Hypoxia and TP53 deficiency for induced pluripotent stem cell-like properties in gastrointestinal cancer.

Abstract

Induced pluripotent stem (iPS)-like cancer cells (iPC) by the introduction of defined transcription factors reduce the prevalence of the malignant phenotype of digestive system cancer cells, but the induction efficiency is low. The role of hypoxia and TP53 deficiency in iPC cell generation remain unclear. Cellular reprogramming was performed by retroviral infection with OCT3/4, SOX2, KLF4 and c-MYC of wild-type HCT116 colorectal cancer cells and mutant TP53-deficient HCT116 cells. Cells were cultured in normoxia (21% O2) or hypoxia (5% O2) for 30 days after transduction, and the response to hypoxia and comparison of cellular proliferation, invasion and tumourigenesis before and after iPC cell generation were studied. iPC cell generation from wild-type HCT116 cells in hypoxia was approximately 4-times greater than in normoxia (p<0.05), and TP53 deficiency increased conversion efficiency significantly in normoxia (p<0.05). Significant involvement of hypoxia-inducible factors was observed in an immature carbohydrate epitope, Tra-1-60+, colony formation. Generated iPC cells exhibited multi-differentiation potential. Although the iPC cells in hypoxia exhibited reduced proliferation, invasiveness and tumourigenicity, TP53 deficiency in iPC cells resulted in higher tumourigenicity than in wild-type cells. Both hypoxia and TP53 deficiency increase iPC cell generation. TP53 deficiency can also result in deleterious mutations, whereas hypoxia may impact molecular targets of epigenome normalisation.

• Authors: Hiromitsu Hoshino, Hiroaki Nagano, Naotsugu Haraguchi, Shimpei Nishikawa, Akira Tomokuni, Yoshihiro Kano, Takahito Fukusumi, Toshiyuki Saito, Miyuki Ozaki, Daisuke Sakai, Taroh Satoh, Hidetoshi Eguchi, Mitsugu Sekimoto, Yuichiro Doki, Masaki Mori, Hideshi Ishii
• Journal: International journal of oncology (Int J Oncol) Vol. 40 Issue 5 Pg. 1423-30 (May 2012) ISSN: 1791-2423 [Electronic] Greece
• PMID: 22293932 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• KLF4 protein, human
• Klf4 protein, mouse
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• MYC protein, human
• Octamer Transcription Factor-3
• POU5F1 protein, human
• Proto-Oncogene Proteins c-myc
• SOX2 protein, human
• SOXB1 Transcription Factors
• TP53 protein, human
• Tumor Suppressor Protein p53

Topics

• Animals
• Cell Differentiation
• Cell Hypoxia
• Cell Proliferation
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Gene Expression Regulation, Neoplastic
• Genetic Vectors
• HCT116 Cells
• Humans
• Induced Pluripotent Stem Cells (metabolism, pathology)
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Lentivirus (genetics)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Invasiveness
• Neoplasm Transplantation
• Neoplastic Stem Cells (metabolism, pathology)
• Octamer Transcription Factor-3 (genetics, metabolism)
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• RNA Interference
• Retroviridae (genetics)
• SOXB1 Transcription Factors (genetics, metabolism)
• Time Factors
• Transfection
• Tumor Burden
• Tumor Suppressor Protein p53 (deficiency, genetics)