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Ghufran H, Azam M, Mehmood A, et al. Standardization of diethylnitrosamine-induced hepatocellular carcinoma rat model with time based molecular assessment. Exp Mol Pathol. 2021;123:104715doi: 10.1016/j.yexmp.2021.104715.
Ghufran, H., Azam, M., Mehmood, A., Butt, H., & Riazuddin, S. (2021). Standardization of diethylnitrosamine-induced hepatocellular carcinoma rat model with time based molecular assessment. Experimental and molecular pathology, 123104715. https://doi.org/10.1016/j.yexmp.2021.104715
Ghufran, Hafiz, et al. "Standardization of diethylnitrosamine-induced hepatocellular carcinoma rat model with time based molecular assessment." Experimental and molecular pathology vol. 123 (2021): 104715. doi: https://doi.org/10.1016/j.yexmp.2021.104715
Ghufran H, Azam M, Mehmood A, Butt H, Riazuddin S. Standardization of diethylnitrosamine-induced hepatocellular carcinoma rat model with time based molecular assessment. Exp Mol Pathol. 2021 Dec;123:104715. doi: 10.1016/j.yexmp.2021.104715. Epub 2021 Oct 23. PMID: 34699901.
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Exp Mol Pathol. 2021 Dec;123:104715. doi: 10.1016/j.yexmp.2021.104715. Epub 2021 Oct 23.

Standardization of diethylnitrosamine-induced hepatocellular carcinoma rat model with time based molecular assessment.

Experimental and molecular pathology

Hafiz Ghufran, Maryam Azam, Azra Mehmood, Hira Butt, Sheikh Riazuddin

Affiliations

  1. National Centre of Excellence in Molecular Biology, 87-West Canal Bank Road, University of the Punjab, Lahore, Pakistan.
  2. National Centre of Excellence in Molecular Biology, 87-West Canal Bank Road, University of the Punjab, Lahore, Pakistan; Allama Iqbal Medical Research Centre, Jinnah Burn and Reconstructive Surgery Centre, Lahore, Pakistan. Electronic address: [email protected].

PMID: 34699901 DOI: 10.1016/j.yexmp.2021.104715

Abstract

This study was intended (1) to develop a robust animal model for hepatocellular carcinoma (HCC) research, in which HCC tumors develop in a background of fibrosis or cirrhosis; and (2) to explore time-dependent regulatory changes in key molecular markers during disease advancement and HCC development. With the aim of establishing such HCC model, male Sprague-Dawley rats were injected with diethylnitrosamine (DEN) at a dose of 30 mg/kg twice a week for 10 weeks then once a week from 12th to 16th weeks. The rats were kept under observation until 18th week. At defined time intervals (2nd, 4th, 12th, and 18th week), serum biomarkers and microscopic components of tissue samples were used to investigate the chronic progression of liver disease, while gene and protein analysis was used to monitor expression patterns during HCC development. DEN-intoxicated rats manifested inflammation at week 4, fibrosis at week 12 and cirrhosis with early HCC tumors at week 18. Molecular analysis revealed that key markers of inflammation (Il-1β, Il-6, and Tnf-α), fibrosis (Tgf-β1, Col1α1, Col3α1, and Timp-1), and angiogenesis (Hif1-α and Vegf) were promptly (P ≤ 0.001) up-regulated at week 4, week 12 and week 18, respectively. Oxidative stress (iNos, Cyp2e1, and Sod1) and pro-apoptotic (Bax) markers showed significant upregulation from week 4 to week 12. However, Sod1 and Bax expressions dropped after week 12 and reached a minimum at 18th week. Strikingly, expressions of anti-apoptotic (Bcl-2) and cell proliferation (Pcna, Hgf, and Afp) markers were abruptly increased at week 18. Collectively, we describe an 18-week HCC model in DEN-intoxicated rats that exhibit chronic inflammation, oxidative imbalance, advance fibrosis/cirrhosis, halted apoptosis, and angiogenic sprouting, progressively.

Copyright © 2021. Published by Elsevier Inc.

Keywords: Cytokines; Diethylnitrosamine; Hepatocellular carcinoma; Molecular markers; Pathogenesis; Rat model

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