Transforming growth factor-β1-induced epithelial-mesenchymal transition in human esophageal squamous cell carcinoma via the PTEN/PI3K signaling pathway

Abstract

Epithelial-mesenchymal transition (EMT) is a crucial step for the invasive and metastatic properties of malignant tumor cells during tumor progression. Numerous signaling pathways are involved in the process of EMT in cancer, such as the EMT-inducing signal transforming growth factor (TGF)-β and the recently demonstrated PTEN/PI3K signaling pathway. To date, no data have been reported concerning the influence of PTEN/PI3K signaling pathway on EMT in human esophageal squamous cell carcinoma (ESCC) and how TGF-β1 and PTEN/PI3K act through multiple interconnected signaling pathways to trigger events associated with EMT and tumor progression. Our data showed that the PTEN/PI3K pathway was active in human ESCC tissues in vivo, particularly in ESCC with decreased E-cadherin and increased vimentin protein expression, poor differentiation, deep invasion and lymph node metastasis, which are responsible for EMT and tumor progression. In addition, in the human ESCC cell line (EC-1) in vitro, TGF-β1 treatment markedly induced EMT, including morphological alterations, a decrease of E-cadherin and an increase of vimentin levels and enhanced mobility and invasiveness. Furthermore, the PTEN/PI3K pathway was also activated in the process of TGF-β1-induced EMT in EC-1 cells in vitro, whereas inhibition of the PTEN/PI3K pathway by using pcDNA3.1 PTEN partially blocked TGF-β1-induced EMT and reduced mobility and invasiveness. These studies suggest that TGF-β1 and the PTEN/PI3K signaling pathway contribute to EMT and the PTEN/PI3K signaling pathway is a key regulator of TGF-β1‑induced EMT in ESCC. Disruption of the PTEN/PI3K pathway involved in TGF-β1-induced EMT may provide possible routes for therapeutic intervention to ESCC.

Role of matrix metalloproteinase-9 in transforming growth factor-β1-induced epithelial–mesenchymal transition in esophageal squamous cell carcinoma

“…Here, we demonstrated that TGF-β1 induces changes in the morphology of ESCC cells and their transition from epithelial to mesenchymal phenotype. This change was shown to be accompanied by the downregulation of E-cadherin and upregulation of vimentin expression, which is consistent with the data obtained in the previous studies 12,13…”

Low expression of microRNA-202 is associated with the metastasis of esophageal squamous cell carcinoma

“…Previous studies have demonstrated that oncogenes, such as p53, c-Myc, matrix metallopepti- dase 9 and human sterile alpha motif domain-containing 9, are abnormally expressed in ESCC tissues (22)(23)(24). Furthermore, increased expression levels of transforming growth factor-β may stimulate the PTEN/PI3K pathway and promote epithelial-mesenchymal transition in the human esophageal epithelium (25). Epithelial-mesenchymal transition is a risk factor for ESCC, as cell junctions are disrupted and the invasive ability of ESCC is enhanced (26).…”

Correlation between TGF-β1 gene 29 T > C single nucleotide polymorphism and clinicopathological characteristics of osteosarcoma

“…On the other hand, it promotes the growth, invasion, and metastasis of tumor by increasing synthesis of collagen in vascular endothelial cells. Besides, TGF-β1 can also affect epithelial-mesenchymal transition (EMT) and tumor growth by affecting PTEN-PI3K signal pathway [26]. The survival analysis shows that patients carrying TT genotype have got apparently a decrease in their recurrence-free survival time in comparison with patients carrying CC genotype.…”