The Role of Pea3 Group Transcription Factors in Esophageal Squamous Cell Carcinoma

Abstract

The transcription factors Pea3, Erm, and Er81 can promote cancer initiation and progression in various types of solid tumors. However, their role in esophageal squamous cell carcinoma (ESCC) has not been elucidated. In this study, we found that the expression levels of Pea3 and Erm, but not that of Er81, were significantly higher in ESCC compared with nontumor esophageal epithelium. A high level of Pea3 expression was significantly correlated with a shorter overall survival in a cohort of 81 patients with ESCC and the subgroup with N1 stage tumor (WilcoxonGehan test, P ‫؍‬ 0.016 and P ‫؍‬ 0.001, respectively). Pea3 was overexpressed in seven ESCC cell lines compared with two immortalized esophageal cell lines. Pea3 knockdown reduced cell proliferation and suppressed nonadherent growth, migration, and invasion in ESCC cells in vitro. In addition, Pea3 knockdown in ESCC cells resulted in a down-regulation of phospho-Akt and matrix metalloproteinase 13, whereas a significant positive correlation in the expression levels was observed between Pea3 and phospho-Akt (r ‫؍‬ 0.281, P < 0.013) and between Pea3 and matrix metalloproteinase 13 in the human specimens (r ‫؍‬ 0.462, P < 0.001). Moreover, Pea3 modulated the sensitivity of EC109 cells to doxorubicin, probably via reduced activity of the phosphatidylinositol 3-kinase-Akt-mammalian target of Rapamycin complex 1 pathway on Pea3 knockdown. In conclusion, our results suggest that Pea3 plays an important role in the progression of ESCC. Esophageal squamous cell carcinoma (ESCC) is common among Asian populations. 1 Despite recent advances in the detection of the premalignant lesions and the development of combination therapies, its incidence is increasing, and its outcome remains poor. [2][3][4] Given the poor prognosis of ESCC and its high incidence rate, it is increasingly important to understand the initiation and progression of this type of cancer and to identify the associated prognostic factors.Pea3, Erm, and Er81 belong to the Pea3 subgroup of the Ets transcription factor family. This group of proteins contains several functional domains, and the individual members demonstrate extensive amino acid sequence similarities. 5 The roles of these proteins in mammary gland development and tumorigenesis have also been extensively studied and reviewed. 6 -8 Pea3 group transcription factors promote metastatic development and cancer progression through transcriptional activation of metastasis-related genes, such as matrix metalloproteinases (MMPs) 9 -13 and cyclooxygenase (COX)-2. 14,15 Overexpression of Pea3 also increases the motility and invasiveness of lung cancer cells via activation of the pathway and an increase in COX-2 expression. 16 -18 The prognostic significance of Pea3 has also been demonstrated in various solid tumors. Pea3 is overexpressed in mouse metastatic mammary adenocarcinoma 19 and in human breast cancer, in which its overexpression is also correlated with HER-2 expression and poor prognosis. 20 -23

A novel crosstalk between CCAR2 and AKT pathway in the regulation of cancer cell proliferation

“…16, 28, 29, 30 Moreover, it was previously shown that CCAR2 regulates breast and colon cancer progression by acting respectively as PEA3 and PROX-1 transcription factors co-activator 7, 17 and, of note also these proteins are implicated in AKT pathway regulation. 31, 32 …”

SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas

“…Among them, ETV4, a member of the Ets family of transcription factors, was notable for both its correlation with SOX2 in primary SCCs and its previously reported role in SCC pathogenesis (35). ETV4 has also been reported to be overexpressed in airway basal cells (31), thus linking it to a SOX2-p63-positive cell population.…”

ETV1, 4 and 5: An oncogenic subfamily of ETS transcription factors

“…Likewise, ETV4 and ETV1 are overexpressed in esophageal adenocarcinomas and may cooperate with activated MAPKs in stimulating proliferation and invasion of OE33 esophageal squamous cancer cells [162]. Another report posits that ETV4 and ETV5, but not ETV1, are overexpressed in esophageal squamous cell carcinomas and that ETV4 expression correlates with a shorter overall survival [163]. Also, ETV4 is upregulated in ovarian tumors and its expression correlated with reduced survival [41,164].…”