Introduction: Cancer stem cell (CSC) hypothesis was first proposed in acute myeloid leukemia and it has been demonstrated that solid human tumors such as liver cancer also contain CSCs. These cells are a small subpopulation of cells responsible for high rates of tumor relapse and metastasis because of their abilities to self-renew and differentiate leading to a new tumor and cellular heterogeneity in local or distant organs. CSCs have been identified in the most common type of primary liver cancer, hepatocellular carcinoma (HCC), the fifth leading cause of cancer, which ranks second in cancer-related death worldwide. Literature review: Hepatic CSCs could be identified through different cell surface markers eg; CD13, CD24, CD44, CD90 (THY1), CD133, epithelial cell adhesion molecule, EpCAM (CD326), intercellular adhesion molecule-1 (ICAM-1) and OV6. Moreover, it is indicated that additional factors such as miR-181 and LIN28 contribute to stemness features of these cells in HCC. More investigations for identifying hepatic CSCs have revealed that several biological signaling pathways such as WNT/β-catenin, NOTCH, Hedgehog, AKT and TGF- beta pathways are deregulated leading to self-renewal, tumorigenicity, metastasis and chemoresistance of these cells. Conclusion: Identification and utilizing key components of these abnormal pathways could be considered as effective targets for eliminating hepatic CSCs. A novel effective therapy is forced differentiation of CSCs. In hepatocytes, WNT/β- catenin signaling is inhibited by nemo-like kinase (NLK) and differentiation is induced by caudal type homeobox transcription factor 2 (CDX2) and GATA6, which are hepatic transcriptional regulators of differentiation. MiR-181 promotes the stem cell-like features of HCC cells by directly targeting mRNAs that encode CDX2, GATA6 and NLK. Inhibition of miR-181 led to a reduction in EpCAM(+) HCC cell quantity and tumor initiating ability and therefore, inhibition of miR-181 may eradicate HCC. Peptide nucleic acids (PNAs) are DNA analogues in which the sugar-phosphate backbones are replaced by N-(2-aminoethyl) glycine units. These molecules efficiently hybridize with complementary DNA and RNA, forming Watson-Crick double helices. PNAs have a higher affinity for RNA than for DNA, are more specific and are resistant to DNases and proteases. Hence, specific PNAs can be used for inhibition of miR-181 leading to differentiation of HCC CSCs.

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