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 presented.)-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 presented.)-catenin-overexpressing, more aggressive, and resistant to the conventional anticancer agents, Cisplatin and Doxorubicin, when compared to (Formula presented.)-catenin-downregulated group. We demonstrated that marked upregulation of (Formula presented.)-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 presented.)-catenin and its downstream effector genes, abolished hepatosphere formation and reversed the (Formula presented.)-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.

Original languageEnglish
Pages (from-to)1-20
Number of pages20
JournalAmerican Journal of Chinese Medicine
DOIs
Publication statusAccepted/In press - May 24 2018

Fingerprint

Catenins
Neoplastic Stem Cells
Diterpenes
Liver Neoplasms
Wnt Signaling Pathway
Down-Regulation
Hepatocellular Carcinoma
Neoplasms
Adult Stem Cells
Phytochemicals
Antineoplastic Agents
Doxorubicin
Cisplatin
Population
ovatodiolide
Flow Cytometry
Carcinogenesis
Up-Regulation
Therapeutics
Recurrence

Keywords

  • Canonical Wnt Pathway
  • Chemoresistance
  • Hepatocellular Carcinoma
  • Liver Cancer Stem Cell
  • Ovatodiolide

ASJC Scopus subject areas

  • Complementary and alternative medicine

Cite this

@article{f6aad7fff4b54631b98de9433d445370,
title = "Downregulation of Cancer Stemness by Novel Diterpenoid Ovatodiolide Inhibits Hepatic Cancer Stem Cell-Like Traits by Repressing Wnt/β-Catenin Signaling",
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 presented.)-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 presented.)-catenin-overexpressing, more aggressive, and resistant to the conventional anticancer agents, Cisplatin and Doxorubicin, when compared to (Formula presented.)-catenin-downregulated group. We demonstrated that marked upregulation of (Formula presented.)-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 presented.)-catenin and its downstream effector genes, abolished hepatosphere formation and reversed the (Formula presented.)-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.",
keywords = "Canonical Wnt Pathway, Chemoresistance, Hepatocellular Carcinoma, Liver Cancer Stem Cell, Ovatodiolide",
author = "Mingche Liu and Bamodu, {Oluwaseun Adebayo} and Kuo, {Kuang Tai} and Lee, {Wei Hwa} and Lin, {Yen Kuang} and Wu, {Alexander T.H.} and Hsiao M and Tzeng, {Yew Min} and Yeh, {Chi Tai} and Tsai, {Jo Ting}",
year = "2018",
month = "5",
day = "24",
doi = "10.1142/S0192415X18500477",
language = "English",
pages = "1--20",
journal = "American Journal of Chinese Medicine",
issn = "0192-415X",
publisher = "World Scientific Publishing Co. Pte Ltd",

}

TY - JOUR

T1 - Downregulation of Cancer Stemness by Novel Diterpenoid Ovatodiolide Inhibits Hepatic Cancer Stem Cell-Like Traits by Repressing Wnt/β-Catenin Signaling

AU - Liu, Mingche

AU - Bamodu, Oluwaseun Adebayo

AU - Kuo, Kuang Tai

AU - Lee, Wei Hwa

AU - Lin, Yen Kuang

AU - Wu, Alexander T.H.

AU - M, Hsiao

AU - Tzeng, Yew Min

AU - Yeh, Chi Tai

AU - Tsai, Jo Ting

PY - 2018/5/24

Y1 - 2018/5/24

N2 - 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 presented.)-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 presented.)-catenin-overexpressing, more aggressive, and resistant to the conventional anticancer agents, Cisplatin and Doxorubicin, when compared to (Formula presented.)-catenin-downregulated group. We demonstrated that marked upregulation of (Formula presented.)-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 presented.)-catenin and its downstream effector genes, abolished hepatosphere formation and reversed the (Formula presented.)-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.

AB - 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 presented.)-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 presented.)-catenin-overexpressing, more aggressive, and resistant to the conventional anticancer agents, Cisplatin and Doxorubicin, when compared to (Formula presented.)-catenin-downregulated group. We demonstrated that marked upregulation of (Formula presented.)-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 presented.)-catenin and its downstream effector genes, abolished hepatosphere formation and reversed the (Formula presented.)-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.

KW - Canonical Wnt Pathway

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KW - Hepatocellular Carcinoma

KW - Liver Cancer Stem Cell

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