IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway

Abstract

Cancer-associated fibroblasts (CAFs), as the activated fibroblasts in tumor stroma, are important modifiers of tumor progression. However, the molecular mechanisms underlying the tumor-promoting properties of CAFs in gastric cancer remain unclear. Here, we show that CAFs isolated from gastric cancer produce significant amounts of interleukin-6 (IL-6). CAFs enhances the migration and EMT of gastric cancer cells through the secretion of IL-6 that activates Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT3) pathway in gastric cancer cells, while deprivation of IL-6 using a neutralizing antibody or inhibition of JAK/STAT3 pathway with specific inhibitor AG490 markedly attenuates these phenotypes in gastric cancer cells induced by CAFs. Moreover, silencing IL-6 expression in CAFs or inhibiting JAK2/STAT3 pathway in gastric cancer cells impairs tumor peritoneal metastasis induced by CAFs in vivo. Taken together, these results suggest that CAFs in the tumor microenvironment promote the progression of gastric cancer through IL-6/JAK2/STAT3 signaling, and IL-6 targeted therapy could be a complementary approach against gastric cancer by exerting their action on stromal fibroblasts.

Circular RNA circHIAT1 inhibits proliferation and epithelial‐mesenchymal transition of gastric cancer cell lines through downregulation of miR‐21

“…Its activation plays a key role in invasion and metastasis of many tumors, including GC. [ 15 ] Here, we investigate the roles and potential regulatory mechanisms of circHIAT1 in GC.…”

Snail Enhances Glycolysis in the Epithelial-Mesenchymal Transition Process by Targeting FBP1 in Gastric Cancer

“…Epithelial-mesenchymal transition (EMT), a well-characterized embryological process, has been identified to play a critical role in tumor progression, including invasion and metastasis, by which cancer cells could gain aggressive characteristics [4, 5]. In the process of EMT, the hallmark is the loss of epithelial cells phenotypic characteristics by losing their cell polarity and the epithelial markers (E-cadherin) and gaining of mesenchymal cells characteristics through acquiring the mesenchymal markers (N-cadherin, vimentin).…”

“…In the process of EMT, the hallmark is the loss of epithelial cells phenotypic characteristics by losing their cell polarity and the epithelial markers (E-cadherin) and gaining of mesenchymal cells characteristics through acquiring the mesenchymal markers (N-cadherin, vimentin). Therefore, these transformed epithelial cells acquire fibroblast-like properties and exhibit reduced cell-cell adhesion and increased motility [4, 6, 7]. The enhanced motility and invasiveness afforded by EMT is critical in the initiation of metastasis for cancer progression [4, 8, 9].…”

“…Therefore, these transformed epithelial cells acquire fibroblast-like properties and exhibit reduced cell-cell adhesion and increased motility [4, 6, 7]. The enhanced motility and invasiveness afforded by EMT is critical in the initiation of metastasis for cancer progression [4, 8, 9]. However, the metastasis process induced by EMT is a highly inefficient process during cancer progression [10].…”

Molecular Pathogenesis of Gastric Adenocarcinoma

“…These characteristics are usually associated with poor prognostics. Moreover, tumor-related stromal ibroblasts secrete small molecules, such as IL-6 to stimulate cell growth, as well as factors associated with TGF-β signaling, triggering epithelial-mesenchymal transition (EMT) [68][69][70].…”