Copy number gain and oncogenic activity of YWHAZ/14‐3‐3ζ 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. Low-level copy number gains are 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 to study gene amplifications in HNSCC and located novel and uncharacterized regions in primary tumor samples. Gain on chromosome 8q22.3, the location of YWHAZ (14-3-3f), is found in 30-40% HNSCC cases. Data obtained from fluorescence in situ hybridization and immunohistochemistry on HNSCC tissue microarrays confirmed frequent low-level YWHAZ copy number gain and protein overexpression. YWHAZ mRNA was frequently upregulated in patients' tumor tissues. Furthermore, YWHAZ RNAi significantly suppressed the growth rate of HNSCC cell lines, and overexpression of YWHAZ in HaCaT immortalized human skin keratinocytes promotes overgrowth, as well as morphological changes. Reduced YWHAZ 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 YWHAZ is a candidate proto-oncogene and deserves further investigation into its role in HNSCC carcinogenesis. ' 2009 UICC

Targeting 14-3-3zeta in cancer therapy

“…Gene gains of 14-3-3zeta on chromosome 8q22.3 are found in 30-40% head and neck squamous cell carcinoma cases. 15 Frequent high-level gains of 14-3-3zeta copy number, high messenger RNA and protein level are also observed in these patients' tumor tissues. Furthermore, 14-3-3zeta RNAi significantly suppresses the growth rate of head and neck squamous cell carcinoma cell lines, and overexpression of 14-3-3zeta in HaCaT-immortalized human skin keratinocytes promotes overgrowth, as well as morphological changes.…”

“…Transient blockade of 14-3-3zeta expression by small interfering RNA (siRNA) in cancer cells effectively reduces the onset and growth of tumor xenografts in vivo. [13][14][15]20,21,27,34,43 In the cancer cells, 14-3-3zeta is commonly associated with some pro-apoptotic proteins upon phosphorylation with survival-mediating kinases, such as Akt. Phosphorylation of 14-3-3zeta by c-Jun N-terminal kinase releases the proapoptotic proteins Bad and FOXO3a from 14-3-3zeta, and antagonizes the effects of Akt signaling.…”

“…15,43 However, how does 14-3-3zeta protein involve in the cell cycle? There are some cues to be inferred in some reports.…”

“…13 The importance of 14-3-3zeta in the formation and progression of cancer has been emphasized within several tumor types. [14][15][16][17][18][19][20][21][22][23][24] In this review, we will investigate the role of 14-3-3zeta in cancer and suggest a new target in anticancer therapy.…”

“…Sometimes, cytoplasmic and nuclear expression is observed even in the same tissue. 19 14-3-3zeta-positive expression occurs in the lung cancer, [25][26][27][28] liver cancer, 21 uterus, breast carcinoma, 14 stomach cancer, 29 head and neck squamous cell carcinoma 15 and so on. In addition, 14-3-3zeta protein expression is elevated in the breast cancer, 14 36 which shows 14-3-3zeta overexpression also occurred in cervical, ovarian, skin, pancreatic, prostate and urothelial tumors.…”