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首页> 外文期刊>The Journal of Clinical Investigation: The Official Journal of the American Society for Clinical Investigation >Reciprocal interplay between thyroid hormone and microRNA-21 regulates hedgehog pathway-driven skin tumorigenesis
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Reciprocal interplay between thyroid hormone and microRNA-21 regulates hedgehog pathway-driven skin tumorigenesis

机译：甲状腺激素和 microRNA-21 之间的相互相互作用调节刺猬通路驱动的皮肤肿瘤发生

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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.
机译：甲状腺激素失活（TH 失活）酶 3 型碘甲状腺原氨酸脱碘酶 （D3） 是一种癌胎蛋白，在成年生活中很少表达，但已被证明在增殖和肿瘤的情况下被重新激活。D3 终止肿瘤微环境中的 TH 作用，从而增强癌细胞增殖。然而，D3 的病理作用和 TH 代谢在癌症中的作用尚未得到充分探索。在这里，我们描述了基底细胞癌 （BCC） 皮肤肿瘤中 TH 作用与癌症相关 microRNA-21 （miR21） 之间的相互调节。我们发现，除了在转录水平上受到 TH 的负调控外，miR21 还通过增加 D3 水平来减弱 TH 信号。miR21 正向调节 D3 的能力是由肿瘤抑制基因 GRHL3 介导的，GRHL3 是一种迄今为止未被识别的 D3 转录抑制剂。最后，在 BCC 小鼠模型中，角质形成细胞特异性 D3 耗竭显着降低了肿瘤生长。总之，我们的研究结果将 TH 作用确立为多种致癌途径的关键枢纽，并为 TH 代谢参与 BCC 肿瘤发生提供了功能和机制证据。此外，我们的研究结果确定了 miR21/GRHL3/D3 轴，该轴可降低肿瘤微环境中的 TH，并有可能作为 BCC 的治疗方法靶向。

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