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Dicer 的过表达导致 let-7 MicroRNA 水平降低,从而促进口腔癌细胞的增殖。

Overexpression of dicer as a result of reduced let-7 MicroRNA levels contributes to increased cell proliferation of oral cancer cells.

机构信息

Department of Oral Biology, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610-0424, USA.

出版信息

Genes Chromosomes Cancer. 2010 Jun;49(6):549-59. doi: 10.1002/gcc.20765.

Abstract

Recent reports have demonstrated that Dicer, an RNase III endonuclease required for microRNA (miRNA) maturation, is aberrantly expressed in different types of cancer. Furthermore, Dicer has been reported to be regulated by the let-7 family of miRNA genes. We hypothesize that Dicer is aberrantly expressed in oral cancer cells due to altered expressions of let-7 and that Dicer contributes to the development and progression of the disease. Western blot examination of Dicer protein levels in four head and neck squamous cell carcinoma (HNSCC) cell lines, including two oral cancer cell lines, demonstrated that Dicer had between 4- and 24-fold higher expression levels when compared to normal human primary gingival epithelial cells. Furthermore, five of six oral cancer tissues analyzed by indirect immunofluorescence had increased Dicer protein expression, compared to normal gingival epithelial tissue. The Dicer mRNA levels were not found to correlate well with protein expression in the HNSCC cell lines, suggesting that Dicer protein expression was post-transcriptionally regulated. Analysis of let-7a and let-7b levels in HNSCC cell lines by real-time PCR demonstrated that let-7b, but not let-7a, was significantly reduced in the HNSCC cell lines compared to control cells. Lastly, transfection of oral cancer cells with chemically synthesized let-7b and small interfering RNAs targeting Dicer significantly inhibited cell proliferation up to 83% and >100%, respectively, as early as 3 days post-transfection. Together, these data demonstrate that elevated expression levels of Dicer in oral cancer cells correlate with downregulation of let-7b and increased cell proliferation.

摘要

最近的报告表明,Dicer(一种 RNA 酶 III 内切酶,是 miRNA(微小 RNA)成熟所必需的)在不同类型的癌症中异常表达。此外,已经有报道称 Dicer 受 let-7 家族 miRNA 基因的调控。我们假设由于 let-7 的表达改变,口腔癌细胞中 Dicer 异常表达,并且 Dicer 有助于疾病的发展和进展。Western blot 检测四种头颈部鳞状细胞癌(HNSCC)细胞系(包括两种口腔癌细胞系)中的 Dicer 蛋白水平,结果显示与正常人类原代牙龈上皮细胞相比,Dicer 的表达水平高 4-24 倍。此外,通过间接免疫荧光分析的 6 份口腔癌组织中,与正常牙龈上皮组织相比,Dicer 蛋白表达增加。在 HNSCC 细胞系中,Dicer mRNA 水平与蛋白表达没有很好的相关性,表明 Dicer 蛋白表达受到转录后调控。通过实时 PCR 分析 HNSCC 细胞系中的 let-7a 和 let-7b 水平,结果表明与对照细胞相比,HNSCC 细胞系中 let-7b 而非 let-7a 显著减少。最后,用化学合成的 let-7b 转染口腔癌细胞和针对 Dicer 的小干扰 RNA 转染,分别在转染后 3 天内使细胞增殖抑制高达 83%和>100%。综上所述,这些数据表明口腔癌细胞中 Dicer 的高表达水平与 let-7b 的下调和细胞增殖增加相关。

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