![]() ![]() (D) The level of mir-192 was shown in non-tumor tissues from 17 human organs in TCGA database. From 1 to 18, they are Liver, Colon, Brain, Small intestine, Kidney, Testis, Cerebellum, Bone marrow, Spinal cord, Thymus, Spleen, Lung, Skeletal muscle, Salivary gland, Placenta, Prostate, Adrenal gland, and Uterus. (C) miR-192–5p expression was examined in 18 normal adult organs via qRT-PCR. (B) Reads distribution of the top 10 most abundant mature miRNAs in human hepatocytes (left) and the top 10 most abundant miRNA precursors in human non-tumor liver tissues from HCC Cohort 2 (right). Un-paired t-test was used for Cohort 1 and non-parametric test was for Cohort 2. (A) Expression levels of mature miR-192–5p and mir-192 precursor in five groups of CSC + HCCs and CSC - HCCs from miRNA array data of HCC Cohort 1 (left) and Cohort 2 (right). (F) GSEA analysis was performed to identify functionally related “gene sets” with statistically significant enrichment, using miR-192–5p related genes identified from Cohort 1. (E) Kaplan-Meier curves of overall survival and time to recurrence according to miR-192–5p levels (tertile division). (D) Kaplan-Meier curves of overall survival and time to recurrence of two identified HCC groups by 14 CSC-miRNAs. The positive (Red bar) and negative (green bar) statuses of five CSC biomarkers are labeled correspondingly for each case. The relative intensity of miR-192–5p in tumor was ranked. (C) Hierarchical clustering analysis of 14 miRNAs revealed two different groups. The abundance of 14 miRNAs (representing 25 miRNA probes) in non-tumor tissues from HCC patients was shown in the heat map. ![]() (B) Venn Diagram analysis of miRNAs that were significantly (p<0.05) altered in CSC + HCCs vs. For each biomarker, red and green dots referred to HCC patients with the top 25% expression levels (CSC + HCCs), and patients with the bottom 25% levels (CSC - HCCs), respectively. (A) Relative levels of five different hepatic CSC biomarkers. ©2018 American Association for Cancer Research. SIGNIFICANCE: miR-192-5p and its regulatory pathway is significantly abolished in multiple groups of HCC expressing high levels of CSC markers, which may represent a key event for hepatic carcinogenesis. #ACTIVATION KEY FOR CSC ORION 18 DRIVER#This circuit may be the driver that steers liver cells toward hepatic CSC cells, leading to hepatic carcinogenesis. This study reveals the circuit from hypermethylation of the mir-192 promoter through the increase in PABPC4 as a shared genetic regulatory pathway in various groups of primary CSC + HCC. Both TP53 mutation and hypermethylation of the mir-192 promoter impeded transcriptional activation of miR-192-5p in HCC cell lines and primary CSC + HCC. Suppressing miR-192-5p in HCC cells significantly increased multiple CSC populations and CSC-related features through targeting PABPC4. miR-192-5p, the top-ranked CSC miRNA, was liver-abundant and -specific and markedly downregulated in all five groups of CSC + HCC from two independent cohorts ( n = 613). Through miRNA profile analysis in an HCC cohort ( n = 241) for five groups of CSC + HCC tissues, i.e., EpCAM +, CD90 +, CD133 +, CD44 +, and CD24 + HCC, we identified a 14-miRNA signature commonly altered among these five groups of CSC + HCC. Various cancer stem cell (CSC) biomarkers have been identified for hepatocellular carcinoma (HCC), but little is known about the implications of heterogeneity and shared molecular networks within the CSC population. ![]()
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