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

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

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 4

Targeted D3 depletion drastically reduces the tumorigenic potential of BCC cells in nude mice.

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Targeted D3 depletion drastically reduces the tumorigenic potential of B...
(A and B) 1 × 106 per 100 μl of control CRISPR-CTR cells (CTR), stable miR21-overexpressing (miR) BCC cells, CRISPR/Cas9-D3KO cells (D3KO), and double D3KO-miR cells were injected s.c. into the flanks of nude mice. Mice were collected 3 weeks after injection, and tumors were measured as indicated in Methods. (C) Tumor volume was measured with a caliper for 3 weeks in CTR, miR, and D3KO-miR cells deriving tumors. (D and E) Tumor weight and volume measured 3 weeks after cell injection. (F and G) Tumor sections were analyzed by H&E staining and by immunofluorescence for Ki-67 and TUNEL expression in the indicated tumors. Scale bars: 100 μm. Right: Percentage of Ki-67–positive and TUNEL-positive cells. *P < 0.05, **P < 0.01, ***P < 0.001.