MicroRNA-155 Is Regulated by the Transforming Growth Factor β/Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA

TLDR

Transforming growth factor beta signaling promotes metastasis in advanced cancers, yet the contribution of microRNAs to TGF‑β–induced cell migration and invasion remains poorly understood. Using a 515‑miRNA microarray, the authors identified 28 miRNAs deregulated by TGF‑β in normal murine mammary epithelial cells, showing that miR‑155 induction and promoter activity are Smad4‑dependent. miR‑155 is markedly upregulated by TGF‑β, and its knockdown blocks EMT, tight‑junction loss, migration, and invasion, while ectopic miR‑155 reduces RhoA, disrupts junctions, and these effects are largely reversed by RhoA re‑expression; elevated miR‑155 is frequently found in invasive breast cancers, indicating its potential as a therapeutic target.

Abstract

Transforming growth factor beta (TGF-beta) signaling facilitates metastasis in advanced malignancy. While a number of protein-encoding genes are known to be involved in this process, information on the role of microRNAs (miRNAs) in TGF-beta-induced cell migration and invasion is still limited. By hybridizing a 515-miRNA oligonucleotide-based microarray library, a total of 28 miRNAs were found to be significantly deregulated in TGF-beta-treated normal murine mammary gland (NMuMG) epithelial cells but not Smad4 knockdown NMuMG cells. Among upregulated miRNAs, miR-155 was the most significantly elevated miRNA. TGF-beta induces miR-155 expression and promoter activity through Smad4. The knockdown of miR-155 suppressed TGF-beta-induced epithelial-mesenchymal transition (EMT) and tight junction dissolution, as well as cell migration and invasion. Further, the ectopic expression of miR-155 reduced RhoA protein and disrupted tight junction formation. Reintroducing RhoA cDNA without the 3' untranslated region largely reversed the phenotype induced by miR-155 and TGF-beta. In addition, elevated levels of miR-155 were frequently detected in invasive breast cancer tissues. These data suggest that miR-155 may play an important role in TGF-beta-induced EMT and cell migration and invasion by targeting RhoA and indicate that it is a potential therapeutic target for breast cancer intervention.