Up-regulation of extracellular matrix in 5-FU resistant Hela carcinoma cells
ECM, a complex network which is composed of a variety of macromolecules surrounding cells, provides cells with spatial structure and physical support, mediates multiple signal pathways, and plays an important role in cancer progression, invasion and metastasis, and drug resistance (Langhans, 2018). Integrin could be involved in CAM-DR by binding to ECM (e.g., collagen I) and activate drug efflux of ABC transporters to develop drug resistance (Baltes et al., 2020).It was found that ECM participated in the regulation of cell cycle by stimulating integrin mediated PI3K activation to protect small cell lung cancer from damages caused by radiotherapy and chemotherapy (Hodkinson et al., 2007). Consistent with these findings, we found in this study the expression of ECM including laminin and collagen was increased in the 3D MTSs (Figure. 4 and Figure. 5A-D ), meanwhile the molecular function of integrin binding was also increased in the 3D MTSs (Table S3 and Table S4 ), including up-regulation of ITGB1 and ITGA5 on the mRNA and protein level, respectively (Figure. 5A ). These significance difference between 2D monolayer and 3D MTSs may contribute to the increase of resistance to 5-FU. Therefore, ECM would become a potential target for improving the effect of anticancer therapy.