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