Abstract
Tumor-initiating stem-like cells (TICs) are resistant to chemotherapy and associated with hepatocellular carcinoma (HCC) caused by HCV and/or alcohol-related chronic liver injury. Using HCV Tg mouse models and patients with HCC, we isolated CD133(+) TICs and identified the pluripotency marker NANOG as a direct target of TLR4, which drives the tumor-initiating activity of TICs. These TLR4/NANOG-dependent TICs were defective in the TGF-β tumor suppressor pathway. Functional oncogene screening of a TIC cDNA library identified Yap1 and Igf2bp3 as NANOG-dependent genes that inactivate TGF-β signaling. Mechanistically, we determined that YAP1 mediates cytoplasmic retention of phosphorylated SMAD3 and suppresses SMAD3 phosphorylation/activation by the IGF2BP3/AKT/mTOR pathway. Silencing of both YAP1 and IGF2BP3 restored TGF-β signaling, inhibited pluripotency genes and tumorigenesis, and abrogated chemoresistance of TICs. Mice with defective TGF-β signaling (Spnb2(+/-) mice) exhibited enhanced liver TLR4 expression and developed HCC in a TLR4-dependent manner. Taken together, these results suggest that the activated TLR4/NANOG oncogenic pathway is linked to suppression of cytostatic TGF-β signaling and could potentially serve as a therapeutic target for HCV-related HCC.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AC133 Antigen
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antigens, CD / metabolism
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Antineoplastic Agents / pharmacology
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Base Sequence
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Carcinoma, Hepatocellular / drug therapy
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology*
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Cell Separation
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Drug Resistance, Neoplasm
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Flow Cytometry
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Gene Expression Regulation, Neoplastic
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Gene Knockdown Techniques
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Glycoproteins / metabolism
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Homeodomain Proteins / metabolism
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Humans
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Inhibitory Concentration 50
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Liver Neoplasms / drug therapy
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology*
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Mice, Transgenic
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Nanog Homeobox Protein
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Neoplastic Stem Cells / metabolism*
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Niacinamide / analogs & derivatives
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Niacinamide / pharmacology
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Oncogenes
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Peptides / metabolism
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Phenylurea Compounds / pharmacology
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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RNA, Small Interfering / genetics
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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Signal Transduction
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Sirolimus / pharmacology
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Smad Proteins / metabolism
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Sorafenib
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Spheroids, Cellular / metabolism
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / metabolism*
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Transcription Factors
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Transcriptional Activation
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism*
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Tumor Burden
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
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YAP-Signaling Proteins
Substances
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AC133 Antigen
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Adaptor Proteins, Signal Transducing
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Antigens, CD
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Antineoplastic Agents
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Glycoproteins
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Homeodomain Proteins
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IGF2BP3 protein, human
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NANOG protein, human
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Nanog Homeobox Protein
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PROM1 protein, human
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Peptides
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Phenylurea Compounds
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Phosphoproteins
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Prom1 protein, mouse
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RNA, Small Interfering
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RNA-Binding Proteins
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Smad Proteins
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TLR4 protein, human
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Toll-Like Receptor 4
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Transcription Factors
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Transforming Growth Factor beta
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YAP-Signaling Proteins
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YAP1 protein, human
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Niacinamide
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Sorafenib
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Sirolimus
Associated data
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GEO/GSE45646
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GEO/GSM1111249
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GEO/GSM1111250