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Comparative study of the effects of PEGylated interferon-α2a versus 5-fluorouracil on cancer stem cells in a rat model of hepatocellular carcinoma

Tumor Biology

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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.

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Acknowledgments

The present study was completely funded by Cairo University.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt

    Tarek Kamal Motawi, Noha Ahmed El-Boghdady & Hebatullah Samy Helmy

  2. Department of Pathology, National Cancer Institute, Cairo University, Cairo, 11796, Egypt

    Abeer Mostafa El-Sayed

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  1. Tarek Kamal Motawi
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  2. Noha Ahmed El-Boghdady
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Correspondence to Hebatullah Samy Helmy.

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Motawi, T.K., El-Boghdady, N.A., El-Sayed, A.M. et al. Comparative study of the effects of PEGylated interferon-α2a versus 5-fluorouracil on cancer stem cells in a rat model of hepatocellular carcinoma. Tumor Biol. 37, 1617–1625 (2016). https://doi.org/10.1007/s13277-015-3920-2

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