Dishevelled 1-Regulated Superpotent Cancer Stem Cells Mediate Wnt Heterogeneity and Tumor Progression in Hepatocellular Carcinoma

Wen-Ying Liao; Chung-Chi Hsu; Tze-Sian Chan; Chia-Jui Yen; Wei-Yu Chen; Hung-Wei Pan; Kelvin K Tsai

doi:10.1016/j.stemcr.2020.02.003

Dishevelled 1-Regulated Superpotent Cancer Stem Cells Mediate Wnt Heterogeneity and Tumor Progression in Hepatocellular Carcinoma

Stem Cell Reports. 2020 Mar 10;14(3):462-477. doi: 10.1016/j.stemcr.2020.02.003.

Authors

Wen-Ying Liao¹, Chung-Chi Hsu², Tze-Sian Chan³, Chia-Jui Yen⁴, Wei-Yu Chen⁵, Hung-Wei Pan⁶, Kelvin K Tsai⁷

Affiliations

¹ Graduate Institute of Clinical Medicine, Wan Fang Hospital, Taipei Medical University, 250 Wuxing St., Xinyi, Taipei 11031, Taiwan; Laboratory of Advanced Molecular Therapeutics, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan.
² Graduate Institute of Clinical Medicine, Wan Fang Hospital, Taipei Medical University, 250 Wuxing St., Xinyi, Taipei 11031, Taiwan; School of Medicine, College of Medicine, I-Shou University, Kaohsiung City 84001, Taiwan.
³ Laboratory of Advanced Molecular Therapeutics, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan; School of Medicine, College of Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan; Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan; Integrative Therapy Center for Gastroenterologic Cancers, Taipei Medical University, Taipei 11031, Taiwan.
⁴ Division of Hemato-oncology, Department of Medicine, National Cheng-Kung University Hospital, Tainan 70403, Taiwan.
⁵ Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan.
⁶ School of Medicine, College of Medicine, I-Shou University, Kaohsiung City 84001, Taiwan.
⁷ Graduate Institute of Clinical Medicine, Wan Fang Hospital, Taipei Medical University, 250 Wuxing St., Xinyi, Taipei 11031, Taiwan; Laboratory of Advanced Molecular Therapeutics, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan; Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan; Integrative Therapy Center for Gastroenterologic Cancers, Taipei Medical University, Taipei 11031, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan; National Institute of Cancer Research, National Health Research Institutes (NHRIs), Zhunan 35053, Taiwan. Electronic address: tsaik@tmu.edu.tw.

Abstract

Various populations of cancer stem cells (CSCs) have been identified in hepatocellular carcinoma (HCC). Wnt signaling is variably activated in HCC and regulates CSCs and tumorigenesis. We explored cell-to-cell Wnt and stemness heterogeneity in HCC by labeling freshly isolated cancer cells with a Wnt-specific reporter, thereby identifying a small subset (0.4%-8.9%) of Wnt-activity^high cells. Further cellular subset analysis identified a refined subset of Wnt-activity^highALDH1⁺EpCAM⁺ triple-positive (TP) cells as the most stem-like, phenotypically plastic, and tumorigenic among all putative CSC populations. These TP "superpotent CSCs" (spCSCs) specifically upregulate the expression of dishevelled 1 (DVL1) through the antagonism between abnormal spindle-like microcephaly-associated (ASPM) and the ubiquitin ligase complex Cullin-3/KLHL-12. Subsequent functional and molecular studies revealed the role of DVL1 in controlling spCSCs and their tumorigenic potential. These findings provide the mechanistic basis of the Wnt and stemness heterogeneity in HCC and highlight the important role of DVL1^high spCSCs in tumor progression.

Keywords: ASPM; Dishevelled-1; Wnt; cancer stem cells; hepatocellular carcinoma; heterogeneity; prognostic marker; ubiquitin ligase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Biomarkers, Tumor / metabolism
Carcinogenesis / metabolism
Carcinogenesis / pathology
Carcinoma, Hepatocellular / metabolism*
Carcinoma, Hepatocellular / pathology*
Cullin Proteins / metabolism
Disease Progression*
Dishevelled Proteins / metabolism*
Epistasis, Genetic
Genetic Testing
Green Fluorescent Proteins / metabolism
Hep G2 Cells
Humans
Liver Neoplasms / metabolism*
Liver Neoplasms / pathology*
Neoplastic Stem Cells / metabolism*
Nerve Tissue Proteins / metabolism
Phenotype
Prognosis
Wnt Signaling Pathway*

Substances

ASPM protein, human
Adaptor Proteins, Signal Transducing
Biomarkers, Tumor
Cullin Proteins
DVL1 protein, human
Dishevelled Proteins
KLHL12 protein, human
Nerve Tissue Proteins
Green Fluorescent Proteins