title: Comparative study of the effects of PEGylated interferon-α2a versus 5-fluorouracil on cancer stem cells in a rat model of hepatocellular carcinoma.
abstract: Cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) possess tumor-initiating, metastatic, and drug resistance properties. This study was conducted to evaluate the effects of PEGylated interferon-α2a (PEG-IFN-α2a) and 5-fluorouracil (5-FU) on the expression of CSC markers and on specific pathways that contribute to the propagation of CSCs in HCC. HCC was initiated in rats using a single intraperitoneal dose of diethylnitrosamine (DENA) (200 mg/kg) and promoted by weekly subcutaneous injections of carbon tetrachloride (CCl4) for 6 weeks. After the appearance of dysplastic nodules, the animals received PEG-IFN-α2a or 5-FU for 8 weeks. CSC markers (OV6, CD90) and molecules related to transforming growth factor β (TGF-β) and other signaling pathways were assessed in hepatic tissues. The PEG-IFN-α2a treatment effectively suppressed the hepatic expression of OV6 and CD90, ameliorated the diminished hepatic expression of TGF-β receptor II (TGF-βRII) and β2-spectrin (β2SP), and significantly reduced the elevated hepatic expression of TGF-β1, interleukin6 (IL6), signal transducer and activator of transcription3 (STAT3), and vascular endothelial growth factor (VEGF). In contrast, the 5-FU treatment failed to reduce the overexpression of CSC markers and barely affected the disrupted TGF-β signaling. Furthermore, it had no effect on angiogenesis or nitrosative stress. PEG-IFN-α2a, but not 5-FU, could reduce the propagation of CSCs during the progression of HCC by upregulating the disrupted TGF-β signaling, suppressing the IL6/STAT3 pathway and reducing angiogenesis.
authors: Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
authors: Tarek Kamal
authors: TK
authors: Motawi
authors: Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
authors: Noha Ahmed
authors: NA
authors: El-Boghdady
authors: Department of Pathology, National Cancer Institute, Cairo University, Cairo, 11796, Egypt.
authors: Abeer Mostafa
authors: AM
authors: El-Sayed
authors: Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt. hebatallah.helmi@pharma.cu.edu.eg.
authors: Hebatullah Samy
authors: http://orcid.org/0000-0002-1236-5547
authors: HS
authors: Helmy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a; D005472:Fluorouracil
keywords: 5-Fluorouracil; Cancer stem cells; Hepatocellular carcinoma; PEGylated interferon-α2a