Research Papers:

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

Chia-Huei Lee _, Shih-Han Syu, Ko-Jiunn Liu, Pei-Yi Chu, Wen-Chan Yang, Pinpin Lin and Wan-Yu Shieh

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Oncotarget. 2015; 6:38866-38880. https://doi.org/10.18632/oncotarget.5640

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Chia-Huei Lee1, Shih-Han Syu1, Ko-Jiunn Liu1, Pei-Yi Chu2,3, Wen-Chan Yang1, Pinpin Lin4,5, Wan-Yu Shieh1

1National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan

2School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan

3Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan

4National Environmental Health Research Center, National Health Research Institutes, Zhunan, Taiwan

5Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan

Correspondence to:

Chia-Huei Lee, e-mail: [email protected]

Keywords: interleukine-1beta, epidermal growth factor receptor (EGFR), CXCL1, CXCR2, oral squamous cell carcinoma (OSCC)

Received: April 28, 2015     Accepted: September 29, 2015     Published: October 09, 2015


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 hypothesized that IL-1β transactivates EGFR through the CXCL1–CXCR2 axis in OSCC. In this study, we demonstrated that tyrosine phosphorylation of EGFR is crucial for the IL-1β-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-1β 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-1β 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-1β-mediated EGFR phosphorylation and proliferation of DOK cells. Neutralizing antibodies against IL-1β or CXCL1 markedly inhibited the constitutive or IL-1β-induced tyrosine phosphorylation of EGFR in OSCC cells. IL-1β transactivates EGFR through the CXCL1-CXCR2 axis, revealing a novel molecular network in OSCC that is associated with autocrine IL-1β and EGFR signaling.

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