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Interleukin-1 beta transactivates epidermal growth factor receptor via the CXCL1-CXCR2 axis in oral cancer.


ABSTRACT: Hyperactivation of the epidermal growth factor receptor (EGFR) pathways and chronic inflammation are common characteristics of oral squamous cell carcinoma (OSCC). Previously, we reported that OSCC cells secrete interleukin-1 beta (IL-1?), which promotes the proliferation of the oral premalignant cell line, DOK, and stimulates DOK and OSCC cells to produce the chemokine CXCL1. CXCL1 functions through CXCR2, a G protein-coupled receptor that transactivates EGFR in ovarian and lung cancers. We hypothesized that IL-1? transactivates EGFR through the CXCL1-CXCR2 axis in OSCC. In this study, we demonstrated that tyrosine phosphorylation of EGFR is crucial for the IL-1?-mediated proliferation and subsequent bromodeoxyuridine (BrdU) incorporation of DOK cells because the EGFR inhibitors AG1478 and erlotinib inhibit these abilities in a dose-dependent manner. Addition of IL-1? instantly enhanced CXCL1 expression and secretion (within 15 min) in the DOK and OSCC cell lines. Furthermore, tyrosine phosphorylation of EGFR was significantly enhanced in DOK (1 h) and OSCC (20 min) cell lines after IL-1? treatment, and both cell lines were inhibited on the addition of an IL-1 receptor antagonist (IL-1Ra). CXCL1 treatment resulted in EGFR phosphorylation, whereas the knockdown of CXCL1 expression by lentivirus-mediated shRNA or the addition of the CXCR2 antagonist SB225002 dramatically reduced IL-1?-mediated EGFR phosphorylation and proliferation of DOK cells. Neutralizing antibodies against IL-1? or CXCL1 markedly inhibited the constitutive or IL-1?-induced tyrosine phosphorylation of EGFR in OSCC cells. IL-1? transactivates EGFR through the CXCL1-CXCR2 axis, revealing a novel molecular network in OSCC that is associated with autocrine IL-1? and EGFR signaling.

SUBMITTER: Lee CH 

PROVIDER: S-EPMC4770743 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Interleukin-1 beta transactivates epidermal growth factor receptor via the CXCL1-CXCR2 axis in oral cancer.

Lee Chia-Huei CH   Syu Shih-Han SH   Liu Ko-Jiunn KJ   Chu Pei-Yi PY   Yang Wen-Chan WC   Lin Pinpin P   Shieh Wan-Yu WY  

Oncotarget 20151101 36


Hyperactivation of the epidermal growth factor receptor (EGFR) pathways and chronic inflammation are common characteristics of oral squamous cell carcinoma (OSCC). Previously, we reported that OSCC cells secrete interleukin-1 beta (IL-1β), which promotes the proliferation of the oral premalignant cell line, DOK, and stimulates DOK and OSCC cells to produce the chemokine CXCL1. CXCL1 functions through CXCR2, a G protein-coupled receptor that transactivates EGFR in ovarian and lung cancers. We hyp  ...[more]

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