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Cancer Prevention Research
Cancer Prevention Research
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Research Article

Targeting the Cholecystokinin Receptor: A Novel Approach for Treatment and Prevention of Hepatocellular Cancer

Martha D. Gay, Anita Safronenka, Hong Cao, Felice H. Liu, Zoe X. Malchiodi, Robin D. Tucker, Alexander Kroemer, Narayan Shivapurkar and Jill P. Smith
Martha D. Gay
1Department of Medicine, Georgetown University College of Medicine, Washington, DC.
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Anita Safronenka
1Department of Medicine, Georgetown University College of Medicine, Washington, DC.
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Hong Cao
1Department of Medicine, Georgetown University College of Medicine, Washington, DC.
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Felice H. Liu
1Department of Medicine, Georgetown University College of Medicine, Washington, DC.
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  • ORCID record for Felice H. Liu
Zoe X. Malchiodi
2Department of Oncology, Georgetown University College of Medicine, Washington, DC.
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Robin D. Tucker
3Department of Pathology, Georgetown University College of Medicine, Washington, DC.
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Alexander Kroemer
4MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington DC.
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Narayan Shivapurkar
1Department of Medicine, Georgetown University College of Medicine, Washington, DC.
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Jill P. Smith
1Department of Medicine, Georgetown University College of Medicine, Washington, DC.
2Department of Oncology, Georgetown University College of Medicine, Washington, DC.
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  • For correspondence: jps261@georgetown.edu
DOI: 10.1158/1940-6207.CAPR-20-0220 Published January 2021
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Abstract

Hepatocellular carcinoma (HCC) is the fastest growing cancer worldwide in part due to the obesity epidemic and fatty liver disease, particularly nonalcoholic steatohepatitis (NASH). Chronic inflammation with the release of cytokines and chemokines with activation of hepatic stellate cells results in changes of the liver extracellular matrix (ECM) that predisposes to the development of HCC. Blood levels of the gastrointestinal peptide cholecystokinin (CCK) are increased in humans and mice consuming a high-fat diet. We found that the CCK-B receptor (CCK-BR) expression increased in the livers of mice with NASH. Treatment of mice with a CCK-BR antagonist, proglumide, prevented NASH, lowered hepatic inflammatory cytokines and chemokines, reduced oxidative stress, decreased F4/80+ hepatic macrophages, and prevented HCC. CCK-AR and CCK-BR expression was increased in both murine and human HCC cell lines compared with that of normal liver, and CCK stimulated the growth of wild-type and CCK-A receptor knockout HCC cells in vitro, but not CCK-BR knockout cells suggesting that the CCK-BR mediates proliferation. Proglumide therapy significantly reduced growth by 70% and 73% in mice bearing Dt81Hepa1–6 or in RIL-75 HCC tumors, respectively. IHC of a human liver tissue array with a selective CCK-BR antibody revealed staining of human HCC and no staining in normal liver.

Prevention Relevance: This investigation demonstrates the role of the gastrointestinal peptide cholecystokinin (CCK) in hepatocellular carcinoma (HCC) and how CCK-BR blockade reverses the premalignant state of the hepatic extracellular matrix hence, rendering it less susceptible to the development of HCC. Thereby, CCK-BR blockade is a novel approach for the prevention/treatment of HCC.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).

  • Cancer Prev Res 2021;14:17–30

  • Received May 5, 2020.
  • Revision received August 21, 2020.
  • Accepted October 15, 2020.
  • Published first October 28, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Prevention Research: 14 (1)
January 2021
Volume 14, Issue 1
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Targeting the Cholecystokinin Receptor: A Novel Approach for Treatment and Prevention of Hepatocellular Cancer
Martha D. Gay, Anita Safronenka, Hong Cao, Felice H. Liu, Zoe X. Malchiodi, Robin D. Tucker, Alexander Kroemer, Narayan Shivapurkar and Jill P. Smith
Cancer Prev Res January 1 2021 (14) (1) 17-30; DOI: 10.1158/1940-6207.CAPR-20-0220

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Targeting the Cholecystokinin Receptor: A Novel Approach for Treatment and Prevention of Hepatocellular Cancer
Martha D. Gay, Anita Safronenka, Hong Cao, Felice H. Liu, Zoe X. Malchiodi, Robin D. Tucker, Alexander Kroemer, Narayan Shivapurkar and Jill P. Smith
Cancer Prev Res January 1 2021 (14) (1) 17-30; DOI: 10.1158/1940-6207.CAPR-20-0220
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