Supplementary Material for: MicroRNA-93 Targets p21 and Promotes Proliferation in Mycosis Fungoides T Cells

<b><i>Background:</i></b> 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 situ<i></i>in MF lesions and linked dysregulated miR-93 expression to advanced stages of MF. However, the pathophysiological role of miR-93 in MF is unknown. <b><i>Objective:</i></b> 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. <b><i>Methods/Results:</i></b> 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. <b><i>Conclusions:</i></b> 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.

**背景：**
蕈样肉芽肿（Mycosis fungoides, MF）是最常见的皮肤T细胞淋巴瘤（cutaneous T-cell lymphoma, CTCL）类型，属于淋巴增殖性疾病，以恶性T细胞在皮肤慢性炎症环境中增殖为核心特征。目前MF的发病本质尚未完全阐明，但异常微小RNA（microRNA, miR）的表达与功能似乎在其发病及疾病进展中发挥关键作用，且被提议作为潜在的疾病标志物。近期已有研究报道MF皮损中存在miR-93的异常表达，并将miR-93表达失调与MF的晚期病程相关联。然而，miR-93在MF中的病理生理作用仍未明确。
**研究目的：**
本研究首次提供证据表明，miR-93可靶向作用于细胞周期调控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细胞的增殖。
**方法与结果：**
研究发现，在源自MF患者的恶性T细胞系中抑制miR-93，可上调p21的表达并抑制恶性细胞增殖。值得注意的是，组蛋白去乙酰化酶抑制剂伏立诺他（Vorinostat, SAHA）可降低恶性T细胞内miR-93的表达水平，并增强p21的表达。更为关键的是，转染miR-93模拟物可部分阻断SAHA诱导的p21表达上调。
**结论：**
本研究证实，具有潜在致癌性的miR-93高表达可抑制细胞周期抑制剂p21的表达，进而促进恶性T细胞的增殖。此外，本研究证明SAHA可通过（至少部分通过）抑制miR-93的表达来诱导p21的表达。