The pro-oncogenic effect of the lncRNA H19 in the development of chronic inflammation-mediated hepatocellular carcinoma

Lika Gamaev; Lina Mizrahi; Tomer Friehmann; Nofar Rosenberg; Orit Pappo; Devorah Olam; Evelyne Zeira; Keren Bahar Halpern; Stefano Caruso; Jessica Zucman-Rossi; Jonathan H. Axelrod; Eithan Galun; Daniel S. Goldenberg

doi:10.1038/s41388-020-01513-7

The pro-oncogenic effect of the lncRNA H19 in the development of chronic inflammation-mediated hepatocellular carcinoma

Lika Gamaev, Lina Mizrahi, Tomer Friehmann, Nofar Rosenberg, Orit Pappo, Devorah Olam, Evelyne Zeira, Keren Bahar Halpern, Stefano Caruso, Jessica Zucman-Rossi, Jonathan H. Axelrod, Eithan Galun, Daniel S. Goldenberg^*

^*Corresponding author for this work

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

19 Scopus citations

Abstract

The oncofetal long noncoding RNA (lncRNA) H19 is postnatally repressed in most tissues, and re-expressed in many cancers, including hepatocellular carcinoma (HCC). The role of H19 in carcinogenesis is a subject of controversy. We aimed to examine the role of H19 in chronic inflammation-mediated hepatocarcinogenesis using the Mdr2/Abcb4 knockout (Mdr2-KO) mouse, a well-established HCC model. For this goal, we have generated Mdr2-KO/H19-KO double knockout (dKO) mice and followed spontaneous tumor development in the dKO and control Mdr2-KO mice. Cellular localization of H19 and effects of H19 loss in the liver were determined in young and old Mdr2-KO mice. Tumor incidence and tumor load were both significantly decreased in the liver of dKO versus Mdr2-KO females. The expression levels of H19 and Igf2 were variable in nontumor liver tissues of Mdr2-KO females and were significantly downregulated in most matched tumors. In nontumor liver tissue of aged Mdr2-KO females, H19 was expressed mainly in hepatocytes, and hepatocyte proliferation was increased compared to dKO females. At an early age, dKO females displayed lower levels of liver injury and B-cell infiltration, with higher percentage of binuclear hepatocytes. In human samples, H19 expression was higher in females, positively correlated with cirrhosis (in nontumor liver samples) and negatively correlated with CTNNB1 (beta-catenin) mutations and patients’ survival (in tumors). Our data demonstrate that the lncRNA H19 is pro-oncogenic during the development of chronic inflammation-mediated HCC in the Mdr2-KO mouse model, mainly by increasing liver injury and decreasing hepatocyte polyploidy in young mice.

Original language	American English
Pages (from-to)	127-139
Number of pages	13
Journal	Oncogene
Volume	40
Issue number	1
DOIs	https://doi.org/10.1038/s41388-020-01513-7
State	Published - 7 Jan 2021
Externally published	Yes

Bibliographical note

Funding Information:
Funding Robert H. Benson Living Trust and Selma Kron Foundation to student fellowships. DSG is supported by the Kamea Scientific Foundation of the Israeli Government. JHA was supported by ISF 923/ 14. SC was supported by a funding from Labex OncoImunology and CARPEM. The JZR group was supported by INSERM, Ligue Nationale contre le Cancer (Equipe Labellisée), Labex OncoImmu-nology (investissement d’avenir), grant IREB, Coup d’Elan de la Fondation Bettencourt-Schueller, the SIRIC CARPEM, Raymond Rosen Award from the Fondation pour le Recherche Médicale, Prix René and Andrée Duquesne—Comité de Paris Ligue Contre le Cancer and Fondation Mérieux. The work of EG was supported by the: ERC advance—GA No. 786575—RxmiRcanceR, Deutsche For-schungsgemeinschaft (DFG) SFB841 project C3, NIH CA197081-02, MOST, ISF collaboration with Canada (2473/2017), personal ISF (486/2017), ICORE–ISF (41/2011), and by DKFZ-MOST.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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10.1038/s41388-020-01513-7

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Gamaev, L., Mizrahi, L., Friehmann, T., Rosenberg, N., Pappo, O., Olam, D., Zeira, E., Bahar Halpern, K., Caruso, S., Zucman-Rossi, J., Axelrod, J. H., Galun, E., & Goldenberg, D. S. (2021). The pro-oncogenic effect of the lncRNA H19 in the development of chronic inflammation-mediated hepatocellular carcinoma. Oncogene, 40(1), 127-139. https://doi.org/10.1038/s41388-020-01513-7

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title = "The pro-oncogenic effect of the lncRNA H19 in the development of chronic inflammation-mediated hepatocellular carcinoma",

abstract = "The oncofetal long noncoding RNA (lncRNA) H19 is postnatally repressed in most tissues, and re-expressed in many cancers, including hepatocellular carcinoma (HCC). The role of H19 in carcinogenesis is a subject of controversy. We aimed to examine the role of H19 in chronic inflammation-mediated hepatocarcinogenesis using the Mdr2/Abcb4 knockout (Mdr2-KO) mouse, a well-established HCC model. For this goal, we have generated Mdr2-KO/H19-KO double knockout (dKO) mice and followed spontaneous tumor development in the dKO and control Mdr2-KO mice. Cellular localization of H19 and effects of H19 loss in the liver were determined in young and old Mdr2-KO mice. Tumor incidence and tumor load were both significantly decreased in the liver of dKO versus Mdr2-KO females. The expression levels of H19 and Igf2 were variable in nontumor liver tissues of Mdr2-KO females and were significantly downregulated in most matched tumors. In nontumor liver tissue of aged Mdr2-KO females, H19 was expressed mainly in hepatocytes, and hepatocyte proliferation was increased compared to dKO females. At an early age, dKO females displayed lower levels of liver injury and B-cell infiltration, with higher percentage of binuclear hepatocytes. In human samples, H19 expression was higher in females, positively correlated with cirrhosis (in nontumor liver samples) and negatively correlated with CTNNB1 (beta-catenin) mutations and patients{\textquoteright} survival (in tumors). Our data demonstrate that the lncRNA H19 is pro-oncogenic during the development of chronic inflammation-mediated HCC in the Mdr2-KO mouse model, mainly by increasing liver injury and decreasing hepatocyte polyploidy in young mice.",

author = "Lika Gamaev and Lina Mizrahi and Tomer Friehmann and Nofar Rosenberg and Orit Pappo and Devorah Olam and Evelyne Zeira and {Bahar Halpern}, Keren and Stefano Caruso and Jessica Zucman-Rossi and Axelrod, {Jonathan H.} and Eithan Galun and Goldenberg, {Daniel S.}",

note = "Funding Information: Funding Robert H. Benson Living Trust and Selma Kron Foundation to student fellowships. DSG is supported by the Kamea Scientific Foundation of the Israeli Government. JHA was supported by ISF 923/ 14. SC was supported by a funding from Labex OncoImunology and CARPEM. The JZR group was supported by INSERM, Ligue Nationale contre le Cancer (Equipe Labellis{\'e}e), Labex OncoImmu-nology (investissement d{\textquoteright}avenir), grant IREB, Coup d{\textquoteright}Elan de la Fondation Bettencourt-Schueller, the SIRIC CARPEM, Raymond Rosen Award from the Fondation pour le Recherche M{\'e}dicale, Prix Ren{\'e} and Andr{\'e}e Duquesne—Comit{\'e} de Paris Ligue Contre le Cancer and Fondation M{\'e}rieux. The work of EG was supported by the: ERC advance—GA No. 786575—RxmiRcanceR, Deutsche For-schungsgemeinschaft (DFG) SFB841 project C3, NIH CA197081-02, MOST, ISF collaboration with Canada (2473/2017), personal ISF (486/2017), ICORE–ISF (41/2011), and by DKFZ-MOST. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

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doi = "10.1038/s41388-020-01513-7",

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Gamaev, L, Mizrahi, L, Friehmann, T, Rosenberg, N, Pappo, O, Olam, D, Zeira, E, Bahar Halpern, K, Caruso, S, Zucman-Rossi, J, Axelrod, JH, Galun, E & Goldenberg, DS 2021, 'The pro-oncogenic effect of the lncRNA H19 in the development of chronic inflammation-mediated hepatocellular carcinoma', Oncogene, vol. 40, no. 1, pp. 127-139. https://doi.org/10.1038/s41388-020-01513-7

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T1 - The pro-oncogenic effect of the lncRNA H19 in the development of chronic inflammation-mediated hepatocellular carcinoma

AU - Gamaev, Lika

AU - Mizrahi, Lina

AU - Friehmann, Tomer

AU - Rosenberg, Nofar

AU - Pappo, Orit

AU - Olam, Devorah

AU - Zeira, Evelyne

AU - Bahar Halpern, Keren

AU - Caruso, Stefano

AU - Zucman-Rossi, Jessica

AU - Axelrod, Jonathan H.

AU - Galun, Eithan

AU - Goldenberg, Daniel S.

N1 - Funding Information: Funding Robert H. Benson Living Trust and Selma Kron Foundation to student fellowships. DSG is supported by the Kamea Scientific Foundation of the Israeli Government. JHA was supported by ISF 923/ 14. SC was supported by a funding from Labex OncoImunology and CARPEM. The JZR group was supported by INSERM, Ligue Nationale contre le Cancer (Equipe Labellisée), Labex OncoImmu-nology (investissement d’avenir), grant IREB, Coup d’Elan de la Fondation Bettencourt-Schueller, the SIRIC CARPEM, Raymond Rosen Award from the Fondation pour le Recherche Médicale, Prix René and Andrée Duquesne—Comité de Paris Ligue Contre le Cancer and Fondation Mérieux. The work of EG was supported by the: ERC advance—GA No. 786575—RxmiRcanceR, Deutsche For-schungsgemeinschaft (DFG) SFB841 project C3, NIH CA197081-02, MOST, ISF collaboration with Canada (2473/2017), personal ISF (486/2017), ICORE–ISF (41/2011), and by DKFZ-MOST. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2021/1/7

Y1 - 2021/1/7

N2 - The oncofetal long noncoding RNA (lncRNA) H19 is postnatally repressed in most tissues, and re-expressed in many cancers, including hepatocellular carcinoma (HCC). The role of H19 in carcinogenesis is a subject of controversy. We aimed to examine the role of H19 in chronic inflammation-mediated hepatocarcinogenesis using the Mdr2/Abcb4 knockout (Mdr2-KO) mouse, a well-established HCC model. For this goal, we have generated Mdr2-KO/H19-KO double knockout (dKO) mice and followed spontaneous tumor development in the dKO and control Mdr2-KO mice. Cellular localization of H19 and effects of H19 loss in the liver were determined in young and old Mdr2-KO mice. Tumor incidence and tumor load were both significantly decreased in the liver of dKO versus Mdr2-KO females. The expression levels of H19 and Igf2 were variable in nontumor liver tissues of Mdr2-KO females and were significantly downregulated in most matched tumors. In nontumor liver tissue of aged Mdr2-KO females, H19 was expressed mainly in hepatocytes, and hepatocyte proliferation was increased compared to dKO females. At an early age, dKO females displayed lower levels of liver injury and B-cell infiltration, with higher percentage of binuclear hepatocytes. In human samples, H19 expression was higher in females, positively correlated with cirrhosis (in nontumor liver samples) and negatively correlated with CTNNB1 (beta-catenin) mutations and patients’ survival (in tumors). Our data demonstrate that the lncRNA H19 is pro-oncogenic during the development of chronic inflammation-mediated HCC in the Mdr2-KO mouse model, mainly by increasing liver injury and decreasing hepatocyte polyploidy in young mice.

AB - The oncofetal long noncoding RNA (lncRNA) H19 is postnatally repressed in most tissues, and re-expressed in many cancers, including hepatocellular carcinoma (HCC). The role of H19 in carcinogenesis is a subject of controversy. We aimed to examine the role of H19 in chronic inflammation-mediated hepatocarcinogenesis using the Mdr2/Abcb4 knockout (Mdr2-KO) mouse, a well-established HCC model. For this goal, we have generated Mdr2-KO/H19-KO double knockout (dKO) mice and followed spontaneous tumor development in the dKO and control Mdr2-KO mice. Cellular localization of H19 and effects of H19 loss in the liver were determined in young and old Mdr2-KO mice. Tumor incidence and tumor load were both significantly decreased in the liver of dKO versus Mdr2-KO females. The expression levels of H19 and Igf2 were variable in nontumor liver tissues of Mdr2-KO females and were significantly downregulated in most matched tumors. In nontumor liver tissue of aged Mdr2-KO females, H19 was expressed mainly in hepatocytes, and hepatocyte proliferation was increased compared to dKO females. At an early age, dKO females displayed lower levels of liver injury and B-cell infiltration, with higher percentage of binuclear hepatocytes. In human samples, H19 expression was higher in females, positively correlated with cirrhosis (in nontumor liver samples) and negatively correlated with CTNNB1 (beta-catenin) mutations and patients’ survival (in tumors). Our data demonstrate that the lncRNA H19 is pro-oncogenic during the development of chronic inflammation-mediated HCC in the Mdr2-KO mouse model, mainly by increasing liver injury and decreasing hepatocyte polyploidy in young mice.

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The pro-oncogenic effect of the lncRNA H19 in the development of chronic inflammation-mediated hepatocellular carcinoma

Abstract

Bibliographical note

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