miR-145-5p Suppresses Tumor Cell Migration, Invasion and Epithelial to Mesenchymal Transition by Regulating the Sp1/NF-κB Signaling Pathway in Esophageal Squamous Cell Carcinoma

Abstract

MicroRNAs (miRNAs) play important roles in the progression of human cancer. Although previous reports have shown that miR-145-5p is down-regulated in esophageal squamous cell carcinoma (ESCC), the roles and mechanisms of down-regulation of miR-145-5p in ESCC are still largely unknown. Using microRNA microarray and Gene Expression Omnibus (GEO) datasets, we confirmed that miR-145-5p was down-regulated in ESCC tissues. In vitro assays revealed that ectopic miR-145-5p expression repressed cell proliferation, migration, invasion and epithelial to mesenchymal transition (EMT). miR-145-5p also reduced the expressions of cell cycle genes including cyclin A2 (CCNA2), cyclin D1 (CCND1) and cyclin E1 (CCNE1), the EMT-associated transcription factor Slug, and matrix metalloproteinases (MMPs) including MMP2, MMP7 and MMP13. Furthermore, miR-145-5p mimics reduced candidate target gene specificity protein 1 (Sp1) and nuclear factor κ B (NF-κB) (p65) both in mRNA and protein levels. Knockdown of Sp1 phenocopied the effects of miR-145-5p overexpression on cell cycle regulators, EMT and the expression of NF-κB (p65). Importantly, inhibition of the NF-κB signaling pathway or knockdown of NF-κB (p65) phenocopied the effects of miR-145-5p on the migration, invasion and EMT of ESCC cells. In conclusion, our results suggested that miR-145-5p plays tumor-suppressive roles by inhibiting esophageal cancer cell migration, invasion and EMT through regulating the Sp1/NF-κB signaling pathway.

miR‑539 suppresses the proliferation, migration, invasion and epithelial mesenchymal transition of pancreatic cancer cells through targeting SP1

“…Xia et al (49) reported that the downregulation of SP1 could reduce the proliferation rate of ovarian cancer cells and restrain tumor metastasis. Mei et al (50) revealed that certain miRNAs may suppress the multiplication, migration and EMT of esophageal cancer cells by targeting SP1. Notably, it was discovered that the overexpression of miR-539 inhibited the effects of SP1 on Pca cell lines, and that SP1-silencing reversed the effect of low expression of miR-539, showing that miR-539 was involved in the occurrence and development of Pca through targeting SP1.…”

CircDUSP16 promotes the tumorigenesis and invasion of gastric cancer by sponging miR-145-5p

“…It was reported that miR-145-5p expression is decreased in breast cancer and esophageal carcinoma, and its downregulation is associated with distal metastasis, tumor differentiation, and poor survival in GC patients [29][30][31]. miR-145-5p suppresses the proliferation and invasion by targeting SOX2 or SP1 [29,31], and promotes GC differentiation by targeting KLF5 [30]. Herein, we found that miR-145-5p expression was downregulated in GC tissue samples, and its low expression was an independent prognostic factor of poor survival in GC patients.…”

The Microrna-143/145 Cluster in Tumors: A Matter of Where and When

“…The expression of both miR-143 and miR-145 is reduced in esophageal squamous cell carcinoma clinical samples [71,72], where their overexpression was shown to downregulate mesenchymal markers, reducing cell migration and metastatic ability [71,72]. miR-145 ectopic expression inhibited cell migration by reducing the levels of FASCIN1 (FSCN1), an actin bundling protein involved in cytoskeletal dynamics, and regulating several EMT features in several breast cancer cell lines [73].…”

“…Finally, proteins involved in cell-cell adhesion and cell motility can be targeted by both microRNAs. For example, the cell-cell adhesion protein JAM-A [102] and the actin bundling protein FSCN1 [55,72,[102][103][104][105] have both been described as miR-145 targets, suggesting inhibition of cell adhesion and movement. Indeed, overexpression of miR-145 in breast cancer cell lines decreased actin stress fibers, and miR-143 was shown to regulate ADDUCIN 3 [106] and FIBRONECTIN [21,49], leading to reduced cell migration.…”