Abstract
ZNF750 is one novel significantly mutated gene identified in esophageal squamous cell carcinoma (ESCC) using next-generation sequencing. However, its clinically relevant and potential mechanisms have remained elusive. Using genomic sequencing of 612 ESCC patients, we analyzed the associations of ZNF750 mutations with clinicopathologic features and its prognostic value. We further investigated the function and underlying mechanism of ZNF750 in angiogenesis. The results showed ZNF750 mutations/deletions are significantly associated with malignant progression and poor prognosis of ESCC patients. Decreased ZNF750 in ESCC cells induces enhanced angiogenesis of human umbilical vein endothelial cells (HUVECs) and human arterial endothelial cells (HAECs), and the effect may be indirectly mediated by FOXC2. RNA-seq and ChIP shows lncRNA DANCR is a direct downstream target of ZNF750. Furtherly, knockdown ZNF750 evokes DANCR expression, which prevents miR-4707-3p to interact with FOXC2 as a microRNA sponge in a ceRNA manner, leading to enhanced FOXC2 signaling and angiogenesis. In contrast, ZNF750 expression reverses the effect. Our study reveals a novel mechanism of ZNF750, highlights a significance of ZNF750 as a metastatic and prognostic biomarker, and offers potential therapeutic targets for ESCC patients harboring ZNF750 mutations.
Highlights
Esophageal squamous cell carcinoma (ESCC), the major type of esophageal cancers in China accounting for over 477,900 new cases and 375,000 deaths recorded annually, remains one of the most lethal of malignancies and a major health burden[1]
All FASTQ files are going to be uploaded to Genome Sequence Archive (GSA) in Beijing Institute of Genomics (BIG) Data Center, the accession number is HRA000021, that will be publicly accessible at http://bigd.big.ac.cn/gsa
(see figure on previous page) Fig. 1 Genetic alterations of ZNF750 across 612 ESCC genomes. a The mutation sites and types in CDS region of ZNF750 across 612 ESCC genomes. b The significant focal SCNA filtered by GISTCI across 508 ESCC genomes. c Heatmap of CNV log[2] ratio of read coverage across 71 ESCC individuals in 17q25.3 and ZNF750 regions and detected significant deletion of ZNF750. d, e ZNF750 copy number was assayed by qRT-PCR in BDESCC0122, BDESCC0481, BDESCC0177 and BDESCC0189
Summary
Esophageal squamous cell carcinoma (ESCC), the major type of esophageal cancers in China accounting for over 477,900 new cases and 375,000 deaths recorded annually, remains one of the most lethal of malignancies and a major health burden[1]. Bi et al Cell Death and Disease (2020)11:296 number amplifications occurring in SOX2, TERT, FGFR1, MDM1, and common deletions of RB1 etc[4,5,6,7]. Of these genes, ZNF750, a nuclear factor that plays a critical role in control of terminal epidermal differentiation gene program[8,9], was frequently disrupted by somatic inactivating mutations on 17q25.34,6. ZNF750 inhibited the malignant progression of oral squamous cell carcinoma by regulating tumor vascular microenvironment[11]. The molecular mechanism underlying ZNF750 contributes to tumorigenesis and the clinically relevant of genetic changes of ZNF750 in ESCC remain largely unresolved
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
