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Study on the mechanism of circ-PDE5A inhibiting the progression of esophageal squamous cell carcinoma

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE250413 | GEO | 2024/01/15

REPOSITORIES: GEO

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Project description:Esophageal cancer remains a dominating cause of cancer-associated death and has shown a sharp increase of more than 6-fold increase rates all over the world. It is divided into two main pathological types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Though the treatment has been improved a lot, the prognosis is still very poor with overall survival rate at 5 year was 15%-25%. Elaiophylin is a novel autophagy inhibitor at the late stage, which is a C2 symmetric macrolides separated from Streptomyces niger. However, the function of it in esophageal cancer was never explored. EIF4B is an important component of eukaryotic transcription initiation complex, which can be recruited to the 5’ untranslated region (5’UTR) of the mRNA. In recent years, eIF4B was suggested to play an important role in the progression of a various cancer cells. In the study we presented here, we firstly confirmed that the Elaiophylin was a novel autophagy inhibitor in ESCC cells. Moreover, Elaiophylin can inhibit the proliferation and migration of ESCCs, and promotes apoptosis. Then, we using RNA-seq to identify the genes which were regulated by Elaiophylin and verify them by RT-qPCR assay. Finally, we found the activity of PI3K/AKT pathway was inhibited by Elaiophylin. And the mRNA and protein expression level of eIF4B was both downregulated by Elaiophylin. In order to further confirm whether eIF4B is a target of Elaiophylin, we transfected a EIF4B-OE plasmid to ESCC cells, and found that the eIF4B overexpression could block the effect which was resulted from Elaiophylin. And by transfecting a shRNA to ESCC cells, we found that knockdown of eIF4B could inhibit the proliferation and migration of ESCC cells and promotes apoptosis when compared with the control group. All the results suggest that Elaiophylin could inhibit the proliferation, invasion of ESCC cells and promote its apoptosis by targeting the eIF4B via PI3K/AKT signaling pathway. This result identified that the Elaiophylin might serve as a promising therapeutic medicine for esophageal cancer.

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Study on the mechanism of circ-PDE5A inhibiting the progression of esophageal squamous cell carcinoma

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