MicroRNA-206 (miR-206) has demonstrated tumor suppressive effects in a variety of cancers. Numerous studies have identified aberrantly expressed targets of miR-206 that contribute to tumor progression and metastasis, however, the broader gene-networks and pathways regulated by miR-206 remain poorly defined. Here, we have ectopically expressed miR-206 in lung adenocarcinoma cell lines and tumors to identify differentially expressed genes, and study the effects on tumor growth and metastasis. In H1299 tumor xenograft assays, stable expression of miR-206 suppressed both tumor growth and metastasis in mice. Profiling of xenograft tumors using small RNA sequencing and a targeted panel of tumor progression and metastasis-related genes revealed a network of genes involved in TGF-β signalling that were regulated by miR-206. Among these were the TGFB1 ligand, as well as direct transcriptional targets of Smad3. Other differentially expressed genes included components of the extracellular matrix involved in TGF-β activation and signalling, including Thrombospondin-1, which is responsible for the activation of latent TGF-β in the stroma. In cultured lung adenocarcinoma cells treated with recombinant TGF-β, ectopic expression of miR-206 impaired canonical signalling, and expression of TGF-β target genes linked to epithelial-mesenchymal transition. This was due at least in part to the suppression of Smad3 protein levels in lung adenocarcinoma cells with ectopic miR-206 expression. Together, these findings indicate that miR-206 can suppress tumor progression and metastasis by limiting autocrine production of TGF-β, and highlight the potential utility of TGF-β inhibitors for the treatment of lung adenocarcinomas.

MicroRNA-206（miR-206）在多种癌症中均表现出抑癌作用。许多研究已经确定了miR-206异常表达的靶标，这些靶标有助于肿瘤的进展和转移，但是，miR-206调控的更广泛的基因网络和途径仍然定义不清。在这里，我们在肺腺癌细胞系和肿瘤中异位表达了miR-206，以鉴定差异表达的基因，并研究其对肿瘤生长和转移的影响。在H1299肿瘤异种移植测定中，miR-206的稳定表达抑制了小鼠的肿瘤生长和转移。使用小分子RNA测序和肿瘤进展及与转移相关的基因的靶向研究，对异种移植肿瘤进行了分析，揭示了由miR-206调控的涉及TGF-β信号传导的基因网络。其中包括TGFB1配体以及Smad3的直接转录靶标。其他差异表达的基因包括参与TGF-β活化和信号传导的细胞外基质成分，包括Thrombospondin-1，它负责基质中潜在TGF-β的活化。在用重组TGF-β处理的培养的肺腺癌细胞中，miR-206的异位表达损害了常规信号传导，并且TGF-β靶基因的表达与上皮-间质转化有关。这至少部分是由于异位miR-206表达抑制了肺腺癌细胞中Smad3蛋白水平的缘故。总之，这些发现表明miR-206可通过限制TGF-β的自分泌产生来抑制肿瘤的进展和转移，