MicroRNAs Cooperatively Inhibit a Network of Tumor Suppressor Genes to Promote Pancreatic Tumor Growth and Progression
MicroRNAs Cooperatively Inhibit a Network of Tumor Suppressor Genes to Promote Pancreatic Tumor Growth and Progression
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DOI：
10.1053/j.gastro.2013.10.010
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发表时间：
2014-01-01
期刊：
影响因子：
29.4
通讯作者：
Jiao, Long R.
中科院分区：
文献类型：
--
作者：
Frampton, Adam E.;Castellano, Leandro;Jiao, Long R.
背景与目的：目前还没有对胰腺导管腺癌（PDAC）细胞中microRNA（miRNAs）活性改变的综合效应进行广泛分析，目前还不清楚这些可能如何影响肿瘤进展或患者结局。方法：我们结合了来自miRNA和信使RNA（mRNA）表达谱的数据和生物信息学分析，以鉴定PDAC细胞系（PANC-1和MIA PaCa-2）和患者PDAC样本中的miRNA-mRNA调控网络。我们利用这些信息来鉴定对肿瘤发生贡献最大的miRNAs。研究结果：我们鉴定了3种miRNAs（MIR 21、MIR 23 A和MIR 27 A），它们作为肿瘤抑制基因网络的协同阻遏物，包括PDCD 4、BTG 2和NEDD 4L。MIR 21、MIR 23 A和MIR 27 A的抑制在减少培养物中PDAC细胞的增殖和小鼠中异种移植肿瘤的生长方面具有协同作用。抑制水平大于单独MIR 21的抑制水平。在来自患者的91个PDAC样本中，高水平的MIR 21、MIR 23 A和MIR 27 A的组合与手术切除后较短的存活时间相关。结论：在综合数据分析中，我们确定了有助于PDAC生长的功能性miRNA mRNA相互作用。这些发现表明，miRNAs共同作用促进肿瘤进展;治疗策略可能需要抑制几种miRNAs。
BACKGROUND & AIMS: There has not been a broad analysis of the combined effects of altered activities of microRNAs (miRNAs) in pancreatic ductal adenocarcinoma (PDAC) cells, and it is unclear how these might affect tumor progression or patient outcomes. METHODS: We combined data from miRNA and messenger RNA (mRNA) expression profiles and bioinformatic analyses to identify an miRNA-mRNA regulatory network in PDAC cell lines (PANC-1 and MIA PaCa-2) and in PDAC samples from patients. We used this information to identify miRNAs that contribute most to tumorigenesis. RESULTS: We identified 3 miRNAs (MIR21, MIR23A, and MIR27A) that acted as cooperative repressors of a network of tumor suppressor genes that included PDCD4, BTG2, and NEDD4L. Inhibition of MIR21, MIR23A, and MIR27A had synergistic effects in reducing proliferation of PDAC cells in culture and growth of xenograft tumors in mice. The level of inhibition was greater than that of inhibition of MIR21 alone. In 91 PDAC samples from patients, high levels of a combination of MIR21, MIR23A, and MIR27A were associated with shorter survival times after surgical resection. CONCLUSIONS: In an integrated data analysis, we identified functional miRNA mRNA interactions that contribute to growth of PDACs. These findings indicate that miRNAs act together to promote tumor progression; therapeutic strategies might require inhibition of several miRNAs.