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Correlation of alpha-fetoprotein expression in normal hepatocytes during development with tyrosine phosphorylation and insulin receptor expression.

ABSTRACT: The molecular mechanism of hepatic cell growth and differentiation is ill defined. In the present study, we examined the putative role of tyrosine phosphorylation in normal rat liver development and in an in vitro model, the alpha-fetoprotein-producing (AFP+) and AFP-nonproducing (AFP-) clones of the McA-RH 7777 rat hepatoma. We demonstrated in vivo and in vitro that the AFP+ phenotype is clearly associated with enhanced tyrosine phosphorylation, as assessed by immunoblotting and flow cytometry. Moreover, immunoprecipitation of proteins with anti-phosphotyrosine antibody showed that normal fetal hepatocytes expressed the same phosphorylation pattern as stable AFP+ clones and likewise for adult hepatocytes and AFP- clones. The tyrosine phosphorylation of several proteins, including the beta-subunit of the insulin receptor, insulin receptor substrate-1, p85 regulatory subunit of phosphatidylinositol-3-kinase, and ras-guanosine triphosphatase-activating protein, was observed in AFP+ clones, whereas the same proteins were not phosphorylated in AFP- clones. We also observed that fetal hepatocytes and the AFP+ clones express 4 times more of the insulin receptor beta-subunit compared with adult hepatocytes and AFP- clones and, accordingly, that these AFP+ clones were more responsive to exogenous insulin in terms of protein tyrosine phosphorylation. Finally, growth rate in cells of AFP+ clones was higher than that measured in cells of AFP- clones, and inhibition of phosphatidylinositol-3-kinase by LY294002 and Wortmannin blocked insulin- and serum-stimulated DNA synthesis only in cells of AFP+ clones. These studies provide evidences in support of the hypothesis that signaling via insulin prevents hepatocyte differentiation by promoting fetal hepatocyte growth.

SUBMITTER: Khamzina L

PROVIDER: S-EPMC25332 | biostudies-literature | 1998 May

REPOSITORIES: biostudies-literature

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Correlation of alpha-fetoprotein expression in normal hepatocytes during development with tyrosine phosphorylation and insulin receptor expression.

Khamzina L L Borgeat P P

Molecular biology of the cell 19980501 5

The molecular mechanism of hepatic cell growth and differentiation is ill defined. In the present study, we examined the putative role of tyrosine phosphorylation in normal rat liver development and in an in vitro model, the alpha-fetoprotein-producing (AFP+) and AFP-nonproducing (AFP-) clones of the McA-RH 7777 rat hepatoma. We demonstrated in vivo and in vitro that the AFP+ phenotype is clearly associated with enhanced tyrosine phosphorylation, as assessed by immunoblotting and flow cytometry. ...[more]

PMID: 9571242

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Project description:INTRODUCTION:serum alpha-fetoprotein (AFP) was routinely employed as a tumor marker for screening, diagnosis, and treatment follow-up of hepatocellular carcinoma (HCC). However, a substantial proportion of HCC patients had normal AFP level even at an advanced disease status. Few studies to date had tried to explore the nature and behavior of this normal AFP HCC (N-HCC). The purpose of this study was to investigate the clinicopathological characteristics and survival outcome of N-HCC after operation. In addition, potential tumor markers for N-HCC were also sought in an attempt to augment diagnostic ability. METHODS:between 2005 and 2015, patients with hepatocellular carcinoma who were treated with hepatectomy in Chang Gung Memorial Hospital Linkou branch were divided into two groups according to their preoperative serum AFP level (<15 ng/mL: NHCC; ?15 ng/mL: abnormal AFP HCC (A-HCC)). Patient demographic data and clinicopathological variables were collected. Kaplan-Meier and Cox regression multivariate analyses were performed to identify significant risk factors for disease-free survival (DFS) and overall survival (OS) for N-HCC. ELISA and immunohistochemical (IHC) studies were employed to determine the diagnostic accuracy of various tumor markers. RESULTS:a total of 1616 patients (78% male) who underwent liver resection for HCC were included in this study. Of them, 761 patients (47.1%) were N-HCC. N-HCC patients were significantly older with more comorbidities and less hepatitis virus infections. Furthermore, N-HCC had fewer early recurrences (49.6% vs. 60.8%, p < 0.001) and better DFS (44.6 months vs. 23.6 months, p < 0.001) and OS (94.5 months vs. 81.7 months, p < 0.001). Both ELISA and IHC studies demonstrated that glypican-3 (GPC3) would be a promising diagnostic tumor marker for N-HCC. CONCLUSION:N-HCC patients were significantly older and had less hepatitis virus infections or cirrhosis. Their tumors tended to be smaller, less vascular invaded, and well-differentiated. The carcinogenesis of N-HCC may thus not be identical to that of typical HCC. GPC3 would be a promising tumor marker for diagnosing N-HCC. Further study is warranted to validate our findings.

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Correlation of alpha-fetoprotein expression in normal hepatocytes during development with tyrosine phosphorylation and insulin receptor expression.

Publications

Correlation of alpha-fetoprotein expression in normal hepatocytes during development with tyrosine phosphorylation and insulin receptor expression.

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