed to elucidate the prognostic implications of miR­200a and its biological function in HCC. Quantitative polymerase chain reaction was used to evaluate miR­200a expression. Western blotting was performed to evaluate the protein level. Gain-of-function studies were performed to evaluate the roles of miR­200a in HCC. Our results revealed that miR­200a was frequently downregulated in HCC. In addition, multivariate analysis confirmed that miR­200a was significantly associated with the overall survival of HCC patients. In vitro assays demonstrated that miR­200a suppressed the proliferation of HCC cells by induction of G1 phase arrest. Furthermore, CDK6 was identified as a novel functional target of miR­200a. Our data indicate that miR­200a functions as a potential tumor suppressor in HCC.