Kohnken Rebecca, Kodigepalli Karthik M, Mishra Anjali, Porcu Pierluigi, Wu Li
Center of Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210, USA.
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA; Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, OH, 43210, USA.
Leuk Res. 2017 Jan;52:58-66. doi: 10.1016/j.leukres.2016.11.010. Epub 2016 Nov 17.
Sézary syndrome (SS) is a rare subtype of cutaneous T-cell lymphoma (CTCL) that is characterized by aggressive spread of neoplastic CD4+ T-cells from the skin into the bloodstream with metastasis to visceral organs. The deoxynucleoside triphosphohydrolase SAMHD1 is highly expressed in normal CD4+ T-cells, while its expression is down-regulated in CD4+ T-cells from SS patients. MicroRNA (miR) dysregulation is an important epigenetic mechanism in the pathogenesis and progression of SS. MiR-181 has been shown to inhibit SAMHD1 expression in cell lines and was identified as an important prognostic biomarker in CTCL. However, whether SAMHD1 is down-regulated by miR-181 in primary CD4+ T-cells of SS patients is unknown. Compared to normal CD4+ T-cells, SAMHD1 protein expression is significantly reduced in transformed CD4+ T-cell lines and CD4+ T-cells from SS patients, which inversely correlates with increased miR-181 levels in these cells. Over-expression of miR-181b in primary CD4+ T-cells from healthy donors significantly decreased SAMHD1 protein level, but not mRNA level. In contrast, inhibition of miR-181 in a CD4+ T-cell line significantly increased the level of SAMHD1 protein expression. Our results demonstrate that miR-181 is an important regulator of SAMHD1 protein expression in neoplastic CD4+ T-cells, likely through a mechanism of translational inhibition.
赛塞里综合征（SS）是皮肤T细胞淋巴瘤（CTCL）的一种罕见亚型，其特征是肿瘤性CD4 + T细胞从皮肤侵袭性扩散至血液，并转移至内脏器官。脱氧核苷三磷酸水解酶SAMHD1在正常CD4 + T细胞中高表达，而在SS患者的CD4 + T细胞中其表达下调。微小RNA（miR）失调是SS发病机制和进展中的一种重要表观遗传机制。已证明miR - 181在细胞系中可抑制SAMHD1表达，并被确定为CTCL中的一种重要预后生物标志物。然而，在SS患者的原发性CD4 + T细胞中，SAMHD1是否被miR - 181下调尚不清楚。与正常CD4 + T细胞相比，在转化的CD4 + T细胞系和SS患者的CD4 + T细胞中，SAMHD1蛋白表达显著降低，这与这些细胞中miR - 181水平升高呈负相关。在健康供体的原发性CD4 + T细胞中过表达miR - 181b可显著降低SAMHD1蛋白水平，但不影响mRNA水平。相反，在一个CD4 + T细胞系中抑制miR - 181可显著增加SAMHD1蛋白表达水平。我们的结果表明，miR - 181可能通过翻译抑制机制，是肿瘤性CD4 + T细胞中SAMHD1蛋白表达的重要调节因子。
