Abstract
AbstractCancer is a disorder with various genetic and epigenetic alterations. Genetic alterations such as mutations, i.e., substitutions, amplifications, and deletions of nucleotide sequences, are largely irreversible, whereas epigenetic alterations can be modified by pharmacological agents that target components of the epigenetic machinery. Recent studies have showed that introduction of defined factors such as those encoded by c-MYC, SOX2, OCT3/4, and KLF4 in normal somatic cells results in their dedifferentiation into induced pluripotent stem (iPS) cells. In addition, we have reported that these iPS factors induce the development of induced multipotent cancer (iPC) cells from gastrointestinal cancer cells by reducing tumor aggressiveness. The efficiency of iPS reprogramming increased when p53 was inhibited. The study of cancer cells suggests that the p53 pathways might be involved in the aggressive phenotypes of iPC cells in a long-term culture. However, the roles of gain-of-function oncogenic mutations in TP53, which is a key tumor suppressor gene, remain to be elucidated. We investigated reprogramming efficiency of iPS generation in human diploid fibroblasts that were co-transfected with TP53 mutants and defined factors. The results suggest that mutations in those TP53 regions that are involved in DNA contact might play a critical role in the efficiency of iPS generation. Taken together, our studies suggest 2 roles of TP53 mutations in reprogramming: (1) the structural mutations might contribute to, or collaborate with, other mutations to regulate the maintenance of genomic stability; (2) the DNA-contact mutations could affect the downstream target genes, which may be distinct from those involved in wild-type p53 function. These molecular manipulations of tumorigenicity and enhancement of cellular reprogramming efficiency by the p53 pathway will open an attractive and useful avenue for future medicine.
Highlights
Whether complete cellular reprogramming occurred through epigenomic modifications, rather than by the cell fusion approach, remained debatable, the discovery that complete reprogramming could be achieved by introducing defined transcription factors Oct4, Sox2, Klf4, and c-Myc into the terminally differentiated somatic fibroblasts of mouse [1] and human origins [2] was an important breakthrough
We recently showed that gastrointestinal cancer cells acquired multipotential differentiation ability on introducing defined factors, i.e., the gene expression profiles of mesoderm and ectoderm appeared in those gastrointestinal cancer cells of endodermal origin (induced multipotent cancer cells) [4]
Following induced pluripotent stem (iPS) factor-mediated reprogramming of HuCC-T1 cholangiocellular carcinoma cells harboring gain-of-function mutations, the expression of all embryonic stem (ES)-like genes, except activated endogenous c-MYC, was downregulated in the induced multipotent cancer (iPC) cells, suggesting a role of such oncogenic mutations in the reactivation of malignant phenotype in long-term culture in vitro [5], presumably via the accumulation of further mutations or increased genomic instability
Summary
Whether complete cellular reprogramming occurred through epigenomic modifications, rather than by the cell fusion approach, remained debatable, the discovery that complete reprogramming could be achieved by introducing defined transcription factors Oct4 ( known as Pou5f1), Sox2, Klf4, and c-Myc into the terminally differentiated somatic fibroblasts of mouse [1] and human origins [2] was an important breakthrough. Following iPS factor-mediated reprogramming of HuCC-T1 cholangiocellular carcinoma cells harboring gain-of-function mutations, the expression of all ES-like genes, except activated endogenous c-MYC, was downregulated in the iPC cells, suggesting a role of such oncogenic mutations in the reactivation of malignant phenotype in long-term culture in vitro [5], presumably via the accumulation of further mutations or increased genomic instability.
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