[Show abstract][Hide abstract] ABSTRACT: Background:
Increasing evidence showed that miRNAs serve as modulators of human cancer, either as oncogene or tumor suppressors. Cisplatin resistance is the most common cause of chemotherapy failure in gastric cancer (GC). However, the roles of miRNAs in cisplatin resistance of GC remain largely unknown. The aim of the study was to identify a novel miRNA/gene pathway that regulates the sensitivity of GC cells to cisplatin.
In this study, we chose miR-223 by qRT-PCR analysis, the most significantly up-regulated miRNA in GC, to investigate its formation of DDP-resistant phenotype of GC cells and possible molecular mechanisms.
We found that miR-223 was most significantly up-regulated miRNA in DDP-resistant GC cells compared with parental GC cells. Besides, its expression was also significantly up-regulated in GC tissues. FBXW7 was identified as the direct and functional target gene of miR-223. Overexpression of FBXW7 could mimic the effect of miR-223 down-regulation and silencing of FBXW7 could partially reverse the effect of miR-223 down-regulation on DDP resistance of DDP-resistant GC cells. Besides, miR-223 and FBXW7 could affect the G1/S transition of cell cycle by altering some certain cell cycle regulators. Furthermore, miR-223 was found to be significantly up-regulated in H. pylori infected tissues and cells, suggesting that H. pylori infection may lead to GC development and DDP resistance.
Our findings revealed the roles of miR-223/FBXW7 signaling in the DDP resistance of GC cells and targeting it will be a potential strategic approach for reversing the DDP resistance in human GC.
Preview · Article · Dec 2015 · Journal of Experimental & Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Background:
Current diagnostic procedures of cancers are invasive and non-specific. MicroRNAs (miRNAs) have become promising molecular markers for gastric cancer (GC) predication. However, there have been inconsistencies in the literature regarding the suitability of circulating miRNAs for early detection of cancers.
We performed a comprehensive meta-analysis to integrate an evaluation index for diagnostic accuracy of miR-223 in diagnosing cancer patients. Furthermore, we conducted an independent validation set of 50 gastric cancer patients and 50 healthy controls comparing miR-223 expression. We also analyzed miR-223 expression in vitro.
A total of 11 studies met the inclusion criteria and therefore included in this meta-analysis. We found that miR-223 yielded a pooled area under ROC curve (AUC) of 0.89 (sensitivity: 81%, specificity: 84%) in discriminating cancer from controls. In our validation test, plasma miR-223 levels in GC patients were significantly higher than that in healthy controls (P<0.01). ROC curve analysis showed that AUC was 0.812 with a sensitivity of 70% and specificity of 80%. Moreover, the expression trend of miR-223 in plasma samples was in accordance with that of tissue and cell samples.
Current evidences suggested that plasma miR-223 could be a reliable and non-invasive biomarker for cancer diagnosis. Further large-scale prospective studies are necessary to validate their potential applicability in human cancer diagnosis.
No preview · Article · Sep 2015 · International Journal of Clinical and Experimental Medicine
[Show abstract][Hide abstract] ABSTRACT: MiR-141 and long noncoding RNA MEG3 have been independently reported to be tumor suppressor genes in various cancers. However, their expression has never been previously associated with gastric cancer (GC).
To investigate the interaction of miR-141 and MEG3 in GC.
QRT-PCR was used to detect miR-141, MEG3, and E2F3 in gastric tissues and cells. CCK-8 and flow cytometry analysis were used to detect cell functions. Western blot and luciferase activity were used to identify E2F3 as one of the direct targets of miR-141.
We found that expression of both miR-141 and MEG3 was significantly reduced in GC compared with levels in matched nonmalignant tissues. Positive correlation between miR-141 and MEG3 was found in both tumor tissues and control tissues. Furthermore, the over-expression of either miR-141 or MEG3 in 7901 and MKN45 cells inhibited cell proliferation and cell cycle progression and promoted cell apoptosis. E2F3 was identified as a target of miR-141, and its inhibition significantly reduced MEG3 expression. E2F3 expression was also found to be negatively associated with both MEG3 and miR-141. E2F3 over-expression partly reversed the changes caused by transfection of miR-141 mimic, and inhibition of miR-141 or MEG3 overrides MEG3- or miR-141-induced modulation of cell growth in GC.
These findings together suggested that miR-141 could be interacting with MEG3 and targeting E2F3, and these factors may play important anti-tumor effects in GC pathogenesis and provide therapeutic targets in the clinics.
No preview · Article · Aug 2015 · Digestive Diseases and Sciences
[Show abstract][Hide abstract] ABSTRACT: Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are regarded as useful tools for cancer detection, particularly for the early stage; however, little is known about their diagnostic impact on gastric cancer (GC). We hypothesized that GC-related lncRNAs might release into the circulation during tumor initiation and could be utilized to detect and monitor GC. 8 lncRNAs which previously found to be differently expressed in GC were selected as candidate targets for subsequent circulating lncRNA assay. After validating in 20 pairs of tissues and plasma in training set, H19 was selected for further analysis in another 70 patients and 70 controls. Plasma level of H19 was significantly higher in GC patients compared with normal controls (p < 0.0001). By receiver operating characteristic curve (ROC) analysis, the area under the ROC curve (AUC) was 0.838; p < 0.001; sensitivity, 82.9%; specificity, 72.9%). Furthermore, H19 expression enabled the differentiation of early stage GC from controls with AUC of 0.877; sensitivity, 85.5%; specificity, 80.1%. Besides, plasma levels of H19 were significantly lower in postoperative samples than preoperative samples (p = 0.001). In conclusion, plasma H19 could serve as a potential biomarker for diagnosis of GC, in particular for early tumor screening.
Full-text · Article · Jun 2015 · Scientific Reports
[Show abstract][Hide abstract] ABSTRACT: Background. Several studies have shown a possible involvement of Helicobacter pylori (H. pylori) infection in individuals with hyperemesis gravidarum (HG), but the relationship remains controversial. This meta-analysis was performed to validate and strengthen the association between HG and H. pylori infection. Methods. PubMed, Embase, and Web of Science databases up to March 20, 2014, were searched to select studies on the prevalence of H. pylori infection between pregnant women with HG and the normal pregnant control subjects. Results. Of the HG cases, 1289 (69.6%) were H. pylori-positive; however, 1045 (46.2%) were H. pylori-positive in control group. Compared to the non-HG normal pregnant controls, infection rate of H. pylori was significantly higher in pregnant women with HG (OR = 3.34, 95% CI: 2.32–4.81,
). Subgroup analysis indicated that H. pylori infection was a risk factor of HG in Asia, Africa, and Oceania, especially in Africa (OR = 12.38, 95% CI: 7.12–21.54,
). Conclusions. H. pylori should be considered one of the risk factors of HG, especially in the developing countries. H. pylori eradication could be considered to relieve the symptoms of HG in some intractable cases.
Preview · Article · Apr 2015 · Gastroenterology Research and Practice
[Show abstract][Hide abstract] ABSTRACT: Background. Some studies have shown the possible involvement of Helicobacter pylori (H. pylori) infection in chronic urticaria, but the relationship remains controversial. The aim of this meta-analysis was to quantitatively assess the association between H. pylori infection and chronic urticaria. Methods. Observational studies comparing the prevalence of H. pylori infection in patients with chronic urticaria and control subjects were identified through a systematic search in MEDLINE and EMBASE up to July 2014. H. pylori infection was confirmed by serological or nonserological tests. For subgroup analyses, studies were separated by region, publication year, and H. pylori detection method to screen the potential factors resulting in heterogeneity. Results. 16 studies involving 965 CU cases and 1235 controls were included. Overall, the prevalence of H. pylori infection was higher in urticarial patients than in controls (OR = 1.66; 95% CI: 1.12–2.45;
). This result persisted in subanalysis of nine high-quality studies (OR = 1.36; 95% CI: 1.03–1.80;
). Subgroup analysis showed that detection method of H. pylori is also a potential influential factor for the overall results. Conclusions. Our present meta-analysis suggests that H. pylori infection is significantly, though weakly, associated with an increased risk of chronic urticaria.
Preview · Article · Apr 2015 · Gastroenterology Research and Practice
[Show abstract][Hide abstract] ABSTRACT: Epidemiological studies have indicated that patients with chronic Helicobacter pylori infection have an increased risk of developing type 2 diabetes mellitus, but the underlying mechanisms remain largely unknown. This study aimed to investigate whether H. pylori infection contributes to the development of insulin resistance, as well as the underlying mechanisms both in vivo and in vitro.
The effect of H. pylori infection on glucose metabolism was evaluated in humans and mouse models. The role of the c-Jun/miR-203/suppressor of cytokine signaling 3 (SOCS3) pathway in H. pylori-induced insulin resistance was determined in vitro and was validated in vivo.
Average fasting glucose levels were increased in patients (P = 0.012) and mice (P = 0.004) with H. pylori infection. Diabetic mice with H. pylori infection showed impaired glucose metabolism and insulin tolerance and hyperinsulinemia. Furthermore, H. pylori infection impaired insulin signaling in primary hepatocytes. H. pylori infection could upregulate SOCS3, a well-known insulin signaling inhibitor, by downregulating miR-203. SOCS3 overexpression interfered with insulin signaling proteins, and knockdown of SOCS3 alleviated H. pylori-induced impairment of insulin signaling. The transcription factor c-Jun, which affects gene expression, was induced by H. pylori infection and suppressed miR-203 expression.
Our results demonstrated that H. pylori infection induced hepatic insulin resistance by the c-Jun/miR-203/SOCS3 signaling pathway and provide possible implications with regard to resolving insulin resistance.
No preview · Article · Feb 2015 · Journal of Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: Abstract Several microRNAs (miRNA) have been implicated in H. pylori related gastric cancer (GC). However, the molecular mechanism of miRNAs in gastric cancer has not been fully understood. In this study, we reported that miR-101 is significantly down-regulated in H. pylori positive tissues and cells and in tumor tissues with important functional consequences. Ectopic expression of miR-101 dramatically suppressed cell proliferation and colony formation by inducing G1-phase cell-cycle arrest. We found that miR-101 strongly reduced the expression of SOCS2 oncogene in GC cells. Similar to the restoring miR-26 expression, SOCS2 down-regulation inhibited cell growth and cell-cycle progression, whereas SOCS2 over-expression rescued the suppressive effect of miR-101. Mechanistic investigations revealed that miR-101 suppressed the expression of c-myc, CDK2, CDK4, CDK6, CCND2, CCND3, and CCNE2, while promoted tumor suppressor p14, p16, p21 and p27 expression. In clinical specimens, SOCS2 was over-expressed in tumors and H. pylori positive tissues and its mRNA levels were inversely correlated with miR-101 expression. Taken together, our results indicated that miR-101 functions as a growth-suppressive miRNA in H. pylori related GC, and that its suppressive effects are mediated mainly by repressing SOCS2 expression.
No preview · Article · Jan 2015 · Cancer biology & therapy
[Show abstract][Hide abstract] ABSTRACT: Cirrhosis is a severe threat to public health. Some studies have suggested that cirrhosis is associated with Helicobacter pylori infection, but the results remain controversial. This meta-analysis was conducted to quantify the association between cirrhosis and H. pylori infection. Published articles on H. pylori prevalence in patients with cirrhosis were collected to assess the potential associations between H. pylori infection and cirrhosis risk. Twenty-one eligible studies were included for the analysis. Data on publication year, geographic region, and etiology were summarized. Metaregression models and subgroup analyses were established to screen the factors for heterogeneity. Of the 322 articles retrieved, 21 met the inclusion criteria. These studies involved 6135 cases, with a total H. pylori infection rate of 52.26%. This meta-analysis showed significant difference in H. pylori infection between patients with cirrhosis and controls [odd ratio (OR)=2.05, 95% confidence interval (CI): 1.33-3.18, P<0.0001]. The subgroup analysis revealed, in contrast to Asia (OR=0.90, 95% CI: 0.48-1.66, P<0.0001), Europe (OR=2.98, 95% CI: 2.02-4.39, P<0.0001), and America (OR=4.75, 95% CI: 1.42-15.95, P=0.249), a significantly higher prevalence of H. pylori infection in patients with cirrhosis. On the basis of etiology, there was a higher prevalence of H. pylori infection due to primary biliary cirrhosis (OR=1.75, 95% CI: 1.15-2.64, P=0.147) and viral cirrhosis (OR=2.66, 95% CI: 1.24-5.71, P<0.0001) compared with alcohol cirrhosis (OR=0.77, 95% CI: 0.04-16.59, P<0.0001). The pooled data suggest that there is a significantly high prevalence of H. pylori infection in patients with cirrhosis. Large-scale and multicenter studies are needed to further investigate the relation between cirrhosis and H. pylori infection. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
No preview · Article · Dec 2014 · European Journal of Gastroenterology & Hepatology
[Show abstract][Hide abstract] ABSTRACT: Background
Previous meta-analyses reported that probiotics improve the effectiveness of Helicobacter pylori (H. pylori) eradication during antibiotic therapy, while results regarding a possible reduction of side effects remained inconclusive. Moreover, the effectiveness of different strains of probiotics has not been studied so far. It is further conceivable that probiotics will produce additional effects only if antibiotics are relatively ineffective.
This meta-analysis includes eligible randomized controlled trials examining effects of probiotics supplementation on eradication rates (ER) and side effects, published up to May 2014. Sub-group analysis was performed to compare different probiotic strains and antibiotic therapies with different effectiveness in controls (ER <80% vs.>80%). Publication bias was assessed with funnel plots and Harbord's test. The quality of the trials was assessed with the Cochrane risk of bias tool.
Thirty-three RCTs involving a total of 4459 patients met the inclusion criteria in case of eradication rates of which 20 assessed total side effects in addition. Overall, the pooled eradication rate in probiotics supplementation groups was significantly higher than in controls (ITT analysis: RR 1.122, 95% CI 1.086–1.159, PP analysis: RR 1.114, 95% CI 1.070–1.159). Sub group-analysis could, however, confirm this finding only for four individual strains (Lactobacillus acidophilus, Lactobacillus casei DN-114001, Lactobacillus gasseri, and Bifidobacterium infantis 2036) and for relatively ineffective antibiotic therapies. There was a significant difference between groups in the overall incidence of side effects (RR 0.735, 95% CI 0.598–0.902). This result was, however, only confirmed for non-blinded trials.
The pooled data suggest that supplementation with specific strains of probiotics compared with eradication therapy may be considered an option for increasing eradication rates, particularly when antibiotic therapies are relatively ineffective. The impact on side effects remains unclear and more high quality trials on specific probiotic strains and side effects are thus needed.
[Show abstract][Hide abstract] ABSTRACT: Several microRNAs (miRNA) have been implicated in H. pylori related gastric cancer (GC). However, the molecular mechanism of miRNAs in GC has not been fully understood. In this study, we reported that miR-203 is significantly down-regulated in H. pylori positive tissues and cells and in tumor tissues with important functional consequences. Ectopic expression of miR-203 dramatically suppressed cell proliferation and invasion. We found that miR-203 strongly reduced the expression of CASK oncogene in GC cells. Similar to the restoring miR-203 expression, CASK down-regulation inhibited cell growth and invasion, whereas CASK over-expression rescued the suppressive effect of miR-203. These results can also be found in nude mice. In clinical specimens, CASK was over-expressed in tumors and H. pylori positive tissues and its mRNA levels were inversely correlated with miR-203 expression. Taken together, our results indicated that miR-203 functions as a growth-suppressive miRNA in H. pylori related GC, and that its suppressive effects are mediated mainly by repressing CASK expression.
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer is an aggressive malignancy with an extremely poor prognosis. The human ether-a-go-go-related potassium channel (HERG1) is a human rapid delayed rectifier, which is involved in many crucial cellular events. In this article, we find that HERG1 expression is dramatically increased both in pancreatic cancer tissues and cell lines, and that increased HERG1 expression is significantly related to the development of pancreatic cancer. HERG1 silencing in pancreatic cancer-derived cell lines PANC-1 and CFPAC-1 strongly inhibits their malignant capacity in vitro as well as tumorigenicity and metastasis in nude mice. In addition, HERG1 is identified as a direct target of miR-96, which is downregulated in pancreatic cancer tissues and cell lines. Ectopic expression of miR-96 represses the HERG1 expression in pancreatic cancer and significantly inhibits malignant behavior of pancreatic cancer cells in vitro and in vivo.
Collectively, our findings suggest that miR-96 acts as a tumor suppressor in pancreatic cancer and may therefore serve as a useful therapeutic target for the development of new anticancer therapy.
[Show abstract][Hide abstract] ABSTRACT: Background
The molecular mechanism between Helicobacter pylori (H. pylori) infection and gastric cancer remained largely unknown. In this study, we determined the role of miRNA in H. pylori induced gastric cancer.
Methods and Results
We found that miR-204 was decreased in H. pylori positive tissues by qRT-PCR. Knockdown of miR-204 enhanced the invasion and proliferation ability of gastric cancer cells in vitro. Luciferase assay revealed that SOX4 was target gene of miR-204, which was found up-regulated in H. pylori positive tissues. Down-regulation of miR-204 and over-expression of SOX4 promoted epithelial-mesenchymal transition process.
Taken together, our findings demonstrated that miR-204 may act as a tumor suppressor in H. pylori induced gastric cancer by targeting SOX4.