Identificação de potenciais biomarcadores em carcinoma epidermóide de esôfago a partir de análise randômica de expressão gênica

Abstract

Esophageal cancer is one of the most prevalent and lethal tumors worldwide and in Brazil. The most common histological subtype is esophageal squamous cell carcinoma (ESCC), corresponding to approximately 80% of the cases. Large-scale analysis of gene expression has been helpful in comprehending the carcinogenesis process of different tumor types and improving the therapeutic management of cancer patients. Few studies have assessed global gene expression by DNA microarray technique in ESCC to date. Only three studies were conducted in Western populations. After analyzing the global gene expression by DNA microarray in 15 pairs of ESCC and non-tumor mucosa samples, we identified 1064 differentially expressed genes (DEG). The upregulated genes in tumors were mainly related to controlling the cell cycle, proliferation, and DNA repair. On the other hand, the downregulated genes were related to metabolic processes and epidermal differentiation. The comparative analysis between tumors and healthy mucosa showed 437 overexpressed and 98 downregulated genes in ESCC, while the comparison between adjacent non-tumor mucosa and healthy esophageal samples showed 27 DEG. The PI3KR3 and AKT3 genes, members of the PI3K-AKT signaling pathway, were upregulated in ESCC, and their expression levels could predict potential malignant changes in the esophageal epithelium. Furthermore, an increase in FSCN1 expression was observed in tumors compared with the paired non-tumor adjacent tissue and in the non-tumor mucosa compared to the healthy mucosa. The expression levels of FSCN1 were an independent prognosis biomarker for ESCC patients and a predictor of changes in the esophageal epithelium. Since cell cycle control was one of the enriched pathways in our analyses, we evaluated the expression profile of FOXM1 and members of its signaling pathway. FOXM1 was overexpressed in ESCC compared to the non-tumor adjacent tissue and the healthy mucosa, and its expression showed high sensitivity and specificity for identifying changes in the esophageal epithelium. All upregulated targets of FOXM1 identified in the microarray analysis were validated by real-time PCR, and MMP12 expression was shown to be an independent prognosis predictor for ESCC patients. Functional analyses modulating FOXM1 expression were performed in the TE1 cell line, but no changes in cell viability, proliferation, or cell cycle were observed