Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of cancer stemness is believed to reduce the efficacy of current therapies against hepatocellular carcinoma (HCC). Understanding of the stemness-regulating signaling pathways incurred by a specific etiology can facilitate the development of novel targets for individualized therapy against HCC. Niche environments, such as virus-induced inflammation, may play a crucial role. However, the mechanisms linking inflammation and stemness expression in HCC remain unclear. Here we demonstrated the distinct role of inflammatory mediators in expressions of stemness-related properties involving the pluripotent octamer-binding transcription factor 4 (OCT4) in cell migration and drug resistance of hepatitis B virus-related HCC (HBV-HCC). We observed positive immunorecognition for macrophage chemoattractant protein 1 (MCP-1)/CD68 and OCT4/NANOG in HBV-HCC tissues. The inflammation-conditioned medium (inflamed-CM) generated by lipopolysaccharide-stimulated U937 human leukemia cells significantly increased the mRNA and protein levels of OCT4/NANOG preferentially in HBV-active (HBV+HBsAg+) HCC cells. The inflamed-CM also increased the side population (SP) cell percentage, green fluorescent protein (GFP)-positive cell population, and luciferase activity of OCT4 promoter-GFP/luciferase in HBV-active HCC cells. Furthermore, the inflamed-CM upregulated the expressions of insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) and activated IGF-IR/Akt signaling in HBV-HCC. The IGF-IR phosphorylation inhibitor picropodophyllin (PPP) suppressed inflamed-CM-induced OCT4 and NANOG levels in HBV+HBsAg+ Hep3B cells. Forced expression of OCT4 significantly increased the secondary sphere formation and cell migration, and reduced susceptibility of HBV-HCC cells to cisplatin, bleomycin, and doxorubicin. Taking together, our results show that niche inflammatory mediators play critical roles in inducing the expression of stemness-related properties involving IGF-IR activation, and the upregulation of OCT4 contributes to cancer migration and drug resistance of HBV-HCC cells. Findings in this paper would provide potential targets for a therapeutic strategy targeting on inflammatory environment for HBV-HCC.
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PMID:Inflammation Promotes Expression of Stemness-Related Properties in HBV-Related Hepatocellular Carcinoma. 2812 44

Significance: Neoplasms contain tumor-initiating stem-like cells (TICs) that drive malignant progression and tumor growth with drug resistance. TICs proliferate through a self-renewal process in which the two daughter cells differ in their proliferative potential, with one retaining the self-renewing phenotype and another displaying the differentiated phenotype. Recent Advances: Cancer traits (hepatocellular carcinoma) are triggered by alcoholism, obesity, and hepatitis B or C virus (HBV and HCV), including genetic changes, angiogenesis, defective tumor immunity, immortalization, metabolic reprogramming, excessive and prolonged inflammation, migration/invasion/metastasis, evasion of cell cycle arrest, anticell death, and compensatory regeneration/proliferation. Critical Issues: This review describes how metabolic reprogramming in mitochondria promotes self-renewal and oncogenicity of TICs. Pluripotency transcription factors (TFs), NANOG, OCT4, MYC, and SOX2, contribute to cancer progression by mitochondrial reprogramming, leading to the genesis of TICs and cancer. For example, oxidative phosphorylation (OXPHOS) and fatty acid metabolism are identified as major pathways contributing to pluripotency TF-mediated oncogenesis. Future Directions: Identification of novel metabolic pathways provides potential drug targets for neutralizing the activity of highly malignant TICs found in cancer patients. Antioxid. Redox Signal. 28, 1080-1089.
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PMID:Pluripotency Transcription Factors and Metabolic Reprogramming of Mitochondria in Tumor-Initiating Stem-like Cells. 2925 36

Human hepatocytes are a primary site of infection and replication of the hepatitis B virus (HBV). It is tempting to conclude that tissue specificity is controlled via virus-hepatocyte specific interactions at various steps during the viral lifecycle. However, the molecular mechanisms underlying hepatotropism of HBV are not fully clear. To address this issue, this study aims to identify hepatic factors that contribute to the regulation of the lifecycles of hepatitis viruses- especially HBV- and to clarify their regulatory mechanisms. We established oval-like cell lines (Hdo cells) by introducing a set of reprogramming factors (OCT3/4, SOX2, KLF4, LIN28, and NANOG) into human hepatoma HuH7 cells that are susceptible to HBV. Hdo cells exhibit a bi-directional differentiation potential. We found that Hdo cells maintained support for the replication of HBV but not of HCV. The level of particle-associated HBV DNA secreted into the culture medium was higher in the Hdo cells. Still, the HBs antigen level was lower than in parental HuH7 cells, suggesting that the regulation of HBV gene expression was affected by the reprogramming of HuH7 cells. A microarray analysis determined that the expression of host factors was largely comparable among of HuH7 and Hdo cells. In contrast, Hdo cells lost their susceptibility to HCV infection and to replication of the viral subgenome replicon RNA. Our results suggest that epigenetic reprogramming of human hepatoma cells potentially changes their permissivity to HBV. Furthermore, Hdo cells can be used as powerful tools to identify cellular determinants that change their expression during reprogramming or hepatic differentiation.
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PMID:The susceptibility of human hepatoma-derived oval-like cells to hepatitis B virus infection. 3194 38

Alcoholism synergizes the development of the hepatocellular carcinoma (HCC) in patients infected with hepatitis B or C virus (HBV or HCV). Tumor-initiating stem-like cells (TICs) are refractory to therapy and have expression of stemness transcription factors. Leaky-gut-derived endotoxin stimulates TLR4-NANOG pathway that skews asymmetric cell division and that metabolically reprograms hepatocytes/liver progenitor cells, leading to self-renewal. TICs isolated from mouse HCC models or human HCCs are tumorigenic and have p53 degradation via phosphorylation of the protective protein NUMB and its dissociation from p53 by the oncofetal protein TBC1D15. Furthermore, dysregulation of lncRNA promotes genesis of TICs, leading to HCC development. This review describes roles of cell fate decision, metabolic reprogramming and lncRNA for TIC genesis and liver oncogenesis. This project was supported by NIH grants 1R01AA018857-01, 5R21AA025470, P50AA11999 (Animal Core, Morphology Core, and Pilot Project Program), R24AA012885 (Non-Parenchymal Liver Cell Core) and pilot project funding (5P30DK048522-13).
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PMID:Cell fate, metabolic reprogramming and lncRNA of tumor-initiating stem-like cells induced by alcohol. 3217 51