miR-185 通过靶向 SOX9 和调节 Wnt 信号通路抑制非小细胞肺癌细胞增殖和侵袭。
miR‑185 inhibits non‑small cell lung cancer cell proliferation and invasion through targeting of SOX9 and regulation of Wnt signaling.
机构信息
Department of Cardiac‑Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.
Center of Translational Medicine, Medical School of Yangzhou University, Yangzhou, Jiangsu 225000, P.R. China.
出版信息
Mol Med Rep. 2018 Jan;17(1):1742-1752. doi: 10.3892/mmr.2017.8050. Epub 2017 Nov 14.
SRY-box 9 (SOX9) is an important transcription factor required for development, which has additionally been reported to be an independent prognostic indicator for the survival of patients with non‑small cell lung cancer (NSCLC). Accumulating evidence has indicated that dysregulation of microRNAs (miRNAs/miRs) may contribute to the initiation and progression of cancer. SOX9 may be regulated by a number of miRNAs in different types of cancer, including in NSCLC. The present study sought to identify novel candidate miRNAs associated with SOX9 in NSCLC using online tools, and investigated the detailed functions of miR‑185, which suppressed SOX9 mRNA expression most strongly out of the candidate miRNAs. It was observed that ectopic miR‑185 expression significantly suppressed NSCLC cell proliferation, invasion and migration. Using luciferase reporter gene and RNA immunoprecipitation assays, SOX9 was confirmed to be a direct target of miR‑185. In addition, the downstream Wnt signaling‑associated factors β‑catenin and c‑Myc proto‑oncogene protein (Myc) were demonstrated to be inhibited by miR‑185 overexpression. SOX9, β‑catenin and c‑Myc mRNA expression was significantly upregulated in NSCLC tissues, and was inversely correlated with miR‑185 expression. The results of the present study demonstrated that rescuing miR‑185 expression in NSCLC, thereby inhibiting SOX9 expression and the downstream Wnt signaling, and leading to the suppression of NSCLC cell proliferation, invasion and migration, may be a promising strategy for the treatment of NSCLC.
性别决定区 Y 框 9(SRY-box 9,SOX9)是发育所必需的重要转录因子,此外,其已被报道为非小细胞肺癌(non-small cell lung cancer,NSCLC)患者生存的独立预后指标。越来越多的证据表明,微小 RNA(microRNA,miRNA/miRs)的失调可能导致癌症的发生和进展。SOX9 可能在不同类型的癌症中受到多种 miRNA 的调控,包括 NSCLC。本研究旨在利用在线工具鉴定与 NSCLC 中 SOX9 相关的新型候选 miRNA,并研究候选 miRNA 中对 SOX9 mRNA 表达抑制作用最强的 miR-185 的详细功能。结果发现,过表达 miR-185 可显著抑制 NSCLC 细胞的增殖、侵袭和迁移。通过荧光素酶报告基因和 RNA 免疫沉淀测定,证实 SOX9 是 miR-185 的直接靶基因。此外,过表达 miR-185 可抑制 Wnt 信号相关因子β-连环蛋白和 c-Myc 原癌基因蛋白(Myc)。miR-185 在 NSCLC 组织中的表达显著上调,与 SOX9 的表达呈负相关,且与β-连环蛋白和 c-Myc mRNA 的表达呈负相关。本研究结果表明,恢复 NSCLC 中的 miR-185 表达,从而抑制 SOX9 表达和下游的 Wnt 信号,进而抑制 NSCLC 细胞的增殖、侵袭和迁移,可能是治疗 NSCLC 的一种有前途的策略。