TY - JOUR
T1 - Long-term culture following ES-like gene-induced reprogramming elicits an aggressive phenotype in mutated cholangiocellular carcinoma cells
AU - Nagai, Ken ichi
AU - Ishii, Hideshi
AU - Miyoshi, Norikatsu
AU - Hoshino, Hiromitsu
AU - Saito, Toshiyuki
AU - Sato, Tetsuya
AU - Tomimaru, Yoshito
AU - Kobayashi, Shogo
AU - Nagano, Hiroaki
AU - Sekimoto, Mitsugu
AU - Doki, Yuichiro
AU - Mori, Masaki
PY - 2010/4/30
Y1 - 2010/4/30
N2 - 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.
AB - 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.
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U2 - 10.1016/j.bbrc.2010.03.176
DO - 10.1016/j.bbrc.2010.03.176
M3 - Article
C2 - 20381452
AN - SCOPUS:77951623640
VL - 395
SP - 258
EP - 263
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 2
ER -
