Tumor-suppressive microRNA-206 as a dual inhibitor of MET and EGFR oncogenic signaling in lung squamous cell carcinoma
Tumor-suppressive microRNA-206 as a dual inhibitor of MET and EGFR oncogenic signaling in lung squamous cell carcinoma
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DOI：
10.3892/ijo.2014.2802
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发表时间：
2015-03-01
影响因子：
5.2
通讯作者：
Inoue, Hiromasa
中科院分区：
文献类型：
--
作者：
Mataki, Hiroko;Seki, Naohiko;Inoue, Hiromasa
癌基因肝细胞生长因子受体 (MET) 的表达和 MET 蛋白的磷酸化与非小细胞肺癌 (NSCLC) 患者对表皮生长因子受体 (EGFR) 治疗中使用的酪氨酸激酶抑制剂 (TKI) 的原发性和获得性耐药相关。因此，同时抑制这两种受体酪氨酸激酶（RTK）应该可以改善疾病治疗。我们之前对肺鳞状细胞癌（lung-SCC）的 microRNA (miRNA) 表达特征的研究表明，microRNA-206 (miR-206) 在肺鳞状细胞癌组织中显着减少，表明 miR-206 在该疾病中发挥肿瘤抑制因子的作用。此外，推定的 miR-206 结合位点在 miRNA 数据库中的 MET 和 EGFR RTK 的 3'-UTR 中进行了注释。该研究的目的是研究 miR-206 在肺 SCC 中的功能意义，并确认癌细胞中 miR-206 的表达对 MET 和 EGFR 致癌信号传导的抑制。我们发现成熟的 miR-206 的恢复通过下调 MET 和 EGFR 的 mRNA 和蛋白水平抑制 EBC-1 细胞中的癌细胞增殖、迁移和侵袭。有趣的是，癌细胞中 miR-206 的恢复抑制了 ERK1/2 和 AKT 信号传导的磷酸化。在肺鳞状细胞癌的临床标本中观察到MET和EGFR的过度表达。抑癌miR-206抑制MET和EGFR激活的双重信号网络，这些发现将为肺鳞状细胞癌发生的新分子机制和治疗该疾病的新治疗方法提供新的见解。
Expression of the oncogene hepatocyte growth factor receptor (MET) and phosphorylation of the MET protein have been associated with both primary and acquired resistance to tyrosine kinase inhibitors (TKIs) used in therapy targeting the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancers (NSCLCs). Therefore, simultaneous inhibition of both of these receptor tyrosine kinases (RTKs) should improve disease treatment. Our previous study of microRNA (miRNA) expression signatures of lung squamous cell carcinoma (lung-SCC) revealed that microRNA-206 (miR-206) was significantly reduced in lung-SCC tissues, suggesting that miR-206 functions as a tumor suppressor in the disease. Furthermore, putative miR-206 binding sites were annotated in the 3'-UTRs of MET and EGFR RTKs in miRNA databases. The aim of the study was to investigate the functional significance of miR-206 in lung-SCC and to confirm the inhibition of both MET and EGFR oncogenic signaling by expression of miR-206 in cancer cells. We found that restoration of mature miR-206 inhibited cancer cell proliferation, migration, and invasion in EBC-1 cells through downregulation of both mRNA and protein levels of MET and EGFR. Interestingly, phosphorylation of ERK1/2 and AKT signaling were inhibited by restoration of miR-206 in cancer cells. Overexpression of MET and EGFR were observed in clinical specimens of lung-SCC. Tumor-suppressive miR-206 inhibited dual signaling networks activated by MET and EGFR, and these findings will provide new insights into the novel molecular mechanisms of lung-SCC oncogenesis and new therapeutic approaches for the treatment of this disease.