Abstract
Esophageal cancer is the eighth most common cancer globally. Transforming growth factor β regulator 4 (TBRG4) and caveolin-1 (CAV-1) are implicated in tumor progression. The aim of this study was to investigate the expressions of TBRG4 and CAV-1 in esophageal squamous cell carcinoma (ESCC), and their relationship with reactive oxygen species (ROS) formation. Human ESCC cell lines (EC9706, TE-1, and Eca109), and normal esophageal mucosal cell line (Het-1) were used in this study. The silencing of TBRG4 and/or CAV-1 by sh-RNA or overexpression of CAV-1 after TBRG4 knockdown was used to assess ROS levels. The results showed that down-regulation of TBRG4 reduced CAV-1 expression, and promoted ROS formation in ESCCs (p < 0.01). However, CAV-1 overexpression increased the expression level of TBRG4, but decreased ROS level in EC9706 cells (p < 0.01). Similarly, TBRG4 knockdown significantly reduced CAV-1 expression, promoted ROS formation, and caused cell cycle arrest at G0/G1 phase (p < 0.01). Caveolin-1 (CAV-1) knockdown also promoted cell apoptosis, cellular ROS formation and cell cycle arrest at G0/G1 phase (p < 0.01). However, CAV-1 overexpression in sh-TBRG4-treated EC9706 cells significantly upregulated TBRG4 expression, but significantly reduced the level of ROS, and inhibited cell-cycle arrest and apoptosis (p < 0.01). The enhancements in bcl-2/bax ratio, cytochrome c expression, and ROS levels by sh-TBRG4 were significantly reversed by CAV-1 overexpression in EC9706 cells. These results show that the upregulated expression of TBRG4 or CAV-1 promotes ESCC progression via regulation of intracellular ROS levels and inhibition of mitochondria-dependent apoptotic pathway.
Highlights
Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer, with 79 % incidence in Asia alone [1]
TBRG4 knockdown induced G0/G1 phase arrest in EC9706 cells; 75.98 % of the cells were in G1 phase, 3.03 % were in G2/M phase, and 20.99 % were in S phase
CAV-1 were significantly higher in human ESCCs (EC9706, TE-1 and Eca109 cells) than in normal esophageal mucosal cells (Het-1), and was 3 folds higher in EC9706 cells at both protein and mRNA levels
Summary
Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer, with 79 % incidence in Asia alone [1]. Caveolin-1 (CAV-1) is highly expressed in tumors such as prostate, pancreatic, and lung cancers. In lung cancer cell line (H1299), TBRG4 knockdown downregulates the expression of CAV-1, thereby inhibiting proliferation of the cells via induction of apoptosis [10]. The roles of TBRG4 and CAV-1 in ESCC remain unknown. An understanding of their interaction may offer a novel strategy for treatment of ESCC and improvement of clinical outcomes. Caveolin-1 (CAV-1) promotes the proliferation and migration of lung cancer cells via a mechanism involving the PI3K/Akt pathway. The relationship between ROS and CAV-1 expression in ESCC remains largely unknown. The aim of this study was to investigate the expressions of TBRG4 and CAV-1 in ESCC, and their relationship with ROS formation
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