2. Academic Validation
  3. Areca nut-induced metabolic reprogramming and M2 differentiation promote OPMD malignant transformation

Areca nut-induced metabolic reprogramming and M2 differentiation promote OPMD malignant transformation

  • J Exp Clin Cancer Res. 2024 Aug 20;43(1):233. doi: 10.1186/s13046-024-03163-z.
Shyng-Shiou F Yuan 1 2 3 4 5 6,  Leong-Perng Chan 7 8 9,  Hieu D H Nguyen 10,  Chang-Wei Su 10 11,  Yuk-Kwan Chen 10 12,  Jeff Yi-Fu Chen 13,  Shigetaka Shimodaira 14 15 16 17,  Stephen Chu-Sung Hu 18 19,  Steven Lo 20 21,  Yen-Yun Wang 22 23 24
Affiliations

Affiliations

  • 1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 2 Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
  • 3 Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
  • 4 Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
  • 5 Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 6 Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, Center for Intelligent Drug Systems and Smart Biodevices (IDS2B), National Yang Ming Chiao Tung University, 75 Bo-Ai Street, Hsinchu, Taiwan.
  • 7 Cohort Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 8 Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 9 Department of Otorhinolaryngology-Head and Neck Surgery, Kaohsiung Municipal Ta-Tung Hospital and Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
  • 10 School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, No.100, Shih-Chuan 1st Road, Sanmin Dist., Kaohsiung, 80708, Taiwan.
  • 11 Division of Oral and Maxillofacial Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
  • 12 Division of Oral Pathology & Maxillofacial Radiology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
  • 13 Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 14 Department of Regenerative Medicine, Kanazawa Medical University, Kahoku, Ishikawa, 920-0293, Japan.
  • 15 Center for Regenerative Medicine, Kanazawa Medical University Hospital, Kahoku, Ishikawa, 920-0293, Japan.
  • 16 Division of Stem Cell Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Kahoku, Ishikawa, 920-0293, Japan.
  • 17 Department of Transfusion Medicine and Cell Processing, Tokyo Women's Medical University, Shinjuku, Tokyo, 162-8666, Japan.
  • 18 Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
  • 19 Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
  • 20 Canniesburn Regional Plastic Surgery and Burns Unit, Glasgow, G4 0SF, UK.
  • 21 College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
  • 22 Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan. wyy@kmu.edu.tw.
  • 23 Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan. wyy@kmu.edu.tw.
  • 24 School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, No.100, Shih-Chuan 1st Road, Sanmin Dist., Kaohsiung, 80708, Taiwan. wyy@kmu.edu.tw.
PMID: 39160581 DOI: 10.1186/s13046-024-03163-z
Abstract

Background: Betel quid and its major ingredient, areca nut, are recognized by IARC as major risk factors in oral Cancer development. Areca nut extract (ANE) exposure has been linked to OPMD progression and malignant transformation to OSCC. However, the detailed mechanism through which ANE acts on other cell types in the oral microenvironment to promote oral carcinogenesis remains elusive.

Methods: Immunoprofiling of macrophages associated with OPMD and OSCC was carried out by immunohistochemical and immunofluorescence staining. Phosphokinase and cytokine arrays and western blotting were performed to determine the underlying mechanisms. Transwell assays were used to evaluate the migration-promoting effect of ANE. Hamster model was finally applied to confirm the in vivo effect of ANE.

Results: We reported that M2 macrophages positively correlated with oral Cancer progression. ANE induced M2 macrophage differentiation, CREB phosphorylation and VCAM-1 secretion and increased Mitochondrial Metabolism. Conditioned medium and VCAM-1 from ANE-treated macrophages promoted migration and mesenchymal phenotypes in oral precancer cells. In vivo studies showed that ANE enhanced M2 polarization and related signaling pathways in the oral buccal tissues of hamsters.

Conclusion: Our study provides novel mechanisms for areca nut-induced oral carcinogenesis, demonstrating that areca nut promotes M2 macrophage differentiation and secretion of oncogenic cytokines that critically activate malignant transformation of oral premalignant cells.

Keywords

Areca nut; Macrophage; Mitochondrial metabolism; OPMD; OSCC.

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