Department of Nuclear Medicine, Shanghai 10th People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
J Clin Endocrinol Metab. 2013 Aug;98(8):E1305-13. doi: 10.1210/jc.2012-3602. Epub 2013 Jun 24.
MicroRNAs (miRNAs) are strongly implicated in many cancers, including papillary thyroid carcinoma (PTC), which is the most common malignancy in thyroid tissue. Recently, miRNA-155 (miR-155) has been proved to play a substantial role in liposarcoma and breast cancer, but its functions in the context of PTC remain unknown.
The objective was to investigate the potential involvement of miR-155 in PTC.
Expression levels of miR-155 were assessed via quantitative real-time PCR in 20 pairs of human PTC and adjacent normal tissues and in 4 human PTC cell lines. Lentiviral miR-155 overexpression models were performed in TPC-1 and CGTH-W3 cells, and the effects on cell growth were evaluated. We have searched for miR-155 targets and identified the hypothesis that miR-155 could promote tumor growth of PTC by targeted regulation of adenomatous polyposis coli (APC) expression and activating the Wnt/β-catenin signaling.
MiR-155 levels were markedly increased in PTC specimens and PTC cell lines. Overexpression of miR-155 dramatically promoted PTC cell viability and colony formation in vitro, whereas miR-155 depletion reduced these parameters. Further studies revealed that APC is a novel miR-155 target, because miR-155 bound directly to its 3'-untranslated region and reduced both the mRNA and protein levels of APC. Similar to the miR-155 over-expression, APC downregulation promoted cell growth, whereas rescued APC expression reversed the promotive effect of miR-155. Furthermore, miR-155 overexpression resulted in activation of β-catenin and induction of several downstream genes including c-Myc, cyclin D1, TCF-1. and LEF-1. Depletion of β-catenin partially prevented miR-155-induced tumor cell viability and colony formation. In xenograft animal experiments, we found overexpressed miR-155 effectively promoted tumor growth of PTC cells.
Our results indicate that miR-155 functions as an oncogene in PTC. By targeting APC, miR-155 efficiently regulates the Wnt/β-catenin signaling. And miR-155 may be a potential therapeutic or diagnostic/prognostic target for treating PTC.
MicroRNAs（miRNAs）在包括甲状腺乳头状癌（PTC）在内的许多癌症中具有重要作用，PTC 是甲状腺组织中最常见的恶性肿瘤。最近，miR-155（miR-155）已被证明在脂肪肉瘤和乳腺癌中发挥了重要作用，但它在 PTC 中的功能尚不清楚。
本研究旨在探讨 miR-155 参与 PTC 的潜在机制。
通过实时定量 PCR 检测 20 对人 PTC 组织及其相应癌旁组织和 4 个人 PTC 细胞系中 miR-155 的表达水平。构建 miR-155 过表达慢病毒载体，在 TPC-1 和 CGTH-W3 细胞中过表达 miR-155，评估其对细胞生长的影响。通过靶基因预测软件预测 miR-155 的靶基因，并验证 miR-155 是否通过靶向调控腺瘤性结肠息肉病基因（APC）表达和激活 Wnt/β-catenin 信号通路促进 PTC 肿瘤的生长。
miR-155 在 PTC 标本和 PTC 细胞系中表达明显升高。过表达 miR-155 可显著促进 PTC 细胞的体外增殖和集落形成，而 miR-155 下调则降低了这些参数。进一步研究表明，APC 是 miR-155 的一个新的靶基因，因为 miR-155 可以直接与其 3'-UTR 结合，降低 APC 的 mRNA 和蛋白水平。与 miR-155 过表达相似，下调 APC 表达可促进细胞生长，而恢复 APC 表达则可逆转 miR-155 的促增殖作用。此外，miR-155 过表达可导致 β-catenin 激活和下游基因如 c-Myc、cyclin D1、TCF-1 和 LEF-1 的诱导。β-catenin 下调部分阻止了 miR-155 诱导的肿瘤细胞活力和集落形成。在异种移植动物实验中，我们发现过表达 miR-155 可有效促进 PTC 细胞的肿瘤生长。
本研究结果表明，miR-155 在 PTC 中作为癌基因发挥作用。通过靶向 APC，miR-155 可有效调节 Wnt/β-catenin 信号通路。miR-155 可能是治疗 PTC 的一种有潜力的治疗或诊断/预后靶点。
