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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number56
JournalCancers
Volume12
Issue number1
DOIs
Publication statusPublished - Jan 2020

Keywords

  • Cancer-associated fibroblasts
  • Extracellular vesicles
  • MiR-21-5p/STAT3/β-catenin signaling
  • Oral squamous cell carcinoma
  • Ovatodiolide
  • Tumor microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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