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Prevention of hepatocellular carcinoma by targeting MYCN-positive liver cancer stem cells with acyclic retinoid
- Source :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Year :
- 2018
-
Abstract
- Significance Hepatocellular carcinoma (HCC) is a highly lethal cancer, partly because of its high rate of recurrence, which is caused by the presence of liver cancer stem cells (CSCs). Here, using a selective chemopreventive agent, acyclic retinoid (ACR), as a bioprobe, we identified MYCN, which is mostly recognized as an oncogene in neuroblastoma, as a therapeutic target of ACR for HCC through a selective deletion of MYCN+ liver CSCs. We also demonstrated that the expression of MYCN in HCC served as a prognostic biomarker and positively correlated with recurrence of de novo HCC after curative treatment. Our study highlighted MYCN as a biomarker and therapeutic target in drug discovery for screening chemopreventive agents against the recurrence of HCC.<br />Hepatocellular carcinoma (HCC) is a highly lethal cancer that has a high rate of recurrence, in part because of cancer stem cell (CSC)-dependent field cancerization. Acyclic retinoid (ACR) is a synthetic vitamin A-like compound capable of preventing the recurrence of HCC. Here, we performed a genome-wide transcriptome screen and showed that ACR selectively suppressed the expression of MYCN, a member of the MYC family of basic helix–loop–helix–zipper transcription factors, in HCC cell cultures, animal models, and liver biopsies obtained from HCC patients. MYCN expression in human HCC was correlated positively with both CSC and Wnt/β-catenin signaling markers but negatively with mature hepatocyte markers. Functional analysis showed repressed cell-cycle progression, proliferation, and colony formation, activated caspase-8, and induced cell death in HCC cells following silencing of MYCN expression. High-content single-cell imaging analysis and flow cytometric analysis identified a MYCN+ CSC subpopulation in the heterogeneous HCC cell cultures and showed that these cells were selectively killed by ACR. Particularly, EpCAM+ cells isolated using a cell-sorting system showed increased MYCN expression and sensitivity to ACR compared with EpCAM− cells. In a long-term (>10 y) follow-up study of 102 patients with HCC, MYCN was expressed at higher levels in the HCC tumor region than in nontumor regions, and there was a positive correlation between MYCN expression and recurrence of de novo HCC but not metastatic HCC after curative treatment. In summary, these results suggest that MYCN serves as a prognostic biomarker and therapeutic target of ACR for liver CSCs in de novo HCC.
- Subjects :
- 0301 basic medicine
cancer stem cell
Medical Sciences
Carcinoma, Hepatocellular
Antineoplastic Agents
Tretinoin
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cancer stem cell
MYCN Positive
MYCN
medicine
Animals
Humans
Letters
Neoplasm Metastasis
neoplasms
Wnt Signaling Pathway
N-Myc Proto-Oncogene Protein
Multidisciplinary
acyclic retinoid
business.industry
Liver Neoplasms
Cancer
Epithelial cell adhesion molecule
hepatocellular carcinoma
Biological Sciences
medicine.disease
Epithelial Cell Adhesion Molecule
Prognosis
digestive system diseases
Gene Expression Regulation, Neoplastic
030104 developmental biology
chemistry
030220 oncology & carcinogenesis
Hepatocellular carcinoma
Cancer research
Neoplastic Stem Cells
Field cancerization
Stem cell
Liver cancer
business
transcriptome
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 115
- Issue :
- 19
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....08f152e6030731a3d4623a9141f63bf0