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Downregulation of Cancer Stemness by Novel Diterpenoid Ovatodiolide Inhibits Hepatic Cancer Stem Cell-Like Traits by Repressing Wnt/[Formula: see text]-Catenin Signaling.

Authors
  • Liu, Mingche1, 2, 3
  • Bamodu, Oluwaseun Adebayo4, 5
  • Kuo, Kuang-Tai6
  • Lee, Wei-Hwa7
  • Lin, Yen-Kuang8
  • Wu, Alexander T H9
  • M, Hsiao10
  • Tzeng, Yew-Min11, 12
  • Yeh, Chi-Tai4, 5
  • Tsai, Jo-Ting13, 14
  • 1 * Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 2 † Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 3 ‡‡ Department of Urology, Taipei Medical University Hospital, Taipei, Taiwan. , (Taiwan)
  • 4 §§ Department of Hematology and Oncology, Cancer Center, Taipei Medical University - Shuang Ho Hospital, New Taipei City, Taiwan. , (Taiwan)
  • 5 ¶¶ Department of Medical Research & Education, Taipei Medical University - Shuang Ho Hospital, New Taipei City, Taiwan. , (Taiwan)
  • 6 ‡ Division of Thoracic Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 7 § Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 8 ¶ Biostatistics and Research Consultation Center, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 9 ∥ The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 10 ∥∥ Genomics Research Center, Academia Sinica, Taipei, Taiwan. , (Taiwan)
  • 11 *** Center for General Education, National Taitung University, Taitung, Taiwan. , (Taiwan)
  • 12 ††† Department of Applied Chemistry, Chaoyang University of Technology, Taichung, Taiwan. , (Taiwan)
  • 13 ** Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
  • 14 †† Department of Radiation Oncology, Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan. , (Taiwan)
Type
Published Article
Journal
The American journal of Chinese medicine
Publication Date
Jan 01, 2018
Volume
46
Issue
4
Pages
891–910
Identifiers
DOI: 10.1142/S0192415X18500477
PMID: 29792038
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The hierarchical tumor propagation or cancer stem cells (CSCs) model of carcinogenesis postulates that like physiologic adult stem cell (ASC), the CSCs positioned at the apex of any tumor population form the crux of tumor evolution with a constitutive regenerative capacity and differentiation potential. The propagation and recurrence of the characteristically heterogeneous and therapy-resistant hepatocellular carcinoma (HCC), adds to accumulating evidence to support this CSCs model. Based on the multi-etiologic basis of HCC formation which among others, focuses on the disruption of the canonical Wnt signaling pathway, this study evaluated the role of cembrane-type phytochemical, Ovatodiolide, in the modulation of the Wnt/[Formula: see text]-catenin pathway, and its subsequent effect on liver CSCs' activities. Our fluorescence-activated cell sorting (FACS) and quantitative RT-PCR analyses of side population (SP) indicated that CD133+ cells were [Formula: see text]-catenin-overexpressing, more aggressive, and resistant to the conventional anticancer agents, Cisplatin and Doxorubicin, when compared to [Formula: see text]-catenin-downregulated group. We demonstrated that marked upregulation of [Formula: see text]-catenin and its downstream targets effectively enhanced hepatosphere formation, with an associated induction of CD133, OCT4 and Sox2 expression and also caused an significant enhancement of HCC proliferation. However, treatment with Ovatodiolide induced downregulation of [Formula: see text]-catenin and its downstream effector genes, abolished hepatosphere formation and reversed the [Formula: see text]-catenin-associated enhancement of HCC growth. In summary, we demonstrated for the first time that Ovatodiolide suppressed the canonical Wnt signaling pathway, and inhibited the generation of liver CSCs; Thus, projecting Ovatodiolide as a putatively effective therapeutic agent for anti-HCC target therapy.

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