MiR-17/106b seed family regulates p21 in Hodgkin's lymphoma
MiR-17/106b seed family regulates p21 in Hodgkin's lymphoma
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DOI：
10.1002/path.2958
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发表时间：
2011-12-01
影响因子：
7.3
通讯作者：
van den Berg, Anke
中科院分区：
文献类型：
--
作者：
Gibcus, Johan H.;Kroesen, Bart-Jan;van den Berg, Anke
霍奇金淋巴瘤(HL)是一种B细胞来源的淋巴瘤，以少数丧失正常B细胞表型的恶性霍奇金Reed-Sternberg(HRS)细胞为特征。细胞周期和凋亡途径的改变可能有助于其抵抗细胞凋亡和持续的细胞周期进展。CDKN1A在细胞周期停滞和细胞凋亡中起关键作用，它编码p21(waf/cip1)(P21)。P21受P53调控，在细胞核内可作为细胞周期抑制因子发挥作用，在细胞质中可作为细胞凋亡抑制因子发挥作用。我们观察了40例中24例不同数目的HRS细胞中p53、p21和p-p21的表达。10例HL患者HRS细胞表达miR-17和miR-106a。MIR-17/106b种子家族成员、CDKN1ARNA和p21蛋白在HL细胞系中的表达水平存在差异。在荧光素酶报告实验中，我们发现miR-17/106b有效地靶向了HL细胞中的CDKN1A3‘UTR，并在抗miR-17处理KM-H2细胞时上调了p21蛋白的水平。功能研究表明，在KM-H2中miR-17/106b下调后，p21介导的G(1)期停滞，而U-HO1和L428则未观察到G1期停滞。这种差异不能用3‘非编码区的差异、p21的细胞位置或细胞周期进程中的表达变化来解释。观察到miR-17/106b：CDKN1A比率与对miR-17抑制的反应性有很强的相关性，即KM-H2的比率较低，而两个无反应的HL细胞系的比率极高。综上所述，我们发现miR-17/106b调控HL细胞中p21蛋白的表达，并且miR-17/106b介导的抑制作用依赖于miRNA：靶基因的比例。因此，在HL中，miR-17/106b的高表达有助于P53途径的功能障碍，从而也导致了恶性表型。版权所有(C)2011年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Hodgkin's lymphoma (HL) is a B cell-derived lymphoma characterized by a minority of malignant Hodgkin Reed-Sternberg (HRS) cells that have lost their normal B cell phenotype. Alterations in the cell cycle and apoptosis pathways might contribute to their resistance to apoptosis and sustained cell cycle progression. A key player in both cell cycle arrest and apoptosis is CDKN1A, encoding p21(waf/cip1) (p21). P21 is regulated by p53 and can function as a cell cycle inhibitor when in the nucleus or as an apoptosis inhibitor when localized in the cytoplasm. We observed expression of p53, p21 and p-p21 in a variable number of HRS cells in 24 of 40 cases. Expression of miR-17 and miR-106a was detected in HRS cells of 10 HL cases. MiR-17/106b seed family members, CDKN1A RNA and p21 protein levels were variable in HL cell lines. We showed effective targeting of the CDKN1A 3' UTR by miR-17/106b in HL cell lines in a luciferase reporter assay and up-regulation of p21 protein levels upon anti-miR-17 treatment of KM-H2 cells. Functional studies indicated a p21-mediated G(1) arrest after miR-17/106b down-regulation in KM-H2, whereas no G1 arrest was observed for U-HO1 and L428. This difference could not be explained by differences in the 3' UTR, the cellular location of p21 or expression variation during cell cycle progression. A strong correlation was observed for the miR-17/106b: CDKN1A ratio and the responsiveness to miR-17 inhibition, ie a low ratio in KM-H2 and an extremely high ratio in the two unresponsive HL cell lines. In conclusion, we show that miR-17/106b regulates p21 protein levels in HL and that the effect of miR-17/106b-mediated inhibition depends on the miRNA : target gene ratio. Thus, in HL high miR-17/106b expression contributes to a dysfunctional p53 pathway and thereby also to the malignant phenotype. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.