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Epiregulin reprograms cancer-associated fibroblasts and facilitates oral squamous cell carcinoma invasion via JAK2-STAT3 pathway.
- Source :
-
Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2019 Jun 24; Vol. 38 (1), pp. 274. Date of Electronic Publication: 2019 Jun 24. - Publication Year :
- 2019
-
Abstract
- Background: Local 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.<br />Methods: Five 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.<br />Results: Here, 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.<br />Conclusions: EREG 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.
- Subjects :
- Animals
Carcinoma, Squamous Cell genetics
Carcinoma, Squamous Cell mortality
Carcinoma, Squamous Cell pathology
Cell Line, Tumor
Epiregulin genetics
Female
Fibroblasts metabolism
Gene Expression Regulation, Neoplastic
Humans
Janus Kinase 2 metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Mouth Neoplasms genetics
Mouth Neoplasms mortality
Mouth Neoplasms pathology
Neoplasm Invasiveness
STAT3 Transcription Factor metabolism
Signal Transduction
Xenograft Model Antitumor Assays
Cancer-Associated Fibroblasts metabolism
Carcinoma, Squamous Cell metabolism
Epiregulin metabolism
Epithelial-Mesenchymal Transition
Mouth Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1756-9966
- Volume :
- 38
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of experimental & clinical cancer research : CR
- Publication Type :
- Academic Journal
- Accession number :
- 31234944
- Full Text :
- https://doi.org/10.1186/s13046-019-1277-x