Src-FAK Signaling Mediates Interleukin 6-Induced HCT116 Colorectal Cancer Epithelial–Mesenchymal Transition

Abstract

Colorectal cancer is one of the most prevalent and lethal malignancies, affecting approximately 900,000 individuals each year worldwide. Patients with colorectal cancer are found with elevated serum interleukin-6 (IL-6), which is associated with advanced tumor grades and is related to their poor survival outcomes. Although IL-6 is recognized as a potent inducer of colorectal cancer progression, the detail mechanisms underlying IL-6-induced colorectal cancer epithelial–mesenchymal transition (EMT), one of the major process of tumor metastasis, remain unclear. In the present study, we investigated the regulatory role of IL-6 signaling in colorectal cancer EMT using HCT116 human colorectal cancer cells. We noted that the expression of epithelial marker E-cadherin was reduced in HCT116 cells exposed to IL-6, along with the increase in a set of mesenchymal cell markers including vimentin and α-smooth muscle actin (α-SMA), as well as EMT transcription regulators—twist, snail and slug. The changes of EMT phenotype were related to the activation of Src, FAK, ERK1/2, p38 mitogen-activated protein kinase (p38MAPK), as well as transcription factors STAT3, κB and C/EBPβ. IL-6 treatment has promoted the recruitment of STAT3, κB and C/EBPβ toward the Twist promoter region. Furthermore, the Src-FAK signaling blockade resulted in the decline of IL-6 induced activation of ERK1/2, p38MAPK, κB, C/EBPβ and STAT3, as well as the decreasing mesenchymal state of HCT116 cells. These results suggested that IL-6 activates the Src-FAK-ERK/p38MAPK signaling cascade to cause the EMT of colorectal cancer cells. Pharmacological approaches targeting Src-FAK signaling may provide potential therapeutic strategies for rescuing colorectal cancer progression.

Targeting staphylococcal enterotoxin B binding to CD28 as a new strategy for dampening superantigen-mediated intestinal epithelial barrier dysfunctions

“…IFN-γ was found to synergize with TNF-α in inducing TJs disruption and ZO-1 deregulation, favouring both MLCK expression and activation in Caco-2 cells ( 53 , 71 , 72 ). IL-6, a critical pathogenic cytokine in several inflammatory diseases, including IBD ( 73 ), enhances intestinal epithelial permeability by impairing TJs integrity and downregulating E-cadherin expression ( 51 , 74 , 75 ). IL-22, a cytokine of the IL-10 family, whose levels increase in colonic tissues and in the peripheral blood of IBD patients ( 76 ), was found to increase TJs permeability ( 54 , 77 ) by downregulating the expression of both ZO-1 and E-cadherin ( 78 ).…”

Role of STAT3 in cancer cell epithelial‑mesenchymal transition (Review)

“…In a study by Zhang et al ( 62 ), IHC analysis revealed that activation of STAT3 was conversely correlated with E-cadherin expression in HCC. In addition, it has been demonstrated that IL-6 treatment leads to E-cadherin downregulation in HCT116 colorectal carcinoma cells ( 69 ). Although there are two putative STAT3-binding sites in the E-cadherin promoter region, STAT3 may not directly bind to the E-cadherin promoter; instead, it may function via regulating the major EMT-TFs, including Snail, Slug, Twist and ZEB1, to influence E-cadherin expression ( 66 , 69 ).…”

Roles and inhibitors of FAK in cancer: current advances and future directions

“…The activated ERK further promotes cell contraction and stimulates tumor cell movement by driving actin polymerization and edge protrusion adhesion turnover ( Samson et al, 2022 ). FAK has been identified as a significant regulatory factor for interleukin-6 induced EMT in colorectal cancer ( Huang et al, 2023 ). In DGC, the loss of CDH1 (encoding E-cadherin, a key regulator of the EMT) and RHOA Y42C mutation in gastric organs of engineered mice co-activate the FAK/AKT/β-catenin and YAP-TAZ pathways, promoting the transformation of normal gastric epithelial cells into highly invasive DGC cells ( Zhang et al, 2020 ).…”