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Cancer stem cell self-renewal as a therapeutic target in human oral cancer

Oncogene volume 38, pages 5440–5456 (2019)Cite this article

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Abstract

Tumor recurrence following treatment remains a major clinical challenge in oral cavity cancer. Cancer stem cells (CSCs) have been isolated from human oral cancers and been considered as the driving force of tumor recurrence and metastasis. However, it still remains unclear whether targeting CSCs in oral cancer is a clinically relevant strategy to combat cancer recurrence and metastasis. Here, using clinical cancer specimens and patient-derived xenografts, we show that the self-renewal regulator BMI1 is highly expressed in CSCs of oral cavity squamous cell carcinoma. Inhibition of BMI1 decreases oral CSCs’ self-renewal and tumor-initiating potential. Treatment of pre-established human oral cancer xenografts with a BMI1 inhibitor resulted in abrogation of tumor progression and reduced the frequency of CSCs in the xenografts. Remarkably, the BMI1 inhibitor has therapeutic effects in cisplatin-resistant tumors and can reduce metastases initiated by circulating CSCs. Mechanistically, BMI1-inhibition leads to oral CSC necroptotic cell death, which underlies the self-renewal impairment after inhibiting BMI1. Our data provide a pre-clinical proof-of-concept that targeting BMI1-related CSC self-renewal is a clinically relevant anti-cancer therapy in human oral cavity squamous cell carcinoma.

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Funding

This work was supported in parts by the Department of Otolaryngology-Head & Neck Surgery and Cancer Center at Loma Linda University, and by institutional grants GCAT 2140225, GCAT 2150204, and GRASP 2140307.

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Author notes

  1. Jinwei Hu

    Present address: Department of Head and Neck Surgery, Fontana Medical Center, Kaiser Permanente, Fontana, CA, 92335, USA

  2. These authors contributed equally: Jinwei Hu, Saied Mirshahidi

Authors and Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA

    Jinwei Hu, Alfred Simental, Steve C. Lee, Pedro A. De Andrade Filho, Nathaniel R. Peterson & Xiangpeng Yuan

  2. Cancer Center Biospecimen Laboratory, Loma Linda University Medical Center, Loma Linda, CA, 92354, USA

    Saied Mirshahidi

  3. Department of Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA

    Saied Mirshahidi, Penelope Duerksen-Hughes & Xiangpeng Yuan

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Contributions

JH, SM, and XY conceived and designed the study. AS, SCL, PD, and NRP provided human samples. JH, SM, and XY performed experiments. JH, SM, AS, SCL, PD, NRP, PD, and XY contributed to experimental design and data analysis. JH contributed to tissue data analysis, images, and expertize. JH, SM, SCL, PD, and XY contributed to manuscript writing. All authors revised and edited the manuscript.

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Correspondence to Xiangpeng Yuan.

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Hu, J., Mirshahidi, S., Simental, A. et al. Cancer stem cell self-renewal as a therapeutic target in human oral cancer. Oncogene 38, 5440–5456 (2019). https://doi.org/10.1038/s41388-019-0800-z

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