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Reciprocal interplay between thyroid hormone and microRNA-21 regulates hedgehog pathway–driven skin tumorigenesis
Daniela Di Girolamo, … , Domenico Salvatore, Monica Dentice
Daniela Di Girolamo, … , Domenico Salvatore, Monica Dentice
Published May 9, 2016
Citation Information: J Clin Invest. 2016;126(6):2308-2320. https://doi.org/10.1172/JCI84465.
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Research Article Oncology Article has an altmetric score of 3

Reciprocal interplay between thyroid hormone and microRNA-21 regulates hedgehog pathway–driven skin tumorigenesis

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Abstract

The thyroid hormone–inactivating (TH-inactivating) enzyme type 3 iodothyronine deiodinase (D3) is an oncofetal protein that is rarely expressed in adult life but has been shown to be reactivated in the context of proliferation and neoplasms. D3 terminates TH action within the tumor microenvironment, thereby enhancing cancer cell proliferation. However, the pathological role of D3 and the contribution of TH metabolism in cancer have yet to be fully explored. Here, we describe a reciprocal regulation between TH action and the cancer-associated microRNA-21 (miR21) in basal cell carcinoma (BCC) skin tumors. We found that, besides being negatively regulated by TH at the transcriptional level, miR21 attenuates the TH signal by increasing D3 levels. The ability of miR21 to positively regulate D3 was mediated by the tumor suppressor gene GRHL3, a hitherto unrecognized D3 transcriptional inhibitor. Finally, in a BCC mouse model, keratinocyte-specific D3 depletion markedly reduced tumor growth. Together, our results establish TH action as a critical hub of multiple oncogenic pathways and provide functional and mechanistic evidence of the involvement of TH metabolism in BCC tumorigenesis. Moreover, our results identify a miR21/GRHL3/D3 axis that reduces TH in the tumor microenvironment and has potential to be targeted as a therapeutic approach to BCC.

Authors

Daniela Di Girolamo, Raffaele Ambrosio, Maria A. De Stefano, Giuseppina Mancino, Tommaso Porcelli, Cristina Luongo, Emery Di Cicco, Giulia Scalia, Luigi Del Vecchio, Annamaria Colao, Andrzej A. Dlugosz, Caterina Missero, Domenico Salvatore, Monica Dentice

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Figure 3

The miR21/GRHL3 axis regulates D3 expression and TH intracellular concentration.

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The miR21/GRHL3 axis regulates D3 expression and TH intracellular concen...
(A) D3 protein levels were measured by Western blot from BCC cells transfected with miR21, GRHL3, and the 2 expression plasmids together. Lysates were also probed with anti-Flag antibody as control of Flag-GRHL3 transfection efficiency. (B) BCC cells were transfected with miR21 and miR21 plus 2 different siRNAs for GRHL3 knockdown. Anti-GRHL3 antibody was used as internal control of GRHL3 knockdown. (C and D) The Dio3 promoter was cotransfected with the indicated constructs together with CMV-renilla as internal control. Luciferase activity was measured and reported as means ± SD of the LUC/renilla ratios from at least 3 separate experiments, performed in duplicate. (E) The T3-responsive promoter TRE3-TK-Luc was cotransfected in BCC cells with the indicated plasmids. Luciferase activity was measured as in C and D. *P < 0.05, **P < 0.01. (F) The miR21/GRHL3/D3 axis regulates intracellular T3 availability.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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