Gene expression最新文献_第10页

Heat Stress and Thermal Ablation Induce Local Expression of Nerve Growth Factor Inducible (VGF) in Hepatocytes and Hepatocellular Carcinoma: Preclinical and Clinical Studies. 热应激和热消融诱导肝细胞和肝细胞癌局部表达神经生长因子(VGF):临床前和临床研究

Gene expression Pub Date : 2018-12-14 Epub Date: 2018-07-04 DOI: 10.3727/105221618X15305531034617

Scott M Thompson, Danielle E Jondal, Kim A Butters, Bruce E Knudsen, Jill L Anderson, Lewis R Roberts, Matthew R Callstrom, David A Woodrum

{"title":"Heat Stress and Thermal Ablation Induce Local Expression of Nerve Growth Factor Inducible (VGF) in Hepatocytes and Hepatocellular Carcinoma: Preclinical and Clinical Studies.","authors":"Scott M Thompson, Danielle E Jondal, Kim A Butters, Bruce E Knudsen, Jill L Anderson, Lewis R Roberts, Matthew R Callstrom, David A Woodrum","doi":"10.3727/105221618X15305531034617","DOIUrl":"https://doi.org/10.3727/105221618X15305531034617","url":null,"abstract":"The purposes of this study were to test the hypothesis that heat stress and hepatic thermal ablation induce nerve growth factor inducible (VGF) and to determine intrahepatic versus systemic VGF expression induced by thermal ablation in vivo and in patients. Hepatocytes and HCC cells were subjected to moderate (45°C) or physiologic (37°C) heat stress for 10 min and assessed for VGF expression at 0-72 h post-heat stress (n ≥ 3 experiments). Orthotopic N1S1 HCC-bearing rats were randomized to sham or laser thermal ablation (3 W × 90 s), and liver/serum was harvested at 0-7 days postablation for analysis of VGF expression (n ≥ 6 per group). Serum was collected from patients undergoing thermal ablation for HCC (n = 16) at baseline, 3-6, and 18-24 h postablation and analyzed for VGF expression. Data were analyzed using ordinary or repeated-measures one-way analysis of variance and post hoc pairwise comparison with Dunnett's test. Moderate heat stress induced time-dependent VGF mRNA (3- to 15-fold; p < 0.04) and protein expression and secretion (3.1- to 3.3-fold; p < 0.05). Thermal ablation induced VGF expression at the hepatic ablation margin at 1 and 3 days postablation but not remote from the ablation zone or distant intrahepatic lobe. There was no detectable serum VGF following hepatic thermal ablation in rats and no increase in serum VGF following HCC thermal ablation in patients at 3-6 and 18-24 h postablation compared to baseline (0.71- and 0.63-fold; p = 0.27 and p = 0.16, respectively). Moderate heat stress induces expression and secretion of VGF in HCC cells and hepatocytes in vitro, and thermal ablation induces local intrahepatic but not distant intrahepatic or systemic VGF expression in vivo.","PeriodicalId":12502,"journal":{"name":"Gene expression","volume":"19 1","pages":"37-47"},"PeriodicalIF":0.0,"publicationDate":"2018-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3727/105221618X15305531034617","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36284571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

HNF4α Regulates CSAD to Couple Hepatic Taurine Production to Bile Acid Synthesis in Mice. HNF4α调节CSAD对小鼠肝脏牛磺酸生成与胆汁酸合成的耦合作用。

Gene expression Pub Date : 2018-08-22 Epub Date: 2018-06-05 DOI: 10.3727/105221618X15277685544442

Yifeng Wang, David Matye, Nga Nguyen, Yuxia Zhang, Tiangang Li

{"title":"HNF4α Regulates CSAD to Couple Hepatic Taurine Production to Bile Acid Synthesis in Mice.","authors":"Yifeng Wang, David Matye, Nga Nguyen, Yuxia Zhang, Tiangang Li","doi":"10.3727/105221618X15277685544442","DOIUrl":"https://doi.org/10.3727/105221618X15277685544442","url":null,"abstract":"Cysteine dioxygenase 1 (CDO1) converts cysteine to cysteine sulfinic acid, which can be further converted by cysteine sulfinic acid decarboxylase (CSAD) to hypotaurine for taurine production. This cysteine catabolic pathway plays a major role in regulating hepatic cysteine homeostasis. Furthermore, taurine is used for bile acid conjugation, which enhances bile acid solubility and physiological function in the gut. Recent studies show that this cysteine catabolic pathway is repressed by bile acid signaling, but the molecular mechanisms have not been fully elucidated. The mechanisms of bile acid and farnesoid X receptor (FXR) regulation of hepatic CSAD expression were studied in mice and hepatocytes. We showed that hepatocyte nuclear factor 4α (HNF4α) bound the mouse CSAD proximal promoter and induced CSAD transcription. FXR-induced small heterodimer partner (SHP) repressed mouse CSAD gene transcription via interacting with HNF4α as a repressor. Consistent with this model, cholic acid feeding, obeticholic acid administration, and liver HNF4α knockdown reduced hepatic CSAD expression, while liver SHP knockout and apical sodium-dependent bile acid transporter (ASBT) inhibitor treatment induced hepatic CSAD expression in mice. Furthermore, TNF-α also inhibited CSAD expression, which may be partially mediated by reduced HNF4α in mouse hepatocytes. In contrast, bile acids and GW4064 did not inhibit CSAD expression in human hepatocytes. This study identified mouse CSAD as a novel transcriptional target of HNF4α. Bile acids and cytokines repress hepatic CSAD, which closely couples taurine production to bile acid synthesis in mice. The species-specific regulation of CSAD reflects the differential preference of bile acid conjugation to glycine and taurine in humans and mice, respectively.","PeriodicalId":12502,"journal":{"name":"Gene expression","volume":"18 3","pages":"187-196"},"PeriodicalIF":0.0,"publicationDate":"2018-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3727/105221618X15277685544442","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36195514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 8

Direct Comparison of the Thioacetamide and Azoxymethane Models of Type A Hepatic Encephalopathy in Mice. 甲硫代乙酰胺与偶氮氧甲烷模型小鼠A型肝性脑病的直接比较。

Gene expression Pub Date : 2018-08-22 Epub Date: 2018-06-12 DOI: 10.3727/105221618X15287315176503

Stephanie Grant, Matthew McMillin, Gabriel Frampton, Anca D Petrescu, Elaina Williams, Victoria Jaeger, Jessica Kain, Sharon DeMorrow

{"title":"Direct Comparison of the Thioacetamide and Azoxymethane Models of Type A Hepatic Encephalopathy in Mice.","authors":"Stephanie Grant, Matthew McMillin, Gabriel Frampton, Anca D Petrescu, Elaina Williams, Victoria Jaeger, Jessica Kain, Sharon DeMorrow","doi":"10.3727/105221618X15287315176503","DOIUrl":"https://doi.org/10.3727/105221618X15287315176503","url":null,"abstract":"Acute liver failure is a devastating consequence of hepatotoxic liver injury that can lead to the development of hepatic encephalopathy. There is no consensus on the best model to represent these syndromes in mice, and therefore the aim of this study was to classify hepatic and neurological consequences of azoxymethane- and thioacetamide-induced liver injury. Azoxymethane-treated mice were euthanized at time points representing absence of minor and significant stages of neurological decline. Thioacetamide-treated mice had tissue collected at up to 3 days following daily injections. Liver histology, serum chemistry, bile acids, and cytokine levels were measured. Reflexes, grip strength measurement, and ataxia were calculated for all groups. Brain ammonia, bile acid levels, cerebral edema, and neuroinflammation were measured. Finally, in vitro and in vivo assessments of blood-brain barrier function were performed. Serum transaminases and liver histology demonstrate that both models generated hepatotoxic liver injury. Serum proinflammatory cytokine levels were significantly elevated in both models. Azoxymethane-treated mice had progressive neurological deficits, while thioacetamide-treated mice had inconsistent neurological deficits. Bile acids and cerebral edema were increased to a higher degree in azoxymethane-treated mice, while cerebral ammonia and neuroinflammation were greater in thioacetamide-treated mice. Blood-brain barrier permeability exists in both models but was likely not due to direct toxicity of azoxymethane or thioacetamide on brain endothelial cells. In conclusion, both models generate acute liver injury and hepatic encephalopathy, but the requirement of a single injection and the more consistent neurological decline make azoxymethane treatment a better model for acute liver failure with hepatic encephalopathy.","PeriodicalId":12502,"journal":{"name":"Gene expression","volume":"18 3","pages":"171-185"},"PeriodicalIF":0.0,"publicationDate":"2018-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3727/105221618X15287315176503","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36215769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 24

Liver and Pancreas: Do Similar Embryonic Development and Tissue Organization Lead to Similar Mechanisms of Tumorigenesis? 肝脏和胰腺:相似的胚胎发育和组织结构导致相似的肿瘤发生机制吗?

Gene expression Pub Date : 2018-08-22 Epub Date: 2018-03-26 DOI: 10.3727/105221618X15216414278706

Elsa Ghurburrun, Ivan Borbath, Frédéric P Lemaigre, Patrick Jacquemin

引用次数: 14

Stat3 Regulates Liver Progenitor Cell-Driven Liver Regeneration in Zebrafish. Stat3调节斑马鱼肝脏祖细胞驱动的肝脏再生。

Gene expression Pub Date : 2018-08-22 Epub Date: 2018-04-24 DOI: 10.3727/105221618X15242506133273

Mehwish Khaliq, Sungjin Ko, Yinzi Liu, Hualin Wang, Yonghua Sun, Lila Solnica-Krezel, Donghun Shin

{"title":"Stat3 Regulates Liver Progenitor Cell-Driven Liver Regeneration in Zebrafish.","authors":"Mehwish Khaliq, Sungjin Ko, Yinzi Liu, Hualin Wang, Yonghua Sun, Lila Solnica-Krezel, Donghun Shin","doi":"10.3727/105221618X15242506133273","DOIUrl":"10.3727/105221618X15242506133273","url":null,"abstract":"After liver injury, regeneration manifests as either (1) hepatocytes proliferating to restore the lost hepatocyte mass or (2) if hepatocyte proliferation is compromised, biliary epithelial cells (BECs) dedifferentiating into liver progenitor cells (LPCs), which subsequently differentiate into hepatocytes. Following pharmacogenetic ablation of hepatocytes in Tg(fabp10a:CFP-NTR) zebrafish, resulting in severe liver injury, signal transducer and activator of transcription 3 (Stat3) and its target gene and negative regulator, socs3a, were upregulated in regenerating livers. Using either Stat3 inhibitors, JSI-124 and S3I-201, or stat3 zebrafish mutants, we investigated the role of Stat3 in LPC-driven liver regeneration. Although Stat3 suppression reduced the size of regenerating livers, BEC dedifferentiation into LPCs was unaffected. However, regenerating livers displayed a delay in LPC-to-hepatocyte differentiation and a significant reduction in the number of BECs. While no difference in cell death was detected, Stat3 inhibition significantly reduced LPC proliferation. Notably, stat3 mutants phenocopied the effects of Stat3 chemical inhibitors, although the mutant phenotype was incompletely penetrant. Intriguingly, a subset of socs3a mutants also displayed a lower number of BECs in regenerating livers. We conclude that the Stat3/Socs3a pathway is necessary for the proper timing of LPC-to-hepatocyte differentiation and establishing the proper number of BECs during LPC-driven liver regeneration.","PeriodicalId":12502,"journal":{"name":"Gene expression","volume":"18 3","pages":"157-170"},"PeriodicalIF":0.0,"publicationDate":"2018-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3727/105221618X15242506133273","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36040199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 14

Hepatocyte Wnts Are Dispensable During Diethylnitrosamine and Carbon Tetrachloride-Induced Injury and Hepatocellular Cancer. 肝细胞wnt在二乙基亚硝胺和四氯化碳诱导的损伤和肝细胞癌中是不可缺少的。

Gene expression Pub Date : 2018-08-22 Epub Date: 2018-03-08 DOI: 10.3727/105221618X15205148413587

Morgan Preziosi, Minakshi Poddar, Sucha Singh, Satdarshan P Monga

{"title":"Hepatocyte Wnts Are Dispensable During Diethylnitrosamine and Carbon Tetrachloride-Induced Injury and Hepatocellular Cancer.","authors":"Morgan Preziosi, Minakshi Poddar, Sucha Singh, Satdarshan P Monga","doi":"10.3727/105221618X15205148413587","DOIUrl":"https://doi.org/10.3727/105221618X15205148413587","url":null,"abstract":"Activation of the Wnt/β-catenin signaling is reported in large subsets of hepatocellular carcinoma (HCC). Upregulation of Wnt genes is one contributing mechanism. In the current study, we sought to address the role of hepatocyte-derived Wnts in a model of hepatic injury, fibrosis, and carcinogenesis. We subjected hepatocyte-specific Wntless knockout mice (HP-KO), unable to secrete Wnts from hepatocytes, and littermate controls (HP-CON) to diethylnitrosamine and carbon tetrachloride (DEN/CCl4) and harvested at 3, 5, and 6 months for histological and molecular analysis. Analysis at 5 months displayed increased hepatic expression of several Wnts and upregulation of some, but not all, β-catenin targets, without mutations in Ctnnb1. At 5 months, HP-CON and HP-KO had comparable tumor burden and injury; however, HP-KO uniquely showed small CK19+ foci within tumors. At 6 months, both groups were moribund with comparable tumor burden and CK19 positivity. While HCC histology was indistinguishable between the groups, HP-KO exhibited increased active β-catenin and decreased c-Myc, Brd4, E-cadherin, and others. Hepatic injury, inflammation, and fibrosis were also indistinguishable at 3 months between both groups. Thus, lack of Wnt secretion from hepatocytes did not affect overall injury, fibrosis, or HCC burden, although there were protein expression differences in the tumors occurring in the two groups.","PeriodicalId":12502,"journal":{"name":"Gene expression","volume":"18 3","pages":"209-219"},"PeriodicalIF":0.0,"publicationDate":"2018-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3727/105221618X15205148413587","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35894722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11

α7-nAChR Knockout Mice Decreases Biliary Hyperplasia and Liver Fibrosis in Cholestatic Bile Duct-Ligated Mice. α7-nAChR敲除小鼠可减少胆汁淤积性胆管结扎小鼠的胆道增生和肝纤维化。

Gene expression Pub Date : 2018-08-22 Epub Date: 2018-03-26 DOI: 10.3727/105221618X15216453076707

Laurent Ehrlich, April O'Brien, Chad Hall, Tori White, Lixian Chen, Nan Wu, Julie Venter, Marinda Scrushy, Muhammad Mubarak, Fanyin Meng, David Dostal, Chaodong Wu, Terry C Lairmore, Gianfranco Alpini, Shannon Glaser

{"title":"α7-nAChR Knockout Mice Decreases Biliary Hyperplasia and Liver Fibrosis in Cholestatic Bile Duct-Ligated Mice.","authors":"Laurent Ehrlich, April O'Brien, Chad Hall, Tori White, Lixian Chen, Nan Wu, Julie Venter, Marinda Scrushy, Muhammad Mubarak, Fanyin Meng, David Dostal, Chaodong Wu, Terry C Lairmore, Gianfranco Alpini, Shannon Glaser","doi":"10.3727/105221618X15216453076707","DOIUrl":"https://doi.org/10.3727/105221618X15216453076707","url":null,"abstract":"α7-nAChR is a nicotinic acetylcholine receptor [specifically expressed on hepatic stellate cells (HSCs), Kupffer cells, and cholangiocytes] that regulates inflammation and apoptosis in the liver. Thus, targeting α7-nAChR may be therapeutic in biliary diseases. Bile duct ligation (BDL) was performed on wild-type (WT) and α7-nAChR-/- mice. We first evaluated the expression of α7-nAChR by immunohistochemistry (IHC) in liver sections. IHC was also performed to assess intrahepatic bile duct mass (IBDM), and Sirius Red staining was performed to quantify the amount of collagen deposition. Immunofluorescence was performed to assess colocalization of α7-nAChR with bile ducts (costained with CK-19) and HSCs (costained with desmin). The mRNA expression of α7-nAChR, Ki-67/PCNA (proliferation), fibrosis genes (TGF-β1, fibronectin-1, Col1α1, and α-SMA), and inflammatory markers (IL-6, IL-1β, and TNF-α) was measured by real-time PCR. Biliary TGF-β1 and hepatic CD68 (Kupffer cell marker) expression was assessed using IHC. α7-nAChR immunoreactivity was observed in both bile ducts and HSCs and increased following BDL. α7-nAChR-/- BDL mice exhibited decreased (i) bile duct mass, liver fibrosis, and inflammation, and (ii) immunoreactivity of TGF-β1 as well as expression of fibrosis genes compared to WT BDL mice. α7-nAChR activation triggers biliary proliferation and liver fibrosis and may be a therapeutic target in managing extrahepatic biliary obstruction.","PeriodicalId":12502,"journal":{"name":"Gene expression","volume":"18 3","pages":"197-207"},"PeriodicalIF":0.0,"publicationDate":"2018-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3727/105221618X15216453076707","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35948223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Endocrine Adiponectin-FGF15/19 Axis in Ethanol-Induced Inflammation and Alcoholic Liver Injury. 内分泌脂联素- fgf15 /19轴在乙醇诱导炎症和酒精性肝损伤中的作用

Gene expression Pub Date : 2018-05-18 Epub Date: 2017-11-02 DOI: 10.3727/105221617X15093738210295

Min You, Zhou Zhou, Michael Daniels, Alvin Jogasuria

{"title":"Endocrine Adiponectin-FGF15/19 Axis in Ethanol-Induced Inflammation and Alcoholic Liver Injury.","authors":"Min You, Zhou Zhou, Michael Daniels, Alvin Jogasuria","doi":"10.3727/105221617X15093738210295","DOIUrl":"https://doi.org/10.3727/105221617X15093738210295","url":null,"abstract":"Alcoholic liver disease (ALD) is the most prevalent form of liver disease, encompassing a spectrum of progressive pathological changes from steatosis to steatohepatitis to fibrosis/cirrhosis and hepatocellular carcinoma. Alcoholic steatosis/steatohepatitis is the initial stage of ALD and a major risk factor for advanced liver injuries. Adiponectin is a hormone secreted from adipocytes. Fibroblast growth factor (FGF) 15 (human homolog, FGF19) is an ileum-derived hormone. Adipocyte-derived adiponectin and gut-derived FGF15/19 regulate each other, share common signaling cascades, and exert similar beneficial functions. Emerging evidence has revealed that dysregulated adiponectin-FGF15/19 axis and impaired hepatic adiponectin-FGF15/19 signaling are associated with alcoholic liver damage in rodents and humans. More importantly, endocrine adiponectin-FGF15/19 signaling confers protection against ethanol-induced liver damage via fine tuning the adipose-intestine-liver crosstalk, leading to limited hepatic inflammatory responses, and ameliorated alcoholic liver injury. This review is focused on the recently discovered endocrine adiponectin-FGF15/19 axis that is emerging as an essential adipose-gut-liver coordinator involved in the development and progression of alcoholic steatohepatitis.","PeriodicalId":12502,"journal":{"name":"Gene expression","volume":"18 2","pages":"103-113"},"PeriodicalIF":0.0,"publicationDate":"2018-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3727/105221617X15093738210295","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35218392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 15

The Effect of Selective c-MET Inhibitor on Hepatocellular Carcinoma in the MET-Active, β-Catenin-Mutated Mouse Model. 选择性c-MET抑制剂对met活性、β- catenin突变小鼠肝癌的影响

Gene expression Pub Date : 2018-05-18 Epub Date: 2018-02-06 DOI: 10.3727/105221618X15174108894682

Na Zhan, Adeola Adebayo Michael, Kaiyuan Wu, Gang Zeng, Aaron Bell, Junyan Tao, Satdarshan P Monga

{"title":"The Effect of Selective c-MET Inhibitor on Hepatocellular Carcinoma in the MET-Active, β-Catenin-Mutated Mouse Model.","authors":"Na Zhan, Adeola Adebayo Michael, Kaiyuan Wu, Gang Zeng, Aaron Bell, Junyan Tao, Satdarshan P Monga","doi":"10.3727/105221618X15174108894682","DOIUrl":"https://doi.org/10.3727/105221618X15174108894682","url":null,"abstract":"Simultaneous mutations in CTNNB1 and activation of c-MET occur in 9%-12.5% of patients with hepatocellular carcinoma (HCC). Coexpression of c-MET-V5 and mutant β-catenin-Myc in mouse liver by sleeping beauty transposon/transposase and hydrodynamic tail vein injection (SB-HTVI) led to the development of HCC with 70% molecular identity to the clinical subset. Using this model, we investigated the effect of EMD1214063, a highly selective c-MET inhibitor. Five weeks after SB-HTVI when tumors were established, EMD1214063 (10 mg/kg) was administered by gastric gavage as a single agent on 5-day-on/3-day-off schedule, compared to vehicle only control. Mice were harvested at 8 or 11 weeks posttreatment. Decreased p-MET, p-AKT, p-STAT3, and p-ERK proved in vivo efficacy of EMD1214063. We observed lower Ki-67, PCNA, V5-tag, and cyclin D1 after EMD1214063 treatment only at 8 weeks. Overall, no significant differences were observed in tumor burden between the groups, although EMD1214063 marginally but significantly improved overall survival by 1.5-2 weeks. Tumors remained α-fetoprotein+, did not show any differences in inflammation, and lacked fibrosis in either group. In conclusion, c-MET inhibition alone had a minor effect on Met-β-catenin HCC at the early stages of HCC development. Thus, a single therapy with the c-MET inhibitor will be insufficient for sustained response in Met-β-catenin HCC requiring assessment of additional combinations.","PeriodicalId":12502,"journal":{"name":"Gene expression","volume":"18 2","pages":"135-147"},"PeriodicalIF":0.0,"publicationDate":"2018-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3727/105221618X15174108894682","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35800626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 15

Deciphering the Spectrum of Mitochondrial DNA Mutations in Hepatocellular Carcinoma Using High-Throughput Sequencing. 利用高通量测序技术破译肝癌线粒体DNA突变谱。

Gene expression Pub Date : 2018-05-18 Epub Date: 2018-02-20 DOI: 10.3727/105221618X15185539348147

Chang Yu, Xuefeng Wang, Lifeng Huang, Ying Tong, Lili Chen, Hailong Wu, Qiang Xia, Xiaoni Kong

{"title":"Deciphering the Spectrum of Mitochondrial DNA Mutations in Hepatocellular Carcinoma Using High-Throughput Sequencing.","authors":"Chang Yu, Xuefeng Wang, Lifeng Huang, Ying Tong, Lili Chen, Hailong Wu, Qiang Xia, Xiaoni Kong","doi":"10.3727/105221618X15185539348147","DOIUrl":"https://doi.org/10.3727/105221618X15185539348147","url":null,"abstract":"Accumulation of mitochondrial DNA (mtDNA) mutations has been proposed to contribute to the initiation and progression of tumors. By using high-throughput sequencing strategies, we measured 33 specimens including 11 hepatocellular carcinoma (HCC) tissues, 11 corresponding adjacent tissues, and 11 normal liver tissues. We identified 194 single nucleotide variants (SNVs; including insert and deletion) in 33 liver tissues, and 13 somatic novel mutations were detected, including 7 mutations in the coding region. One of the seven somatic mutations (T7609C, 91.09%) is synonymous, which does not change amino acid coding; the other four somatic mutations (T6115C, 65.74%; G8387A, 12.23%; G13121A, 93.08%; and T14180C, 28.22%) could result in amino acid substitutions, potentially leading to mitochondrial dysfunction. Furthermore, two mutations in tRNA might influence amino acid transportation. Consistent with a previous study, we also found that mtDNA copy number was significantly reduced in HCC tissues. Therefore, we established a mitochondrial genome depletion cell line ρ0 and revealed that mtDNA loss reduced proliferation and migration in HCC cells but promoted their resistance to 5-fluorouracil. Our results suggested that somatic mtDNA mutations may cause mitochondrial dysfunction and affect chemoresistance of HCC cells. These new identified somatic mutations may serve as a reference for future studies of cancer mitochondrial genomes.","PeriodicalId":12502,"journal":{"name":"Gene expression","volume":"18 2","pages":"125-134"},"PeriodicalIF":0.0,"publicationDate":"2018-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3727/105221618X15185539348147","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35848500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 9