Repression of Smad4 by miR-205 moderates TGF-β-induced epithelial-mesenchymal transition in A549 cell lines

Abstract

The TGF-β/Smad signaling pathway plays important roles in cancer cell proliferation, apoptosis, differentiation, angiogenesis and epithelial-mesenchymal transition (EMT), which is the key event in the early stages of cancer metastasis and enhances the capability of cell migration and invasion. Smad4 acts as the only Co-Smad of TGF/Smad signaling pathway and plays the key role in TGF-β-mediated EMT. Nevertheless, the mRNA regulation mechanisms of Smad4 in human non-small cell lung cancer (NSCLC) remains largely unclear. Computational algorithms predicted that the 3'-UTR of Smad4 is a target of miR‑205. Here, we validated that miR‑205 could directly bind to 3'-UTR of Smad4 by luciferase assays. Moreover, we investigated the functional roles of miR‑205 and its molecular link to Smad4 in lung cancer cells. In this study, we confirmed that overexpression of miR‑205 suppressed the expression of Smad4, in turn, weakened the TGF-β/Smad signaling pathway and inhibited TGF-β/Smad4-induced EMT, invasion and migration ultimately. Furthermore, this study shows that miR‑205 can serve as a promising therapeutic target of highly aggressive NSCLC.

miR‐130a‐3p regulated TGF‐β1‐induced epithelial‐mesenchymal transition depends on SMAD4 in EC‐1 cells

“…Qiao et al informed that miR‐34a repressed EMT in human cholangiocarcinoma by directing SMAD4 through the TGF‐β/Smad signaling pathway. Zeng et al reported the suppression of SMAD4 by miR‐205 regulates TGF‐β‐induced EMT in Squamous cell carcinoma cell lines. In our experiments, we first introduced TGF‐β1 exogenously to induce EMT progression in cells.…”

“…It is well‐known that miRNAs are involved in the progression of EMT in cancer by directly regulating the expression of their specific target at the posttranscriptional level. It has been indicated that miRNAs play an irreplaceable part in TGF‐β‐induced EMT . Mengtao Ma et al found that MAGI2 promotes TGF‐β1‐induced EMT and migration and invasion of breast cancer cells under the direct action of miR‐487a .…”

“…The intracellular effectors (SMAD2/SMAD3) are phosphorylated by the activated type I receptors, which come into being a complex with SMAD4 and are transported to the nucleus for transcriptional regulation . As a key molecule in the TGF‐β signaling pathway, SMAD4 undoubtedly plays an irreplaceable role in the TGF‐β‐mediated EMT . However, the mechanism of action of SMAD4 in the progression of EMT in esophageal cancer remains to be studied.…”

USP17 is upregulated in osteosarcoma and promotes cell proliferation, metastasis, and epithelial–mesenchymal transition through stabilizing SMAD4

“…22,23 Moreover, SMAD4 has been found to play a key role in EMT. [24][25][26] In order to determine the detailed mechanism of USP17 on EMT, we performed co-immunoprecipitation (co-IP) analysis to detect the interaction between USP17 and SMAD4. The results indicated that USP17 interacted with SMAD4, but there is no interaction between USP17 and SMAD3 ( Figure 5(a)).…”

MiR‐182 inhibits kidney fibrosis by regulating transforming growth factor β1/Smad3 pathway in autosomal dominant polycystic kidney disease

“…Activated TGF‐β receptor regulates transcription of nuclear material through Smad2, 3, and 4 . In the tissues of human kidney and animal models with diabetic nephropathy, hypertensive nephropathy, or PKD, both Smad2 and Smad3 expression were increased.…”