EMT-associated up-regulation of L1CAM provides insights into L1CAM-mediated integrin signalling and NF-κB activation

Abstract

Expression of L1 cell adhesion molecule (L1CAM) is associated with poor prognosis in a variety of human carcinomas including breast, ovarian and pancreatic ductal adenocarcinoma (PDAC). Recently we reported that L1CAM induces sustained nuclear factor kappa B (NF-κB) activation by augmenting the autocrine production of interleukin 1 beta (IL-1β), a process dependent on interaction of L1CAM with integrins. In the present study, we demonstrate that transforming growth factor β1 (TGF-β1) treatment of breast carcinoma (MDA-MB231) and PDAC (BxPc3) cell lines induces an EMT (epithelial to mesenchymal transition)-like phenotype and leads to the expression of L1CAM. In MDA-MB231 cells, up-regulation of L1CAM augmented expression of IL-1β and NF-κB activation, which was reversed by depletion of L1CAM, L1CAM-binding membrane cytoskeleton linker protein ezrin, β1-integrin or focal adhesion kinase (FAK). Over-expression of L1CAM not only induced NF-κB activation but also mediated the phosphorylation of FAK and Src. Phosphorylation was not induced in cells expressing a mutant form of L1CAM (L1-RGE) devoid of the integrin-binding site. FAK- and Src-phosphorylation were inhibited by knock-down of various components of the integrin signalling pathway such as β1- and α5-integrins, integrin-linked kinase (ILK), FAK and the phosphoinositide 3-kinase (PI3K) subunit p110β. In summary, these results reveal that during EMT, L1CAM promotes IL-1β expression through a process dependent on integrin signalling and supports a motile and invasive tumour cell phenotype. We also identify important novel downstream effector molecules of the L1CAM-integrin signalling crosstalk that help to understand the molecular mechanisms underlying L1CAM-promoted tumour progression.

LEFTY2 Controls Migration of Human Endometrial Cancer Cells via Focal Adhesion Kinase Activity (FAK) and miRNA-200a

“…As a regulator of focal adhesion dynamics, FAK is a critical mediator of signaling events between cells and their extracellular matrix. Up-regulation of FAK was seen in both endometrial hyperplasia and carcinoma, implying that FAK may play an important role in epithelial-mesenchymal transition (EMT) [66][67][68][69][70][71] and migration [32][33][34][35][36] during endometrial carcinogenesis [72]. According to our results both, LEFTY2 and PF 573228, decrease phosphorylation of FAK, an observation pointing to inactivation of FAK [73].…”

Effect of IL-17A on the Migration and Invasion of NPC Cells and Related Mechanisms

“…And IL-17A was also reported to increase the expression of MMPs via activating NF-κB pathway in many cells [15], [21]. NF-κB also palyes an important role in the induction and maintenance of EMT [22], [23]. So we next detected whether the promoting effect of IL-17A on MMP-2/-9 expressions in NPC cells was also by activating NF-κB or not.…”

IL-8 induces the epithelial-mesenchymal transition of renal cell carcinoma cells through the activation of AKT signaling

“…However, there are various other signaling pathways such as the nuclear factor-κB signaling pathway that also are important in the induction and maintenance of EMT (42). The impact that EMT plays on tumor metastasis is still controversial (43)(44)(45). To better understand the exact mechanisms of tumor metastasis and its association with EMT and IL-8, further studies are required to characterize other signaling pathways, as well as the phenotype of RCC cells, in the future.…”