Abstract
BackgroundLocal resident normal fibroblasts (NFs) are the major source of cancer-associated fibroblasts (CAFs), which are distinguishable from NFs by their tumor-supportive properties. However, the mechanism and the effects underlying the transition of NFs to CAFs in oral squamous cell carcinoma (OSCC) remain unclear.MethodsFive pairs of matching primary NFs and CAFs derived from OSCC patients were sent for RNA sequencing. Epiregulin (EREG) expression was analyzed by IHC in fibroblasts from OSCC patients. The role of EREG in the NF-CAF transition and the consequential effects on OSCC progression were examined by upregulation/downregulation of EREG in NFs/CAFs both in vitro and in vivo.ResultsHere, we identified epiregulin (EREG) as the most remarkably upregulated gene in CAFs. High EREG expression in CAFs correlated with higher T stage, deeper invasion and inferior worst pattern of invasion (WPOI) in OSCC patients and predicted shorter overall survival. Overexpression of EREG in NFs activated the CAF phenotype. Mechanistically, the JAK2/STAT3 pathway was enhanced by EREG in parallel with increased IL-6 expression, which could be inhibited by the JAK2 inhibitor AG490. Recombinant IL-6 upregulated the JAK2/STAT3/EREG pathway in a feedback loop. Moreover, EREG-induced CAF activation promoted the epithelial-mesenchymal transition (EMT) necessary for migration and invasion, which was dependent on JAK2/STAT3 signaling and IL-6. In vivo, EREG expression in stroma fibroblasts promoted tumor growth with high stromal α-SMA, phospho-JAK2/STAT3, and IL-6 expression and upregulated EMT in HSC3 cells.ConclusionsEREG is essential for the NF-CAF transformation needed to induce EMT of tumor cells in a JAK2-STAT3- and IL-6-dependent manner in OSCC.
Highlights
Local resident normal fibroblasts (NFs) are the major source of cancer-associated fibroblasts (CAFs), which are distinguishable from NFs by their tumor-supportive properties
EREG expression is higher in CAFs than in matched NFs As an abnormal activated form of NFs, CAFs differ from NFs with distinct phenotypes and functions
We carried out genomic analysis to identify differentially expressed genes between matching NFs and CAFs obtained from 5 oral squamous cell carcinoma (OSCC) patients as previously reported [17]
Summary
Local resident normal fibroblasts (NFs) are the major source of cancer-associated fibroblasts (CAFs), which are distinguishable from NFs by their tumor-supportive properties. The mechanism and the effects underlying the transition of NFs to CAFs in oral squamous cell carcinoma (OSCC) remain unclear. Cancer-associated fibroblasts (CAFs), as a major cellular component of the tumor stroma, coevolve with cancer cells and contribute. Wang et al Journal of Experimental & Clinical Cancer Research (2019) 38:274 mechanisms underlying the transition from NFs to CAFs remain largely unclear. Further clarification of the mechanism underlying the transition from NFs to CAFs is important for cancer diagnosis and therapy. As CAFs function to myofibroblasts in wound healing, we hypothesized that EREG might participate in the transition of NFs to the CAF phenotype from the very start of NF activation, promoting tumor progression
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