Influence of interleukin gene polymorphisms on development of acute pancreatitis: a systematic review and meta-analysis.

Several epidemiological studies have assessed the associations of interleukin (IL) gene polymorphisms with acute pancreatitis (AP) in different populations. However, the results were inconclusive. Therefore, we performed the present study to comprehensively evaluate the associations of IL gene polymorphisms and susceptibility to AP. Systematic searches of the PubMed, Web of Science, Embase, CNKI, CBMdisc and Google Scholar until February 27, 2013, as well as hand searching of the references of identified articles were performed. Data were extracted using standardized forms and odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of associations. All statistical analyses were performed using Stata 11.0. Ten studies were included in our final combined analysis, covering a total of 1,220 AP cases and 1,351 controls. The results showed evidence for significant association between IL-8 -251 T/A (rs4073) polymorphism and AP risk, suggesting that IL-8 -251 A allele was associated with an increased risk of AP (for A allele vs. T allele: OR = 1.36, 95 % CI 1.05-1.76, p = 0.02; for A/A vs. T/T: OR = 2.28, 95 % CI 1.08-4.81, p = 0.03; for A/A+T/A vs. T/T: OR = 1.40, 95 % CI 1.11-1.77, p = 0.005). However, there were no significant associations between IL-1ß (IL-1ß +3954 C/T (rs1143634) and IL-1ß -511 C/T (rs16944)), IL-6 (IL-6 -174 G/C (rs1800795) and IL-6 -634 C/G (rs1800796)) and IL-10 (IL-10 -1082 A/G (rs1800896), IL-10 -819 C/T (rs1800871) and IL-10 -592 C/A (rs1800872)) gene polymorphisms and AP risk. In summary, the current study suggests that the IL-8 -251 T/A polymorphism is associated with an increased risk of AP. In addition, there were no significant associations between IL-1ß, IL-6 and IL-10 gene polymorphisms and AP risk.

MicroRNA-375 represses tumor angiogenesis and reverses resistance to sorafenib in hepatocarcinoma.

Sorafenib was originally identified as an inhibitor of multiple oncogenic kinases and remains the first-line systemic therapy for advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) have been reported to play critical roles in the initiation, progression, and drug resistance of HCC. In this study, we aimed to identify sorafenib-induced miRNAs and demonstrate their regulatory roles. First, we identified that the expression of the tumor-suppressive miRNA miR-375 was significantly induced in hepatoma cells treated with sorafenib, and miR-375 could exert its antiangiogenic effect partially via platelet-derived growth factor C (PDGFC) inhibition. Then, we demonstrated that sorafenib inhibited PDGFC expression by inducing the expression of miR-375 and a transcription factor, achaete-scute homolog-1 (ASH1), mediated the induction of miR-375 by sorafeinb administration in hepatoma cells. Finally, we verified that the expression of miR-375 was reduced in sorafenib-resistant cells and that the restoration of miR-375 could resensitize sorafenib-resistant cells to sorafenib partially by the degradation of astrocyte elevated gene-1 (AEG-1). In conclusion, our data demonstrate that miR-375 is a critical determinant of HCC angiogenesis and sorafenib tolerance, revealing a novel miRNA-mediated mechanism underlying sorafenib treatment.

Programmed Death Ligand-1 (PD-L1) Regulated by NRF-2/MicroRNA-1 Regulatory Axis Enhances Drug Resistance and Promotes Tumorigenic Properties in Sorafenib-Resistant Hepatoma Cells.

Sorafenib, a multityrosine kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC), but the clinical response to sorafenib is seriously limited by drug resistance. Programmed death ligand-1 (PD-L1) is one of the most important inhibitory molecules involved in tumor immune evasion. Recently, it has been reported that PD-L1 could play crucial roles in drug resistance of many kinds of cancers. However, the expression, function, and regulation of PD-L1 in sorafenib-resistant hepatoma cells remain unclear. In this study, we reported that PD-L1 was overexpressed in sorafenib-resistant hepatoma cells, and shRNA-mediated PD-L1 depletion attenuated drug resistance and suppressed the migration, invasion, colony formation, and tumorigenesis in sorafenib-resistant hepatoma cells in vitro and in vivo. Mechanistic investigations indicated that loss of microRNA-1 (miR-1), a tumor-suppressive microRNA, contributed to the PD-L1 upregulation in sorafenib-resistant hepatoma cells, and PD-L1 was a direct regulatory target of miR-1. Further study revealed that an oncogenic transcriptional factor, nuclear factor E2-related factor 2 (NRF-2), was induced in sorafenib-resistant hepatoma cells and inhibited expression of miR-1 in vitro. From molecular mechanism insight back to the functional verification, we eventually demonstrated that miR-1 executed its tumor-suppressive effects on drug resistance and other malignant properties in sorafenib-resistant hepatoma cells partially by PD-L1 inhibition in vitro and in vivo. In conclusion, our data suggested that a NRF-2/miR-1/PD-L1 regulatory axis contributed to the development and maintenance of drug resistance and other tumorigenic properties in sorafenib-resistant hepatoma cells and provided a potential therapeutic target for overcoming sorafenib resistance in HCC.

MicroRNA-1 promotes apoptosis of hepatocarcinoma cells by targeting apoptosis inhibitor-5 (API-5).

Although microRNA-1 (miR-1) is a known liver cancer suppressor, the role of miR-1 in apoptosis of hepatoma cells has remained largely unknown. Our study shows that ectopic miR-1 overexpression induced apoptosis of liver hepatocellular carcinoma (HepG2) cells. Apoptosis inhibitor 5 (API-5) was found to be a potential regulator of miR-1 induced apoptosis, using a bioinformatics approach. Furthermore, an inverse relationship between miR-1 and API-5 expression was observed in human liver cancer tissues and adjacent normal liver tissues. Negative regulation of API-5 expression by miR-1 was demonstrated to promote apoptosis of HepG2 cells. Our study provides a novel regulatory mechanism of miR-1 in the apoptosis of hepatoma cells.

No association between IL-1RN VNTR and the risk of duodenal ulcer: a meta-analysis.

The aim of this study was to perform a meta-analysis to investigate a more authentic association between interleukin-1 RN variable number of tandem repeats (IL-1RN VNTR) and duodenal ulcer (DU). Systematic searches of electronic databases Embase, PubMed and Web of Science were performed. Statistical analyses were conducted using software Stata 11.0. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were applied. Publication bias was tested by Begg's funnel plot and Egger's regression test. A total of 16 studies including 2115 cases and 3622 controls were included in our final meta-analysis. There was no evidence of significant association between IL-1RN VNTR and DU (allelic model: OR = 1.04, 95% CI = 0.87-1.26; additive model: OR = 0.85, 95% CI = 0.62-1.16; dominant model: OR = 1.06, 95% CI = 0.92-1.23; and recessive model: OR = 0.83, 95% CI = 0.61-1.12). Significant protective associations were found in additive model (OR = 0.51, 95% CI = 0.31-0.83) and recessive model (OR = 0.45, 95% CI = 0.28-0.73) in Caucasian subgroup. In conclusion, our meta-analysis suggests that there is no evidence of significant association between IL-1RN VNTR and DU with or without Helicobacter pylori infection in overall population, whereas significant association is found by subgroup analyses which showed protective effect of IL-1RN allele 2 against DU risk in Caucasian population.