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KLF4 functions as an oncogene in promoting cancer stem cell-like characteristics in osteosarcoma cells

Acta Pharmacologica Sinica (2018) | Download Citation

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Abstract

Despite more effective chemotherapy combined with limb-salvage surgery for the osteosarcoma treatment, survival rates for osteosarcoma patients have stagnated over the past three decades due to the poor prognosis. Osteosarcoma cancer stem cells (OSCs) are responsible for the growth and metastasis of osteosarcoma. The existence of OSCs offers a theoretical explanation for therapeutic failures including tumor recurrence, metastasis, and drug resistance. Understanding the pathways that regulate properties of OSCs may shed light on mechanisms that lead to osteosarcoma and suggest better modes of treatment. In this study, we showed that the expression level of Kruppel-like factor 4 (KLF4) is highly associated with human osteosarcoma cancer stemness. KLF4-overexpressed osteosarcoma cells displayed characteristics of OSCs: increased sphere-forming potential, enhanced levels of stemness-associated genes, great chemoresistance to adriamycin and CDDP, as well as more metastasis potential. Inversely, KLF4 knockdown could reduce colony formation in vitro and inhibit tumorigenesis in vivo, supporting an oncogenic role for KLF4 in osteosarcoma pathogenesis. Furthermore, KLF4 was shown to activate the p38 MAPK signaling pathway to promote cancer stemness. Altogether, our studies uncover an essential role for KLF4 in regulation of OSCs and identify KLF4–p38 MAPK axis as a potential therapeutic target for osteosarcoma treatment.

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Acknowledgements

We would like to acknowledge Dr. D.B. Kohn for providing lentivirus pR Δ 8.9 and pMD.G plasmids. This work was supported by grants from the National Natural Science Foundation of China (No. 81473227) and grants from the International Science & Technology Cooperation Program of China (2014DFE30050), the Fundamental Research Funds for the Central Universities (2017XZZX011-04) and the Zhejiang Provincial Natural Science Foundation of China (No. LY17H310004) (to D.Z.).

Author contributions

M-dY, Q-jH, BY, X-tQ, and Y-lL designed the research project; X-tQ, Y-lL, D-fZ, TX, and BL performed the experiments; X-tQ and Y-lL analyzed the data; Y-qZ, LF, J-qG, and L-sY contributed reagents; and M-dY, X-tQ, and Y-lL wrote the manuscript.

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Author notes

  1. These authors contributed equally: Xiao-tian Qi, Yang-ling Li.

Affiliations

  1. Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    • Xiao-tian Qi
    • , Yang-ling Li
    • , Yan-qi Zhang
    • , Tong Xu
    • , Bin Lu
    • , Jian-qing Gao
    • , Lu-shan Yu
    • , Di-feng Zhu
    • , Bo Yang
    • , Qiao-jun He
    •  & Mei-dan Ying
  2. Department of Pharmacy, The Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, 310008, China

    • Yan-qi Zhang
  3. Cancer Research Program, Max Delbrueck Center for Molecular Medicine in the Helmholtz Society, Berlin, Germany

    • Liang Fang
  4. Center for Drug Safety Evaluation and Research of Zhejiang University, Zhejiang University, Hangzhou, 310058, China

    • Di-feng Zhu

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The authors declare no competing interests.

Corresponding author

Correspondence to Mei-dan Ying.

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DOI

https://doi.org/10.1038/s41401-018-0050-6