Epigenetic Silencing of MicroRNA-203 Dysregulates ABL1 Expression and Drives Helicobacter-Associated Gastric Lymphomagenesis
Epigenetic Silencing of MicroRNA-203 Dysregulates ABL1 Expression and Drives Helicobacter-Associated Gastric Lymphomagenesis
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DOI：
10.1158/0008-5472.can-10-3907
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发表时间：
2011-05-15
期刊：
影响因子：
11.2
通讯作者：
Mueller, Anne
中科院分区：
文献类型：
--
作者：
Craig, Vanessa J.;Cogliatti, Sergio B.;Mueller, Anne
胃粘膜相关淋巴组织B细胞淋巴瘤（MALT淋巴瘤）发生于感染幽门螺杆菌的慢性炎症粘膜。在这里，我们使用患者的材料，原发性胃淋巴瘤细胞培养物，和疾病的临床前模型，以检查microRNA（miRNA）介导的转录后调节的作用，特别是对miR-203和它的目标ABL 1-在胃MALT淋巴瘤的发生。基于微阵列的miRNA表达谱显示，在人类MALT淋巴瘤样本中，推定的肿瘤抑制miRNA miR-203强烈下调，这是由于miR-203基因座的广泛启动子超甲基化，与淋巴瘤活检组织中miR-203靶点ABL 1的失调相一致，与来自相同患者的匹配相邻正常材料相比。用去甲基化剂处理淋巴瘤B细胞导致miR-203表达增加和ABL 1的伴随下调，证实了该miRNA的表观遗传调节。通过转染人淋巴瘤细胞系或通过慢病毒转导灭活的原代MALT淋巴瘤细胞异位再表达miR-203足以在体外防止肿瘤细胞增殖。类似地，用ABL抑制剂伊马替尼和达沙替尼治疗原发性MALT淋巴瘤细胞阻止了肿瘤细胞生长。最后，我们表明，伊马替尼治疗荷瘤小鼠诱导MALT淋巴瘤消退的疾病的临床前模型，涉及ABL 1在MALT淋巴瘤的进展。总之，我们的研究结果表明，从胃炎到MALT淋巴瘤的转化是由miR-203启动子甲基化的表观遗传调控，并确定ABL 1作为治疗这种恶性肿瘤的新靶点。Cancer Res; 71（10）; 3616-24. (C)2011年AACR。
Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) develops in the chronically inflamed mucosa of patients infected with the bacterial pathogen Helicobacter pylori. Here we use patient material, primary gastric lymphoma cell cultures, and a preclinical model of the disease to examine the role of microRNA (miRNA)-mediated posttranscriptional regulation-focusing in particular on miR-203 and its target ABL1-in gastric MALT lymphomagenesis. Microarray-based miRNA expression profiling revealed a strong downregulation of the putative tumor suppressor miRNA miR-203 in human MALT lymphoma samples, which resulted from extensive promoter hypermethylation of the miR-203 locus and coincided with the dysregulation of the miR-203 target ABL1 in lymphoma biopsies compared with matched adjacent normal material from the same patients. Treatment of lymphoma B cells with demethylating agents led to increased miR-203 expression and the concomitant downregulation of ABL1, confirming the epigenetic regulation of this miRNA. Ectopic reexpression of miR-203 by transfection of a human lymphoma cell line or lentiviral transduction of explanted primary MALT lymphoma cells was sufficient to prevent tumor cell proliferation in vitro. Similarly, the treatment of primary MALT lymphoma cells with the ABL inhibitors imatinib and dasatinib prevented tumor cell growth. Finally, we show that the treatment of tumor-bearing mice with imatinib induces MALT lymphoma regression in a preclinical model of the disease, implicating ABL1 in MALT lymphoma progression. In summary, our results show that the transformation from gastritis to MALT lymphoma is epigenetically regulated by miR-203 promoter methylation and identify ABL1 as a novel target for the treatment of this malignancy. Cancer Res; 71(10); 3616-24. (C) 2011 AACR.