Dishevelled 1-Regulated Superpotent Cancer Stem Cells Mediate Wnt Heterogeneity and Tumor Progression in Hepatocellular Carcinoma
Summary: 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 w...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-03-01
|
| Series: | Stem Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221367112030059X |
| _version_ | 1818047039400837120 |
|---|---|
| author | Wen-Ying Liao Chung-Chi Hsu Tze-Sian Chan Chia-Jui Yen Wei-Yu Chen Hung-Wei Pan Kelvin K. Tsai |
| author_facet | Wen-Ying Liao Chung-Chi Hsu Tze-Sian Chan Chia-Jui Yen Wei-Yu Chen Hung-Wei Pan Kelvin K. Tsai |
| author_sort | Wen-Ying Liao |
| collection | DOAJ |
| description | Summary: 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-activityhigh cells. Further cellular subset analysis identified a refined subset of Wnt-activityhighALDH1+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 DVL1high spCSCs in tumor progression. : In this article, Tsai and colleagues investigated the Wnt and stemness heterogeneity in HCC and identified a novel subset of Wnt-activityhigh “superpotent cancer stem cells” (spCSCs). The existence of spCSCs is independent of β-catenin mutations and its proportion correlates with poor prognosis in patients with HCC. Mechanistically, spCSCs are positively regulated by the Wnt-ASPM-DVL1 signaling axis through protein-protein interactions. Keywords: Dishevelled-1, Wnt, cancer stem cells, hepatocellular carcinoma, heterogeneity, ASPM, ubiquitin ligase, prognostic marker |
| first_indexed | 2024-12-10T09:59:27Z |
| format | Article |
| id | doaj.art-1424c1640622477d9db3d11114a2ae15 |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-12-10T09:59:27Z |
| publishDate | 2020-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-1424c1640622477d9db3d11114a2ae152022-12-22T01:53:23ZengElsevierStem Cell Reports2213-67112020-03-01143462477Dishevelled 1-Regulated Superpotent Cancer Stem Cells Mediate Wnt Heterogeneity and Tumor Progression in Hepatocellular CarcinomaWen-Ying Liao0Chung-Chi Hsu1Tze-Sian Chan2Chia-Jui Yen3Wei-Yu Chen4Hung-Wei Pan5Kelvin K. Tsai6Graduate Institute of Clinical Medicine, Taipei Medical University, 250 Wuxing St., Xinyi, Taipei 11031, Taiwan; Laboratory of Advanced Molecular Therapeutics, Taipei Medical University, Taipei 11031, TaiwanGraduate Institute of Clinical Medicine, Taipei Medical University, 250 Wuxing St., Xinyi, Taipei 11031, Taiwan; School of Medicine, College of Medicine, I-Shou University, Kaohsiung City 84001, TaiwanLaboratory of Advanced Molecular Therapeutics, Taipei Medical University, Taipei 11031, Taiwan; School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Division of Gastroenterology, Department of Internal Medicine, Taipei Medical University, Taipei 11031, Taiwan; Integrative Therapy Center for Gastroenterologic Cancers, Taipei Medical University, Taipei 11031, TaiwanDivision of Hemato-oncology, Department of Medicine, National Cheng-Kung University Hospital, Tainan 70403, TaiwanDepartment of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei 11031, TaiwanSchool of Medicine, College of Medicine, I-Shou University, Kaohsiung City 84001, TaiwanGraduate Institute of Clinical Medicine, Taipei Medical University, 250 Wuxing St., Xinyi, Taipei 11031, Taiwan; Laboratory of Advanced Molecular Therapeutics, Taipei Medical University, Taipei 11031, Taiwan; Division of Gastroenterology, Department of Internal Medicine, 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; Corresponding authorSummary: 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-activityhigh cells. Further cellular subset analysis identified a refined subset of Wnt-activityhighALDH1+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 DVL1high spCSCs in tumor progression. : In this article, Tsai and colleagues investigated the Wnt and stemness heterogeneity in HCC and identified a novel subset of Wnt-activityhigh “superpotent cancer stem cells” (spCSCs). The existence of spCSCs is independent of β-catenin mutations and its proportion correlates with poor prognosis in patients with HCC. Mechanistically, spCSCs are positively regulated by the Wnt-ASPM-DVL1 signaling axis through protein-protein interactions. Keywords: Dishevelled-1, Wnt, cancer stem cells, hepatocellular carcinoma, heterogeneity, ASPM, ubiquitin ligase, prognostic markerhttp://www.sciencedirect.com/science/article/pii/S221367112030059X |
| spellingShingle | Wen-Ying Liao Chung-Chi Hsu Tze-Sian Chan Chia-Jui Yen Wei-Yu Chen Hung-Wei Pan Kelvin K. Tsai Dishevelled 1-Regulated Superpotent Cancer Stem Cells Mediate Wnt Heterogeneity and Tumor Progression in Hepatocellular Carcinoma Stem Cell Reports |
| title | Dishevelled 1-Regulated Superpotent Cancer Stem Cells Mediate Wnt Heterogeneity and Tumor Progression in Hepatocellular Carcinoma |
| title_full | Dishevelled 1-Regulated Superpotent Cancer Stem Cells Mediate Wnt Heterogeneity and Tumor Progression in Hepatocellular Carcinoma |
| title_fullStr | Dishevelled 1-Regulated Superpotent Cancer Stem Cells Mediate Wnt Heterogeneity and Tumor Progression in Hepatocellular Carcinoma |
| title_full_unstemmed | Dishevelled 1-Regulated Superpotent Cancer Stem Cells Mediate Wnt Heterogeneity and Tumor Progression in Hepatocellular Carcinoma |
| title_short | Dishevelled 1-Regulated Superpotent Cancer Stem Cells Mediate Wnt Heterogeneity and Tumor Progression in Hepatocellular Carcinoma |
| title_sort | dishevelled 1 regulated superpotent cancer stem cells mediate wnt heterogeneity and tumor progression in hepatocellular carcinoma |
| url | http://www.sciencedirect.com/science/article/pii/S221367112030059X |
| work_keys_str_mv | AT wenyingliao dishevelled1regulatedsuperpotentcancerstemcellsmediatewntheterogeneityandtumorprogressioninhepatocellularcarcinoma AT chungchihsu dishevelled1regulatedsuperpotentcancerstemcellsmediatewntheterogeneityandtumorprogressioninhepatocellularcarcinoma AT tzesianchan dishevelled1regulatedsuperpotentcancerstemcellsmediatewntheterogeneityandtumorprogressioninhepatocellularcarcinoma AT chiajuiyen dishevelled1regulatedsuperpotentcancerstemcellsmediatewntheterogeneityandtumorprogressioninhepatocellularcarcinoma AT weiyuchen dishevelled1regulatedsuperpotentcancerstemcellsmediatewntheterogeneityandtumorprogressioninhepatocellularcarcinoma AT hungweipan dishevelled1regulatedsuperpotentcancerstemcellsmediatewntheterogeneityandtumorprogressioninhepatocellularcarcinoma AT kelvinktsai dishevelled1regulatedsuperpotentcancerstemcellsmediatewntheterogeneityandtumorprogressioninhepatocellularcarcinoma |