Abstract
BackgroundCancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment, have prominent roles in the development of solid tumors as stromal targets. However, the underlying mechanism of CAFs’ function in oral squamous cell carcinoma (OSCC) development remains unclear. Here, we investigated the role of lysyl oxidase (LOX) expression in CAFs in tumor stromal remodeling and the mechanism of its effect on OSCC progression.MethodsMultiple immunohistochemistry (IHC) staining was performed to detect the correlation of CAFs and LOX in the stroma of OSCC specimens, as well as the correlation with clinicopathological parameters and prognosis. The expression of LOX in CAFs were detected by RT-qPCR and western blot. The effects of LOX in CAFs on the biological characteristics of OSCC cell line were investigated using CCK-8, wound-healing and transwell assay. CAFs were co-cultured with type I collagen in vitro, and collagen contraction test, microstructure observation and rheometer were used to detect the effect of CAFs on remodeling collagen matrix. Then, collagen with different stiffness were established to investigate the effect of matrix stiffness on the progression of OSCC. Moreover, we used focal adhesion kinase (FAK) phosphorylation inhibitors to explored whether the increase in matrix stiffness promote the progression of OSCC through activating FAK phosphorylation pathway.ResultsLOX was colocalized with CAFs in the stroma of OSCC tissues, and its expression was significantly related to the degree of malignant differentiation and poor prognosis in OSCC. LOX was highly expressed in CAFs, and its knockdown impaired the proliferation, migration, invasion and EMT process of OSCC cells. The expression of LOX in CAFs can catalyze collagen crosslinking and increase matrix stiffness. Furthermore, CAFs-derived LOX-mediated increase in collagen stiffness induced morphological changes and promoted invasion and EMT process in OSCC cells by activating FAK phosphorylation pathway.ConclusionsOur findings suggest that CAFs highly express LOX in the stroma of OSCC and can remodel the matrix collagen microenvironment, and the increase in matrix stiffness mediated by CAFs-derived LOX promotes OSCC development through FAK phosphorylation pathway. Thus, LOX may be a potential target for the early diagnosis and therapeutic treatment of OSCC.
Highlights
Cancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment, have prominent roles in the development of solid tumors as stromal targets
Expression of lysyl oxidase (LOX) in the stroma of oral squamous cell carcinoma (OSCC) is associated with CAFs The fibroblast marker FAP, the epithelial marker EPCAM, and LOX were stained by multiplex immunohistochemical (IHC) staining to evaluate the expression distribution of LOX in OSCC tissues
We found that LOX was highly expressed both in the epithelium and stroma of OSCC (Fig. 1A)
Summary
Cancer-associated fibroblasts (CAFs), the most abundant cells in the tumor microenvironment, have prominent roles in the development of solid tumors as stromal targets. We investigated the role of lysyl oxidase (LOX) expression in CAFs in tumor stromal remodeling and the mechanism of its effect on OSCC progression. The tumor microenvironment (TME), a complex meshwork of extracellular matrix (ECM) macromolecules, plays an important role in tumor progression. As a main component of TME, cancer-associated fibroblasts (CAFs) are of great importance for ECM production and interstitial tissue remodeling in the disturbed homeostasis [5], which can induce stiffness and hypoxia in the matrix [6]. There has been a consensus that mechanical stimulation in the TME, such as the alteration of matrix stiffness, can have an impact on the development of solid tumors by a variety of signaling pathways, and promote invasion and metastasis [7]. The relationship between CAFs and matrix stiffness and the mechanism of CAFs remodeling ECM are especially worthy of further study
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