In PLC, a number of studies have shown that Bmi1 contributes to the maintenance of tumor-initiating supplier u0126 SP cells[94] and can cooperate with other oncogenic signals to promote hepatic carcinogenesis in vivo[95]. Our empirical

results suggest that Bmi1 is highly expressed in patients with PLC and correlates positively with the proliferation and invasiveness of human hepatoma cells[96,97]. Furthermore, Chiba et al[64,65] observed that forced expression of Bmi1 promotes the self-renewal of LSCs, and the transplantation of such cells that have been clonally expanded from single LSC produces tumors that exhibit the histologic features of cHCC-CC. The above results indicate that Bmi1 plays a crucial role in the oncogenic transformation of LSCs and therefore drives cancer initiation. Wnt signaling pathway The Wnt signaling pathways are ancient and evolutionarily conserved pathways that transmit signals from outside of a cell through cell surface receptors

to the inside of the cell and regulate cell-to-cell interactions. Wnt signaling is one of the most well studied molecular pathways during the human life span and involves a large number of proteins that are required for basic developmental processes such as embryonic development, cell fate determination, cell proliferation, cell migration, and cell polarity, in a variety of species and organs[98]. Three major categories of Wnt signaling pathways are recognized: the canonical Wnt pathway in which the cytoplasmic protein β-catenin is a key mediator, the noncanonical planar cell polarity pathway (β-catenin independent), and the noncanonical Wnt/calcium pathway. Activation of the canonical Wnt/β-catenin pathway causes an accumulation of β-catenin in the cytoplasm and its eventual translocation into the nucleus to act as a transcriptional coactivator of transcription factors. Without Wnt signaling, β-catenin would

not accumulate in the cytoplasm because it would be degraded by a destruction complex[99]. Ever since its initial discovery, Wnt signaling has had an association with cancer[100]. There is substantial evidence to suggest that dysregulation of Wnt signaling is critical for the initiation and progression of PLC[101,102]. Wnt signaling pathways, particularly the canonical Cilengitide Wnt/β-catenin pathway, are also involved in the self-renewal and maintenance of embryonic and adult stem cells, and as recent findings demonstrated, in CSCs. Functional characterization of LCSCs has revealed that Wnt/β-catenin pathways were critical for inducing the stem cell properties of hepatoma cells and in promoting self-renewal, tumorigenicity, and chemoresistance[103]. In the aforementioned HBx-mediated tumorigenic effects, Wang et al[63] suggest that HBx may enable LSCs with tumorigenic potential via activation of the Wnt/β-catenin signaling pathway.