CEBPG promotes esophageal squamous cell carcinoma progression by enhancing PI3K-AKT signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA657203 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12454227.fastq.gz | Fastqsanger.gz | |||
| SRR12454228.fastq.gz | Fastqsanger.gz | |||
| SRR12454229.fastq.gz | Fastqsanger.gz | |||
| SRR12454230.fastq.gz | Fastqsanger.gz |
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Project description:CCAAT enhancer binding proteins (CEBPs) have critical roles in the physiological and pathological processes. However, the characteristics and contributions of CEBPs in esophageal squamous cell carcinoma (ESCC) is unknown. Here, we showed that most of CEBPs (including CEBPA, CEBPB, CEBPE, CEBPG, CEBPZ) were upregulated and amplified in ESCC. Of note, high CEBPG expression is a prognostic factor for the poor survival of patients with ESCC. Moreover, the ESCC specific transcription factor TP63 activates the expression of CEBPG by directly binding to its distal enhancer. Functionally, CEBPG significantly enhances the proliferation and migration of ESCC cells in vitro and in vivo. Mechanistically, CEBPG enhances the PI3K-AKT signaling pathways through directly binding to distal enhancer or/and promoter of downstream target genes, such as CCND1, MYC and CDK2 etc. These findings provide important characteristics and contributions insights into CEBPs dysregulation in ESCC and elucidate a crucial role for CEBPG in the progression of ESCC, which highlights its potential therapeutic target for patients.
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Project description:Objective: Esophageal squamous carcinoma (ESCC) is one of the most common gastrointestinal tumors, and the PI3K/AKT signaling pathway plays a key role in the development of ESCC. circRNAs have been reported to be involved in the regulation of PI3K/AKT signaling, but the underlying mechanisms are unclear. This study aimed to identify protein-coding circRNAs and investigate their function in ESCC. Design: Differential expression of circRNAs between ESCC tissues and adjacent normal tissues was identified using circRNA microarray analysis. A novel protein encoded by circ-PDE5A was identified by LC-MS/MS. Molecular biological methods were used to explore the biological functions and regulatory mechanisms of circ-PDE5A and its encoded PDE5A-500aa novel protein in ESCC. Construction of a nanoplatform for the coupling of circRNAs to investigate the therapeutic translation value of circ-PDE5A. Results: We found that circ-PDE5A expression was downregulated in ESCC cells and tissues, and its low expression was associated with later clinicopathological staging and poorer prognosis. Functionally, circ-PDE5A inhibited ESCC proliferation and metastasis in vitro and in vivo by encoding the novel PDE5A-500aa protein, which was identified as a key player in regulating PI3K/AKT signaling activation in ESCC. Mechanistically, the novel PDE5A-500aa protein binds directly to PIK3IP1 and promotes USP14-mediated deubiquitination of the k48-linked polyubiquitin chain at residue K198 of PIK3IP1, thereby attenuating PI3K/AKT pathway in ESCC. In addition, the circ-PDE5A plasmid-coupled reduction-responsive nanoplatform successfully inhibited ESCC growth and metastasis. Conclusions: circ-PDE5A represents an epigenetic mechanism regulating PI3K/ATK signaling and serves as a novel and promising therapeutic target and prognostic marker for ESCC.
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Project description:CCAAT/enhancer binding proteins (CEBPs, including CEBPA, CEBPB, CEBPD, CEBPE, CEBPG, and CEBPZ) play critical roles in a variety of physiological and pathological processes. However, the molecular characteristics and biological significance of CEBPs in esophageal squamous cell carcinoma (ESCC) have rarely been reported. Here, we show that most of the CEBPs are upregulated and accompanied with copy number amplifications in ESCC. Of note, high CEBPG expression is regulated by the ESCC specific transcription factor TP63 and serves as a prognostic factor for poor survival in ESCC patients. Functionally, CEBPG significantly promotes the proliferation and migration of ESCC cells both in vitro and in vivo. Mechanistically, CEBPG activates the PI3K-AKT signaling pathway through directly binding to distal enhancers and/or promoters of genes involved in this pathway, including genes of CCND1, MYC, CDK2, etc. These findings provide new insights into CEBPs dysregulation in ESCC and elucidate a crucial role for CEBPG in the progression of ESCC, highlighting its potential therapeutic value for ESCC treatment.
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