Centro di Ricerca Biomedica Applicata e Dipartimento di Medicina Interna, Policlinico S.Orsola-Malpighi e Università di Bologna, Bologna, Italy.
Cancer Res. 2010 Jun 15;70(12):5184-93. doi: 10.1158/0008-5472.CAN-10-0145. Epub 2010 May 25.
MicroRNAs (miRNA) have rapidly emerged as modulators of gene expression in cancer in which they may have great diagnostic and therapeutic import. MicroRNA-199a-3p (miR-199a-3p) is downregulated in several human malignancies including hepatocellular carcinoma (HCC). Here, we show that miR-199a-3p targets mammalian target of rapamycin (mTOR) and c-Met in HCC cells. Restoring attenuated levels of miR-199a-3p in HCC cells led to G(1)-phase cell cycle arrest, reduced invasive capability, enhanced susceptibility to hypoxia, and increased sensitivity to doxorubicin-induced apoptosis. These in vitro findings were confirmed by an analysis of human HCC tissues, which revealed an inverse correlation linking miR-199a-3p and mTOR as well as a shorter time to recurrence after HCC resection in patients with lower miR-199a-3p expression. These results suggest that tactics to regulate mTOR and c-Met by elevating levels of miR-199a-3p may have therapeutic benefits in highly lethal cancers such as HCC.
微小 RNA（miRNA）迅速成为癌症基因表达的调节剂，它们可能具有重要的诊断和治疗意义。miR-199a-3p 在包括肝细胞癌（HCC）在内的几种人类恶性肿瘤中下调。在这里，我们表明 miR-199a-3p 在 HCC 细胞中靶向哺乳动物雷帕霉素靶蛋白（mTOR）和 c-Met。在 HCC 细胞中恢复减弱的 miR-199a-3p 水平导致 G1 期细胞周期停滞、侵袭能力降低、对缺氧的敏感性增加以及对阿霉素诱导的细胞凋亡的敏感性增加。这些体外发现得到了人类 HCC 组织分析的证实，该分析揭示了 miR-199a-3p 与 mTOR 之间的负相关，以及 miR-199a-3p 表达水平较低的患者 HCC 切除后复发时间更短。这些结果表明，通过提高 miR-199a-3p 水平来调节 mTOR 和 c-Met 的策略可能对 HCC 等高度致命的癌症具有治疗益处。
