BACKGROUND Hepatitis B virus(HBV) is a cause of hepatocellular carcinoma(HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have ...BACKGROUND Hepatitis B virus(HBV) is a cause of hepatocellular carcinoma(HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation and has implications in early diagnosis and treatment.AIM To elucidate HBV oncogenesis in HCC and identify potential therapeutic targets.METHODS We employed our Search, Tag, Analyze, Resource platform to conduct a meta-analysis of public data from National Center for Biotechnology Information’s Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent nontumor samples and analyzed results with ingenuity pathway analysis.RESULTS Our analysis revealed liver X receptors/retinoid X receptor(RXR) activation and farnesoid X receptor/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene rab-like protein 6(RABL6). The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. We conducted survival analysis that demonstrated increased mortality with higher RABL6 expression. Additionally, homeobox A10(HOXA10) was a top upstream regulator and was strongly upregulated in our analysis. HOXA10 has recently been demonstrated to contribute to HCC pathogenesis in vitro. Our causal analysis suggests an in vivo role through downregulation of tumor suppressors and other mechanisms.CONCLUSION This meta-analysis describes possible roles of RABL6 and HOXA10 in the pathogenesis of HBV-related HCC. RABL6 and HOXA10 represent potential therapeutic targets and warrant further investigation.展开更多
BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease in the United States and globally.The currently understood model of pathogenesis consists of a‘multiple hit’hypothesis in w...BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease in the United States and globally.The currently understood model of pathogenesis consists of a‘multiple hit’hypothesis in which environmental and genetic factors contribute to hepatic inflammation and injury.AIM To examine the genetic expression of NAFLD and non-alcoholic steatohepatitis(NASH)tissue samples to identify common pathways that contribute to NAFLD and NASH pathogenesis.METHODS We employed the Search Tag Analyze Resource for Gene Expression Omnibus platform to search the The National Center for Biotechnology Information Gene Expression Omnibus to elucidate NAFLD and NASH pathology.For NAFLD,we conducted meta-analysis of data from 58 NAFLD liver biopsies and 60 healthy liver biopsies;for NASH,we analyzed 187 NASH liver biopsies and 154 healthy liver biopsies.RESULTS Our results from the NAFLD analysis reinforce the role of altered metabolism,inflammation,and cell survival in pathogenesis and support recently described contributors to disease activity,such as altered androgen and long non-coding RNA activity.The top upstream regulator was found to be sterol regulatory element binding transcription factor 1(SREBF1),a transcription factor involved in lipid homeostasis.Downstream of SREBF1,we observed upregulation in CXCL10,HMGCR,HMGCS1,fatty acid binding protein 5,paternally expressed imprinted gene 10,and downregulation of sex hormone-binding globulin and insulin-like growth factor 1.These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver.Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis.Top canonical pathways,disease networks,and disease functions were related to cholesterol synthesis,lipid metabolism,adipogenesis,and metabolic disease.Top upstream regulators included proinflammatory cytokines tumor necrosis factor and IL1B,PDGF BB,and beta-estradiol.Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism,extracellular matrix deposition,and tumor suppression.Lastly,we found riciribine(an AKT inhibitor)and ZSTK-474(a PI3K inhibitor)as potential drugs that targeted the differential gene expression in our dataset.CONCLUSION In this study we describe several molecular processes that may correlate with NAFLD disease and progression.We also identified ricirbine and ZSTK-474 as potential therapy.展开更多
文摘BACKGROUND Hepatitis B virus(HBV) is a cause of hepatocellular carcinoma(HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation and has implications in early diagnosis and treatment.AIM To elucidate HBV oncogenesis in HCC and identify potential therapeutic targets.METHODS We employed our Search, Tag, Analyze, Resource platform to conduct a meta-analysis of public data from National Center for Biotechnology Information’s Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent nontumor samples and analyzed results with ingenuity pathway analysis.RESULTS Our analysis revealed liver X receptors/retinoid X receptor(RXR) activation and farnesoid X receptor/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene rab-like protein 6(RABL6). The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. We conducted survival analysis that demonstrated increased mortality with higher RABL6 expression. Additionally, homeobox A10(HOXA10) was a top upstream regulator and was strongly upregulated in our analysis. HOXA10 has recently been demonstrated to contribute to HCC pathogenesis in vitro. Our causal analysis suggests an in vivo role through downregulation of tumor suppressors and other mechanisms.CONCLUSION This meta-analysis describes possible roles of RABL6 and HOXA10 in the pathogenesis of HBV-related HCC. RABL6 and HOXA10 represent potential therapeutic targets and warrant further investigation.
文摘BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease in the United States and globally.The currently understood model of pathogenesis consists of a‘multiple hit’hypothesis in which environmental and genetic factors contribute to hepatic inflammation and injury.AIM To examine the genetic expression of NAFLD and non-alcoholic steatohepatitis(NASH)tissue samples to identify common pathways that contribute to NAFLD and NASH pathogenesis.METHODS We employed the Search Tag Analyze Resource for Gene Expression Omnibus platform to search the The National Center for Biotechnology Information Gene Expression Omnibus to elucidate NAFLD and NASH pathology.For NAFLD,we conducted meta-analysis of data from 58 NAFLD liver biopsies and 60 healthy liver biopsies;for NASH,we analyzed 187 NASH liver biopsies and 154 healthy liver biopsies.RESULTS Our results from the NAFLD analysis reinforce the role of altered metabolism,inflammation,and cell survival in pathogenesis and support recently described contributors to disease activity,such as altered androgen and long non-coding RNA activity.The top upstream regulator was found to be sterol regulatory element binding transcription factor 1(SREBF1),a transcription factor involved in lipid homeostasis.Downstream of SREBF1,we observed upregulation in CXCL10,HMGCR,HMGCS1,fatty acid binding protein 5,paternally expressed imprinted gene 10,and downregulation of sex hormone-binding globulin and insulin-like growth factor 1.These molecular changes reflect low-grade inflammation secondary to accumulation of fatty acids in the liver.Our results from the NASH analysis emphasized the role of cholesterol in pathogenesis.Top canonical pathways,disease networks,and disease functions were related to cholesterol synthesis,lipid metabolism,adipogenesis,and metabolic disease.Top upstream regulators included proinflammatory cytokines tumor necrosis factor and IL1B,PDGF BB,and beta-estradiol.Inhibition of beta-estradiol was shown to be related to derangement of several cellular downstream processes including metabolism,extracellular matrix deposition,and tumor suppression.Lastly,we found riciribine(an AKT inhibitor)and ZSTK-474(a PI3K inhibitor)as potential drugs that targeted the differential gene expression in our dataset.CONCLUSION In this study we describe several molecular processes that may correlate with NAFLD disease and progression.We also identified ricirbine and ZSTK-474 as potential therapy.
