Objective
To investigate the regulatory effect and mechanism of microRNA-146 (miR-146) in graft rejection after liver transplantation (LT).
Methods
Orthotopic LT models of two groups were established using two-cuff technique. In the allotransplantation model group (experimental group), Lewis rats were used as the donors and BN rats as the recipients. In the isotransplantation model group (control group), Lewis rats were used as both the donors and recipients, with 3 rats in each group. At 7 d after LT, liver tissues were collected for histopathological examination and microRNA high-throughput sequencing. The GO and KEGG signaling pathways of miR-146 target genes were analyzed using bioinformatics website.
Results
Histopathological examination revealed that the rejection activity index (RAI) of liver tissues in the experimental group was 8.4±0.5 and the rats were diagnosed with severe acute rejection. In the control group, the RAI was 1.5±0.5 and the rats were diagnosed with no graft rejection. High-throughput sequencing showed that among 22 microRNAs which were probably closely associated with graft rejection, the expression levels of 21 were significantly up-regulated in the experimental group compared with those in the control group. Two of the 21 up-regulated microRNAs, miR-146a-5P and miR-146b-5P, were members of miR-146 family, and their expression levels were respectively 1.1 and 2.3 times of those in the control group. GO and KEGG signaling pathway analysis revealed that miR-146a-5P and miR-146b-5P participated in multiple immune-related signaling pathways via the target genes interleukin-1 receptor-associated kinase 1 (IRAK1), nuclear factor of activated T-cells 5 (NFAT5) and tumor necrosis factor receptor-associated protein family 6 (TRAF6).
Conclusions
The up-regulated expression levels of miR-146a-5P and miR-146b-5P are correlated with the incidence of graft rejection in rat with allogeneic LT. The mechanism is probably mediating multiple immune-related signaling pathways through regulating the expression of IRAK1, NFAT5 and TRAF6.
Key words:
MicroRNAs; Liver transplantation; Graft rejection; miR-146
Prognostic value of miR-17-5p in cancers: a meta-analysis Weihao Kong,* Yusheng Cheng,* Hao Liang,* Qiangxing Chen, Cuicui Xiao, Kun Li, Zenan Huang, Jian Zhang Department of Liver Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China *These authors contributed equally to this work Background: Studies have shown that miR-17-5p plays an important role in the development of cancer. The aim of this meta-analysis was to quantitatively analyze the association of miR-17-5p with prognosis in various cancers. Materials and methods: We searched the PubMed, EMBASE, Web of Science, and Cochrane library databases for relevant studies through August 2017. The prognostic data and clinicopathological features of overall survival (OS) and disease-free survival (DFS) were extracted to investigate the association between miR-17-5p expression and tumor prognosis. In addition, odds ratios (ORs) were used to assess the correlations between miR-17-5p expression and clinicopathological characteristics. Results: A total of ten studies were incorporated into this systematic review, and we found that high miR-17-5p expression can predict poor OS for malignancies (combined hazard ratio [HR]=1.87; 95% confidence interval [CI], 1.37–2.55; P=0.000) as well as poor DFS (combined HR=1.60; 95% CI, 1.05–2.44; P=0.027). Further subgroup analyses suggested that high miR-17-5p expression was related to poor OS in Asian patients (combined HR=1.92; 95% CI, 1.37–2.71; P=0.000) and the serum/plasma sample source subgroup (combined HR=2.13; 95% CI, 1.36–3.31; P=0.001). The combined OR indicated that the expression of miR-17-5p was associated with lymph node invasion (OR=1.28; 95% CI, 1.05–1.56; P=0.016) and venous invasion (OR=1.92; 95% CI, 1.40–2.63; P=0.000). Conclusion: Elevated expression of miR-17-5p suggested a poor prognosis in cancer patients and may serve as a new tumor marker to monitor cancer development and progression. Keywords: miR-17-5p, cancer, prognosis, meta-analysis
The purpose of this study is to evaluate the effects of chemotherapy and radiotherapy on the prognosis of unresectable HCC patients with portal and/or hepatic vein invasion.A retrospective analysis of unresectable HCC patients with portal and/or hepatic vein invasion registered in the Surveillance, Epidemiology, End Results (SEER) database was performed. The propensity score-matching (PSM) method was used to balance differences between groups. Overall survival (OS) and cancer-specific survival (CSS) were the interesting endpoints. OS was calculated from the date of diagnosis to the date of death caused by any cause or the last follow-up. CSS was defined as the interval between the date of diagnosis and date of death due only to HCC or last follow-up. OS and CSS were analyzed by using Kaplan-Meier analysis, Cox proportional hazards model, and Fine-Gray competing-risk model.A total of 2,614 patients were included. 50.2% patients received chemotherapy or radiotherapy and 7.5% patients received both chemotherapy and radiotherapy. Compared to the untreated group, chemotherapy or radiotherapy (COR) (HR = 0.538, 95% CI 0.495-0.585, p < 0.001) and chemotherapy and radiotherapy (CAR) (HR = 0.371, 95% CI 0.316-0.436, p < 0.001) showed better OS. In the COR group, Cox analysis results showed AFP, tumor size, N stage and M stage were independent risk factor of OS. Competing-risk analysis results showed AFP, tumor size and M stage were independent risk factor of CSS. In the CAR group, AFP and M stage were independent risk factors of OS. Competing-risk analysis results showed M stage were independent risk factor of CSS. Kaplan Meier analysis showed chemotherapy combined with radiotherapy significantly improves OS (10.0 vs. 5.0 months, p < 0.001) and CSS (10.0 vs. 6.0 months, p = 0.006) than monotherapy.AFP positive and distant metastasis are the main risk factors affecting OS and CSS of unresectable HCC patients with portal and/or hepatic vein invasion. Chemotherapy combined with radiotherapy significantly improves OS and CSS of unresectable HCC patients with portal and/or hepatic vein invasion.
To determine whether p21-activated Kinase (PAK) 6 is a prognostic and predictive marker in gastric cancer (GC) and to construct a classifier that can identify a subset of patients who are highly sensitive to 5-fluorouracil/oxaliplatin chemotherapy. We retrospectively analyzed the expression levels of PAK6, cyclooxygenase 2, p21WAF1, Ki-67, excision repair cross-complementing gene 1, and thymidylate synthase in 242 paraffin-embedded GC specimens of the training cohort by immunohistochemistry. Then, we used support vector machine (SVM)-based methods to develop a predictive classifier for chemotherapy (chemotherapy score - CS-SVM classifier). Further validation was performed in an independent cohort of 279 patients. High PAK6 expression was associated with poor prognosis and increased chemoresistance to 5-FU/oxaliplatin chemotherapy. The CS-SVM classifier distinguished patients with stage II and III GC into low- and high-CS-SVM groups, with significant differences in the 5-year disease-free survival (DFS) and overall survival (OS) in chemotherapy patients. Moreover, chemotherapy significantly prolonged the DFS and OS of the high CS-SVM patients in the training and validation cohorts. In conclusion, PAK6 was an independent prognostic factor and increased chemoresistance. The CS-SVM classifier distinguished a subgroup of stage II and III patients who would highly benefit from chemotherapy, thus facilitating patient counseling and individualizing the management.
Metabolic dysfunction-associated fatty liver disease (MAFLD) is now the most prevalent chronic liver disease worldwide, with an increasing incidence rate. MAFLD is a heterogeneous disease that can have a low or high-risk profile for developing severe liver disease in its natural course. Recent evidence has highlighted the critical role of RNA methylation modification in the pathogenesis of various liver diseases. However, it remains unclear whether the RNA N1-methyladenosine (m1A) modification of immune cells could potentially contribute to the pathogenesis and heterogeneity of MAFLD. To address this issue, we conducted an integrated bioinformatics analysis of MAFLD bulk and single-cell RNA sequencing (scRNA-seq) data to pinpoint m1A regulators in the network. This was followed by a description of the immune landscape, pathway enrichment analysis, and molecular subtyping. The expression patterns of m1A regulatory genes stratify MAFLD into two molecular subtypes, Cluster 1 and Cluster 2. These subtypes demonstrate different immune cell infiltration with distinct inflammation characteristics, which suggest different immune-inflammatory responses in the liver. Notably, Cluster 2 is associated with pro-inflammation and may be more likely to lead to progressive stages of MAFLD. Through intersection analysis of weighted gene co-expression network analysis (WGCNA) and m1A regulatory genes, three true hub genes (ALKBH1, YTHDC1, and YTHDF3) were identified, all of which were strongly correlated with infiltrating immune cells. The specific signaling pathways involved in the three core genes were derived from genomic variation analysis. Furthermore, scRNA-seq data from 33,168 cells from six liver samples identified 26 cell clusters and eight cell types, with endothelial cells, macrophages, and monocytes showing the most significant differences between MAFLD and normal controls. The cell-cell communication network between immune cells and non-parenchymal cells was extremely sophisticated and changed significantly in MAFLD. In summary, these findings demonstrate the involvement of m1A in MAFLD heterogeneity and emphasize the crucial role of m1A modulation of immune cells in regulating inflammation in MAFLD. These results may suggest potential therapeutic strategies for MAFLD.
Abstract Background Until now, several classification staging system and treatment algorithm for hepatocelluar carcinoma (HCC) has been presented. However, anatomical location is not taken into account in these staging systems. The aim of this study is to investigate whether anatomical sites could predict the postoperative recurrence of HCC patients. Methods 294 HCC patients were enrolled in this retrospective study. A novel score classification based on anatomical sites was established by a Cox regression model and validated in the internal validation cohort. Results HCC patients were stratified according to the novel score classification into three groups (score 0, score 1–3 and score 4–6). The predictive accuracy of the novel recurrence score for HCC patients as determined by the area under the receiver operating characteristic curves (AUCs) at 1, 3, and 5 years (AUCs 0.703, 0.706, and 0.605) was greater than that of the other representative classification systems. These findings were supported by the internal validation cohort. For patients with Barcelona Clinic Liver Cancer (BCLC) 0 and A stage, our data demonstrated that there was no significant difference in recurrence-free survival (RFS) between patients with score 0 and liver transplantation recipients. Additionally, we introduced this novel classification system to guide anatomical liver resection for centrally located liver tumors. Conclusion The novel score classification may provide a reliable and objective model to predict the RFS of HCC after hepatic resection.
Long non-coding RNA small nucleolar RNA host genes (SNHGs) play a critical role in the occurrence and development of tumors. In this study, we aimed to investigate the role of SNHG4 in hepatocellular carcinoma (HCC) and its underlining mechanism.Datasets were acquired from The Cancer Genome Atlas (TCGA) database. lncLocator 2.0 was used to identify the distribution of SNHG4 in HCC cells. Gene expression, Kaplan-Meier survival, microRNA and transcription factor target analyses were performed with the University of Alabama Cancer (UALCAN) Database, Kaplan-Meier Plotter, LinkedOmics, WebGestalt and gene set enrichment analysis, respectively. Gene Ontology and pathway enrichment analyses and assessment of RNA binding proteins were performed by R software, circlncRNAnet and Encyclopedia of RNA Interactomes (ENCORI). In addition, CirclncRNAnet and ENCORI were used to find the correlation between SNHG4 and important proteins, while the prognostic value was assessed with the Human Protein Atlas database and Kaplan-Meier Plotter.Expression of SNHG4 in HCC is higher in HCC tissue than in normal healthy liver tissues and is mainly distributed in the nucleus. SNHG4 positively correlated with poor prognosis (p<0.01 for overall survival and recurrence-free survival). Functional enrichment analysis revealed SNHG4 involvement with regulation of ribosomal RNA synthesis and the RNA processing and surveillance pathway. SNHG4 is closely associated with miR-154 and miR-206, transcription factor target E2F family and the signaling pathway for MAPK/ERK and mTOR. U2 auxiliary factor 2 (U2AF2) showed strong correlation with SNHG4, while low-expression of U2AF2 showed good prognosis.Based on our findings, we infer SNHG4 may play a role in the formation of HCC via regulation of tumor-related pathways.
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