Published in:

23-04-2024 | Hepatocellular Carcinoma | Original Article

DEAD-Box Helicase 17 circRNA (circDDX17) Reduces Sorafenib Resistance and Tumorigenesis in Hepatocellular Carcinoma

Authors: Xiaochuan Zhang, Wenyu Wang, Shanshan Mo, Xueying Sun

Published in: Digestive Diseases and Sciences | Issue 6/2024

Abstract

Background

Hepatocellular carcinoma (HCC) is the most common type of liver malignancy. Despite significant progress in HCC treatment, resistance to chemotherapy and tumor metastasis are the main reasons for the unsatisfactory prognosis of HCC. Circular RNAs (circRNAs) have been extensively documented to play a role in the development of various types of cancer.

Aims

Here, we investigated the role of DEAD-box helicase 17 circRNA (circDDX17) in HCC and its underlying molecular mechanisms.

Methods

Our research employed various techniques including reverse transcription-quantitative polymerase chain reaction (RT-qPCR), cell counting kit-8 (CCK-8), flow cytometry, dual luciferase reporter assay, RNA immunoprecipitation (RIP), and western blot analysis. Additionally, we conducted a tumor xenograft assay to investigate the in vivo function of circDDX17.

Results

Firstly, the expression of circDDX17 was downregulated in HCC tissues and cells. Through functional experiments, it was observed that the overexpression of circDDX17 enhanced the sensitivity of sorafenib, promoted apoptosis, and inhibited the process of epithelial-mesenchymal transition (EMT) in vitro. Additionally, in vivo studies revealed that circDDX17 reduced tumor growth and increased sorafenib sensitivity. Mechanically, circDDX17 competitively combined miR-21-5p to suppress PTEN expression and activate the PI3K/AKT pathway. Furthermore, our rescue assays demonstrated that circDDX17 act as a tumor suppressor by blocking sorafenib resistance and tumorigenesis, while the inhibitory effect caused by circDDX17 upregulation was neutralized when miR-21-5p was overexpressed, PTEN was silenced, or the PI3K/AKT pathway was activated.

Conclusion

Our findings firstly confirmed that circDDX17 suppressed sorafenib resistance and HCC progression by regulating miR-21-5p/PTEN/PI3K/AKT pathway, which may provide novel biomarkers for the diagnosis, treatment and prognosis of HCC.

Graphical Abstract

Schematic illustration showed that the molecular mechanism by which circDDX17 regulates sorafenib resistance and tumor progression of HCC via the miR-21-5p/PTEN/PI3K/AKT pathway. In HCC cells, the expression of circDDX17 was decreased, and overexpression of circDDX17 promoted cell apoptosis, and enhanced sorafenib sensitivity and reduced EMT process. Besides, circDDX17 competitively combined miR-21-5p and miR-21-5p targeted suppression PTEN to regulate the activation of PI3K/AKT pathway, thus promoting the tumorigenesis of HCC.

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Title: DEAD-Box Helicase 17 circRNA (circDDX17) Reduces Sorafenib Resistance and Tumorigenesis in Hepatocellular Carcinoma
Authors: Xiaochuan Zhang
Wenyu Wang
Shanshan Mo
Xueying Sun
Publication date: 23-04-2024
Publisher: Springer US
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Sorafenib
Published in: Digestive Diseases and Sciences / Issue 6/2024
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-024-08401-0

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DEAD-Box Helicase 17 circRNA (circDDX17) Reduces Sorafenib Resistance and Tumorigenesis in Hepatocellular Carcinoma

Abstract

Background

Aims

Methods

Results

Conclusion

Graphical Abstract

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