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CircVPS13C promotes pituitary adenoma growth by decreasing the stability of IFITM1 mRNA via interacting with RRBP1

Oncogene volume 41, pages 1550–1562 (2022)Cite this article

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Abstract

CircRNAs play important roles in a variety of biological processes by acting as microRNA sponges and protein scaffolds or by encoding functional proteins. However, their functions and underlying mechanisms remain largely unknown. Distinctive circRNA patterns were explored by comparing nonfunctioning pituitary adenomas (NFPAs) and normal pituitary tissues with a circRNA array. The biological functions of selected circRNAs were determined in vitro and in vivo. RNA-seq and circRNA pulldown assays were applied to investigate the underlying mechanisms. The circRNA profile of NFPAs is tremendously different from that of normal pituitary tissues. CircVPS13C is significantly upregulated in NFPA samples and cell lines. Gain- and loss-of-function experiments demonstrate that silencing circVPS13C inhibits the proliferation of pituitary tumor cells in vitro and in vivo. Mechanistically, circVPS13C silencing increases the expression of IFITM1 and subsequently activates its downstream genes involved in MAPK- and apoptosis-associated signaling pathways. Rescue experiments show that IFITM1 overexpression partly reverses the biological effects of circVPS13C. Further studies reveal that circVPS13C inhibits IFITM1 expression through a novel mechanism mainly by competitively interacting with RRBP1, a ribosome-binding protein of the endoplasmic reticulum membrane, and thereby alleviating the stability of IFITM1 mRNA. Clinically, circVPS13C expression is markedly higher in high-risk NFPA samples and is downregulated in patient serum 7 days post-transsphenoidal adenoma resection. Our findings suggest that circVPS13C is a critical regulator in the proliferation and development of NFPAs through a novel mechanism, whereby regulating mRNA stability via interacting with ribosome-binding proteins on the endoplasmic reticulum membrane.

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Fig. 1: Differential circRNA expression between NFPA (n = 10) and NP tissues (n = 4) and significantly increased circVPS13C expression in NFPA samples.
Fig. 2: Identification and validation of circVPS13C in pituitary adenoma cells.
Fig. 3: Silencing of circVPS13C inhibits the proliferation of NFPA cells partly by increasing apoptosis.
Fig. 4: Silencing of circVPS13C inhibits cell proliferation partly by upregulating IFITM1 expression.
Fig. 5: CircVPS13C alleviates the stability of IFITM1 mRNA by interacting with RRBP1.
Fig. 6: CircVPS13C suppresses IFITM1 expression by competitively interacting with RRBP1.
Fig. 7: Clinical significance of circVPS13C in NFPAs.

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Data availability

Clinical information of samples and primers used in the present study can be found in supplementary tables. Other original data in our study are available upon request.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China for Young Scholars (grant number 81702479 to XJ), Guangdong Basic and Applied Basic Research Foundation (grant number 2020A151501281 to XJ), Science and Technology Program of Jiangmen, China (grant number 2018630100110019805 to YM), and the Natural Science Foundation of Jiangsu Province (grant number BK20200936 to QD).

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Author notes

  1. These authors contributed equally: Weiyu Zhang, Siyu Chen, Qiu Du.

Authors and Affiliations

  1. Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China

    Weiyu Zhang, Siyu Chen, Qiu Du, Piaopiao Bian, Ke Sai, Yonggao Mou, Zhongping Chen & Xiaobing Jiang

  2. Department of Neurosurgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China

    Weiyu Zhang & Xiang Fan

  3. Department of Neurosurgery, The Affiliated Hospital of Yangzhou University, Yangzhou, China

    Qiu Du

  4. Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

    Piaopiao Bian

  5. Department of Abdominal Oncology, cancer center of the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China

    Yutong Chen

  6. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China

    Zexian Liu & Jian Zheng

  7. Department of Neurosurgery, Jiangmen Central hospital, Jiangmen, China

    Xiaobing Jiang

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Contributions

WZ, SC, QD, PB, and YC carried out experiments and participated in data analysis, statistical analysis, and manuscript preparation. YM, KS, and ZC collected samples. ZL, WZ, and SC participated in data analysis. ZZ, WZ, and XJ participated in writing and proofreading the manuscript. XJ and XF designed the study, were involved in the whole process, and were guarantors of the integrity of the entire study.

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Correspondence to Xiang Fan or Xiaobing Jiang.

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Informed consent, including a tissue sharing clause, was obtained from a family member of the deceased individual before the autopsy. The use of human tissues in the study was approved by the medical ethics committee of Sun Yat-sen University Cancer Center.

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Zhang, W., Chen, S., Du, Q. et al. CircVPS13C promotes pituitary adenoma growth by decreasing the stability of IFITM1 mRNA via interacting with RRBP1. Oncogene 41, 1550–1562 (2022). https://doi.org/10.1038/s41388-022-02186-0

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