miR-181b-3p promotes epithelial–mesenchymal transition in breast cancer cells through Snail stabilization by directly targeting YWHAG

Abstract

Epithelial-mesenchymal transition (EMT) is essential for increased invasion and metastasis during cancer progression. Among the candidate EMT-regulating microRNAs that we previously identified, miR-181b-3p was found to induce EMT in MCF7 breast cancer cells, as indicated by an EMT-characteristic morphological change, increased invasiveness, and altered expression of an EMT marker. Transfection with a miR-181b-3p inhibitor reduced the expression of mesenchymal markers and the migration and invasion of highly invasive breast cancer cells. miR-181b-3p induced the upregulation of Snail, a master EMT inducer and transcriptional repressor of E-cadherin, through protein stabilization. YWHAG was identified as a direct target of miR-181b-3p, downregulation of which induced Snail stabilization and EMT phenotypes. Ectopic expression of YWHAG abrogated the effect of miR-181b-3p, including Snail stabilization and the promotion of invasion. In situ hybridization and immunohistochemical analyses indicated that YWHAG expression was inversely correlated with the expression of miR-181b-3p and Snail in human breast cancer tissues. Furthermore, transfection with miR-181b-3p increased the frequency of metastatic nodule formation in the lungs of mice in experimental metastasis assays using MDA-MB-231 cells. Taken together, our data suggest that miR-181b-3p functions as a metastasis activator by promoting Snail-induced EMT, and may therefore be a therapeutic target in metastatic cancers.

MicroRNA-22 inhibits cell growth and metastasis in breast cancer via targeting of SIRT1

“…For instance, miR-181b-3p promotes epithelial-mesenchymal transition in breast cancer cells through Snail stabilization by directly targeting YWHAG, and thus may promote breast cancer metastasis (9). MiR-429 inhibits migration and invasion of breast cancer cells, and thus acts as a tumor suppressor in breast cancer (11).…”

“…In recent decade, many miRs have been found to have promoting or suppressive effects on breast cancer, such as miR-33b (7), miR-148a (8), miR-181b (9), miR-200b (10), and miR-492 (11). Among these miRs, miR-22 has been reported to act as an oncogene or tumor suppressor (12–14).…”

NEAT1 contributes to breast cancer progression through modulating miR‐448 and ZEB1

“…MicroRNAs can exert oncogenic or suppressive roles on breast cancer. For instance, miR‐181b‐3p can promote EMT process in breast cancer via inhibiting YWHAG (Yoo et al, ). miR‐429 is reported to repress breast cancer (Ye et al, ).…”

Aberrant miRNA promoter methylation and EMT‐involving miRNAs in breast cancer metastasis: Diagnosis and therapeutic implications

“…miR‐182 and miR‐183 suppression could increase E‐cadherin expression and modify mesenchymal phenotypes to normal epithelial morphology (Hannafon, Sebastiani, De Las Morenas, Lu, & Rosenberg, ; Tang et al, ). miR‐181b‐3p, by direct targeting YWHAG and Snail stabilization, activates the EMT in BC cells (Yoo et al, ). Snail stabilization and direct targeting of E‐cadherin by miR‐5003‐3p is also contributed with EMT in BC cells (Figure ) (Kwak et al, ).…”