Long-term culture following ES-like gene-induced reprogramming elicits an aggressive phenotype in mutated cholangiocellular carcinoma cells

Ken ichi Nagai, Hideshi Ishii, Norikatsu Miyoshi, Hiromitsu Hoshino, Toshiyuki Saito, Tetsuya Sato, Yoshito Tomimaru, Shogo Kobayashi, Hiroaki Nagano, Mitsugu Sekimoto, Yuichiro Doki, Masaki Mori

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25 Citations (Scopus)

Abstract

Background: We recently reported that gastrointestinal (GI) cancer cells can be reprogrammed to a pluripotent state by the ectopic expression of defined embryonic stem (ES)-like transcriptional factors. The induced pluripotent cancer (iPC) cells from GI cancer were sensitized to chemotherapeutic agents and differentiation-inducing treatment during a short-term culture, although a phenotype induced by long-term culture needs to be studied. Methods: A long-term cultured (Lc)-iPC cells were produced in GI cancer cell lines by virus-mediated introduction of four ES-like genes-c-MYC, SOX2, OCT3/4, and KLF4-followed by a culture more than three months after iPC cells induction. An acquired state was studied by expression of immature-related surface antigens, Tra-1-60, Tra-1-81, Tra-2-49, and Ssea-4; and epigenetic trimethyl modification at lysine 4 of histone H3. Sensitivity to chemotherapeutic agents and tumorigenicity were studied in Lc-iPC cells. Results: Whereas the introduction of defined factors of iPC cells once induced an immature state and sensitized cells to therapeutic reagents, the endogenous expression of the ES-like genes except for activated endogenous c-MYC was down-regulated in a long-term culture, suggesting a high magnitude of the reprogramming induction by defined factors and the requirement of therapeutic maintenance in Lc-iPC cells from cholangiocellular carcinoma HuCC-T1 cells, which harbor TP53R175H and KRASG12D. The Lc-iPC cells showed resistance to 5-fluorouracil in culture, and high tumorigenic ability with activated endogenous c-MYC in immunodeficient mice. Conclusion: The Lc-iPC cells from HuCC-T1 might be prone to an undesirable therapeutic response because of an association with the activated endogenous c-MYC. To consider the possible therapeutic approach in GI cancer, it would be necessary to develop a predictive method for evaluating the improper reprogramming-associated aggressive phenotype of iPC cells.

Original languageEnglish
Pages (from-to)258-263
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume395
Issue number2
DOIs
Publication statusPublished - Apr 30 2010

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Nagai, K. I., Ishii, H., Miyoshi, N., Hoshino, H., Saito, T., Sato, T., Tomimaru, Y., Kobayashi, S., Nagano, H., Sekimoto, M., Doki, Y., & Mori, M. (2010). Long-term culture following ES-like gene-induced reprogramming elicits an aggressive phenotype in mutated cholangiocellular carcinoma cells. Biochemical and Biophysical Research Communications, 395(2), 258-263. https://doi.org/10.1016/j.bbrc.2010.03.176