Oncogenic role of early growth response-1 in liver cancer through the regulation of the microRNA-675/sestrin 3 and the Wnt/β-catenin signaling pathway

Abstract

Early growth response-1 (EGR1) is a multi-domain protein and an immediate early transcription factor that is induced during liver injury and controls the expression of a variety of genes implicated in metabolism, cell proliferation, and tumorigenesis. Liver cancer (LC) is a highly malignant disease with high mortality worldwide. This study focused on the function of EGR1 in LC development and the mechanism of action. Two LC-related datasets GSE101728 and GSE138178 downloaded from the Gene Expression Omnibus (GEO) database were used for identification of key genes involved in cancer progression. A microarray analysis was conducted to identify differentially expressed microRNAs (miRNAs) after EGR1 knockdown. The target gene of miR-675 was identified by integrated analysis. EGR1 and miR-675 were highly expressed, whereas sestrin 3 (SESN3) was poorly expressed in LC tissues and cells. High EGR1 expression was associated with poor liver function and disease severity in patients with LC. Knockdown of EGR1 weakened proliferation and invasiveness of LC cells. EGR1 bound to the miR-675 promoter and increased its transcription, and miR-675 bound to SESN3 mRNA to induce its downregulation. miR-675 upregulation promoted the malignance of LC cells, but further upregulation of SESN3 reduced invasiveness of cells. SESN3 was enriched in the Wnt/β-catenin signaling. EGR1 and miR-675 activated the Wnt/β-catenin through downregulating SESN3. This study demonstrated that EGR1 promotes the malignant behaviors of LC cells through mediating the miRNA-675/SESN3/ Wnt/β-catenin axis.

B7 family member H4 induces epithelial-mesenchymal transition and promotes the proliferation, migration and invasion of colorectal cancer cells

“…Wnt signaling pathway contributes to EMT when extracellular E-cadherin is degraded, β-catenin is able to translocate into the nucleus to induces EMT [ 30–32 ]. The deregulation of Wnt signaling is implicated in the progression of various cancers, such as papillary thyroid cancer [ 33 ], glioblastoma [ 34 ], breast cancer [ 35 ] and liver cancer [ 36 ]. In CRC, TGF-beta1 positively regulates B7-H4 through miR-155/miR-143 axis, thereby promoting cancer cells immune escape [ 37 ].…”

E2F transcription factor 1 is involved in the phenotypic modulation of esophageal squamous cell carcinoma cells via microRNA-375

“…It is believed that SESN3 represents a core mediator of ROS downstream of the AKT signaling pathway and FOXO transcriptional factors [ 35 ]. Also, it was identified as the downstream target of miR-675 in liver cancer [ 36 ]. The bioinformatics prediction conducted in the present study also verified that SESN3 was not only a gene enriched in the PI3K/AKT signaling, but also a putative target of miR-375 in ESCC cells.…”

The role of microRNAs in hepatocellular carcinoma: Therapeutic targeting of tumor suppressor and oncogenic genes

“…Two LC-related datasets, GSE101728 and GSE138178, obtained from the Gene Expression Omnibus (GEO) database, were used to specify essential genes involved in cancer progression. Microarray analysis was conducted to determine differentially expressed miRs after EGR1 knockdown [ 91 ]. The target gene of miR-675 was identified by integrated analysis.…”

“…EGR1 and miR-675 activated Wnt/β-catenin through down-regulating SESN3. This analysis demonstrated that EGR1 promotes the malignant behaviors of LC cells by mediating the miR-675/SESN3/Wnt/β-catenin axis [ 91 ].…”