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Circular RNA CircSLC22A23 Promotes Gastric Cancer Progression by Activating HNRNPU Expression

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Abstract

Background

Circular RNAs (CircRNAs) play essential roles in cancer occurrence as regulatory RNAs. However, circRNA-mediated regulation of gastric cancer (GC) remains poorly understood.

Aim

The purpose of this study was to investigate the molecular mechanism of circSLC22A23 (hsa_circ_0075504) underlying GC occurrence.

Methods

CircSLC22A23 levels were first quantified by quantitative real-time reverse transcription-polymerase chain reaction in GC cell lines, 80 paired GC tissues and adjacent normal tissues, and 27 pairs of plasma samples from preoperative and postoperative patients with GC. Then circSLC22A23 was knocked-down with short hairpin RNA to analyze its oncogenic effects on the proliferation, migration, and invasion of GC cells. Finally, circRNA-binding proteins and their downstream target genes were identified by RNA pulldown, mass spectrometry, RNA immunoprecipitation, quantitative real-time reverse transcription-polymerase chain reaction, and Western blot assays.

Results

CircSLC22A23 was found to be highly expressed in GC cells, GC tissues, and plasma from GC patients. Knockdown of circSLC22A23 inhibited GC cell proliferation, migration and invasion. RNA pulldown and RNA immunoprecipitation assays verified the interaction between circSLC22A23 and heterogeneous nuclear ribonucleoprotein U (HNRNPU). Knockdown of circSLC22A23 decreased HNRNPU protein levels. Moreover, rescue assays showed that the tumor suppressive effect of circSLC22A23 knockdown was reversed by HNRNPU overexpression. Finally, epidermal growth factor receptor (EGFR) was found to be one of the downstream target genes of HNRNPU that was up regulated by circSLC22A23.

Conclusion

CircSLC22A23 regulated the transcription of EGFR through activation of HNRNPU in GC cells, suggesting that circSLC22A23 may serve as a potential therapeutic target for the treatment of GC.

Graphical Abstract

The mechanism underlying the effects of circSLC22A23 on gastric cancer. CircSLC22A23 regulates EGFR transcription by activating HNRNPU expression, thereby promoting the progression of GC.

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Data availability

The data to support the results of this study are included in the article.

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Acknowledgments

Thanks for the technical support by the Core Facilities, Health Science Center, Ningbo University. Thanks for the assistance of Figdraw (www.figdraw.com; figure ID: OAOTTa3c23) in the mechanism drawing. Thanks to the ENCODE consortium and ENCODE production laboratory, KnockTF database, and hTFtarget database that generate specific datasets for EGFR transcription factor predictions.

Funding

This study was supported by grants from the Zhejiang Provincial Natural Science Foundation of China (No. LGF21H200004), the National Natural Science Foundation of China (No. 81772279), the Ningbo Municipal Bureau of Science and Technology (No. 2021Z133, 2022Z130), and the K.C. Wong Magna Fund in Ningbo University.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, 315211, China

    Xinxin Wu, Chunli Cao, Yaoyao Xie, Shuangshuang Zhang & Junming Guo

  2. Department of Gastroenterology, The Affiliated No. 1 Hospital, Ningbo University, Ningbo, 315211, China

    Xinxin Wu, Zhe Li, Yaoyao Xie, Shuangshuang Zhang & Junming Guo

  3. The Affiliated People’s Hospital, Ningbo University, Ningbo, 315040, China

    Chunli Cao & Weiliang Sun

  4. Institute of Digestive Diseases of Ningbo University, Ningbo, 315211, China

    Junming Guo

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  1. Xinxin Wu
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  2. Chunli Cao
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  3. Zhe Li
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Contributions

J. G. and X. W. designed the study. X. W. and J. G. wrote the manuscript. X. W. and C. C. performed most of the experiments, collected the data. Z. L., Y. X., and S. Z., assisted in the experiments. W. S. designed clinical study and analysis. All authors revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Junming Guo.

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This study was approved by the Ethics Committee of Ningbo University (No. 2017022701), and written informed consent was obtained from all the patients.

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Wu, X., Cao, C., Li, Z. et al. Circular RNA CircSLC22A23 Promotes Gastric Cancer Progression by Activating HNRNPU Expression. Dig Dis Sci 69, 1200–1213 (2024). https://doi.org/10.1007/s10620-024-08291-2

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