Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 7, Pages 2832-2849Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI65859
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Funding
- NIH [1R01AA018857, 5RC2AA019392, P50AA11999, 5P30DK048522-13, R24AA012885, AI83025U19, CA123328, CA108302, R01 CA042857, P01 CA130821, P30 CA016672, P30 DK56338]
- Zumberge Foundation [U19AI83025]
- American Cancer Society [RSG MPC122545, IRG-58-007-48]
- German Research Foundation [SFB-TRR77]
- NIH/NCI [P30 CA 014089]
- NIH/NVRR [S10]
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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 NANO G as a direct target of TLR4, which drives the tumor-initiating activity of TICs. These TLR4/NANOG-dependent TICs were defective in the TGF-beta tumor suppressor pathway. Functional oncogene screening of a TIC cDNA library identified Yap1 and Igf2bp3 as NANOG-dependent genes that inactivate TGF-beta 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-beta signaling, inhibited pluripotency genes and tumorigenesis, and abrogated chemoresistance of TICs. Mice with defective TGF-beta 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-beta signaling and could potentially serve as a therapeutic target for HCV-related HCC.
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