title: 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.forename: Daniela
authors.initials: D
authors.lastname: Di Girolamo
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ambrosio
authors.forename: Maria A
authors.initials: MA
authors.lastname: De Stefano
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Mancino
authors.forename: Tommaso
authors.initials: T
authors.lastname: Porcelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Luongo
authors.forename: Emery
authors.initials: E
authors.lastname: Di Cicco
authors.forename: Giulia
authors.initials: G
authors.lastname: Scalia
authors.forename: Luigi Del
authors.initials: LD
authors.lastname: Vecchio
authors.forename: Annamaria
authors.initials: A
authors.lastname: Colao
authors.forename: Andrzej A
authors.initials: AA
authors.lastname: Dlugosz
authors.forename: Caterina
authors.initials: C
authors.lastname: Missero
authors.forename: Domenico
authors.initials: D
authors.lastname: Salvatore
authors.forename: Monica
authors.initials: M
authors.lastname: Dentice
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002280:Basal Cell Carcinoma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D007453:Iodide Peroxidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D007453:Iodide Peroxidase; D035683:MicroRNAs; D013963:Thyroid Hormones; D014157:Transcription Factors; C473143:GRHL3 protein, human; C524940:MIRN21 microRNA, human; C117274:iodothyronine deiodinase type III; C531950:MIRN21 microRNA, mouse