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Article

A Newly Established Murine Cell Line as a Model for Hepatocellular Cancer in Non-Alcoholic Steatohepatitis

by
Andreas Kroh
1,*,†,
Jeanette Walter
1,†,
Herdit Schüler
2,
Jochen Nolting
1,
Roman Eickhoff
1,
Daniel Heise
1,
Ulf Peter Neumann
1,3,4,5,
Thorsten Cramer
1,3,4,5,
Tom Florian Ulmer
1,3 and
Athanassios Fragoulis
1,6
1
Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany
2
Institute of Human Genetics, Uniklinik RWTH Aachen, 52074 Aachen, Germany
3
Department of Surgery, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands
4
ESCAM—European Surgery Center Aachen Maastricht, 52074 Aachen, Germany
5
ESCAM—European Surgery Center Aachen Maastricht, 6200 MD Maastricht, The Netherlands
6
Department of Anatomy and Cell Biology, Uniklinik RWTH Aachen, 52074 Aachen, Germany
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(22), 5658; https://doi.org/10.3390/ijms20225658
Submission received: 22 October 2019 / Revised: 7 November 2019 / Accepted: 8 November 2019 / Published: 12 November 2019
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Abstract

Non-alcoholic steatohepatitis (NASH) has become a major risk factor for hepatocellular cancer (HCC) due to the worldwide increasing prevalence of obesity. However, the pathophysiology of NASH and its progression to HCC is incompletely understood. Thus, the aim of this study was to generate a model specific NASH-derived HCC cell line. A murine NASH-HCC model was conducted and the obtained cancer cells (N-HCC25) were investigated towards chromosomal aberrations, the expression of cell type-specific markers, dependency on nutrients, and functional importance of mTOR. N-HCC25 exhibited several chromosomal aberrations as compared to healthy hepatocytes. Hepatocytic (HNF4), EMT (Twist, Snail), and cancer stem cell markers (CD44, EpCAM, CK19, Sox9) were simultaneously expressed in these cells. Proliferation highly depended on the supply of glucose and FBS, but not glutamine. Treatment with a second generation mTOR inhibitor (KU-0063794) resulted in a strong decrease of cell growth in a dose-dependent manner. In contrast, a first generation mTOR inhibitor (Everolimus) only slightly reduced cell proliferation. Cell cycle analyses revealed that the observed growth reduction was most likely due to G1/G0 cell cycle arrest. These results indicate that N-HCC25 is a highly proliferative HCC cell line from a NASH background, which might serve as a suitable in vitro model for future investigations of NASH-derived HCC.
Keywords: non-alcoholic steatohepatitis; hepatocellular carcinoma; cell line; mTOR; Everolimus; KU-0063794 non-alcoholic steatohepatitis; hepatocellular carcinoma; cell line; mTOR; Everolimus; KU-0063794

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MDPI and ACS Style

Kroh, A.; Walter, J.; Schüler, H.; Nolting, J.; Eickhoff, R.; Heise, D.; Neumann, U.P.; Cramer, T.; Ulmer, T.F.; Fragoulis, A. A Newly Established Murine Cell Line as a Model for Hepatocellular Cancer in Non-Alcoholic Steatohepatitis. Int. J. Mol. Sci. 2019, 20, 5658. https://doi.org/10.3390/ijms20225658

AMA Style

Kroh A, Walter J, Schüler H, Nolting J, Eickhoff R, Heise D, Neumann UP, Cramer T, Ulmer TF, Fragoulis A. A Newly Established Murine Cell Line as a Model for Hepatocellular Cancer in Non-Alcoholic Steatohepatitis. International Journal of Molecular Sciences. 2019; 20(22):5658. https://doi.org/10.3390/ijms20225658

Chicago/Turabian Style

Kroh, Andreas, Jeanette Walter, Herdit Schüler, Jochen Nolting, Roman Eickhoff, Daniel Heise, Ulf Peter Neumann, Thorsten Cramer, Tom Florian Ulmer, and Athanassios Fragoulis. 2019. "A Newly Established Murine Cell Line as a Model for Hepatocellular Cancer in Non-Alcoholic Steatohepatitis" International Journal of Molecular Sciences 20, no. 22: 5658. https://doi.org/10.3390/ijms20225658

APA Style

Kroh, A., Walter, J., Schüler, H., Nolting, J., Eickhoff, R., Heise, D., Neumann, U. P., Cramer, T., Ulmer, T. F., & Fragoulis, A. (2019). A Newly Established Murine Cell Line as a Model for Hepatocellular Cancer in Non-Alcoholic Steatohepatitis. International Journal of Molecular Sciences, 20(22), 5658. https://doi.org/10.3390/ijms20225658

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