A New Strategy to Find Targets for Anticancer Therapy: Chemokine CXCL14/BRAK Is a Multifunctional Tumor Suppressor for Head and Neck Squamous Cell Carcinoma
In order to find a suppressor(s) of tumor progression in vivo for head and neck squamous cell carcinoma (HNSCC), we searched for molecules downregulated in HNSCC cells when the cells were treated with epidermal growth factor (EGF), whose receptor is frequently overactivated in HNSCC. The expression of BRAK, which is also known as CXC chemokine ligand 14 (CXCL14), was downregulated significantly by the treatment of HNSCC cells with EGF as observed by cDNA microarray analysis followed by reverse-transcriptase polymerase chain reaction analysis and western blotting. The EGF effect on the expression of CXCL14/BRAK was attenuated by the copresence of inhibitors of the EGF receptor, MEK, and ERK. The rate of tumor formation in vivo of BRAK-expressing vector-transfected tumor cells in athymic nude mice or SCID mice was significantly lower than that of mock vector-transfected ones. In addition tumors formed in vivo by the BRAK-expressing cells were significantly smaller than those of the mock-transfected ones. These results indicate that CXCL14/BRAK is a chemokine having suppressive activity toward tumor progression of HNSCC in vivo. Our approach will be useful to find new target molecules to suppress progression of tumors of various origins in addition to HNSCC. 1. Introduction Head and neck cancer is the sixth most common cancer worldwide. The most common type of head and neck cancer is squamous cell carcinoma (HNSCC); disappointingly, despite advances in surgical and other treatments that enhance quality of life and palliative value, survival rates are not improving for this cancer. HNSCC is a collective term for cancers at several sites (for example, the oral cavity, pharynx, and larynx) that have different etiologies and prognoses, even though they share some risk factors, including tobacco smoking and alcohol consumption and by infection with high-risk types of human papilloma virus [7, 8]. Tumors develop in multiple steps [9–11], and tumor progression is dependent on the balance of the expression between tumor progression-promoting and -suppressing genes being in favor of the former at each step [12, 13]. In order to prevent tumor progression, many investigators have searched for molecules that are overexpressed during tumor progression as target molecules for therapeutic drugs and have tried to prevent tumor progression by inhibiting these tumor-promoting molecules. However, drugs for many of the target molecules were not successful for clinical applications owing to the serious side effects of these drugs, which is not surprising because these target
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