Targeting the mRNA-binding protein HuR impairs malignant characteristics of pancreatic ductal adenocarcinoma cells.
Targeting the mRNA-binding protein HuR impairs malignant characteristics of pancreatic ductal adenocarcinoma cells.
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DOI：
10.18632/oncotarget.4743
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发表时间：
2015-09-29
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影响因子：
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通讯作者：
Brody JR
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作者：
Jimbo M;Blanco FF;Huang YH;Telonis AG;Screnci BA;Cosma GL;Alexeev V;Gonye GE;Yeo CJ;Sawicki JA;Winter JM;Brody JR
转录后调控是一种强大的基因表达介质，可以迅速改变参与肿瘤发生的许多转录物的表达。我们之前的研究表明，与正常胰腺组织相比，mrna结合蛋白HuR （ELAVL1）在人胰腺导管腺癌（PDA）标本中升高，其细胞质定位与肿瘤分期增加有关。为了更好地了解HuR在PDA生物学中的作用，并评估其作为候选治疗靶点，我们改变了HuR在PDA细胞系中的表达，并在临床前模型中表征了由此产生的表型。短发夹和小干扰rna沉默HuR可显著降低细胞增殖和非锚定生长，损害迁移和侵袭能力。相比之下，HuR过表达增加了细胞的迁移和侵袭，但对细胞增殖和非锚定生长没有显著影响。重要的是，两种不同的靶向HuR沉默方法在小鼠异种移植物中显示出明显的肿瘤生长损伤。NanoString nCounter®分析表明，HuR调控核心生物过程，强调HuR抑制可能通过转录后调控多种信号通路（如细胞周期、细胞凋亡、DNA修复）来阻碍PDA的活性。综上所述，我们的研究表明，靶向抑制HuR可能是治疗PDA的一种新的、有前途的方法。
Post-transcriptional regulation is a powerful mediator of gene expression, and can rapidly alter the expression of numerous transcripts involved in tumorigenesis. We have previously shown that the mRNA-binding protein HuR (ELAVL1) is elevated in human pancreatic ductal adenocarcinoma (PDA) specimens compared to normal pancreatic tissues, and its cytoplasmic localization is associated with increased tumor stage. To gain a better insight into HuR’s role in PDA biology and to assess it as a candidate therapeutic target, we altered HuR expression in PDA cell lines and characterized the resulting phenotype in preclinical models. HuR silencing by short hairpin and small interfering RNAs significantly decreased cell proliferation and anchorage-independent growth, as well as impaired migration and invasion. In comparison, HuR overexpression increased migration and invasion, but had no significant effects on cell proliferation and anchorage-independent growth. Importantly, two distinct targeted approaches to HuR silencing showed marked impairment in tumor growth in mouse xenografts. NanoString nCounter® analyses demonstrated that HuR regulates core biological processes, highlighting that HuR inhibition likely thwarts PDA viability through post-transcriptional regulation of diverse signaling pathways (e.g. cell cycle, apoptosis, DNA repair). Taken together, our study suggests that targeted inhibition of HuR may be a novel, promising approach to the treatment of PDA.