Department of Functional Genomics, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
J Hum Genet. 2011 Aug;56(8):595-601. doi: 10.1038/jhg.2011.66. Epub 2011 Jul 14.
Our microRNA (miRNA) expression signatures of hypopharyngeal squamous cell carcinoma, maxillary sinus squamous cell carcinoma and esophageal squamous cell carcinoma revealed that miR-375 was significantly reduced in cancer tissues compared with normal epithelium. In this study, we focused on the functional significance of miR-375 in cancer cells and identification of miR-375-regulated novel cancer networks in head and neck squamous cell carcinoma (HNSCC). Restoration of miR-375 showed significant inhibition of cell proliferation and induction of cell apoptosis in SAS and FaDu cell lines, suggesting that miR-375 functions as a tumor suppressor. We adopted genome-wide gene expression analysis to search for miR-375-regulated molecular targets. Gene expression data and luciferase reporter assays revealed that AEG-1/MTDH was directly regulated by miR-375. Cancer cell proliferation was significantly inhibited in HNSCC cells transfected with si-AEG-1/MTDH. In addition, expression levels of AEG-1/MTDH were significantly upregulated in cancer tissues. Therefore, AEG-1/MTDH may function as an oncogene in HNSCC. The identification of novel tumor suppressive miRNA and its regulated cancer pathways could provide new insights into potential molecular mechanisms of HNSCC oncogenesis.
我们的下咽鳞癌、上颌窦鳞癌和食管鳞癌的 microRNA（miRNA）表达谱显示，miR-375 在癌症组织中与正常上皮相比显著降低。在这项研究中，我们专注于 miR-375 在癌细胞中的功能意义，并鉴定头颈部鳞癌（HNSCC）中 miR-375 调节的新的癌症网络。miR-375 的恢复在下咽鳞癌细胞系 SAS 和 FaDu 中显示出对细胞增殖的显著抑制和细胞凋亡的诱导，表明 miR-375 作为肿瘤抑制因子发挥作用。我们采用全基因组基因表达分析来寻找 miR-375 调节的分子靶标。基因表达数据和荧光素酶报告基因实验表明，AEG-1/MTDH 被 miR-375 直接调控。用 si-AEG-1/MTDH 转染的 HNSCC 细胞中，癌细胞增殖显著受到抑制。此外，AEG-1/MTDH 的表达水平在上皮样癌组织中显著上调。因此，AEG-1/MTDH 可能在上皮样癌中作为癌基因发挥作用。新型肿瘤抑制性 miRNA 及其调节的癌症通路的鉴定可为 HNSCC 致癌的潜在分子机制提供新的见解。
