Molecular Deregulation of EPAS1 in the Pathogenesis of Esophageal Squamous Cell Carcinoma

Abstract

Endothelial PAS domain-containing protein 1 (EPAS1) is an angiogenic factor and its implications have been reported in many cancers but not in esophageal squamous cell carcinoma (ESCC). Herein, we aim to examine the genetic and molecular alterations, clinical implications, and functional roles of EPAS1 in ESCC. High-resolution melt-curve analysis and Sanger sequencing were used to detect mutations in EPAS1 sequence. EPAS1 DNA number changes and mRNA expressions were analyzed by polymerase chain reaction. in vitro functional assays were used to study the impact of EPAS1 on cellular behaviors. Overall, 7.5% (n = 6/80) of patients with ESCC had mutations in EPAS1, and eight novel variants (c.1084C>T, c.1099C>A, c.1145_1145delT, c.1093C>G, c.1121T>G, c.1137_1137delG, c.1135_1136insT, and c.1091_1092insT) were detected. Among these mutations, four were frameshift (V382Gfs * 12, A381Lfs * 13, K379Ifs * 6, and K364Nfs * 12) mutations and showed the potential of nonsense mediated mRNA decay (NMD) in computational analysis. The majority of patients showed molecular deregulation of EPAS1 [45% (n = 36/80) DNA amplification, 42.5% (n = 34/80) DNA deletion, as well as 53.7% (n = 43/80) high mRNA expression, 20% (n = 16/80) low mRNA expression]. These alterations of EPAS1 were associated with tumor location and T stages. Patients with stage III ESCC having EPAS1 DNA amplification had poorer survival rates in comparison to EPAS1 DNA deletion (p = 0.04). In addition, suppression of EPAS1 in ESCC cells showed reduced proliferation, wound healing, migration, and invasion in comparison to that of control cells. Thus, the molecular and functional studies implied that EPAS1 plays crucial roles in the pathogenesis of ESCC and has the potential to be used as a prognostic marker and as a therapeutic target.

The relationship between autophagy-related genes and the staging and prognosis of thyroid cancer: a bioinformatics analysis

“…Some research has shown that the expression of EPAS1 in normal tissues of the body is low or has no expression; however, it is abnormally high in malignant tumor tissues, and it is involved in a series of biological behaviors of cancer cells (33). Studies have also shown that EPAS1 plays a vital role in the pathogenesis of esophageal squamous cell carcinoma and may be used as a prognostic marker and therapeutic target (34). The present study showed that EPAS1 differed significantly in the AJCC the relationship with long-term prognosis, no differences in the survival of patients with different expression levels of EPAS1 were found; however, this may be due to the sample size of the study.…”

A comparative study of COVID-19 transcriptional signatures between clinical samples and preclinical cell models in the search for disease master regulators and drug repositioning candidates

“…Besides inflammation, SARS-CoV-2 hijacks cell organelles and cytoskeleton, making profound morphologic changes, such as syncytium formation ( Wen et al, 2020 ). EPAS1 and ATOH8 are both related to cell morphogenesis, migration and proliferation, and such processes are deeply related to cytoskeleton dynamics ( Fang et al, 2014 ; Islam et al, 2020 ; Provenzano and Keely, 2011 ). Indeed, EPAS1 and dexamethasone-activated glucocorticoid receptor NR3C1 promotes PTK6 expression, a tyrosine kinase that regulates RHO/Ras pathway, a critical hub for cytoskeleton organization.…”

Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

“…Eight variations in EPAS1 (c.1084C>T, c.1099C>A, c.1145_1145delT, c.1093C>G, c.1121T>G, c.1137_1137delG, c.1135_1136insT, c.1091_1092insT) were recently detected in 6 out of 80 patients (7.5%) with esophageal squamous cell carcinomas, with the majority of patients carrying these variations experiencing a deregulation of EPAS1 [ 177 ]. These factors directly correlated with tumor location and stage.…”