14-3-3ζ is Amplified, Overexpressed and Possesses Oncogenic Activities in Head and Neck Squamous Cell Carcinoma

Abstract

Gene amplification, a common mechanism for oncogene activation in cancers, has been used in the discovery of novel oncogenes. DNA amplification is frequently observed in head and neck squamous cell carcinomas (HNSCCs) where numerous amplification events and potential oncogenes have already been reported. Recently, we applied restriction landmark genome scanning (RLGS) to study gene amplifications in HNSCC and located novel amplified and uncharacterized regions in primary tumor samples. DNA amplification on 8q22.3, the location of 14-3-3[zeta] (YWHAZ, KCIP-1) is found in 30-40% HNSCC cases. Data obtained from fluorescent in-situ hybridization (FISH) and immunohistochemistry on HNSCC tissue microarrays confirmed frequent low-level 14-3-3[zeta] copy number gains and protein overexpression. 14-3-3[zeta] mRNA was frequently upregulated in patients' tumor tissues. Furthermore, 14-3-3[zeta] RNAi significantly suppressed the growth rate of HNSCC cell lines, and overexpression of 14-3-3[zeta] in HaCaT immortalized human skin keratinocytes promotes its growth, as well as morphological changes. Reduced 14-3-3[zeta] levels increased the G1/G0-phase proportion, decreased the S-phase proportion and the rate of DNA synthesis. Based on this evidence, we suggest that 14-3-3[zeta] is a candidate proto-oncogene and deserves further investigations into its role in HNSCC carcinogenesis.