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

Stem Cell Reports

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:

Published: March 2020

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 cells. Further cellular subset analysis identified a refined subset of Wnt-activityALDH1EpCAM 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 spCSCs in tumor progression.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066362PMC
http://dx.doi.org/10.1016/j.stemcr.2020.02.003DOI Listing

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