Leo Foundation Skin Immunology Research Center, Institute of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Department of Dermatology, Aarhus University Hospital, Skejby, Aarhus, Denmark.
Dermatology. 2021;237(2):277-282. doi: 10.1159/000505743. Epub 2020 Apr 24.
Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL), is a lymphoproliferative disorder characterized by proliferation of malignant T cells in a chronic inflammatory environment in the skin. The nature of MF is still not fully understood, but aberrant microRNA (miR) expression and function seem to play an important role in the pathogenesis and disease progression and have been proposed as a putative disease marker. Recent studies have reported aberrant expression of miR-93 in situin MF lesions and linked dysregulated miR-93 expression to advanced stages of MF. However, the pathophysiological role of miR-93 in MF is unknown.
Here, we provide the first evidence that miR-93 targets the cell cycle regulator cyclin-dependent kinase inhibitor p21 and promotes growth of malignant T cells in MF.
METHODS/RESULTS: Thus, inhibition of miR-93 in MF patient-derived malignant T-cell lines increases expression of p21 and inhibition of malignant proliferation. Notably, treatment with the histone deacetylase inhibitor Vorinostat (SAHA) reduces miR-93 expression and enhances p21 expression in the malignant T cells. Importantly, transfection with an miR-93 mimic partly blocks SAHA-induced p21 expression.
we provide evidence that enhanced expression of the putative oncogenic miR, miR-93, represses the cell cycle inhibitor p21 and promotes proliferation of malignant T cells. Moreover, we demonstrate that SAHA triggers p21 expression - at least partly - through an inhibition of miR-93.
蕈样肉芽肿（MF），最常见的皮肤 T 细胞淋巴瘤（CTCL），是一种以皮肤中恶性 T 细胞的慢性炎症环境中的增殖为特征的淋巴增生性疾病。MF 的性质尚未完全阐明，但异常的 microRNA（miR）表达和功能似乎在发病机制和疾病进展中起着重要作用，并被提议作为潜在的疾病标志物。最近的研究报告了 miR-93 在 MF 病变中的异常表达，并将失调的 miR-93 表达与 MF 的晚期阶段联系起来。然而，miR-93 在 MF 中的病理生理作用尚不清楚。
本研究首次提供证据表明，miR-93 靶向细胞周期调节因子细胞周期蛋白依赖性激酶抑制剂 p21，并促进 MF 中恶性 T 细胞的生长。
方法/结果：因此，在 MF 患者来源的恶性 T 细胞系中抑制 miR-93 可增加 p21 的表达并抑制恶性增殖。值得注意的是，组蛋白去乙酰化酶抑制剂 Vorinostat（SAHA）可降低恶性 T 细胞中的 miR-93 表达并增强 p21 的表达。重要的是，转染 miR-93 模拟物部分阻断了 SAHA 诱导的 p21 表达。
本研究提供了证据表明，假定的致癌 miR，miR-93 的增强表达抑制了细胞周期抑制剂 p21，并促进了恶性 T 细胞的增殖。此外，我们证明了 SAHA 通过抑制 miR-93 触发 p21 表达-至少部分如此。
