microRNA-106b-mediated down-regulation of C1orf24 expression induces apoptosis and suppresses invasion of thyroid cancer.
microRNA-106b-mediated down-regulation of C1orf24 expression induces apoptosis and suppresses invasion of thyroid cancer.
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DOI：
10.18632/oncotarget.4947
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发表时间：
2015-09-29
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影响因子：
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通讯作者：
Cerutti JM
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作者：
Carvalheira G;Nozima BH;Cerutti JM
我们以前发现C1orf24在甲状腺癌中的表达增加。尽管如此，C1orf24去调控的机制还没有完全被理解。已经广泛证明，microRNAs参与了包括癌症在内的多种疾病的转录后基因调控。利用电子计算机预测方法，鉴定了5个与C1orf24 3‘-非翻译区(3’-UTR)结合的microRNAs。选择两种microRNAs(miR-17-5p、miR-106b)和C1orf24在48例甲状腺良恶性病变和5个甲状腺癌细胞系中的表达进行检测。MIR-106b在甲状腺癌标本和甲状腺癌细胞系中表达下调，而C1orf24表达显著上调。为了证明miR-106b能够降低C1orf24的表达，我们用miR-106b模拟基因瞬时转染了甲状腺癌细胞系WRO和TPC1。MiR-106b模拟物的异位表达显著抑制了WRO和TPC1细胞中C1orf24的mRNA和蛋白表达。双荧光素酶分析表明miR-106b通过结合C1orf24的3‘-UTR直接靶向C1orf24。此外，miR-106b介导的C1orf24表达下调增加了细胞的凋亡，抑制了细胞的迁移。此外，我们还证明了针对C1orf24的siRNA显著降低了其表达，抑制了细胞迁移和细胞周期进程，并诱导了细胞凋亡。综上所述，我们的发现不仅为了解C1orf24在甲状腺癌中过表达的分子机制提供了新的见解，而且还表明C1orf24可能促进细胞的增殖和迁移。因此，通过恢复miR-106b功能降低C1orf24水平可能具有治疗意义。
We previously showed that C1orf24 expression is increased in thyroid carcinomas. Nonetheless, the mechanism underlying C1orf24 deregulation is not fully understood. It has been widely demonstrated that microRNAs are involved in post-transcriptional gene regulation in several diseases, including cancer. Using in silico prediction approach, five microRNAs that bind to the 3′-untranslated region (3′-UTR) of C1orf24 were identified. The expression of two selected microRNAs (miR-17-5p, miR-106b) and the expression of C1orf24 were tested in 48 benign and malignant thyroid lesions and in five thyroid carcinoma cell lines. miR-106b was down-regulated in thyroid cancer specimens and thyroid carcinoma cell lines, while C1orf24 expression was markedly increased. To demonstrate that miR-106b reduces C1orf24 expression, follicular (WRO) and papillary (TPC1) thyroid carcinoma cell lines were transiently transfected with miR-106b mimic. Ectopic expression of the miR-106b mimic significantly inhibits C1orf24 mRNA and protein expression in both WRO and TPC1 cells. Dual-luciferase report assays demonstrated that miR-106b directly targets C1orf24 by binding its 3′- UTR. Moreover, miR-106b-mediated down-regulation of C1orf24 expression increased apoptosis and inhibited migration. We additionally demonstrated that siRNA against C1orf24 significantly decreased its expression, inhibited cell migration and cell cycle progression while induced apoptosis. In summary, our findings not only provide new insights into molecular mechanism associated with C1orf24 overexpression in thyroid carcinomas but also show that C1orf24 might increase proliferation and cell migration. Thus, decreasing C1orf24 levels, by restoring miR-106b function, may have therapeutic implications.