ETV4 plays a role on the primary events during the adenoma-adenocarcinoma progression in colorectal cancer

Abstract

Background Colorectal cancer (CRC) is one of the most common cancers worldwide; it is the fourth leading cause of death in the world and the third in Brazil. Mutations in the APC, DCC, KRAS and TP53 genes have been associated with the progression of sporadic CRC, occurring at defined pathological stages of the tumor progression and consequently modulating several genes in the corresponding signaling pathways. Therefore, the identification of gene signatures that occur at each stage during the CRC progression is critical and can present an impact on the diagnosis and prognosis of the patient. In this study, our main goal was to determine these signatures, by evaluating the gene expression of paired colorectal adenoma and adenocarcinoma samples to identify novel genetic markers in association to the adenoma-adenocarcinoma stage transition. Methods Ten paired adenoma and adenocarcinoma colorectal samples were subjected to microarray gene expression analysis. In addition, mutations in APC, KRAS and TP53 genes were investigated by DNA sequencing in paired samples of adenoma, adenocarcinoma, normal tissue, and peripheral blood from ten patients. Results Gene expression analysis revealed a signature of 689 differentially expressed genes (DEG) (fold-change> 2, p< 0.05), between the adenoma and adenocarcinoma paired samples analyzed. Gene pathway analysis using the 689 DEG identified important cancer pathways such as remodeling of the extracellular matrix and epithelial-mesenchymal transition. Among these DEG, the ETV4 stood out as one of the most expressed in the adenocarcinoma samples, further confirmed in the adenocarcinoma set of samples from the TCGA database. Subsequent in vitro siRNA assays against ETV4 resulted in the decrease of cell proliferation, colony formation and cell migration in the HT29 and SW480 colorectal cell lines. DNA sequencing analysis revealed KRAS and TP53 gene pathogenic mutations, exclusively in the adenocarcinomas samples. Conclusion Our study identified a set of genes with high potential to be used as biomarkers in CRC, with a special emphasis on the ETV4 gene, which demonstrated involvement in proliferation and migration.

Oncogenic role and drug sensitivity of ETV4 in human tumors: a pan-cancer analysis

“…For many different cancers, patients with higher ETV4 expression had worse disease prognosis. These data were in accordance with previous studies ( 25 – 27 ). Many studies have confirmed that disordered immunity, MMR genes, and DNA methyltransferases contribute to cancer progression and therapeutic outcome ( 28 – 30 ).…”

Charting the Heterogeneity of Colorectal Cancer Consensus Molecular Subtypes using Spatial Transcriptomics

“…4g), which is 15 known to promote metastasis and cause chemotherapeutic drug resistance in CRC 60 . Additionally, it has been shown that the knockdown of ETV4 leads to a decline in cell proliferation and migration in CRC cell lines 61 . DCN can potentially have an influence on ETV4 activity via the MAPK pathway 62 or again via the downstream signaling of the SRC kinase family (Fig.…”

A comprehensive multi-omics study reveals potential prognostic and diagnostic biomarkers for colorectal cancer

“…The ETV4, also known as ETS variant 4, is a transcription factor that belongs to the ETS transcription factor family and is involved in the regulation of various cellular processes such as cell proliferation, migration, invasion, and differentiation. Studies have shown that over-expression of ETV4 is associated with the progression of different types of cancers, including CRC [73, 74].…”