4.6 Article

MicroRNA-206 suppresses TGF-β signalling to limit tumor growth and metastasis in lung adenocarcinoma

Journal

CELLULAR SIGNALLING
Volume 50, Issue -, Pages 25-36

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2018.06.008

Keywords

Lung cancer; Metastasis; microRNA; miR-206; TGF-beta; Smad3

Categories

Funding

  1. Cancer Research Society [20142]
  2. Canadian Institutes for Health Research [MOP 119562]
  3. Ontario Graduate Scholarship
  4. Terry Fox Transdisciplinary Training Program in Cancer Research at Queen's University

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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-beta 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-beta activation and signalling, including Thrombospondin-1, which is responsible for the activation of latent TGF-beta in the stroma. In cultured lung adenocarcinoma cells treated with recombinant TGF-beta, ectopic expression of miR-206 impaired canonical signalling, and expression of TGF-beta 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-beta, and highlight the potential utility of TGF-beta inhibitors for the treatment of lung adenocarcinomas.

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