Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells.
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.
Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, USA.
Chia-Lin
CL
Chen
Hidekazu
H
Tsukamoto
Jian-Chang
JC
Liu
Claudine
C
Kashiwabara
Douglas
D
Feldman
Linda
L
Sher
Steven
S
Dooley
Samuel W
SW
French
Lopa
L
Mishra
Lydia
L
Petrovic
Joseph H
JH
Jeong
Keigo
K
Machida
D000071916:AC133 Antigen; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002469:Cell Separation; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009857:Oncogenes; D010455:Peptides / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D051785:Smad Proteins / Q000378:metabolism; D000077157:Sorafenib; D018874:Spheroids, Cellular / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins
D000071916:AC133 Antigen; D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; D018398:Homeodomain Proteins; C498780:IGF2BP3 protein, human; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; C000606023:PROM1 protein, human; D010455:Peptides; D010671:Phenylurea Compounds; D010750:Phosphoproteins; C000606024:Prom1 protein, mouse; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D051785:Smad Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D009536:Niacinamide; D000077157:Sorafenib; D020123:Sirolimus