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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 5

Epidermal D3 depletion significantly reduces Gli2-driven BCC-like tumor formation and inhibits miR21 expression.

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Epidermal D3 depletion significantly reduces Gli2-driven BCC-like tumor ...
(A) Genetic D3 depletion was specifically induced in keratinocytes by crossing of K5-Gli2 K14-Cre–/+ with Dio3fl/fl mice. (B) Mice were analyzed at 6 months of age when BCC-like formations were abundant and readily visible on the ears of control (Gli2) mice (n = 11). (C) Histological analysis of ears from Gli2 and Gli2;D3KO mice. H&E stainings were performed on sections of ears from Gli2 and Gli2;D3KO mice. Scale bars: 100 μm. (D) Immunofluorescent staining for PTCH1, K17, K10, and D3 expression. Scale bars: 100 μm. (E) Real-time PCR analysis to measure the expression of the indicated genes in Gli2 versus Gli2;D3KO mice (n = 7). (F and G) miR21 and Grhl3 expression was measured in the ears from Gli2 and Gli2;D3KO mice (n = 7). (H) Schematic representation of the mutual, negative-feedback loop by which TH regulates miR21 and miR21 controls intracellular TH through GRHL3. *P < 0.05, **P < 0.01.

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

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