Yan-Jie Chen

Circulating microRNAs as a Fingerprint for Liver Cirrhosis

Background Sensitive and specific detection of liver cirrhosis is an urgent need for optimal individualized management of disease activity. Substantial studies have identified circulation miRNAs as biomarkers for diverse diseases including chronic liver diseases. In this study, we investigated the plasma miRNA signature to serve as a potential diagnostic biomarker for silent liver cirrhosis. Methods A genome-wide miRNA microarray was first performed in 80 plasma specimens. Six candidate miRNAs were selected and then trained in CHB-related cirrhosis and controls by qPCR. A classifier, miR-106b and miR-181b, was validated finally in two independent cohorts including CHB-related silent cirrhosis and controls, as well as non−CHB-related cirrhosis and controls as validation sets, respectively. Results A profile of 2 miRNAs (miR-106b and miR-181b) was identified as liver cirrhosis biomarkers irrespective of etiology. The classifier constructed by the two miRNAs provided a high diagnostic accuracy for cirrhosis (AUC = 0.882 for CHB-related cirrhosis in the training set, 0.774 for CHB-related silent cirrhosis in one validation set, and 0.915 for non−CHB-related cirrhosis in another validation set). Conclusion Our study demonstrated that the combined detection of miR-106b and miR-181b has a considerable clinical value to diagnose patients with liver cirrhosis, especially those at early stage.

Hepatocellular Carcinoma Cells Induce Regulatory T Cells and Lead to Poor Prognosis via Production of Transforming Growth Factor-β1

Background/Aims: Regulatory T cells (Tregs) are associated with a poor prognosis in hepatocellular carcinoma (HCC). The purpose of the study was to explore the mechanisms of Tregs accumulation in HCC. Methods: We analyzed the frequency of Tregs in HCC by flow cytometry and immunohistochemistry. We also established a transforming growth factor (TGF)-β1-knockdown cell line by lentivirus-mediated RNA interference. Mouse CD4+CD25- T cells were cultured in supernatants from various cell lines. Results: HCC patients had a high frequency of Tregs, and high numbers of Tregs correlated with a poor prognosis. Liver cancer cells induced Treg production by secreting TGF-β1. In vivo experiments indicated that knockdown of TGF-β1 reduced the numbers of Tregs and metastatic nodules in mice. Conclusions: These results indicate that cancer-secreted TGF-β1 may increase Tregs, and TGF-β1 knockdown might impair immunosuppression in the tumor microenvironment by decrease Tregs.

Altered molecular signature of intestinal microbiota in irritable bowel syndrome patients compared with healthy controls: A systematic review and meta-analysis

BACKGROUND Many studies have reported significant changes in intestinal microbiota in irritable bowel syndrome (IBS) patients based on quantitative real-time PCR analysis. AIMS We aimed to review the alterations in intestinal microbiota. METHODS An online search up to June 9, 2016, was conducted. This systematic review and meta-analysis included differential expression of intestinal microbiota in patients with IBS versus healthy controls (HCs) and subgroup analysis. We assessed the quality of the included studies using an original assessment tool. RESULTS A total of 13 articles involving 360 IBS patients and 268 healthy controls were included. The quality assessment scores for these articles ranged from 5 to 8. Significant differences in expression in IBS patients were observed for Lactobacillus (SMD=-0.85, P<0.001, I2=28%), Bifidobacterium (SMD=-1.17, P<0.001, I2=79.3%), and Faecalibacterium prausnitzii (SMD=-1.05, P<0.001, I2=0.0%) but not Bacteroides-Prevotella group, Escherichia coli or other genera or species. Subgroup analysis showed that diarrhea-predominant IBS patients had significantly different expression of Lactobacillus (SMD=-1.81, P<0.001) and Bifidobacterium (SMD=-1.45, P<0.001). CONCLUSION Down-regulation of bacterial colonization including Lactobacillus, Bifidobacterium and F. prausnitzii was observed in IBS patients, particularly in diarrhea-predominant IBS (IBS-D). Microbiota changes participate in the pathogenesis of IBS and may underlie the efficacy of probiotic supplements.

MicroRNA-18a modulates P53 expression by targeting IRF2 in gastric cancer patients

MicroRNA‐18a (miR‐18a) has been reported to be upregulated in gastric cancer (GC) tissues compared with normal gastric tissues. However, little is known about its prognostic value and biological roles.

The ubiquitin–proteasome system and its potential application in hepatocellular carcinoma therapy

The ubiquitin-proteasome system (UPS) is a complicated tightly controlled system in charge of degrading 80-90% of proteins, and is central to regulating cellular function and keeping protein homeostasis. Therefore, the components of UPS attract considerable attention as potential targets for hepatocellular carcinoma (HCC) therapy. The clinical success of bortezomib in multiple myeloma and mantle cell lymphoma patients has set the precedent for therapeutically targeting this pathway. This review will provide an overview of the UPS in HCC and the current status of therapeutic strategies.

Circulating microRNAs as a Fingerprint for Endometrial Endometrioid Adenocarcinoma

Background Endometrial cancer is the most common malignancy of the female genital tract worldwide, and endometrial endometrioid adenocarcinoma (EEC) is the major histological type of endometrial cancer. There is a great need for better markers with high sensitivity and specificity to permit early diagnosis and proper management of EEC. The aim of our study is to identify a miRNA classifier within plasma as a noninvasive biomarker for EEC diagnosis. Methods This study was a retrospective case-control analysis which contained two independent cohorts including 93 participants. First, we screened 375 miRNAs in 29 plasma samples. 9 of the miRNAs were selected to be evaluated their expression by quantitative reverse-transcriptase polymerase chain reaction. A stepwise logistic regression model was then used to establish a new classifier in the validation cohort. Area under the receiver operating characteristic curve was used to evaluate the diagnostic accuracy. Co-expression analysis was used to verify the independence of results. Results miR-15b, -27a, and -223 were found to be differentially expressed in the EEC plasma between the two cohorts and had few connections with other miRNAs. The areas under the curve (AUC) were 0.768, 0.813, and 0.768 for miR-15b, -27a, and 223, respectively. miR-27a and CA125 can be combined as a potential non-invasive biomarker for detecting EEC, with the AUC of 0.894. Conclusion Our study demonstrated three miRNAs, including miR-15b, -27a, and -233 have a good clinical value in EEC diagnosis. The classifier, including miR-27a and CA125, demonstrated a high accuracy in the diagnosis of EEC and might serve as a novel non-invasive biomarker in the future.

Power and Promise of Ubiquitin Carboxyl-terminal Hydrolase 37 as a Target of Cancer Therapy

Ubiquitin carboxyl-terminal hydrolase 37 (UCH37, also called UCHL5), a member of the deubiquitinating enzymes, can suppress protein degradation through disassembling polyubiquitin from the distal subunit of the chain. It has been proved that UCH37 can be activated by proteasome ubiqutin chain receptor Rpn13 and incorporation into the 19S complex. UCH37, which has been reported to assist in the mental development of mice, may play an important role in oncogenesis, tumor invasion and migration. Further studies will allow a better understanding of roles in cell physiology and pathology, embryonic development and tumor formation, hopefully providing support for the idea that UCH37 may constitute a new interesting target for the development of anticancer drugs.

Serum microRNA signatures and metabolomics have high diagnostic value in colorectal cancer using two novel methods

Recently, many new diagnostic biomarkers have been developed for colorectal cancer. We chose 2 methods with high diagnostic efficiency, the detection of serum microRNA and metabolomics based on gas chromatography/mass spectrometry (GC/MS), and aimed to establish appropriate models. We reviewed the diagnostic value of all microRNA identified by previous diagnostic tests. We selected appropriate microRNA to validate their diagnostic efficiency, and determined the optimal combination. We included 85 patients with colorectal cancer (CRC) and 78 healthy controls (HC) and detected the expression of the microRNA. GC/MS analysis was conducted, and we used 3 multivariate statistical methods to establish diagnostic models. The concentrations of carcinoembryonic antigen (CEA) and carbohydrate antigen 19‐9 (CA19‐9) were detected for comparison with the novel models. Ultimately, 62 published studies and 63 microRNA were included in this review. MiR‐21, miR‐29a, miR‐92a, miR‐125b and miR‐223 were selected to further validate their diagnostic value. The serum levels of the 5 microRNA in CRC patients were significantly higher than those in the HC. The combination of miR‐21, miR‐29a, miR‐92a and miR‐125b had the highest area under the curve (AUC) at 0.952, with a sensitivity of 84.7% and a specificity of 98.7%. The GC/MS analysis exhibited an excellent diagnostic value and the AUC reached 1.0. With regard to traditional biomarkers, the AUC of CEA and CA19‐9 were 0.808 and 0.705, respectively. The application prospects are good for microRNA and metabolomics as new diagnostic methods because of their high diagnostic value compared with traditional biomarkers.

Prp19 facilitates invasion of hepatocellular carcinoma via p38 mitogen-activated protein kinase/Twist1 pathway

Pre-mRNA processing factor 19 (Prp19) is involved in many cellular events including pre-mRNA processing and DNA damage response. However, the pathological role of Prp19 in hepatocellular carcinoma (HCC) is still elusive. Here, we reported that Prp19 was increased in most HCC tissues and HCC cell lines, and its overexpression in HCC tissues was positively correlated with vascular invasion, tumor capsule breakthrough and poor prognosis. Prp19 potentiated migratory and invasive abilities of HCC cells in vitro and in vivo. Furthermore Prp19 facilitated Twist1-induced epithelial-mesenchymal transition. Mechanistic insights revealed that Prp19 directly binded with TGF-β-activated kinase1 (TAK1) and promoted the activation of p38 mitogen-activated protein kinase (MAPK), preventing Twist1 from degradation. Finally Prp19/p38 MAPK/Twist1 axis was attested in nude mice xenografts and HCC patient specimens. This work implies that the gain of Prp19 is a critical event during the progression of HCC, making it a promising target for malignancies with aberrant Prp19 expression.

Serum microRNA signatures and metabolomics have high diagnostic value in hepatocellular carcinoma

Background Many new diagnostic biomarkers have been developed for hepatocellular carcinoma (HCC). We selected two methods with high diagnostic value, the detection of serum microRNAs and metabolomics based on gas chromatography/mass spectrometry (GC/MS), and attempted to establish appropriate models. Methods We reviewed the diagnostic efficiencies of all microRNAs identified by previous diagnostic tests. Then we chose appropriate microRNAs to validate the diagnostic efficiencies, and determined the optimal combination. We included 66 patients with HCC and 82 healthy controls (HCs) and detected the expression of the microRNAs. GC/MS analysis was performed, and we used three multivariate statistical methods to establish diagnostic models. The concentration of alpha feto-protein (AFP) was determined for comparison with the novel models. Results 82 published studies and 92 microRNAs were ultimately included in this systematic review. Seven microRNAs were selected for further validation of their diagnostic efficiencies. Among which, miR-21, miR-106b, miR-125b, miR-182 and miR-224 had a significantly different expression in HCC patients. The combination of miR-21, miR-106b and miR-224 had the highest area under the curve (AUC) at 0.950 with a sensitivity of 80.3% and a specificity of 92.7%. The GC/MS analysis exhibited an excellent diagnostic value and the AUC reached 1.0. In comparison, the AUC of the traditional biomarker, AFP, was 0.755. Conclusion MicroRNAs and metabolomics shows promising potential as new diagnostic methods due to their high diagnostic value compared with traditional biomarkers.