SerpinB3 induces dipeptidyl-peptidase IV/CD26 expression and its metabolic effects in hepatocellular carcinoma

Silvano Fasolato; Elisabetta Trevellin; Mariagrazia Ruvoletto; Marnie Granzotto; Giacomo Zanus; Elisa Boscaro; Enrico Babetto; Liliana Terrin; Maria Alberta Battocchio; Francesco Ciscato; Cristian Turato; Santina Quarta; Umberto Cillo; Patrizia Pontisso; Roberto Vettor

doi:10.1016/j.lfs.2018.03.014

SerpinB3 induces dipeptidyl-peptidase IV/CD26 expression and its metabolic effects in hepatocellular carcinoma

Silvano Fasolato, Elisabetta Trevellin, Mariagrazia Ruvoletto, Marnie Granzotto, Giacomo Zanus, Elisa Boscaro, Enrico Babetto, Liliana Terrin, Maria Alberta Battocchio, Francesco Ciscato, Cristian Turato, Santina Quarta, Umberto Cillo, Patrizia Pontisso, Roberto Vettor

Istituto Oncologico Veneto

Research output: Contribution to journal › Article › peer-review

Abstract

AIMS: In hepatocellular carcinoma (HCC), the regulatory protease Dipeptidyl-peptidase IV (DPPIV/CD26), that possesses pro-apoptotic properties, has been found abnormally regulated. The protease inhibitor SerpinB3, exerting anti-apoptotic activity, has also been described to be upregulated, especially in HCCs with poor prognosis. The aim of this study was to investigate the possible relationship between these two molecules in HCC patients and in experimental models.

MATERIALS AND METHODS: DPPIV/CD26 and SerpinB3 expression was measured in liver specimens of 67 patients with HCC. HepG2 and Huh7 cells, stably transfected to overexpress SerpinB3, and respective control cells were used to assess biological and metabolic modifications of DPPIV/CD26 activity induced by this serpin.

KEY FINDINGS: DPPIV/CD26 and SerpinB3 were localized in the same tumoral areas and both molecules were correlated with the grade of tumor differentiation, with the highest values detected in GI tumors. Cell lines over-expressing SerpinB3 displayed upregulation of DPPIV/CD26, likely as a feedback mechanism, due to the DPPIV/CD26 protease activity inhibition by SerpinB3, as confirmed by the similar behavior induced by the inhibitor Sitagliptin. Moreover, they exhibited lower glycogen storage and higher lipid accumulation, typical effects of DPPIV/CD26.

SIGNIFICANCE: A close connection between SerpinB3 and DPPPIV has been identified, but further studies are required to better understand the mechanism by which these proteins communicate and exert metabolic effects in HCC.

Original language	English
Pages (from-to)	134-141
Number of pages	8
Journal	Life Sciences
Volume	200
DOIs	https://doi.org/10.1016/j.lfs.2018.03.014
Publication status	Published - May 1 2018

Keywords

Aged
Antigens, Neoplasm/metabolism
Carcinoma, Hepatocellular/metabolism
Dipeptidyl Peptidase 4/biosynthesis
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Glycogen/metabolism
Hep G2 Cells
Humans
Lipid Metabolism/drug effects
Liver Neoplasms/metabolism
Male
Middle Aged
Neoplasm Proteins/metabolism
Serpins/metabolism
Sitagliptin Phosphate/pharmacology

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10.1016/j.lfs.2018.03.014

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Fasolato, S., Trevellin, E., Ruvoletto, M., Granzotto, M., Zanus, G., Boscaro, E., Babetto, E., Terrin, L., Battocchio, M. A., Ciscato, F., Turato, C., Quarta, S., Cillo, U., Pontisso, P., & Vettor, R. (2018). SerpinB3 induces dipeptidyl-peptidase IV/CD26 expression and its metabolic effects in hepatocellular carcinoma. Life Sciences, 200, 134-141. https://doi.org/10.1016/j.lfs.2018.03.014

Fasolato, S, Trevellin, E, Ruvoletto, M, Granzotto, M, Zanus, G, Boscaro, E, Babetto, E, Terrin, L, Battocchio, MA, Ciscato, F, Turato, C, Quarta, S, Cillo, U, Pontisso, P & Vettor, R 2018, 'SerpinB3 induces dipeptidyl-peptidase IV/CD26 expression and its metabolic effects in hepatocellular carcinoma', Life Sciences, vol. 200, pp. 134-141. https://doi.org/10.1016/j.lfs.2018.03.014

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title = "SerpinB3 induces dipeptidyl-peptidase IV/CD26 expression and its metabolic effects in hepatocellular carcinoma",

abstract = "AIMS: In hepatocellular carcinoma (HCC), the regulatory protease Dipeptidyl-peptidase IV (DPPIV/CD26), that possesses pro-apoptotic properties, has been found abnormally regulated. The protease inhibitor SerpinB3, exerting anti-apoptotic activity, has also been described to be upregulated, especially in HCCs with poor prognosis. The aim of this study was to investigate the possible relationship between these two molecules in HCC patients and in experimental models.MATERIALS AND METHODS: DPPIV/CD26 and SerpinB3 expression was measured in liver specimens of 67 patients with HCC. HepG2 and Huh7 cells, stably transfected to overexpress SerpinB3, and respective control cells were used to assess biological and metabolic modifications of DPPIV/CD26 activity induced by this serpin.KEY FINDINGS: DPPIV/CD26 and SerpinB3 were localized in the same tumoral areas and both molecules were correlated with the grade of tumor differentiation, with the highest values detected in GI tumors. Cell lines over-expressing SerpinB3 displayed upregulation of DPPIV/CD26, likely as a feedback mechanism, due to the DPPIV/CD26 protease activity inhibition by SerpinB3, as confirmed by the similar behavior induced by the inhibitor Sitagliptin. Moreover, they exhibited lower glycogen storage and higher lipid accumulation, typical effects of DPPIV/CD26.SIGNIFICANCE: A close connection between SerpinB3 and DPPPIV has been identified, but further studies are required to better understand the mechanism by which these proteins communicate and exert metabolic effects in HCC.",

keywords = "Aged, Antigens, Neoplasm/metabolism, Carcinoma, Hepatocellular/metabolism, Dipeptidyl Peptidase 4/biosynthesis, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Glycogen/metabolism, Hep G2 Cells, Humans, Lipid Metabolism/drug effects, Liver Neoplasms/metabolism, Male, Middle Aged, Neoplasm Proteins/metabolism, Serpins/metabolism, Sitagliptin Phosphate/pharmacology",

author = "Silvano Fasolato and Elisabetta Trevellin and Mariagrazia Ruvoletto and Marnie Granzotto and Giacomo Zanus and Elisa Boscaro and Enrico Babetto and Liliana Terrin and Battocchio, {Maria Alberta} and Francesco Ciscato and Cristian Turato and Santina Quarta and Umberto Cillo and Patrizia Pontisso and Roberto Vettor",

year = "2018",

month = may,

day = "1",

doi = "10.1016/j.lfs.2018.03.014",

language = "English",

volume = "200",

pages = "134--141",

journal = "Life Sciences",

issn = "0024-3205",

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TY - JOUR

T1 - SerpinB3 induces dipeptidyl-peptidase IV/CD26 expression and its metabolic effects in hepatocellular carcinoma

AU - Fasolato, Silvano

AU - Trevellin, Elisabetta

AU - Ruvoletto, Mariagrazia

AU - Granzotto, Marnie

AU - Zanus, Giacomo

AU - Boscaro, Elisa

AU - Babetto, Enrico

AU - Terrin, Liliana

AU - Battocchio, Maria Alberta

AU - Ciscato, Francesco

AU - Turato, Cristian

AU - Quarta, Santina

AU - Cillo, Umberto

AU - Pontisso, Patrizia

AU - Vettor, Roberto

PY - 2018/5/1

Y1 - 2018/5/1

N2 - AIMS: In hepatocellular carcinoma (HCC), the regulatory protease Dipeptidyl-peptidase IV (DPPIV/CD26), that possesses pro-apoptotic properties, has been found abnormally regulated. The protease inhibitor SerpinB3, exerting anti-apoptotic activity, has also been described to be upregulated, especially in HCCs with poor prognosis. The aim of this study was to investigate the possible relationship between these two molecules in HCC patients and in experimental models.MATERIALS AND METHODS: DPPIV/CD26 and SerpinB3 expression was measured in liver specimens of 67 patients with HCC. HepG2 and Huh7 cells, stably transfected to overexpress SerpinB3, and respective control cells were used to assess biological and metabolic modifications of DPPIV/CD26 activity induced by this serpin.KEY FINDINGS: DPPIV/CD26 and SerpinB3 were localized in the same tumoral areas and both molecules were correlated with the grade of tumor differentiation, with the highest values detected in GI tumors. Cell lines over-expressing SerpinB3 displayed upregulation of DPPIV/CD26, likely as a feedback mechanism, due to the DPPIV/CD26 protease activity inhibition by SerpinB3, as confirmed by the similar behavior induced by the inhibitor Sitagliptin. Moreover, they exhibited lower glycogen storage and higher lipid accumulation, typical effects of DPPIV/CD26.SIGNIFICANCE: A close connection between SerpinB3 and DPPPIV has been identified, but further studies are required to better understand the mechanism by which these proteins communicate and exert metabolic effects in HCC.

AB - AIMS: In hepatocellular carcinoma (HCC), the regulatory protease Dipeptidyl-peptidase IV (DPPIV/CD26), that possesses pro-apoptotic properties, has been found abnormally regulated. The protease inhibitor SerpinB3, exerting anti-apoptotic activity, has also been described to be upregulated, especially in HCCs with poor prognosis. The aim of this study was to investigate the possible relationship between these two molecules in HCC patients and in experimental models.MATERIALS AND METHODS: DPPIV/CD26 and SerpinB3 expression was measured in liver specimens of 67 patients with HCC. HepG2 and Huh7 cells, stably transfected to overexpress SerpinB3, and respective control cells were used to assess biological and metabolic modifications of DPPIV/CD26 activity induced by this serpin.KEY FINDINGS: DPPIV/CD26 and SerpinB3 were localized in the same tumoral areas and both molecules were correlated with the grade of tumor differentiation, with the highest values detected in GI tumors. Cell lines over-expressing SerpinB3 displayed upregulation of DPPIV/CD26, likely as a feedback mechanism, due to the DPPIV/CD26 protease activity inhibition by SerpinB3, as confirmed by the similar behavior induced by the inhibitor Sitagliptin. Moreover, they exhibited lower glycogen storage and higher lipid accumulation, typical effects of DPPIV/CD26.SIGNIFICANCE: A close connection between SerpinB3 and DPPPIV has been identified, but further studies are required to better understand the mechanism by which these proteins communicate and exert metabolic effects in HCC.

KW - Aged

KW - Antigens, Neoplasm/metabolism

KW - Carcinoma, Hepatocellular/metabolism

KW - Dipeptidyl Peptidase 4/biosynthesis

KW - Female

KW - Gene Expression Regulation, Enzymologic

KW - Gene Expression Regulation, Neoplastic

KW - Glycogen/metabolism

KW - Hep G2 Cells

KW - Humans

KW - Lipid Metabolism/drug effects

KW - Liver Neoplasms/metabolism

KW - Male

KW - Middle Aged

KW - Neoplasm Proteins/metabolism

KW - Serpins/metabolism

KW - Sitagliptin Phosphate/pharmacology

U2 - 10.1016/j.lfs.2018.03.014

DO - 10.1016/j.lfs.2018.03.014

M3 - Article

C2 - 29524519

VL - 200

SP - 134

EP - 141

JO - Life Sciences

JF - Life Sciences

SN - 0024-3205

ER -

SerpinB3 induces dipeptidyl-peptidase IV/CD26 expression and its metabolic effects in hepatocellular carcinoma

Abstract

Keywords

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