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Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells
Chia-Lin Chen, … , Joseph H. Jeong, Keigo Machida
Chia-Lin Chen, … , Joseph H. Jeong, Keigo Machida
Published June 10, 2013
Citation Information: J Clin Invest. 2013;123(7):2832-2849. https://doi.org/10.1172/JCI65859.
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Research Article Article has an altmetric score of 8

Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells

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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.

Authors

Chia-Lin Chen, Hidekazu Tsukamoto, Jian-Chang Liu, Claudine Kashiwabara, Douglas Feldman, Linda Sher, Steven Dooley, Samuel W. French, Lopa Mishra, Lydia Petrovic, Joseph H. Jeong, Keigo Machida

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Figure 6

TICs are defective in TGF-β signaling due to SMAD3 pathway interference by YAP1 and IGF2BP3.

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TICs are defective in TGF-β signaling due to SMAD3 pathway interference ...
(A) TGF-β–stimulated PAI-1 promoter activity is lower in TICs than in control cells. This defect is modestly improved with Yap1 or Igf2bp3 shRNA alone and synergistically corrected by both. *P < 0.05, **P < 0.01. (B) Nuclear levels of p-SMAD3 or SMAD3 in TGF-β–treated TICs are increased by Yap1 or Igf2bp3 silencing with respective shRNA and conspicuously by silencing of both genes. (C) Interactions of SMAD7 with YAP1, p-YAP1, and SMAD3 are increased by Igf2bp3 transduction in PIL4 cells expressing YAP1 (PIL4-YAP1 cells), and these interactions are attenuated with Yap1 shRNA (top left). In the same PIL4-YAP1 cells with Igf2bp3 transduction, increased SMAD7 interactions with p-YAP1 and SMAD3 are abrogated by Akt silencing. Conversely, reduced nuclear p-SMAD3 level is increased. Phosphorylation of MST1 and LATS1/2 is increased by overexpression of IGF2BP3 but reduced by Akt silencing. (D) Fluorescent microscopy depicting increased nuclear staining of SMAD3 in TGF-β–treated TICs by silencing Igf2bp3 and Yap1. Dotted circles indicate the outline of nuclei. Original magnification, ×200. (E) Rapa (200 nM) further increases TGF-β–induced nuclear p-SMAD3 level, which is already augmented by silencing Yap1 or Igf2bp3. (F) Igf2bp3/Yap1 silencing but not rapa augments 3TP-Luc promoter activity induced by CA-SMAD3. *P < 0.05.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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