Differentiation-related zinc finger protein 750 suppresses cell growth in esophageal squamous cell carcinoma

Sheyne Sta Ana Choi; Josephine Mun-Yee Ko; Valen Zhuoyou Yu; Lvwen Ning; Maria Li Lung

doi:10.3892/ol.2021.12774

Differentiation-related zinc finger protein 750 suppresses cell growth in esophageal squamous cell carcinoma

Oncol Lett. 2021 Jul;22(1):513. doi: 10.3892/ol.2021.12774. Epub 2021 May 5.

Authors

Sheyne Sta Ana Choi¹, Josephine Mun-Yee Ko¹, Valen Zhuoyou Yu¹, Lvwen Ning¹, Maria Li Lung¹

Affiliation

¹ Department of Clinical Oncology, The University of Hong Kong, Hong Kong, SAR, P.R. China.

Abstract

Esophageal squamous cell carcinoma (ESCC) is a deadly squamous cell carcinoma (SCC) of the esophagus. Development of SCCs is associated with the deregulation of the squamous cell lineage program and/or keratinocyte terminal differentiation by genomic and genetic aberrations; thus, these processes must be tightly controlled to maintain normal squamous cell development. Zinc finger protein 750 (ZNF750) is a gene involved in keratinocyte terminal differentiation and is frequently mutated and putatively silenced in ESCC, which implicates its function as a potential differentiation-related suppressor of ESCC. The present study aimed to elucidate the relationship between ZNF750 function to induce keratinocyte differentiation and tumor suppression in ESCC. The results demonstrated that chemical manipulation of esophageal keratinocyte differentiation in mouse normal esophageal epithelial organoids (mNEEO) implicated the involvement of the mouse homologue of ZNF750, Zfp750, in keratinocyte differentiation in premalignant cells. Bioinformatics analyses of data from high ZNF750-expressing ESCC tumors obtained from public databases and ZNF750-overexpressing ESCC cells compared with low ZNF750-expressing ESCC tumors and GFP-expressing ESCC cells, respectively, revealed enrichment of keratinocyte differentiation-related gene sets in these samples. Finally, the induction through to terminal differentiation of the keratinocyte by all-trans retinoic acid on parental ESCC cell lines led to the upregulation of the terminal differentiation marker Involucrin and a decrease in cell viability similar to that observed in ZNF750-overexpressing ESCC cells. The results of the present study demonstrated a functional link between the ability of ZNF750 to induce cell differentiation through to terminal differentiation and its function as a growth suppressor in ESCC. This study provides improved understanding of the role of ZNF750, a frequently mutated differentiation-related gene in ESCC, and its effects in ESCC pathogenesis.

Keywords: esophageal squamous cell carcinoma; keratinocyte differentiation; squamous cell carcinoma; tumor suppressor gene; zinc finger protein 750.

Grants and funding

This work was funded by the Research Grants Council Collaborative Research Fund (grant no. 106150246), the Theme-based Research Scheme (grant no. T12-701/17-R) and the Asian Cancer Research Fund.