MicroRNA 223 is upregulated in the multistep progression of Barrett's esophagus and modulates sensitivity to chemotherapy by targeting PARP1.
MicroRNA 223 is upregulated in the multistep progression of Barrett's esophagus and modulates sensitivity to chemotherapy by targeting PARP1.
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DOI：
10.1158/1078-0432.ccr-13-0601
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发表时间：
2013-08-01
期刊：
影响因子：
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通讯作者：
Maitra A
中科院分区：
文献类型：
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作者：
Streppel MM;Pai S;Campbell NR;Hu C;Yabuuchi S;Canto MI;Wang JS;Montgomery EA;Maitra A
最近的微阵列和RNA测序研究发现了Barrett食管（BE）相关食管腺癌（EAC）中异常表达的microRNA（miR）。这些miR在EAC起始和进展中的功能意义在很大程度上是未知的。使用定量真实的时间PCR，在来自心脏粘膜、BE、异型增生BE和EAC的显微解剖组织中测定miR-199 a/B-3 p、− 199 a-5 p、− 199 B-5 p、− 200 B、− 200 c、−223和−375的表达水平。通过原位杂交（ISH）验证了miR-223在来自95名EAC患者的前体和EAC中的表达。将miR-223转染到两种EAC细胞系中，并进行体外测定。使用Illumina微阵列鉴定靶基因，并在细胞系和人类标本中验证结果。miR-199家族成员和miR-223在EAC中显著过表达，但只有miR-223在EAC癌变过程中呈阶梯性增加。原位杂交也观察到类似的趋势，这进一步表明miR-223仅在上皮细胞中表达，miR-223过表达的细胞比乱序序列转染的细胞具有统计学显著更高的迁移和侵袭潜力。PARP 1是miR-223在EAC细胞中的直接靶基因。在具有增强的miR-223表达和减少的PARP 1的细胞中观察到对化疗的敏感性增加。miR-223在BE-发育不良-EAC序列期间显著上调。虽然高miR-223水平可能导致侵袭性表型，但我们的研究结果还表明，高miR-223水平的EAC患者可能受益于DNA损伤剂的治疗。
Recent microarray and RNA-sequencing studies have uncovered aberrantly expressed microRNAs (miRs)in Barrett’s esophagus (BE)-associated esophageal adenocarcinoma (EAC). The functional significance of these miRs in EAC initiation and progression is largely unknown. Expression levels of miR-199a/b-3p, −199a-5p, −199b-5p, −200b, −200c, −223, and −375 were determined in microdissected tissues from cardiac mucosa, BE, dysplastic BE, and EAC using quantitative real time PCR. MiR-223 expression was validated in precursors and EACs from 95 EAC patients by in situ hybridization (ISH). MiR-223 was transfected into two EAC cell lines, and in vitro assays were performed. Target genes were identified using Illumina microarray, and results were validated in cell lines and human specimens. MiR-199 family members and miR-223 were significantly over-expressed in EAC, however only miR-223 showed a stepwise increase during EAC carcinogenesis. A similar trend was observed by ISH, which additionally showed that miR-223 is exclusively expressed by the epithelial compartment.MiR-223 over-expressing cells had statistically significantly more migratory and invasive potential than scramble sequence transfected cells. PARP1was identified as a direct target gene of miR-223 in EAC cells. Increased sensitivity to chemotherapy was observed in cells with enforced miR-223 expression and reduced PARP1. MiR-223 is significantly up-regulated during the BE-dysplasia-EAC sequence. Although high miR-223 levels might contribute to an aggressive phenotype, our results also suggest that EAC patients with high miR-223 levels might benefit from treatment with DNA-damaging agents.