Cancer cell reprogramming to identify the genes competent for generating liver cancer stem cells

Abstract

The cancer stem cell (CSC) hypothesis postulates that cancer originates from the malignant transformation of stem/progenitor cells and is considered to apply to many cancers, including liver cancer. Identification that CSCs are responsible for drug resistance, metastasis, and secondary tumor appearance suggests that these populations are novel obligatory targets for the treatment of cancer. Here, we describe our new method for identifying potential CSC candidates. The reprogramming of cancer cells via induced pluripotent stem cell (iPSC) technology is a novel therapy for the treatment and for the study of CSC-related genes. This technology has advantages for studying the interactions between CSC-related genes and the cancer niche microenvironment. This technology may also provide a useful platform for studying the genes involved in the generation of CSCs before and after reprogramming, and for elucidating the mechanisms underlying cancer initiation and progression. The present review summarizes the current understanding of transcription factors involved in the generation of liver CSCs from liver cancer cell-derived iPSCs and how these contribute to oncogenesis, and discusses the modeling of liver cancer development.

Keywords: Induced pluripotent stem cells; Liver cancer; OCT4; Reprogramming; c-JUN oncogene.

Fig. 1

Schematic representation of hypothetical two-hit theory for crosstalk to generate cancer stem cells by reprogramming. Hypothetical two-hit theory for induction of cancer stem cells was represented. Stemness factors (OCT4, SOX2, and NANOG) and oncogene/tumor suppressor genes (oncogenes such as Myc, KLF4, c-JUN, kRAS, etc.; antioncogenes such as p53, Rb, PTEN, BMI1, EZH2, INK4 family, etc.) and epigenetic modification of DNA methylation and histone modification are required for generation of cancer stem cells by reprogramming. We have reported the feedback control of c-JUN and OCT4 is critical for generation of cancer stem like cells [59]. The oncogene c-JUN transactivated genes encoding OCT4, SOX2, and NANOG [60], and the genes of OCT4, SOX2, and NANOG formed the molecular circuitry for stemness and pluripotency [64], and then OCT4 upregulated the expression of c-JUN gene to form the feedback circuit [59]. Taken together, we hypothesize that these feedback circuit might be regulated by the family of the stemness genes and the family of cancer-related oncogenes or tumor suppressor genes