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Combination of 5-fluorouracil and 2-morphilino-8-phenyl-4H-chromen-4-one may inhibit liver cancer stem cell activity

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Tumor Biology

Abstract

This work aims to evaluate the impact of 2-morpholino-8-phenyl-4H-chromen-4-one (LY294002) combined 5-fluorouracil (5-FU) for the activity of CD90+ liver cancer cells derived from the human liver cancer cell line MHCC97H. MHCC97H sphere-forming cells (MSFCs) were amplified in serum-free medium and CD90+ cells were isolated from bulk MSFCs using flow cytometry. The phenotype of these CD90+ cells which show liver cancer stem cells (LCSCs) behavior was validated in vitro and in a xenograft model in nude mice. MSFCs, CD90+ liver cancer cells (CD90+ LCCs), and parental MHCC97H cells were treated with no drug, LY294002 alone, 5-FU alone, or both drugs together and then compared in terms of stem cell-related gene expression, proliferation, and invasion. Stem cell phenotype increased with increasing proportion of CD90+ cells, in ascending order: parental MHCC97H cells, MSFCs, and CD90+ liver cancer cells. LY294002 reduced the expression of CD90, Nanog, SALL4, and SHP2 in a concentration-dependent manner in CD90+ LCCs and MSFCs, but not in parental cells. LY294002 blocked AKT phosphorylation via the PI3K/AKT signaling pathway and inhibited CD90+ LCCs proliferation and tumorigenicity in vitro and in vivo. CD90+ liver cancer cells can express liver cancer stem cell phenotype. LY294002 inhibits the proliferation and invasion of MHCC97H-derived CD90+ LCCs and sensitized CD90+ LCCs-derived tumors to 5-FU in the current study which may provide insight into the association between the LY294002 combined 5-FU and liver cancer stem cell (LCSCs).

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 81160262 and 81260088) and the Guangxi Cancer Institute and Key Laboratory of High-Incidence-Tumor early Prevention and Treatment, Ministry of Education.

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    Authors and Affiliations

    1. Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, China

      Yu-Chong Peng, Shi-Dong Lu, Jian-Hong Zhong, Zhi-Bo **e, Xue-Mei You, Ning-Fu Peng & Le-Qun Li

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    Correspondence to Ning-Fu Peng or Le-Qun Li.

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    This study was approved by the Ethics Committee of the Affiliated Tumor Hospital of Guangxi Medical University; it was performed according to the Declaration of Helsinki 2013 edition. Animal experiments were carried out in compliance with standard protocols approved by the Ethical Committee of Guangxi Medical University and the Committee of Experimental Animal Feeding and Management.

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    Yu-Chong Peng, Shi-Dong Lu and Jian-Hong Zhong contributed equally to this work.

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    Peng, YC., Lu, SD., Zhong, JH. et al. Combination of 5-fluorouracil and 2-morphilino-8-phenyl-4H-chromen-4-one may inhibit liver cancer stem cell activity. Tumor Biol. 37, 10943–10958 (2016). https://doi.org/10.1007/s13277-016-4915-3

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    • DOI: https://doi.org/10.1007/s13277-016-4915-3

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