Elevated Expression of Zinc Finger Protein 703 Promotes Cell Proliferation and Metastasis through PI3K/AKT/GSK-3β Signalling in Oral Squamous Cell Carcinoma

Abstract

Background/Aims: Zinc finger protein 703 (ZNF703), initially identified as a novel oncogene in human breast cancer, is a member of the NET/NlZ family of zinc finger transcription factors. It is recognized that the overexpression of ZNF703 is associated with various types of human cancers, but the role and molecular mechanism of ZNF703 in oral squamous cell carcinoma (OSCC) are unknown. Methods: ZNF703 expression levels were examined in OSCC tissues and non-cancerous tissues by qRT-PCR and immunohistochemistry (IHC). The molecular mechanisms of ZNF703 and its effects on cell growth and metastasis were explored in vitro and in vivo using the CCK8 assay, colony formation assay, cell cycle analysis, migration and invasion assays, wound-healing assay, western blotting and xenograft experiments in nude mice. Results: In this study, ZNF703 was found to be upregulated in OSCC tissues compared to that in normal tissues at both mRNA and protein levels, and its expression level was closely correlated with the overall survival of patients with OSCC. Silencing of the ZNF703 gene in OSCC cells significantly inhibited cell growth and metastasis in vitro and in vivo. Conversely, the overexpression of ZNF703 in OSCC cells promoted cancer growth and metastasis in vitro. Mechanistically, ZNF703 activated the PI3K/AKT/GSK-3β signalling pathway and its downstream effectors, thus regulating the cell cycle and epithelial-mesenchymal transition (EMT). Furthermore, the promotive effects of ZNF703 on cellular proliferation and metastasis could be rescued by LY294002 (a PI3K-specific inhibitor) and MK2206 (an Akt-specific inhibitor). Conclusion: The results show that ZNF703 promotes cell growth and metastasis through PI3K/Akt/GSK-3β signalling in OSCC and that it may be a promising target in the treatment of patients with OSCC.

ZNF703 is an important player in head and neck cancer

“…Yang et al have also reported that elevated ZNF703 protein levels are a prognostic indicator and are associated with shorter survival in HNSCC. A similar association has also been reported for oral squamous cell carcinomas . In accordance with these reports, our results also showed that over‐expression of ZNF703 at the mRNA level was associated with a low survival rate of the patients.…”

“…The PI3K/Akt is a frequently activated pathway in oncogenesis and can stimulate proliferation, survival and invasion of tumour cells while inhibiting apoptosis . In vitro and in vivo analyses have shown that ZNF703 modulates cell‐cycle progression and EMT through the PI3K/Akt/GSK‐3β signalling pathway . In our previous study, we also reported that over‐expression of ZNF703 activates Akt phosphorylation in NSCLC .…”

FGF18 Enhances Migration and the Epithelial-Mesenchymal Transition in Breast Cancer by Regulating Akt/GSK3β/Β-Catenin Signaling

“…Akt/GSK3β signal pathway plays an important role in the development of tumors [40]. Our data indicate that FGF18 may promote breast carcinogenesis through the Akt/GSK3β/β-catenin pathway.…”

Increased expression of ZNF 703 in breast cancer tissue: An opportunity for RNAi–NSAID combinatorial therapy

“…It has been shown that elevated levels of PGE2 due to COX‐2 overexpression directly increases the proliferation of breast cancer cells through increased estrogen level. Since ZNF703 is an estrogen‐sensitive gene, its expression could be affected by COX‐2 overexpression . ZNF703 expression was found to be decreased following treatment with ibuprofen.…”