ArticleJournal of experimental & clinical cancer research : CR2019
Epiregulin reprograms cancer-associated fibroblasts and facilitates oral squamous cell carcinoma invasion via JAK2-STAT3 pathway.
Article in Journal of experimental & clinical cancer research : CR, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 120 citations in OpenAlex.
- EIF2AK2 activates autophagy via JAK2/STAT3 pathway to promote oral squamous cell carcinoma malignancy.Odontology · 2026Article
- Selective antitumor and apoptosis‑inducing effects of the Src inhibitor PP1 in human tongue squamous cell carcinoma cells.International journal of oncology · 2026Article
- Single cell and spatial sequencing analysis of cancer associated fibroblasts in the brain metastasis tumor microenvironment.Communications biology · 2026Article
- Chorus line in oral squamous cell carcinoma: How stromal and immune players orchestrate tumor progression (Review).International journal of molecular medicine · 2026Review
- Single-cell RNA sequencing identifies cancer-associated fibroblast marker genes for determining cancer subtypes in oral squamous cell carcinoma and predicting patient prognosis.Translational cancer research · 2026Article
- Stromal cells contribute to progression, recurrence, and metastasis in oral squamous cell carcinoma: a call for therapy.Journal of translational medicine · 2026Review
- Unraveling the impact of cancer-associated fibroblasts on lymphatic metastasis of head and neck squamous cell carcinoma.Cellular oncology (Dordrecht, Netherlands) · 2025Review
- The regulatory role and mechanism of energy metabolism and immune response in head and neck cancer.Genes & diseases · 2025Review
- Hidden forces: the impact of cancer-associated fibroblasts on non-small cell lung cancer development and therapy.Journal of translational medicine · 2025Review
- Cancer-Associated Fibroblasts Interact with Schwann Cells for Tumor Perineural Invasion by Oral Squamous Cell Carcinoma.Neuroscience bulletin · 2025Article
- AXL promotes inflammatory breast cancer progression by regulating immunosuppressive macrophage polarization.Breast cancer research : BCR · 2025Article
- Fibroblast-immune crosstalk in oral squamous cell carcinoma: from tumor promotion to immune evasion.Frontiers in immunology · 2025Review
- Article
- Application of integrin subunit genes in pancreatic cancer and the construction of a prognosis model.Journal of gastrointestinal oncology · 2024Article
- Tissue Mechanics and Hedgehog Signaling Crosstalk as a Key Epithelial-Stromal Interplay in Cancer Development.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Pathological examination of factors involved in PD-L1 expression in patients with oral tongue squamous cell carcinoma.Maxillofacial plastic and reconstructive surgery · 2024Article
- Crosstalk between CAFs and tumour cells in head and neck cancer.Cell death discovery · 2024Review
- Stromal-derived MAOB promotes prostate cancer growth and progression.Science advances · 2024Article
- Review
- The role of stromal cells in epithelial-mesenchymal plasticity and its therapeutic potential.Discover oncology · 2024Review
9 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
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.
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