Lu Wen-Cheng, Kao Shou-Yen, Yang Cheng-Chieh, Tu Hsi-Feng, Wu Cheng-Hsien, Chang Kuo-Wei, Lin Shu-Chun
Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
Department of Dentistry, National Yang-Ming University, Taipei, Taiwan; Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan.
PLoS One. 2014 Sep 17;9(9):e108049. doi: 10.1371/journal.pone.0108049. eCollection 2014.
Oral squamous cell carcinoma (OSCC) is one of the most prevalent carcinomas worldwide. MicroRNAs (miRNAs) are short, non-coding RNAs that regulate gene expression and modulate physiological or pathological processes including OSCC carcinogenesis. miR-31 has been found to be up-regulated in OSCC and to act as an oncogenic miRNA. However, the molecular mechanism underlying miR-31 up-regulation in OSCC is still obscure. The activation of epidermal growth factor receptor (EGFR) signaling axis plays key roles in driving oral carcinogenesis. Our screening identified that there is up-regulation of miR-31, miR-181b and miR-222 in OSCC cells following EGF treatment. Subsequent analysis showed that EGF treatment led to AKT activation, which then resulted in miR-31 up-regulation. Moreover, EGF treatment and the AKT activation induced by exogenous expression up-regulated C/EBPβ expression. The miR-31 up-regulation induced by EGF was abrogated by AKT inhibition or by the knockdown of C/EBPβ expression. In OSCC cell subclones stably overexpressing the functional isoform of C/EBPβ, miR-31 expression was up-regulated. Curcumin is a natural ingredient exhibiting anti-cancer potential. It was found that curcumin attenuated AKT activation and the up-regulation of C/EBPβ and miR-31 caused by EGF stimulation in OSCC cells. Lastly, concordance across the expression of EGFR, the expression of C/EBPβ and the expression of miR-31 in OSCC tissues was found. This study describes a novel scenario where the up-regulation of miR-31 expression in OSCC is, at least in part, a consequence of EGFR oncogenic activation. Although the AKT activation and C/EBPβ expression after EGF treatment might not be directly linked, both events are the crucial mediators underlying miR-31 up-regulation in the EGFR signaling axis.
口腔鳞状细胞癌（OSCC）是全球最常见的癌症之一。微小RNA（miRNA）是一类短链非编码RNA，可调节基因表达并调控包括OSCC致癌作用在内的生理或病理过程。已发现miR-31在OSCC中上调，并作为一种致癌miRNA发挥作用。然而，OSCC中miR-31上调的分子机制仍不清楚。表皮生长因子受体（EGFR）信号轴的激活在口腔致癌过程中起关键作用。我们的筛选发现，EGF处理后OSCC细胞中miR-31、miR-181b和miR-222上调。随后的分析表明，EGF处理导致AKT激活，进而导致miR-31上调。此外，EGF处理和外源性表达诱导的AKT激活上调了C/EBPβ的表达。AKT抑制或C/EBPβ表达的敲低可消除EGF诱导的miR-31上调。在稳定过表达C/EBPβ功能异构体的OSCC细胞亚克隆中，miR-31表达上调。姜黄素是一种具有抗癌潜力的天然成分。研究发现，姜黄素可减弱EGF刺激引起的OSCC细胞中AKT激活以及C/EBPβ和miR-31的上调。最后，在OSCC组织中发现了EGFR表达量、C/EBPβ表达量和miR-31表达量之间的一致性。本研究描述了一种新情况，即OSCC中miR-31表达上调至少部分是EGFR致癌激活的结果。尽管EGF处理后AKT激活和C/EBPβ表达可能没有直接联系，但这两个事件都是EGFR信号轴中miR-31上调的关键介质。
