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Retraction Open Access | 10.1172/JCI186923

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

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, and Keigo Machida

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Published October 1, 2024 - More info

Published in Volume 134, Issue 19 on October 1, 2024
J Clin Invest. 2024;134(19):e186923. https://doi.org/10.1172/JCI186923.
© 2024 Chen et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 1, 2024 - Version history
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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
Research Article

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

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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Original citation: J Clin Invest. 2013;123(7):2832–2849. https://doi.org/10.1172/JCI65859

Citation for this retraction: J Clin Invest. 2024;134(19):e186923. https://doi.org/10.1172/JCI186923

At the request of the corresponding author, the JCI is retracting this article. The authors recently became aware of incorrect images used in Figures 1A, 1C, 1E, Supplemental Figure 3D, and Supplemental Figure 7B.

The authors apologize for these errors.

Footnotes

See the related article at Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells.

Version history
  • Version 1 (October 1, 2024): Electronic publication
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