IL-1β Induces Fascin Expression and Increases Cancer Invasion

Abstract

Background/aim: Tumor microenvironment plays an important role in tumor growth and metastasis. Cancer cells can promote their growth and malignancy by altering the surrounding stroma. Fascin is an actin-bundling protein that regulates the dynamics of the cytoskeletal structure and plays a significant role in cancer invasion and metastasis. In this study, we observed stromal factors controlling fascin expression in cancer cells and investigated underlying signal transduction pathways.

Materials and methods: Fascin depletion was performed with lentiviral short-hairpin RNA (shRNA) against fascin mRNA and a stable cell line (Fascin^dep) was established. Fascin expression and invasion activity induced by IL-1β treatement were observed through Matrigel-Transwell invasion and 3D culture system. Intermediated signaling molecules involved in fascin expression induced by IL-1β were elucidated using western blotting.

Results: Fascin was more highly expressed in human OSCC cells than normal cells. Cancer invasion activity was decreased by fascin depletion using lentiviral shRNA. However, fascin expression was increased by IL-1β treatement, leading to increased extracellular matrix (ECM) degradation and infiltration into 3-dimensional (3-D) collagen matrix. Specific inhibitors of extracellular signal-regulated kinases-1/2 [ERK1/2, (PD98059)], c-Jun N-terminal kinase [JNK, (SP600125)], nuclear factor kappa light chain enhancer of activted B cells [NF-κB, (parthenolide)], and cAMP response element binding protein [CREB, (CREB inhibitor)] suppressed IL-1β -induced fascin expression. IL-1β induced phosphorylation of ERK1/2, JNK, NF-κB and CREB while IL-1 receptor (IL-1R) antagonist abolished their activation.

Conclusion: IL-1β is a critical inducer of fascin expression. ERK1/2, JNK, NF-κB, and CREB signaling pathways are involved in IL-1β-induced fascin expression and these paracrine signaling pathways can induce cancer cell invasion.

Keywords: 3D culture; IL-1β; antagonist; cancer invasion; fascin.