MicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells.

Abstract

The transforming growth factor β (TGFβ) pathway plays critical roles during cancer cell epithelial-mesenchymal transition (EMT) and metastasis. SMAD7 is both a transcriptional target and a negative regulator of TGFβ signalling, thus mediating a negative feedback loop that may potentially restrain TGFβ responses of cancer cells. Here, however, we show that TGFβ treatment induces SMAD7 transcription but not its protein level in a panel of cancer cells. Mechanistic studies reveal that TGFβ activates the expression of microRNA-182 (miR-182), which suppresses SMAD7 protein. miR-182 silencing leads to SMAD7 upregulation on TGFβ treatment and prevents TGFβ-induced EMT and invasion of cancer cells. Overexpression of miR-182 promotes breast tumour invasion and TGFβ-induced osteoclastogenesis for bone metastasis. Furthermore, miR-182 expression inversely correlates with SMAD7 protein in human tumour samples. Therefore, our data reveal the miR-182-mediated disruption of TGFβ self-restraint and provide a mechanism to explain the unleashed TGFβ responses in metastatic cancer cells.

• Authors: Jingyi Yu, Rong Lei, Xueqian Zhuang, Xiaoxun Li, Gang Li, Sima Lev, Miguel F Segura, Xue Zhang, Guohong Hu
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 13884 (12 20 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 27996004 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MicroRNAs
• Mirn182 microRNA, human
• SMAD7 protein, human
• Smad7 Protein
• Transforming Growth Factor beta

Topics

• Animals
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition (genetics, physiology)
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Neoplasm Invasiveness (genetics, pathology)
• Neoplasm Metastasis (genetics, pathology)
• RNA Interference
• Signal Transduction
• Smad7 Protein (genetics, metabolism)
• Transcriptional Activation
• Transforming Growth Factor beta (metabolism)