Lack of galectin-1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model

Tamara Potikha; Orit Pappo; Lina Mizrahi; Devorah Olam; Sebastián M. Maller; Gabriel A. Rabinovich; Eithan Galun; Daniel S. Goldenberg

doi:10.1096/fj.201900017R

Lack of galectin-1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model

Tamara Potikha, Orit Pappo, Lina Mizrahi, Devorah Olam, Sebastián M. Maller, Gabriel A. Rabinovich, Eithan Galun, Daniel S. Goldenberg^*

^*Corresponding author for this work

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

16 Scopus citations

Abstract

Chronic liver inflammation (CLI) is a risk factor for development of hepatocellular carcinoma (HCC). Galectin-1 (Gal1) is involved in the regulation of inflammation, angiogenesis, and tumorigenesis, exhibiting multiple anti-inflammatory and protumorigenic activities. We aimed to explore its regulatory role in CLI and HCC progression using an established model of CLI-mediated HCC development, Abcb4 [multidrug-resistance 2 (Mdr2)]-knockout (KO) mice, which express high levels of Gal1 in the liver. We generated double-KO (dKO) Gal1-KO/Mdr2-KO mice on C57BL/6 and FVB/N genetic backgrounds and compared HCC development in the generated strains with their parental Mdr2-KO strains. Loss of Gal1 increased liver injury, inflammation, fibrosis, and ductular reaction in dKO mice of both strains starting from an early age. Aged dKO mutants displayed earlier hepatocarcinogenesis and increased tumor size compared with control Mdr2-KO mice. We found that osteopontin, a well-known modulator of HCC development, and oncogenic proteins Ntrk2 (TrkB) and S100A4 were overexpressed in dKO compared with Mdr2-KO livers. Our results demonstrate that in Mdr2-KO mice, a model of CLI-mediated HCC, Gal1-mediated protection from hepatitis, liver fibrosis, and HCC initiation dominates over its known procarcinogenic activities at later stages of HCC development. These findings suggest that anti-Gal1 treatments may not be applicable at all stages of CLI-mediated HCC.—Potikha, T., Pappo, O., Mizrahi, L., Olam, D., Mailer, S. M., Rabinovich, G. A., Galun, E., Goldenberg, D. S. Lack of galectin-1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model. FASEB J. 33, 7995–8007 (2019). www.fasebj.org.

Original language	American English
Pages (from-to)	7995-8007
Number of pages	13
Journal	FASEB Journal
Volume	33
Issue number	7
DOIs	https://doi.org/10.1096/fj.201900017R
State	Published - 1 Jul 2019
Externally published	Yes

Bibliographical note

Funding Information:
The authors thank J. P. Cerliani [Argentinean National Research Council (CONICET)] for advice, and Marion Richardson (Hadassah-Hebrew University Medical Center) for assistance in manuscript preparation. T.P. and D.S.G. were supported by the Kamea Scientific Foundation of the Israeli Government. Work in G.A.R.'s laboratory was supported by grants from Agencia Nacional de Promoción Científica y Tecnológica (PICT 2014-3087), Fundación Sales, Fundación Bunge & Born and the Kenneth Rainin Foundation. The work of E.G. was supported by U.S. National Institutes of Health, National Cancer Institute Grant CA197081-02, the Ministry Of Science and Technology (MOST), the Israeli Science Foundation (ISF) collaboration with Canada (2473/2017), the personal ISF (486/2017), the Israeli Centers Of Research Excellence (ICORE)–ISF (41/2011), and by the Kron, Raskin, and Benson foundations. This work was also supported by the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB841, Project C3). The authors declare no conflicts of interest.

Publisher Copyright:
© FASEB

Keywords

HCC
Mdr2
Ntrk2
S100a4
Spp1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1096/fj.201900017R

Cite this

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title = "Lack of galectin-1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model",

abstract = "Chronic liver inflammation (CLI) is a risk factor for development of hepatocellular carcinoma (HCC). Galectin-1 (Gal1) is involved in the regulation of inflammation, angiogenesis, and tumorigenesis, exhibiting multiple anti-inflammatory and protumorigenic activities. We aimed to explore its regulatory role in CLI and HCC progression using an established model of CLI-mediated HCC development, Abcb4 [multidrug-resistance 2 (Mdr2)]-knockout (KO) mice, which express high levels of Gal1 in the liver. We generated double-KO (dKO) Gal1-KO/Mdr2-KO mice on C57BL/6 and FVB/N genetic backgrounds and compared HCC development in the generated strains with their parental Mdr2-KO strains. Loss of Gal1 increased liver injury, inflammation, fibrosis, and ductular reaction in dKO mice of both strains starting from an early age. Aged dKO mutants displayed earlier hepatocarcinogenesis and increased tumor size compared with control Mdr2-KO mice. We found that osteopontin, a well-known modulator of HCC development, and oncogenic proteins Ntrk2 (TrkB) and S100A4 were overexpressed in dKO compared with Mdr2-KO livers. Our results demonstrate that in Mdr2-KO mice, a model of CLI-mediated HCC, Gal1-mediated protection from hepatitis, liver fibrosis, and HCC initiation dominates over its known procarcinogenic activities at later stages of HCC development. These findings suggest that anti-Gal1 treatments may not be applicable at all stages of CLI-mediated HCC.—Potikha, T., Pappo, O., Mizrahi, L., Olam, D., Mailer, S. M., Rabinovich, G. A., Galun, E., Goldenberg, D. S. Lack of galectin-1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model. FASEB J. 33, 7995–8007 (2019). www.fasebj.org.",

keywords = "HCC, Mdr2, Ntrk2, S100a4, Spp1",

author = "Tamara Potikha and Orit Pappo and Lina Mizrahi and Devorah Olam and Maller, {Sebasti{\'a}n M.} and Rabinovich, {Gabriel A.} and Eithan Galun and Goldenberg, {Daniel S.}",

note = "Funding Information: The authors thank J. P. Cerliani [Argentinean National Research Council (CONICET)] for advice, and Marion Richardson (Hadassah-Hebrew University Medical Center) for assistance in manuscript preparation. T.P. and D.S.G. were supported by the Kamea Scientific Foundation of the Israeli Government. Work in G.A.R.'s laboratory was supported by grants from Agencia Nacional de Promoci{\'o}n Cient{\'i}fica y Tecnol{\'o}gica (PICT 2014-3087), Fundaci{\'o}n Sales, Fundaci{\'o}n Bunge & Born and the Kenneth Rainin Foundation. The work of E.G. was supported by U.S. National Institutes of Health, National Cancer Institute Grant CA197081-02, the Ministry Of Science and Technology (MOST), the Israeli Science Foundation (ISF) collaboration with Canada (2473/2017), the personal ISF (486/2017), the Israeli Centers Of Research Excellence (ICORE)–ISF (41/2011), and by the Kron, Raskin, and Benson foundations. This work was also supported by the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB841, Project C3). The authors declare no conflicts of interest. Publisher Copyright: {\textcopyright} FASEB",

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doi = "10.1096/fj.201900017R",

language = "American English",

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T1 - Lack of galectin-1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model

AU - Potikha, Tamara

AU - Pappo, Orit

AU - Mizrahi, Lina

AU - Olam, Devorah

AU - Maller, Sebastián M.

AU - Rabinovich, Gabriel A.

AU - Galun, Eithan

AU - Goldenberg, Daniel S.

N1 - Funding Information: The authors thank J. P. Cerliani [Argentinean National Research Council (CONICET)] for advice, and Marion Richardson (Hadassah-Hebrew University Medical Center) for assistance in manuscript preparation. T.P. and D.S.G. were supported by the Kamea Scientific Foundation of the Israeli Government. Work in G.A.R.'s laboratory was supported by grants from Agencia Nacional de Promoción Científica y Tecnológica (PICT 2014-3087), Fundación Sales, Fundación Bunge & Born and the Kenneth Rainin Foundation. The work of E.G. was supported by U.S. National Institutes of Health, National Cancer Institute Grant CA197081-02, the Ministry Of Science and Technology (MOST), the Israeli Science Foundation (ISF) collaboration with Canada (2473/2017), the personal ISF (486/2017), the Israeli Centers Of Research Excellence (ICORE)–ISF (41/2011), and by the Kron, Raskin, and Benson foundations. This work was also supported by the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB841, Project C3). The authors declare no conflicts of interest. Publisher Copyright: © FASEB

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Chronic liver inflammation (CLI) is a risk factor for development of hepatocellular carcinoma (HCC). Galectin-1 (Gal1) is involved in the regulation of inflammation, angiogenesis, and tumorigenesis, exhibiting multiple anti-inflammatory and protumorigenic activities. We aimed to explore its regulatory role in CLI and HCC progression using an established model of CLI-mediated HCC development, Abcb4 [multidrug-resistance 2 (Mdr2)]-knockout (KO) mice, which express high levels of Gal1 in the liver. We generated double-KO (dKO) Gal1-KO/Mdr2-KO mice on C57BL/6 and FVB/N genetic backgrounds and compared HCC development in the generated strains with their parental Mdr2-KO strains. Loss of Gal1 increased liver injury, inflammation, fibrosis, and ductular reaction in dKO mice of both strains starting from an early age. Aged dKO mutants displayed earlier hepatocarcinogenesis and increased tumor size compared with control Mdr2-KO mice. We found that osteopontin, a well-known modulator of HCC development, and oncogenic proteins Ntrk2 (TrkB) and S100A4 were overexpressed in dKO compared with Mdr2-KO livers. Our results demonstrate that in Mdr2-KO mice, a model of CLI-mediated HCC, Gal1-mediated protection from hepatitis, liver fibrosis, and HCC initiation dominates over its known procarcinogenic activities at later stages of HCC development. These findings suggest that anti-Gal1 treatments may not be applicable at all stages of CLI-mediated HCC.—Potikha, T., Pappo, O., Mizrahi, L., Olam, D., Mailer, S. M., Rabinovich, G. A., Galun, E., Goldenberg, D. S. Lack of galectin-1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model. FASEB J. 33, 7995–8007 (2019). www.fasebj.org.

AB - Chronic liver inflammation (CLI) is a risk factor for development of hepatocellular carcinoma (HCC). Galectin-1 (Gal1) is involved in the regulation of inflammation, angiogenesis, and tumorigenesis, exhibiting multiple anti-inflammatory and protumorigenic activities. We aimed to explore its regulatory role in CLI and HCC progression using an established model of CLI-mediated HCC development, Abcb4 [multidrug-resistance 2 (Mdr2)]-knockout (KO) mice, which express high levels of Gal1 in the liver. We generated double-KO (dKO) Gal1-KO/Mdr2-KO mice on C57BL/6 and FVB/N genetic backgrounds and compared HCC development in the generated strains with their parental Mdr2-KO strains. Loss of Gal1 increased liver injury, inflammation, fibrosis, and ductular reaction in dKO mice of both strains starting from an early age. Aged dKO mutants displayed earlier hepatocarcinogenesis and increased tumor size compared with control Mdr2-KO mice. We found that osteopontin, a well-known modulator of HCC development, and oncogenic proteins Ntrk2 (TrkB) and S100A4 were overexpressed in dKO compared with Mdr2-KO livers. Our results demonstrate that in Mdr2-KO mice, a model of CLI-mediated HCC, Gal1-mediated protection from hepatitis, liver fibrosis, and HCC initiation dominates over its known procarcinogenic activities at later stages of HCC development. These findings suggest that anti-Gal1 treatments may not be applicable at all stages of CLI-mediated HCC.—Potikha, T., Pappo, O., Mizrahi, L., Olam, D., Mailer, S. M., Rabinovich, G. A., Galun, E., Goldenberg, D. S. Lack of galectin-1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model. FASEB J. 33, 7995–8007 (2019). www.fasebj.org.

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KW - Ntrk2

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DO - 10.1096/fj.201900017R

M3 - Article

C2 - 30897344

AN - SCOPUS:85069235480

SN - 0892-6638

VL - 33

SP - 7995

EP - 8007

JO - FASEB Journal

JF - FASEB Journal

IS - 7

ER -

Lack of galectin-1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model

Abstract

Bibliographical note

Keywords

UN SDGs

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