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Arsenite inhibits the function of CD133+ CD13+ liver cancer stem cells by reducing PML and Oct4 protein expression

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Tumor Biology

Abstract

Cancer stem cells (CSCs) can form new tumors and contribute to post-operative recurrence and metastasis. We showed that CD133+CD13+ hepatocytes isolated from HuH7 cells and primary HCC cells display biochemical and functional characteristics typical of CSCs, suggesting that CD133+CD13+ hepatocytes in primary HCC tumors function as CSCs. We also found that arsenite treatment reduced the viability and stemness of CD133+CD13+ hepatocytes, enhanced the sensitivity of HuH7 cells to pirarubicin, and reduced the tumorigenicity of CD133+CD13+ hepatocytes xenografts in mice. The effects of sodium arsenite treatment in CD133+CD13+ hepatocytes were mediated by the post-transcriptional suppression of PML expression and the inhibition of Oct4, Sox2, and Klf4 expression at the transcriptional level. Incomplete rescue of Oct4 expression in arsenic-treated cells ectopically expressing an siRNA-resistant PML transcript suggested that OCT4 regulation in liver CSCs involves other factors in addition to PML. Our findings provide evidence of a specific role for PML in regulating Oct4 levels in liver CSCs and highlight the clinical importance of arsenic for improving the efficacy of other chemotherapeutic agents and the prevention of post-operative HCC recurrence and metastasis.

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Acknowledgments

This research was supported by grants from the Chinese Medicine Technological Item of Municipal Health Bureau of Chongqing City (grant no. ZY20132047).

Author contributions

S.J. designed the study, analyzed data, and wrote the paper. H.T. collected HCC samples and performed the immunohistochemical and immunofluorescence analyses. Y.J. was involved in designing the study and performed the western blotting. Y.K. performed the qRT-PCR and flow cytometry analyses. Z.T. performed the tumor sphere, cell proliferation, and in vivo tumorigenesis assays. All of the authors discussed the results and contributed to the content of the manuscript.

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Authors and Affiliations

  1. Department of Hepaticbiliary Surgery, Kai Xian Poeples Hospital of Chongqing City, 8#, Ankang Road, Hanfeng Street, Kai County, Chongqing city, 405400, China

    Huaming Tang, Shilong Jin, Zhiming Tan, Zhang Peng & Yuanli Kuang

  2. the Clinical Medical Department, Peking Union Medical College, Zijing Department, Tsinghua University, 328A 27#, Beijing City, China

    Yukai Jin

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  1. Huaming Tang
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  3. Shilong Jin
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Correspondence to Shilong Jin.

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Tang, H., Jin, Y., Jin, S. et al. Arsenite inhibits the function of CD133+ CD13+ liver cancer stem cells by reducing PML and Oct4 protein expression. Tumor Biol. 37, 14103–14115 (2016). https://doi.org/10.1007/s13277-016-5195-7

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  • DOI: https://doi.org/10.1007/s13277-016-5195-7

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