Isoprenaline induces epithelial–mesenchymal transition in gastric cancer cells

Abstract

The emerging role of stress-related signaling in regulating cancer development and progression has been recognized. However, whether stress serves as a mechanism to promote gastric cancer metastasis is not clear. Here, we show that the β2-AR agonist, isoprenaline, upregulates expression levels of CD44 and CD44v8-10 in gastric cancer cells. CD44, a cancer stem cell-related marker, is expressed at high levels in gastric cancer tissues, which strongly correlates with the occurrence of epithelial-mesenchymal transition (EMT)-associated phenotypes both in vivo and in vitro. Combined with experimental observations in two human gastric cancer cell lines, we found that β2-AR signaling can initiate EMT. It led to an increased expression of mesenchymal markers, such as α-SMA, vimentin, and snail at mRNA and protein levels, and conversely a decrease in epithelial markers, E-cadherin and β-catenin. Isoprenaline stimulation of β2-AR receptors activates the downstream target STAT3, which functions as a positive regulator and mediated the phenotypic switch toward a mesenchymal cell type in gastric cancer cells. Our data provide a mechanistic understanding of the complex signaling cascades involving stress-related hormones and their effects on EMT. In light of our observations, pharmacological interventions targeting β2-AR-STAT3 signaling can potentially be used to ameliorate stress-associated influences on gastric cancer development and progression.

β 2 -Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer

“…It will be important to characterize if β 2 AR agonism induces similar behavior in other tumor cell lines and in vivo . Notably, several recent in vitro studies suggest that βAR signaling induces an epithelial-mesenchymal transition in gastric, colon and lung cancer cell lines (Lu et al, 2015; Shan et al, 2014; Zhang et al, 2016). To better understand βAR regulation of epithelial-mesenchymal transition it will be necessary to clarify the molecular mechanisms.…”

Silencing of HMGA2 promotes apoptosis and inhibits migration and invasion of prostate cancer cells

“…Many reports have suggested that EMT has a high correlation with the generation of cancer stem cells, the malignancy of tumour cells and the resistance to anticancer therapies (McConkey et al 2009;Zhang et al 2011;Kayastha et al 2015). It has been demonstrated that HMGA2 has an effect on the EMT in many cancer cells, such as colon (Li et al 2014a, b), gastric (Lu et al 2015) and hepatocellular cancer (Li et al 2014a, b). In addition, numerous studies have verified that invasive ability of cancer cells can be regulated by MMPs (Kessenbrock et al 2010), in which MMP-2 and MMP-9 were reported to be closely associated with advanced tumour stage, increased invasion and metastasis, and shortened survival time (Slattery et al 2013).…”

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…CagA-positive H. pylori infection induces EMT, and CSCs feature in gastric mucosal cells via overexpression of the Wnt/β-catenin signaling pathway [137]. The progression of CSCs is stimulated by EMT-related CD44+ cells' emergence [303][304][305][306][307]. It was hypothesized that overexpression of the regulator of G-protein signaling pathway 1 (RGS1) might promote the transition of stem cells into CSCs [308].…”