Mutational impact in liver stem cells under precancerous alcoholic liver, NASH and PSC disease conditions
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ABSTRACT:
PROVIDER: EGAS00001005384 | EGA |
REPOSITORIES: EGA
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Project description:Stem cells are believed to be the cells-of-origin cancer. Nevertheless, their genome remains remarkably stable during life. To increase insight into how these cells can drive tumorigenesis, we set out to determine the genomic integrity of human adult stem cells from patients with liver disease associated with increased cancer risk. To this end, we characterized genome-wide mutation profiles of single ASCs from livers of patients with alcoholic liver disease, non-alcoholic liver disease and primary sclerosing cholangitis. The patients included in our study received a liver transplant due to their liver disease. Strikingly, we found that ASCs in these livers maintain a stable genome and have comparable mutation rates as healthy human liver ASCs. We did observe more nonsense and nonsynonymous mutations in COSMIC cancer genes that are hit by dominant mutations in tumors in comparison to healthy ASCs (n.s.), including two ASCs in alcoholic liver disease patients with a nonsense mutation in PTPRK. Next, we sequenced 5 biopsies of an alcoholic tumour to identify the mutational patterns in the tumour-initiating ASC. We found that the mutational patterns are, again, similar to healthy liver, but the mutational load is slightly higher. This suggests that the increased cancer risk in the liver disease patients is not caused by an increased mutational load, but rather that the precancerous liver environment promotes outgrowth of cells that would normally be selected against.
| EGAS00001002983 | EGA
Project description:Chronic liver inflammation precedes the majority of hepatocellular carcinomas (HCC). Here, we explore the connection between chronic inflammation and DNA methylation in the liver at the late precancerous stages of HCC development in Mdr2/Abcb4-knockout (Mdr2-KO) mice, a model of inflammation-mediated HCC. Using methylated DNA immunoprecipitation (MeDIP) followed by hybridization with Agilent CpG Islands (CGIs) microarrays we found specific CGIs in 76 genes which were hypermethylated in the Mdr2-KO liver compared to age-matched controls. Methylation of thirty among these genes was highly specific to the studied HCC model. We revealed that in most tested cases, the observed hypermethylation resulted from an age-dependent decrease of methylation of the specific CGIs in control livers with no decrease in mutant mice. Chronic inflammation did not change global levels of DNA methylation in Mdr2-KO liver, but caused a 2-fold decrease of the global 5-hydroxymethylcytosine level in mutants compared to controls. This decrease could result from a less efficient age-dependent demethylation of specific CpG sites in the liver of Mdr2-KO mutants, as described above. Expression of some tested hypermethylated genes was increased in Mdr2-KO livers compared to controls (28%), others were either similarly expressed (44%), or not expressed in the liver (28%). Liver cell fractionation revealed, that the relative hypermethylation of specific CGIs in Mdr2-KO compared to control livers affected either hepatocyte, or non-hepatocyte, or both fractions. There was only episodic correlation between changes of gene methylation and expression in cell fractions. Conclusion: Chronic liver inflammation causes hypermethylation of specific CGIs, which may affect both hepatocytes and non-hepatocyte liver cells. These changes may serve as markers of an increased regenerative activity and of a precancerous microenvironment in the chronically inflamed liver. Two-condition experiment, Mdr2-KO vs Mdr2-/+ liver tissue from 12m-old male FVB strain mice. Biological replicates: 3 control replicates, 3 knockout replicates.
2015-03-01 | E-GEOD-64097 | biostudies-arrayexpress
Project description:Liver cancer progression through increased miR-221 mediated tumorigenesis
| PRJNA558686 | ENA
Project description:Patients with diabetes mellitus (DM) have an epidemiologically higher risk for hepatocellular carcinoma (HCC). In mouse models, administration of streptozotocin (STZ) induces insulin-dependent DM by causing islet beta-cell dysfunction and also induced hepatocellular carcinoma (HCC) after 12 weeks. We attempted to elucidate the carcinogenic mechanism in the precancerous state by using hepatic miRNAs and create precancerous marker using exosomal miRNA. Serum and liver tissues were collected from STZ mice and non-treated mice (CTL mice) at 6, 10 and 12W. Total RNA in liver and exosome were extracted. Histological examination in liver in HE stain and hepatic and exosomal miRNA analysis were serially performed. miRNA and mRNA was analyzed by next-generation sequencing (NGS). The raw data of NGS was analyzed by Principal Component analysis. No inflammation or fibrosis was found in the liver in CTL mice during the observation period. In STZ-treated mice, regeneration and inflammation of hepatocytes was found at 6W and then nodules of atypical hepatocytes were found at 10 and 12 W. Expression of let-7f-5p, miR-21a-5p, 22-3p, and 26a-5p in liver of STZ mice was significantly increased during 6-10W, and these miRNAs controlled several tumor suppressor genes as target genes. We also identified six novel miRNAs associated with precancerous status. Furthermore, miR-122-5p and miR-192-5p in exosome were significantly upregulated in STZ mice in precancerous state. The expression of miRNAs that regulate tumor suppressor genes was enhanced even before carcinogenesis, and the expression of these miRNAs was not affected by liver fibrosis. In addition, the expression pattern of miRNAs in exosome is expected to be a marker for predicting carcinogenesis. Patients with diabetes mellitus (DM) have an epidemiologically higher risk for hepatocellular carcinoma (HCC). In mouse models, administration of streptozotocin (STZ) induces insulin-dependent DM by causing islet beta-cell dysfunction and also induced hepatocellular carcinoma (HCC) after 12 weeks. We attempted to elucidate the carcinogenic mechanism in the precancerous state by using hepatic miRNAs and create precancerous marker using exosomal miRNA. Serum and liver tissues were collected from STZ mice and non-treated mice (CTL mice) at 6, 10 and 12W. Total RNA in liver and exosome were extracted. Histological examination in liver in HE stain and hepatic and exosomal miRNA analysis were serially performed. miRNA and mRNA was analyzed by next-generation sequencing (NGS). The raw data of NGS was analyzed by Principal Component analysis. No inflammation or fibrosis was found in the liver in CTL mice during the observation period. In STZ-treated mice, regeneration and inflammation of hepatocytes was found at 6W and then nodules of atypical hepatocytes were found at 10 and 12 W. Expression of let-7f-5p, miR-21a-5p, 22-3p, and 26a-5p in liver of STZ mice was significantly increased during 6-10W, and these miRNAs controlled several tumor suppressor genes as target genes. We also identified six novel miRNAs associated with precancerous status. Furthermore, miR-122-5p and miR-192-5p in exosome were significantly upregulated in STZ mice in precancerous state. The expression of miRNAs that regulate tumor suppressor genes was enhanced even before carcinogenesis, and the expression of these miRNAs was not affected by liver fibrosis. In addition, the expression pattern of miRNAs in exosome is expected to be a marker for predicting carcinogenesis. Patients with diabetes mellitus (DM) have an epidemiologically higher risk for hepatocellular carcinoma (HCC). In mouse models, administration of streptozotocin (STZ) induces insulin-dependent DM by causing islet beta-cell dysfunction and also induced hepatocellular carcinoma (HCC) after 12 weeks. We attempted to elucidate the carcinogenic mechanism in the precancerous state by using hepatic miRNAs and create precancerous marker using exosomal miRNA. Serum and liver tissues were collected from STZ mice and non-treated mice (CTL mice) at 6, 10 and 12W. Total RNA in liver and exosome were extracted. Histological examination in liver in HE stain and hepatic and exosomal miRNA analysis were serially performed. miRNA and mRNA was analyzed by next-generation sequencing (NGS). The raw data of NGS was analyzed by Principal Component analysis. No inflammation or fibrosis was found in the liver in CTL mice during the observation period. In STZ-treated mice, regeneration and inflammation of hepatocytes was found at 6W and then nodules of atypical hepatocytes were found at 10 and 12 W. Expression of let-7f-5p, miR-21a-5p, 22-3p, and 26a-5p in liver of STZ mice was significantly increased during 6-10W, and these miRNAs controlled several tumor suppressor genes as target genes. We also identified six novel miRNAs associated with precancerous status. Furthermore, miR-122-5p and miR-192-5p in exosome were significantly upregulated in STZ mice in precancerous state. The expression of miRNAs that regulate tumor suppressor genes was enhanced even before carcinogenesis, and the expression of these miRNAs was not affected by liver fibrosis. In addition, the expression pattern of miRNAs in exosome is expected to be a marker for predicting carcinogenesis.
2020-12-22 | GSE153580 | GEO
Project description:Patients with diabetes mellitus (DM) have an epidemiologically higher risk for hepatocellular carcinoma (HCC). In mouse models, administration of streptozotocin (STZ) induces insulin-dependent DM by causing islet beta-cell dysfunction and also induced hepatocellular carcinoma (HCC) after 12 weeks. We attempted to elucidate the carcinogenic mechanism in the precancerous state by using hepatic miRNAs and create precancerous marker using exosomal miRNA. Serum and liver tissues were collected from STZ mice and non-treated mice (CTL mice) at 6, 10 and 12W. Total RNA in liver and exosome were extracted. Histological examination in liver in HE stain and hepatic and exosomal miRNA analysis were serially performed. miRNA and mRNA was analyzed by next-generation sequencing (NGS). The raw data of NGS was analyzed by Principal Component analysis. No inflammation or fibrosis was found in the liver in CTL mice during the observation period. In STZ-treated mice, regeneration and inflammation of hepatocytes was found at 6W and then nodules of atypical hepatocytes were found at 10 and 12 W. Expression of let-7f-5p, miR-21a-5p, 22-3p, and 26a-5p in liver of STZ mice was significantly increased during 6-10W, and these miRNAs controlled several tumor suppressor genes as target genes. We also identified six novel miRNAs associated with precancerous status. Furthermore, miR-122-5p and miR-192-5p in exosome were significantly upregulated in STZ mice in precancerous state. The expression of miRNAs that regulate tumor suppressor genes was enhanced even before carcinogenesis, and the expression of these miRNAs was not affected by liver fibrosis. In addition, the expression pattern of miRNAs in exosome is expected to be a marker for predicting carcinogenesis. Patients with diabetes mellitus (DM) have an epidemiologically higher risk for hepatocellular carcinoma (HCC). In mouse models, administration of streptozotocin (STZ) induces insulin-dependent DM by causing islet beta-cell dysfunction and also induced hepatocellular carcinoma (HCC) after 12 weeks. We attempted to elucidate the carcinogenic mechanism in the precancerous state by using hepatic miRNAs and create precancerous marker using exosomal miRNA. Serum and liver tissues were collected from STZ mice and non-treated mice (CTL mice) at 6, 10 and 12W. Total RNA in liver and exosome were extracted. Histological examination in liver in HE stain and hepatic and exosomal miRNA analysis were serially performed. miRNA and mRNA was analyzed by next-generation sequencing (NGS). The raw data of NGS was analyzed by Principal Component analysis. No inflammation or fibrosis was found in the liver in CTL mice during the observation period. In STZ-treated mice, regeneration and inflammation of hepatocytes was found at 6W and then nodules of atypical hepatocytes were found at 10 and 12 W. Expression of let-7f-5p, miR-21a-5p, 22-3p, and 26a-5p in liver of STZ mice was significantly increased during 6-10W, and these miRNAs controlled several tumor suppressor genes as target genes. We also identified six novel miRNAs associated with precancerous status. Furthermore, miR-122-5p and miR-192-5p in exosome were significantly upregulated in STZ mice in precancerous state. The expression of miRNAs that regulate tumor suppressor genes was enhanced even before carcinogenesis, and the expression of these miRNAs was not affected by liver fibrosis. In addition, the expression pattern of miRNAs in exosome is expected to be a marker for predicting carcinogenesis. Patients with diabetes mellitus (DM) have an epidemiologically higher risk for hepatocellular carcinoma (HCC). In mouse models, administration of streptozotocin (STZ) induces insulin-dependent DM by causing islet beta-cell dysfunction and also induced hepatocellular carcinoma (HCC) after 12 weeks. We attempted to elucidate the carcinogenic mechanism in the precancerous state by using hepatic miRNAs and create precancerous marker using exosomal miRNA. Serum and liver tissues were collected from STZ mice and non-treated mice (CTL mice) at 6, 10 and 12W. Total RNA in liver and exosome were extracted. Histological examination in liver in HE stain and hepatic and exosomal miRNA analysis were serially performed. miRNA and mRNA was analyzed by next-generation sequencing (NGS). The raw data of NGS was analyzed by Principal Component analysis. No inflammation or fibrosis was found in the liver in CTL mice during the observation period. In STZ-treated mice, regeneration and inflammation of hepatocytes was found at 6W and then nodules of atypical hepatocytes were found at 10 and 12 W. Expression of let-7f-5p, miR-21a-5p, 22-3p, and 26a-5p in liver of STZ mice was significantly increased during 6-10W, and these miRNAs controlled several tumor suppressor genes as target genes. We also identified six novel miRNAs associated with precancerous status. Furthermore, miR-122-5p and miR-192-5p in exosome were significantly upregulated in STZ mice in precancerous state. The expression of miRNAs that regulate tumor suppressor genes was enhanced even before carcinogenesis, and the expression of these miRNAs was not affected by liver fibrosis. In addition, the expression pattern of miRNAs in exosome is expected to be a marker for predicting carcinogenesis.
2020-12-22 | GSE153581 | GEO
Project description:Chronic liver inflammation precedes the majority of hepatocellular carcinomas (HCC). Here, we explore the connection between chronic inflammation and DNA methylation in the liver at the late precancerous stages of HCC development in Mdr2/Abcb4-knockout (Mdr2-KO) mice, a model of inflammation-mediated HCC. Using methylated DNA immunoprecipitation (MeDIP) followed by hybridization with Agilent CpG Islands (CGIs) microarrays we found specific CGIs in 76 genes which were hypermethylated in the Mdr2-KO liver compared to age-matched controls. Methylation of thirty among these genes was highly specific to the studied HCC model. We revealed that in most tested cases, the observed hypermethylation resulted from an age-dependent decrease of methylation of the specific CGIs in control livers with no decrease in mutant mice. Chronic inflammation did not change global levels of DNA methylation in Mdr2-KO liver, but caused a 2-fold decrease of the global 5-hydroxymethylcytosine level in mutants compared to controls. This decrease could result from a less efficient age-dependent demethylation of specific CpG sites in the liver of Mdr2-KO mutants, as described above. Expression of some tested hypermethylated genes was increased in Mdr2-KO livers compared to controls (28%), others were either similarly expressed (44%), or not expressed in the liver (28%). Liver cell fractionation revealed, that the relative hypermethylation of specific CGIs in Mdr2-KO compared to control livers affected either hepatocyte, or non-hepatocyte, or both fractions. There was only episodic correlation between changes of gene methylation and expression in cell fractions. Conclusion: Chronic liver inflammation causes hypermethylation of specific CGIs, which may affect both hepatocytes and non-hepatocyte liver cells. These changes may serve as markers of an increased regenerative activity and of a precancerous microenvironment in the chronically inflamed liver.
2015-03-01 | GSE64097 | GEO
Project description:Increased protein translation plays a critical role in cancer development and treatment1,2. However, the molecular mechanism that is involved in this process remains poorly understood. N1-methyladenosine (m1A) methylation in RNA accounts for regulating mRNA translation in a post-transcriptional manner3,4. Here we show that m1A methylation levels are remarkably elevated in hepatocellular carcinoma (HCC) patient tumor tissues, especially in patients with microscopic vascular invasion (MVI). Moreover, m1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. Consistently, TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumors and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylations are required for self-renewal of liver CSCs and tumorigenesis. Mechanistically, TRMT6/TRMT61A-dependent m1A in tRNA boost PPARδ expression, which triggers cholesterol synthesis to activate Hedgehog signaling, driving self-renewal of liver CSCs and tumorigenesis. For potential therapeutic benefit, we further identify a specific inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer with high m1A methylations. Our findings provide novel insights into the function and molecular mechanism of m1A modifications underlying liver tumorigenesis and drug target, which will serve as a new biomarker for HCC and pave a new way to develop more effective therapeutic strategies for HCC patients.
2021-03-01 | GSE147840 | GEO
Project description:AID is an intrinsic DNA mutator enzyme and contributes to tumorigenesis through the accumulation of genetic aberrations. To examine whether mutagenesis induced by AID during inflammation-associated hepatocarcinogenesis depends on the transcriptional levels of the target genes, we performed the gene expression profiling of liver tissues from AID transgenic mice and wild-type mice with and without thioacetamide treatment.
2015-07-10 | GSE62878 | GEO
Project description:Precancerous tissue microenvironment is thought to be important for tumorigenesis when cancer stem-like cells (CSCs) begin to grow, though underlying mechanisms remain unclear. Here, we uncovered critical roles of luminal progenitor cells expressing FRS2β, an inhibitory adaptor for ErbB signaling, to create the cytokines-rich CSC niche in mammary tissues. Deficiency of FRS2β greatly decreased mammary tumorigenesis with decreased tumor stroma in mouse mammary tumor virus (MMTV)-ErbB2 mice. Moreover, FRS2β-deficient precancerous mammary tissues did not allow tumorigenesis derived from xenografted wild type FRS2β tumor cells. Insulin-like growth factor (IGF) 1 and CXC chemokine ligand (CXCL) 12, stemness- and stroma-inducing cytokines, respectively, were expressed at low levels in FRS2β-deficient precancerous mammary cells. Treatment with inhibitors against these cytokines in precancerous mice greatly decreased tumorigenic potential. In addition, human breast cancer tissues in which FRS2β is highly expressed in tumor cells harbor more stroma, and are associated with poor prognosis. Thus, cytokines-rich CSC niche and tumor microenvironment induced by FRS2β expressed in luminal progenitor cells and tumor cells play important roles for tumorigenesis.
2021-09-07 | GSE120034 | GEO
Project description:Liver lymphatic vessels support liver function by draining interstitial fluid, cholesterol, fat, and immune cells for surveillance in the liver draining lymph node. Chronic liver disease is associated with increased inflammation and immune cell infiltrate. However, it is currently unknown if or how lymphatic vessels respond to increased inflammation and immune cell infiltrate in the liver during chronic disease. Here we demonstrate that lymphatic vessel abundance increases in patients with chronic liver disease and is associated with areas of fibrosis and immune cell infiltration. Using single-cell mRNA sequencing and multi-spectral immunofluorescence analysis we identified liver lymphatic endothelial cells and found that chronic liver disease results in lymphatic endothelial cells (LECs) that are in active cell cycle with increased expression of CCL21. Additionally, we found that LECs from patients with NASH adopt a transcriptional program associated with increased IL13 signaling. Moreover, we found that oxidized low density lipoprotein, associated with NASH pathogenesis, induced the transcription and protein production of IL13 in LECs both in vitro and in a mouse model. Finally, we show that oxidized low density lipoprotein reduced the transcription of PROX1 and decreased lymphatic stability. Together these data indicate that LECs are active participants in the liver, expanding in an attempt to maintain tissue homeostasis. However, when inflammatory signals, such as oxidized low density lipoprotein are increased, as in NASH, lymphatic function declines and liver homeostasis is impeded.
2019-04-18 | GSE129933 | GEO