MicroRNA-204-5p inhibits invasion and metastasis of laryngeal squamous cell carcinoma by suppressing forkhead box C1.
MicroRNA-204-5p inhibits invasion and metastasis of laryngeal squamous cell carcinoma by suppressing forkhead box C1.
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MicroRNA-204-5p通过抑制叉头盒C1抑制喉鳞状细胞癌的侵袭和转移。
DOI：
10.7150/jca.19470
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发表时间：
2017
影响因子：
3.9
通讯作者：
Wang B
中科院分区：
文献类型：
--
作者：
Gao W;Wu Y;He X;Zhang C;Zhu M;Chen B;Liu Q;Qu X;Li W;Wen S;Wang B
背景和目标：了解喉鳞状细胞癌（LSCC）侵袭和转移的分子生物学机制对于诊断、治疗和预后至关重要。本研究旨在检测抑癌基因microRNA-204- 5 p（miR-204- 5 p）及其靶基因forkhead box C1（FOXC 1）在人喉鳞癌中的表达，探讨其在喉鳞癌Hep-2和TU-177细胞恶性行为中的作用。研究方法：采用双荧光素酶报告基因检测miR-204- 5 p对FOXC 1 3′非翻译区的调控作用。应用定量RT-PCR方法检测43例新鲜喉鳞癌组织及相应癌旁正常喉粘膜中mRNA的表达。免疫组化法检测FOXC 1蛋白表达。将miR-204- 5 p模拟物和FOXC 1 siRNA转染到喉鳞状细胞癌细胞系Hep-2和TU-177中以观察恶性行为。将miR-204- 5 p模拟物注射到裸鼠中的Hep-2或TU-177异种移植肿瘤中以检查肿瘤生长。 结果如下：miR-204- 5 p mRNA水平在所有43个LSCC样本中低于ANM样本，但FOXC 1水平在LSCC样本中高于ANM样本。III期和IV期癌症和淋巴结N+状态样品的miR-204- 5 p水平低于I期和II期癌症和N 0状态样品。FOXC 1 mRNA和蛋白水平在N+组高于N 0组。miR-204- 5 p在Hep-2和TU-177细胞中的mRNA水平低于ANM组织，但FOXC 1在Hep-2和TU-177细胞中的mRNA水平高于ANM组织。双荧光素酶报告基因测定证明了miR-204- 5 p对FOXC 1 3 'UTR的靶向调节作用。miR-204- 5 p模拟物和FOXC 1 siRNA促进了细胞增殖和集落形成，细胞迁移和侵袭比对照弱。此外，miR-204- 5 p过表达或FOXC 1敲低抑制了LSCC细胞中的EMT过程。体内实验证明，将miR-204- 5 p注射到裸鼠的Hep-2和TU-177异种移植肿瘤中显著抑制肿瘤生长。结论：miR-204- 5 p参与喉鳞癌的侵袭和转移。它对FOXC 1表达具有靶向调节作用;抑制恶性LSCC行为，包括细胞增殖、侵袭和转移，抑制体内肿瘤生长。提示miR-204- 5 p有可能成为喉鳞癌分子治疗的新靶点。
Background and aim: Understanding the molecular biological mechanisms underlying laryngeal squamous cell carcinoma (LSCC) invasion and metastasis is crucial for diagnosis, treatment, and prognosis. We aimed to examine the expression of the tumor suppressor microRNA-204-5p (miR-204-5p) and its target gene, forkhead box C1 (FOXC1), in human LSCC and explore their roles in the malignant behaviors of LSCC Hep-2 and TU-177 cells. Methods: The regulatory effects of miR-204-5p on the 3′ untranslated region of FOXC1 predicted by bioinformatics were tested by dual-luciferase reporter assay. Quantitative RT-PCR was used to detect mRNA expression in 43 fresh samples of LSCC and corresponding adjacent normal mucosa (ANM). FOXC1 protein expression was examined by immunohistochemistry. miR-204-5p mimics and FOXC1 siRNA were transfected into LSCC cell lines Hep-2 and TU-177 to observe malignant behavior. miR-204-5p mimics were injected into Hep-2 or TU-177 xenograft tumors in nude mice to examine tumor growth. Results: The miR-204-5p mRNA level was lower in all 43 LSCC samples than in the ANM samples, but the FOXC1 level was higher in the LSCC samples than in the ANM samples. The miR-204-5p level was lower for stage III and IV cancer and lymph node N+ status samples than for stage I and II cancer and N0 status samples. FOXC1 mRNA and protein levels were higher for N+ than for N0 LSCC. The miR-204-5p mRNA levels were lower in Hep-2 and TU-177 cells than in ANM tissues, but FOXC1 mRNA levels were higher in Hep-2 and TU-177 cells than in ANM tissues. Dual-luciferase reporter assays demonstrated the targeted regulatory effects of miR-204-5p on the FOXC1 3′ UTR. Cell proliferation and colony formation was facilitated with miR-204-5p mimics and FOXC1 siRNA, with weaker cell migration and invasion than the controls. Moreover, miR-204-5p overexpression or FOXC1 knockdown inhibited the EMT process in LSCC cells. In vivo experiments demonstrated that injection of miR-204-5p into Hep-2 and TU-177 xenograft tumors in nude mice significantly inhibited tumor growth. Conclusions: miR-204-5p is involved in the invasion and metastasis of LSCC. It has a targeted regulatory effect on FOXC1 expression; malignant LSCC behaviors, including cell proliferation, invasion, and metastasis, are suppressed, and tumor growth in vivo is inhibited. This suggests that miR-204-5p may be a target for molecular therapy of LSCC in the future.
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