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

Kenly Wuputra,Ya-Han Yang,Wen-Hsin Lin,Chia-Chen Ku,Ming-Ho Tsai,Kung-Kai Kuo,Chang-Shen Lin,Kazunari K Yokoyama

doi:10.1186/s41232-017-0041-x

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.

Highlights

The cancer stem cell (CSC) hypothesis initially proposed for leukemia by J
These stemness transcription factors of KLF4 and MYC (SOX2), OCT4, and NANOG co-occupy the promoter regions of about 350 genes in the genome, and OCT4 occupies more than 90% of the promoter regions bound by the OCT4 and SOX2 in human embryonic stem cell (ESC). These findings suggest that the OCT4–SOX2–NANOG axis is the key cascade for stemness [31]
Kaufhold et al [56] reported the association of Yin Yang 1 (YY1) and CSC transcription factors and that YY1 might be a transcriptional repressor that acts on CSC-associated transcription factors such as BMI1, SOX2, and OCT4. They proposed the existence a regulatory loop involving crosstalk between the nuclear factor kB–phosphatidylinositol 3-kinase (PI3K)–AKT pathway and the downstream controls of target gene products such as YY1, OCT4, SOX2 and BMI1. These findings suggest that most of the genes critical for cancer reprogramming belong to the families of (i) stemness genes, (ii) oncogenes/tumor suppressor genes, and (iii) epigenetic-related genes of DNA or histone modification, and (iv) the INK4 locus mediated by polycomb repressive complex (PRC) family

Summary

Background

The cancer stem cell (CSC) hypothesis initially proposed for leukemia by J. Current cancer cell-reprogramming techniques such as somatic cell nuclear transfer [16] and the generation of induced pluripotent stem cells (iPSCs) [17,18,19] are used to identify oncogenic genes. The generation of iPSCs from cancer cells may provide tools for exploring the mechanisms of tumor initiation and progression in vitro, for studying the heterogeneity and origin of CSCs, and for producing cancer type-specific drug discovery. These reprogramming methods remain a challenge because of the cancer-specific epigenetic state and chromosomal aberrations of cancer cells. Reprograming studies using patient-derived cancer cells have produced solid evidence of the capacity for reversal of the malignant phenotype, and this method holds great promise for breaking the seemingly irreversible state associated with cancer

Methods of reprogramming

Findings

Conclusions