Abstract
The objective of the current study was to investigate the effects of Rap1GAP on invasion and progression of head and neck squamous cell carcinoma (SCC) and the role of matrix metalloproteinase (MMP) 9 and MMP2 in this process. Rap1GAP functions by switching off Rap1, the Ras-like protein that has been associated with carcinogenesis. Previous findings suggest that Rap1GAP acts as a tumor suppressor protein in SCC by delaying the G(1)-S transition of the cell cycle. However, cells transfected with Rap1GAP exhibit a more invasive phenotype than corresponding vector-transfected control cells. MMP2 and MMP9 are enzymes that mediate SCC invasion via degradation of the extracellular matrix. Using SCC cells transfected with empty vector or Rap1GAP, cell invasion and MMP secretion were determined by Matrigel assays and gelatin zymography, respectively. Rap1GAP up-regulated transcription and secretion of MMP2 and MMP9, as assayed by quantitative reverse transcription-PCR and zymography. Furthermore, chemical and RNA interference blockade of MMP2/MMP9 inhibited invasion by Rap1GAP-transfected cells. Immunohistochemical staining of a human oropharyngeal SCC tissue microarray showed that Rap1GAP and MMP9 expression and staining intensity are correlated (P < 0.0001) and that, in early N-stage lesions of SCC, high MMP9 is prognostic of poor disease-specific survival (P < 0.05). Furthermore, Rap1GAP staining is correlated with MMP2 (P < 0.03). MMP2 in combination with N stage has a prognostic effect on time to indication of surgery at primary site. MMP2 intensity is also positively correlated with T stage (P < 0.015). In conclusion, Rap1GAP inhibits tumor growth but induces MMP2- and MMP9-mediated SCC invasion and tumor progression, suggesting a role for this protein as a biomarker for early N-stage, aggressive SCCs.
Highlights
More than 90% of head and neck cancers are squamous cell carcinomas (SCC)
As Rap1GAP up-regulates MMP9 and MMP2 expression in vitro, we investigated whether MMP9 and MMP2 expression was correlated with Rap1GAP expression in SCC tissues
In SCC, proliferation and invasion of malignant keratinocytes lead to tumor growth, spread to regional lymph nodes, and spread to distant sites, which are incompatible with patient survival [34]
Summary
More than 90% of head and neck cancers are squamous cell carcinomas (SCC). It is the fifth most common cancer globally and affects f500,000 individuals [1, 2]. Current treatment regimens for SCC are selected according to tumor size and the presence of metastasis. Early-stage SCC lesions are treated with surgery alone, whereas late-stage lesions are treated with concurrent surgery, radiation, and chemotherapy. Even tumors at the earliest stage of disease may vary dramatically in treatment response and recurrence. A significant number of patients with early-stage SCC who die of disease would likely have benefited from more aggressive treatment. Aggressive surgery and radiation therapy are not appropriate for all SCCs because this treatment is physically and emotionally debilitating. Identification of protein biomarkers that are prognostic of tumor progression and their mechanism of regulation will facilitate treatment selection
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