The Application of Induced Pluripotent Stem Cells Against Liver Diseases: An Update and a Review.

Liver diseases are a major health concern globally, and are associated with poor survival and prognosis of patients. This creates the need for patients to accept the main alternative treatment of liver transplantation to prevent progression to end-stage liver disease. Investigation of the molecular mechanisms underpinning complex liver diseases and their pathology is an emerging goal of stem cell scope. Human induced pluripotent stem cells (hiPSCs) derived from somatic cells are a promising alternative approach to the treatment of liver disease, and a prospective model for studying complex liver diseases. Here, we review hiPSC technology of cell reprogramming and differentiation, and discuss the potential application of hiPSC-derived liver cells, such as hepatocytes and cholangiocytes, in refractory liver-disease modeling and treatment, and drug screening and toxicity testing. We also consider hiPSC safety in clinical applications, based on genomic and epigenetic alterations, tumorigenicity, and immunogenicity.

The anti-alcohol dependency drug disulfiram inhibits the viability and progression of gastric cancer cells by regulating the Wnt and NF-κB pathways.

OBJECTIVE: Disulfiram is commonly used for alcohol abuse; however, recent studies have revealed its potential as an anti-cancer treatment. This study investigated the effects of disulfiram on gastric cancer and its underlying mechanisms of action. METHODS: The gastric cancer cell lines MKN-45 and SGC-7901 were used for all experiments. Cell proliferation was investigated using cell counting kit-8, cell migration and invasion were examined using Transwell assays, the proliferation and metastasis related proteins PCNA and MMP-2, respectively, were detected by ELISA. To explore the underlying molecular mechanisms, we also examined levels of proteins involved in the Wnt and NF-κB pathways by ELISA. RESULTS: Disulfiram significantly inhibited the proliferation, migration, and invasion of gastric cancer cells and decreased PCNA and MMP-2 levels. Additionally, disulfiram-treated MKN-45 and SGC-7901 cells showed reduced expression of Wnt, ß-catenin, and NF-κB. CONCLUSION: Disulfiram regulates the Wnt and NF-κB pathways, and thus could be a potential treatment for managing gastric cancer.

The Roles of microRNAs in Multidrug-Resistance Mechanisms in Gastric Cancer.

Multidrug resistance (MDR) is one of the most significant reasons for the chemotherapeutics failure in gastric cancer. Although accumulating investigations and researches have been made to elucidate the mechanisms of multidrug resistance, the detail is far from completely understood. The importance of microRNAs in cancer chemotherapeutic resistance has been demonstrated recently, which provides a new strategy to overcome multidrug resistance. The different mechanisms are related to the phenomena of MDR itself and the roles of miRNAs in these multi-mechanisms by which MDR is acquired. In turn, the aim of this review was to summarize recent publications of microRNAs in regulating MDR in gastric cancer, thereby potentially developing as targeted therapies. Further unraveling the roles of microRNAs in MDR mechanisms including the ATP-binding cassette (ABC) transporter family, autophagy induction, cancer stem cell regulation, hypoxia induction, DNA damage and repair, epigenetic regulation, and exosomes in gastric cancer will be helpful for us to win the battle against it.

COL4A family: potential prognostic biomarkers and therapeutic targets for gastric cancer.

BACKGROUND: The type IV collagen alpha chain (COL4A) family is a major component of the basement membrane (BM) that has recently been found to be involved in tumor angiogenesis and progression. However, the expression levels and the exact roles of distinct COL4A family members in gastric cancer (GC) have not been completely understood. METHODS: Here, the expression levels of COL4As in GC and normal gastric tissues were calculated by using TCGA datasets and the predicted prognostic values by the GEPIA tool. Furthermore, the cBioPortal and Metascape tools were integrated to analyze the genetic alterations, correlations and potential functions of COL4As, and their frequently altered neighboring genes in GC. RESULTS: Notably, the expression levels of COL4A1/2/4 in GC were higher to those in normal gastric tissues, while the expression levels of COL4A3/5/6 were lower in GC than normal. Survival analysis revealed that lower expression levels of COL4A1/5 led to higher overall survival (OS) rate. Multivariate analysis using the Cox proportional-hazards model indicated that age, gender, pathological grade, metastasis and COL4A5 expression, are independent prognostic factors for OS. However, TNM stage, lymph node metastasis, Lauren's classification, COL4A1-4 and COL4A6 were associated with poor OS but not independent prognostic factors. Function-enriched analysis of COL4As and their frequently altered neighboring genes was involved in tumor proliferation and metastasis in GC. CONCLUSIONS: These results implied that COL4A1/2 were potential therapeutic targets for GC. COL4A3/4/6 might have an impact on gastric carcinogenesis and subsequent progression, whereas COL4A5 was an independent prognostic marker for GC.

Serum miR-551b-3p is a potential diagnostic biomarker for gastric cancer.

BACKGROUND/AIMS: Gastric cancer (GC) is one of the most common gastrointestinal malignancies. Many studies have demonstrated that serum microRNAs have potential applications as non-invasive biomarkers for cancer diagnosis. The aim of the present study was to investigate the expression of serum miR-551b-3p in patients with GC and to explore its potential as a diagnostic biomarker in GC. MATERIALS AND METHODS: The expression of miR-551b-3p was detected using quantitative reverse transcription polymerase chain reaction in preoperative serum samples of 50 patients with GC and 53 healthy individuals. An analysis was performed to determine the correlation between serum miR-551b-3p levels and clinicopathological characteristics of patients with GC. The receiver operating characteristic curve was generated, and the cut-off point of serum miR-551b-3p for the diagnosis of GC was selected. The clinical value of serum miR-551b-3p for GC was analyzed by a consistency test. RESULTS: The expression of serum miR-551b-3p was significantly lower in patients with GC than in healthy individuals (p=0.000). Low level was positively associated with tumor size (p=0.014), depth of invasion (p=0.001), and Tumor-Node-Metastasis stage (p=0.022). The area under the curve for serum miR-551b-3p distinguishing patients with GC from healthy individuals was 0.860 (95% CI: 0.787-0.933, p=0.000), with a specificity of 96.2% and a sensitivity of 70%. The kappa consistency test had a kappa value of 0.667 (p=0.000) in GC. CONCLUSION: Serum miR-551b-3p may potentially serve as a diagnostic biomarker for GC.

Diagnostic accuracy of controlled attenuation parameter (CAP) as a non-invasive test for steatosis in suspected non-alcoholic fatty liver disease: a systematic review and meta-analysis.

BACKGROUND: Controlled attenuation parameter (CAP) is a non-invasive method for diagnosing hepatic steatosis. Despite good diagnostic performance, clinical application of CAP is limited due to the influences of covariates. Here, a systematic review on the performance of CAP in the diagnosis and staging of hepatic steatosis in NAFLD patients was performed. METHODS: The sensitivity, specificity, diagnostic odds ratio (DOR) and area under receiver operating characteristics (AUROC) curves of the pooled data for CAP in diagnosing and staging the mild (Stage 1), moderate (Stage 2) and severe (Stage 3) steatosis in NAFLD patients were assessed. The clinical utility of CAP was evaluated by Fagan plot. Heterogeneity was explored using subgroup analysis. RESULTS: Nine studies involving 1297 patients with liver biopsy-proven NAFLD were analyzed. The pooled sensitivity of CAP in detecting mild hepatic steatosis was 87% with a specificity of 91% and a DOR of 84.35. The pooled sensitivity of CAP in detecting moderate hepatic steatosis was 85% with a specificity of 74% and a DOR of 21.28. For severe steatosis, the pooled sensitivity was 76% with a specificity of 58% and a DOR of 4.70. The mean AUROC value for CAP in the diagnosis of mild, moderate, and severe steatosis was 0.96, 0.82 and 0.70, respectively. A subgroup analysis indicated that variation in the geographic regions, cutoffs, age and body mass index (BMI) could be the potential sources of heterogeneity in the diagnosis of moderate to severe steatosis. CONCLUSIONS: CAP should be cautiously considered as a non-invasive substitute for liver biopsy in clinical practice.

Prognostic significance of pretreatment plasma fibrinogen in patients with hepatocellular and pancreatic carcinomas: A meta-analysis.

BACKGROUND: The high pretreatment plasma fibrinogen has been widely reported to be a possible biomarker for predicting prognosis in hepatocellular carcinoma (HCC) and pancreatic carcinoma (PC), but persuasive conclusion has not been made yet. Thus, we herein conducted a meta-analysis to comprehensively assess the prognostic value of high pretreatment plasma fibrinogen in patients with HCC and PC. METHOD: We systematically searched PubMed, EMBASE, and Web of Science to identify eligible studies from inception to November 10, 2017. RESULTS: Finally, a total of 12 publications with 13 studies were included. Of these eligible studies, 5 publications with 6 studies were about pancreatic cancer and 7 were about HCC. The pooled analysis indicated that high plasm fibrinogen level was significantly related to worse overall survival (OS) in HCC [hazard ratio (HR) = 1.87; 95% confidence interval (CI): 1.55-2.24; P < .01]. Similarly, from our result, it was found that high plasm fibrinogen was also significantly associated with worse OS in PC (HR = 1.56; 95% CI: 1.13-2.15; P < .01). CONCLUSION: Taken together, our meta-analysis confirmed that high plasma fibrinogen level could predict worse survival in HCC and PC.

Prognostic significance of pretreatment plasma fibrinogen level in patients with digestive system tumors: a meta-analysis.

High pretreatment levels of plasma fibrinogen have been widely reported to be a potential predictor of prognosis in digestive system tumors; however, the conclusions are not consistent. Therefore, we performed a meta-analysis to comprehensively assess the prognostic roles of high pretreatment plasma fibrinogen levels in digestive system tumors. We searched for eligible studies in the PubMed, Embase, and Web of Science electronic databases for publications from the database inception to 1 September 2017. The endpoints of interest included overall survival, disease-free survival, and recurrence-free survival. We investigated the relationship between fibrinogenemia and overall survival in colorectal cancer (10 studies), gastric cancer (6), pancreatic cancer (6), hepatocellular carcinoma (7), and esophageal squamous cell carcinoma (10); the pooled results indicated that fibrinogenemia was significantly related to a worse overall survival (hazard ratio (HR) 1.73; 95% confidence interval (CI) 1.52, 1.97; P <0.001; HR 1.71; 95% CI 1.28, 2.28; P <0.001; HR 1.57; 95% CI 1.13, 2.17; P = 0.007; HR 1.89; 95% CI 1.57, 2.27; P <0.001, and HR 1.67; 95% CI 1.35, 2.07; P <0.001). Taken together, an increased pretreatment plasma fibrinogen level was related to worse survival in digestive system tumors, indicating that it could be a useful prognostic marker in these types of tumors.

Molecular mechanisms of lncRNA SMARCC2/miR-551b-3p/TMPRSS4 axis in gastric cancer.

Decreased expression of miR-551b-3p has been identified in gastric cancer tissues but its biological role and underlying mechanism in this malignancy is poorly understood. In this study, we show that the expression of miR-551b-3p negatively correlates with the depth of tumour invasion and lymphatic metastasis, but it positively correlates with tumour differentiation and the patient survival. MiR-551b-3p negatively affects the proliferation, mobility and invasiveness of gastric cancer cells. LncRNA SMARCC2 inhibits the expression of miR-551b-3p through binding to its mRNA response elements in gastric cancer cells. Overexpression of LncRNA SMARCC2 enhances the proliferation and migration of gastric cancer cells, while inhibition of LncRNA SMARCC2 does the opposite. TMPRSS4 is a direct target gene of miR-551b-3p. We conclude that miR-551b-3p functions as a tumour suppressor gene in gastric cancer, and its function is regulated by LncRNA SMARCC2/miR-551b-3p/TMPRSS4 axis.