|
|
|
题名
|
作者
|
年代
|
出处
|
被引量
|
| 1 | Osteopontin increases hepatocellular carcinoma cell growth in a CD44 dependant manner显示文摘AIM:To investigate the role of osteopontin(OPN) and its splice variants in the proliferation of hepatocellular carcinoma(HCC).METHODS:The expression of OPN variants in HCC cell lines as well as HCC tissue samples and nontumour tissue was studied using polymerase chain reaction.OPN variant cDNAs were cloned into a mammalian expression vector allowing both transient expression and the production of stable OPN expressing cell lines.OPN expression was studied in these cells using Western blotting,immunofluoresnce and enzyme linked immunosorbent assay.A CD44 blocking antibody and siRNA targeting of CD44 were used to examine the role of this receptor in the OPN stimulated cell growth observed in culture.Huh-7 cells stably expressing either OPN-A,-B or-C were injected subcutaneously into the flanks of nude mice to observe in vivo tumour growth.Expression of OPN mRNA and protein in these tumours was examined using reverse transcriptionpolymerase chain reaction and immunohistochemistry.RESULTS:OPN is expressed in HCC in 3 forms,the full length OPN-A and 2 splice variants OPN-B and-C.OPN variant expression was noted in HCC tissue as well as cognate surrounding cirrhotic liver tissue.Expression of these OPN variants in the HCC derived cell line Huh-7 resulted in secretion of OPN into the culture medium.Transfer of OPN conditioned media to na ve Huh-7 and HepG2 cells resulted in significant cell growth suggesting that all OPN variants can modulate cell proliferation in a paracrine manner.Furthermore the OPN mediated increase in cellular proliferation was dependent on CD44 as only CD44 positive cell lines responded to OPN conditioned media while siRNA knockdown of CD44 blocked the proliferative effect.OPN expression also increased the proliferation of Huh-7 cells in a subcutaneous nude mouse tumour model,with Huh-7 cells expressing OPN-A showing the greatest proliferative effect.CONCLUSION:This study demonstrates that OPN plays a significant role in the proliferation of HCC through interaction with the cell surface receptor CD44.Modulation of this interaction could represent a novel strategy for the control of HCC. | Renee J Phillips Karla J Helbig Kylie H Van der Hoek Devanshi Seth Michael R Beard | 2012 | World Journal of Gastroenterology2012，18，26： | 12 |
| 2 | Osteopontin is an important mediator of alcoholic liver disease via hepatic stellate cell activation显示文摘AIM: To investigate over-expression of Osteopontin(OPN) pathway expression and mechanisms of action in human alcoholic liver disease(ALD), in vivo and in vitro acute alcohol models. METHODS: OPN pathway was evaluated in livers from patients with progressive stages of human ALD and serum from drinkers with and without liver cirrhosis. In vitro stellate LX2 cells exposed to acute alcohol and in vivo in acute alcoholic steatosis mouse models were also investigated for OPN pathway expression and function. WT and OPN-/- mice were administered an acute dose of alcohol and extent of liver injury was examined by histopathology and liver biochemistry after 16-24 h. The causative role of OPN was studied in OPN knockout animals and in vitro in stellate LX2 cells, utilizing siRNA, aptamer and neutralizing antibodies to block OPN and OPN pathway. OPN pathway expression and downstream functional consequences were measured for signaling by Western blotting, plasmin activation by spectrophotometric assays and cell migration by confocal imaging and quantitation. RESULTS: OPN expression positively correlated with disease severity in patients with progressive stages of ALD. In vivo, associated with alcoholic steatosis, a single dose of acute alcohol significantly increased hepatic OPN mRNA and protein, and a cleaved OPN form in a dose dependent manner. OPN mRNA and secreted OPN also increased in parallel with activation of LX2 stellate cells within 4 h of a single dose of alcohol. Expression of OPN receptors, αvβ3-integrin and CD44, increased in human ALD, and in vivo and in vitro with alcohol administration. This was accompanied by downstream phosphorylation of Akt and Erk, increased mRNA expression of several fibrogenesis, fibrinolysis and extracellular matrix pathway genes, plasmin activation and hepatic stellate cell(HSC) migration. Inhibition of OPN and OPN-receptor mediated signaling partially inhibited alcohol-induced HSC activation, plasmin activity and cell migration. CONCLUSION: OPN is a key mediator of the alcoholinduced effects on hepatic stellate cell functions and liver fibrogenesis. | Devanshi Seth Alastair Duly Paul C Kuo Geoffrey W McCaughan Paul S Haber | 2014 | World Journal of Gastroenterology2014，20，36： | 5 |
| 3 | Direct effeels of alcohol on hepatic fihrinolytie balance:lmpliealions for alcoholie liver disease显示文摘 | Devanshi Seth Philip J ttogg Mark D Gorrell el al | 2008 | Hepatology2008，48，： | 1 |
| 4 | Direct effects of alcohol on hepatic fibrinolytic balance: Implications for alcoholic liver disease显示文摘 | Devanshi Seth Philip J. Hogg Mark D. Gorrell Geoffrey W. McCaughan Paul S. Haber | 2008 | Journal of Hepatology2008，，4： | 1 |
| 5 | Intrahepatic gene expression in human alcoholic hepatitis显示文摘 | Devanshi Seth Mark D. Gorrell Shaun Cordoba Geoffrey W. McCaughan Paul S. Haber | 2006 | Journal of Hepatology2006，，2： | 1 |
| 6 | Gene Expression Profiling of Alcoholic Liver Disease in the Baboon ( Papio hamadryas ) and Human Liver显示文摘 | Devanshi Seth Maria A. Leo Peter H. McGuinness Charles S. Lieber Yvonne Brennan Rohan Williams Xin M. Wang Geoffrey W. McCaughan Mark D. Gorrell Paul S. Haber | 2003 | The American Journal of Pathology2003，，6： | 1 |
| 7 | Alcoholic and non-alcoholic steatohepatitis显示文摘 | Manuela G. Neuman Samuel W. French Barbara A. French Helmut K. Seitz Lawrence E. Cohen Sebastian Mueller Natalia A. Osna Kusum K. Kharbanda Devanshi Seth Abraham Bautista Kyle J. Thompson Iain H. McKillop Irina A. Kirpich Craig J. McClain Ramon Bataller R | 2014 | Experimental and Molecular Pathology2014，，： | 1 |
| 8 | Genetics of alcohol-related hepatocellular carcinoma - its role in risk prediction显示文摘Hepatocellular carcinoma(HCC)is the most common primary liver malignancy,with increasing incidence worldwide.Alcohol-related cirrhosis(AC)accounts for 30%of the global incidence of HCC and HCC-related deaths.With the decline of hepatitis C virus(HCV)and decreasing HCV-related HCC,AC will soon become the leading cause of HCC.Excess alcohol consumption(>80 g per day for>10 years)increases the risk of HCC by 5-fold.However,only up to 35%of excessive drinkers develop cirrhosis and its associated HCC risk.Individual variation in susceptibility to HCC is known,but there is limited information to predict who among the patients is at high risk of progressing to HCC.Clinical risk factors for HCC include male gender,older age,severity of cirrhosis,obesity and presence of type 2 diabetes.In addition to ethnic variability in HCC risk,genetic variants are known to alter the risk of alcohol-related HCC.For example,single nucleotide polymorphisms in PNPLA3(rs738409,C>G)and TM6SF2(rs58542926,C>T)increase the risk of AC-related HCC,whereas HSD17B13(T>A)reduces the risk for HCC.Studies have also confirmed PNPLA3 and TM6SF2 to be independent risk factors for AC-related(but not HCV-related)HCC.Combining genetic risk factors with phenotypic/clinical risk factors has been explored for stratification of patients for HCC development.Risk allele rs378409-G in PNPLA3 when combined with phenotypic/clinical risk factors(BMI,age,sex)has enabled HCC risk stratification of AC patients into low-,intermediate-and high-risk subgroups.Similarly,a combination of the two genetic variants PNPLA3-G and TM6SF2-T has been independently associated with risk of HCC onset.Using a polygenic risk score approach of incorporating several genetic variants,prognostic performance of polygenic risk score that included PNPLA3 rs378409 and TM6SF2 rs58542926 improved HCC prediction better than with either variant alone.Incorporating new variants and risk factors has the potential to build better algorithms/models to predict onset,early diagnosis and treatments for AC-related HCC.However,clinical usefulness of these approaches is yet to be determined. | Ken Liu Gontran Verset Eric Trepo Devanshi Seth | 2020 | Hepatoma Research2020，6，7： | 0 |
您所在的机构暂未开通此部分的功能，请联系管理员