Abstract 3838: Mitogen-activated protein kinase phosphatase-1 deficiency increases susceptibility to 4-nitroquinoline 1-oxide-induced neoplasia in murine squamous oral epithelium

Abstract

Abstract Background: Cytokines and pro-inflammatory factors have critical roles in shaping the malignant transformation that gives rise to head and neck squamous cell carcinoma (HNSCC). Mitogen-activated protein kinases (MAPKs), such as p38, JNK, and ERK, relay information from extracellular signals to control the diverse cellular processes of carcinogenesis. These kinases are negatively regulated by MAPK phosphatases (MKPs), the founding member being mitogen-activated protein kinase phosphatase-1 (MKP-1). Initial studies demonstrated significant over-expression of MKP-1 in human epithelial tumors only in the early phases of disease with levels falling progressively in tumors of higher histological grade and in metastases. We hypothesize low levels of MKP-1 in the HNSCC tumor microenvironment generate high levels of inflammation which promote tumor development and progression. Methods: To address how regulation of inflammatory cytokine expression via MKP-1 activity may affect HNSCC development and progression, we examined the effects of MKP-1 deficiency on a well characterized model for oral squamous cell carcinoma (OSCC), a subset of HNSCC. MKP-1-/- and wild-type mice were treated with 4-nitroquinoline 1-oxide (4NQO), a surrogate for tobacco exposure, in drinking water for 16 weeks and monitored by oral examination for an additional 16 weeks. Tumor size was assessed by volumetric measurement. Histological grading of the tumors and inflammation were performed in a blinded manner by two collaborating pathologists. Results: Our studies demonstrated significantly earlier onset of 4NQO-induced OSCC in MKP-1-/- mice compared with wild-type controls. Tumor size and histological grade were found to be more severe in the MKP-1-/- mice. In addition, tissues surrounding the tumors demonstrated a significantly higher degree of inflammation in MKP-1-/- mice. Remarkably, development of esophageal squamous carcinomas was dramatically enhanced in MKP-1-/- mice treated with 4NQO. Conclusion: These studies demonstrate increased susceptibility of MKP-1-/- mice to 4NQO-induced neoplasia, suggesting an important role for MKP-1 as a negative regulator of HNSCC development. Further work will be done to characterize mechanisms of regulation by assessing levels of MAPK activity and characterizing the pro- and anti-inflammatory milieu of the tumor tissues and supportive stroma. Elucidating the regulation of inflammatory mediators in the tumor microenvironment may reveal critical tumor suppressive interactions mediated by MKP-1 which are lost during cancer initiation and progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3838. doi:10.1158/1538-7445.AM2011-3838