Associations of mRNA:microRNA for the Shared Downstream Molecules of EGFR and Alternative Tyrosine Kinase Receptors in Non-small Cell Lung Cancer.
Associations of mRNA:microRNA for the Shared Downstream Molecules of EGFR and Alternative Tyrosine Kinase Receptors in Non-small Cell Lung Cancer.
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DOI：
10.3389/fgene.2016.00173
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发表时间：
2016
影响因子：
3.7
通讯作者：
Chan LW
中科院分区：
文献类型：
--
作者：
Wang F;Meng F;Wang L;Wong SC;Cho WC;Chan LW
肺癌是全球头号癌症杀手，死亡率极高。大多数属于非小细胞肺癌（NSCLC）。表皮生长因子受体（EGFR）作为治疗药物靶点已被广泛探索。然而，由于获得性耐药，药物反应并不持久。 MicroRNA (miRNA) 是小的非编码内源分子，可以抑制 mRNA 翻译起始并降解 mRNA。我们想知道EGFR和其他酪氨酸激酶受体（TKR）共享的一些下游分子是否进一步交替转导信号，并且一些miRNA在影响这些下游分子的表达中发挥着关键作用。在本研究中，我们研究了与其他 TKR 共享的 EGFR 信号通路中直接 EGFR 下游分子的 mRNA:miRNA 关联，包括 c-MET（肝细胞生长因子受体）、Ron（与 c-MET 相关的蛋白酪氨酸激酶）、PDGFR（血小板源性生长因子受体）和 IGF-1R（胰岛素样生长因子受体-1）。使用多元线性回归和支持向量回归 (SVR) 模型来发现调节这些下游分子 mRNA 的统计显着性和最佳加权 miRNA。这两个模型揭示了相似的 mRNA:miRNA 关联。结果发现，多元回归模型中对mRNA表达影响显着的miRNA，也是SVR模型中权重最大的miRNA。总之，我们有效地确定了一系列有意义的 mRNA:miRNA 关联：磷脂酶 C、gamma 1 (PLCG1) 与 miR-34a、磷酸肌醇-3-激酶、调节亚基 2 (PIK3R2) 与 miR-30a-5p、生长因子受体结合蛋白 2 (GRB2) 与 miR-27a 以及 Janus 激酶 1 (JAK1) 与 miR-302b 和miR-520e。这些关联可以为探索非小细胞肺癌的新机制做出巨大贡献。这些候选miRNA可能被视为治疗获得性耐药的NSCLC的潜在药物靶点。
Lung cancer is the top cancer killer worldwide with high mortality rate. Majority belong to non-small cell lung cancers (NSCLCs). The epidermal growth factor receptor (EGFR) has been broadly explored as a drug target for therapy. However, the drug responses are not durable due to the acquired resistance. MicroRNAs (miRNAs) are small non-coding and endogenous molecules that can inhibit mRNA translation initiation and degrade mRNAs. We wonder if some downstream molecules shared by EGFR and the other tyrosine kinase receptors (TKRs) further transduce the signals alternatively, and some miRNAs play the key roles in affecting the expression of these downstream molecules. In this study, we investigated the mRNA:miRNA associations for the direct EGFR downstream molecules in the EGFR signaling pathway shared with the other TKRs, including c-MET (hepatocyte growth factor receptor), Ron (a protein tyrosine kinase related to c-MET), PDGFR (platelet-derived growth factor receptor), and IGF-1R (insulin-like growth factor receptor-1). The multiple linear regression and support vector regression (SVR) models were used to discover the statistically significant and the best weighted miRNAs regulating the mRNAs of these downstream molecules. These two models revealed the similar mRNA:miRNA associations. It was found that the miRNAs significantly affecting the mRNA expressions in the multiple regression model were also those with the largest weights in the SVR model. To conclude, we effectively identified a list of meaningful mRNA:miRNA associations: phospholipase C, gamma 1 (PLCG1) with miR-34a, phosphoinositide-3-kinase, regulatory subunit 2 (PIK3R2) with miR-30a-5p, growth factor receptor-bound protein 2 (GRB2) with miR-27a, and Janus kinase 1 (JAK1) with miR-302b and miR-520e. These associations could make great contributions to explore new mechanism in NSCLCs. These candidate miRNAs may be regarded as the potential drug targets for treating NSCLCs with acquired drug resistance.
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