Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Jia-Hong Chen; Alexander T H Wu; Oluwaseun Adebayo Bamodu; Vijesh Kumar Yadav; Tsu-Yi Chao; Yew-Min Tzeng; Debabrata Mukhopadhyay; Michael Hsiao; Jih-Chin Lee

doi:10.3390/cancers12010056

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Cancers (Basel). 2019 Dec 24;12(1):56. doi: 10.3390/cancers12010056.

Authors

Jia-Hong Chen^{1

2}, Alexander T H Wu^{3

4}, Oluwaseun Adebayo Bamodu^{5

6}, Vijesh Kumar Yadav^{7

8}, Tsu-Yi Chao^{5

9}, Yew-Min Tzeng^{10

11}, Debabrata Mukhopadhyay¹², Michael Hsiao^{13

14}, Jih-Chin Lee^{15

16}

Affiliations

¹ Graduate and Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
² Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
³ The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
⁴ Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan.
⁵ Department of Hematology and Oncology, Cancer Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan.
⁶ Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan.
⁷ The Program for Translational Medicine, Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
⁸ Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei 11031, Taiwan.
⁹ Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan.
¹⁰ Center for General Education, National Taitung University, Taitung 95092, Taiwan.
¹¹ Department of Life Science, National Taitung University, Taitung 95092, Taiwan.
¹² Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
¹³ Genomics Research Center, Academia Sinica, Taipei City 11529, Taiwan.
¹⁴ Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
¹⁵ Department of Otolaryngology, Head and Neck Surgery Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.
¹⁶ Department of biological science and technology, Institute of bioinformatics and systems biology, National Chiao Tung University, Hsinchu 300, Taiwan.

Abstract

Oral squamous cell carcinoma (OSCC) is among the most commonly diagnosed malignancies in the world. Patients with OSCC often develop treatment resistance, resulting in a poor prognosis. Mounting evidence indicates that interactions between cancerous cells and other components of the tumor microenvironment (TME) determine their response to treatment. Herein, we examined the role of cancer stem cell-derived extracellular vesicles (CSC_EVs) generated from CAL27 and SCC-15 OSCC cells in the development of cisplatin (CDDP) resistance. We demonstrated that CSC_EVs enhance CDDP resistance, clonogenicity, and the tumorsphere formation potential of OSCC cells. Our bioinformatics analyses revealed that OSCC_EVs are enriched with microRNA (miR)-21-5p and are associated with increased metastasis, stemness, chemoresistance, and poor survival in patients with OSCC. Mechanistically, enhanced activity of CSC_EVs was positively correlated with upregulated β-catenin, phosphatidylinositol-3 kinase (PI3K), signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin (mTOR), and transforming growth factor (TGF)-β1 messenger (m)RNA and protein expression levels. CSC_EVs also conferred a cancer-associated fibroblast (CAF) phenotype on normal gingival fibroblasts (NGFs), with the resultant CAFs enhancing the oncogenicity of OSCC cells. Interestingly, treatment with ovatodiolide (OV), the bioactive component of Anisomeles indica, suppressed OSCC tumorigenesis by reducing the cargo content of EVs derived from CSCs, suppressing self-renewal, and inhibiting the NGF-CAF transformation by disrupting EV-TME interactions. Moreover, by suppressing miR-21-5p, STAT3, and mTOR expressions in CSC_EVs, OV re-sensitized CSCs to CDDP and suppressed OSCC tumorigenesis. In vivo, treatment with OV alone or in combination with CDDP significantly reduced the tumor sphere-forming ability and decreased EV cargos containing mTOR, PI3K, STAT3, β-catenin, and miR-21-5p. In summary, our findings provide further strong evidence of OV's therapeutic effect in OSCC.

Keywords: cancer-associated fibroblasts; extracellular vesicles; miR-21-5p/STAT3/β-catenin signaling; oral squamous cell carcinoma; ovatodiolide; tumor microenvironment.

Abstract

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