Side population (SP) cells are a sub-population of cells that are distinct Bosutinib from the main population and exhibits distinguishing stem

cell-like characteristics. In a study of SP cells in different hepatoma cell lines, Chiba et al[73] concluded that SP cells in hepatoma cell lines possess extreme tumorigenic potential, which suggests that a minor population of liver cancer cells harbors LCSC-like properties. A variety of recent studies of hepatoma cell lines and clinical samples suggest that epithelial cell adhesion molecule (EpCAM)[74-76], CD13[77-80], CD24[81-83], CD44[84,85], CD90[86,87], intercellular adhesion molecule-1 (ICAM-1)[88], α2δ1 subunit of voltage-gated calcium channels[89], and OV6[90] may serve as putative LCSC markers. The CSC theory emphasizes the role of LSCs in the hepatocarcinogenesis of PLC. Although the aforementioned proteins and/or molecules have been postulated as putative LCSC markers, no definitive markers have yet been identified directly and widely recognized. Moreover, no LCSCs have been isolated[61]. Therefore, additional studies are needed to obtain a definitive molecular

marker of LCSCs and to isolate LCSCs from PLC cell lines, animal models, and clinical samples. MOLECULAR MECHANISMS INVOLVED IN THE MALIGNANT TRANSFORMATION OF LSCS Based on the studies mentioned above, we can scientifically conclude that PLC may derive from neoplastic transformation of LSCs. However, the underlying molecular mechanisms

are poorly understood. Studies investigating cancer and CSCs show that several key genes and regulatory signaling pathways are oncogenic, such as Bmi1, Wnt, Notch, Hedgehog, and transforming growth factor-β (TGF-β), and therefore are potentially involved in the malignant transformation of LSCs[91]. Here, current knowledge of these pathways is discussed. Polycomb group gene Bmi1 Polycomb group (PcG) proteins are a family of transcriptional repressors that epigenetically remodel chromatin and participate in the establishment and maintenance of cell fates. These proteins play a central role in hematopoiesis, stem cell self-renewal, cellular proliferation and neoplastic development. To date, four distinct PcG-encoded protein complexes have been purified from different species: Polycomb repressive complex 1 (PRC1), PRC2, Pho repressive complex (PhoRC), Batimastat and Polycomb repressive deubiquitinase (PR-DUB)[92]. Bmi1, encoded by the BMI1 gene (B cell-specific Moloney murine leukemia virus integration site 1), is the most important core subunit of the PRC1 complex, which plays a pivotal role in the self-renewal of both normal stem cells and CSCs. Increasing evidence indicates that Bmi1 protein is elevated in many human malignancies including PLC and has a vital effect on tumorigenesis, cancer progression, and the malignant transformation of stem cells.