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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 effect of pegylated interferon-Ü2a (PEG-IFN-Ü2a) and 5-fluorouracil (5-FU) on the expression of CSCs 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 six weeks. After the appearance of dysplastic nodules, the animals received either PEG-IFN-Ü2a or 5-FU for eight weeks. CSCs markers (OV6, CD90) and molecules related to transforming growth factor-Ý (TGF-Ý) and other signaling pathways were assessed in hepatic tissues. PEG-IFN-Ü2a treatment effectively suppressed the hepatic expression of OV6 and CD90, ameliorated the diminished hepatic expression of TGF-Ý receptor II (TGF-ÝRII) and Ý2 spectrin (Ý2SP) and significantly reduced the elevated hepatic expression of TGF-Ý1, interleukin6 (IL6), signal transducer and activator of transcription3 (STAT3) and vascular endothelial growth factor (VEGF). In contrast, 5-FU treatment failed to reduce the over-expression of CSCs markers and barely affected the disrupted TGF-Ý signaling. Furthermore, it had no effect on angiogenesis or nitrosative stress. In conclusion, PEG-IFN-Ü2a, but not 5-FU, could reduce the propagation of CSCs during the progression of HCC by upregulating the disrupted TGF-Ý signaling, suppressing the IL6/STAT3 pathway and reducing angiogenesis