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tRF-33-P4R8YP9LON4VDP inhibits gastric cancer progression via modulating STAT3 signaling pathway in an AGO2-dependent manner

Abstract

It has been demonstrated that tRNA-derived small RNAs (tsRNAs) perform essential functions in the pathophysiology of cancer. In this study, we focused on the possible mechanisms of tRF-33-P4R8YP9LON4VDP (tRF-33) underlying the development of gastric malignancy. In total, 454 tissue samples with different gastric mucosal lesions were collected. The tRF-33 expression level in different cohorts was determined, and its value for diagnostic efficiency and prognosis evaluation were assessed. Cell proliferation assays, Transwell assay, flow cytometry, and xenotransplantation model were used to evaluate its effect on gastric cancer cells. The molecular mechanism was verified by fluorescence in situ hybridization, dual luciferase assay, Western blot, and RNA binding protein immunoprecipitation. The results showed that the expression of tRF-33 exhibited a gradual modification from normal control samples to gastritis tissues, early and latent stage of gastric cancer tissues. Consequently, tRF-33 holds significant potential as a predictive and diagnostic biomarker for gastric malignancy. Over-expression of tRF-33 inhibited gastric cancer cell progression and metastatic viability, and induced cell apoptosis. Tumorigenicity in nude mice showed the suppressive characteristics of tRF-33. Mechanistic investigation revealed that tRF-33 exerted silencing on STAT3 mRNA via binding to AGO2. In conclusion, tRF-33 exhibited values in diagnosing gastric cancer and evaluating its prognosis, and suppressed tumor cell viability by inhibiting STAT3 signaling pathway.

The schematic mechanisms underlying tRF-33 regulating gastric cancer occurrence. tRF-33 binds to AGO2 proteins and then negatively regulates STAT3 expression through targeting its 3′UTR. The downregulated expression of STAT3 results in the decrease of STAT3 and p-STAT3 and further blocks the transcription of the downstream genes and finally inhibits the gastric cancer occurrence. MMP-9, matrix metalloproteinase-9; Bcl-2, B-cell lymphoma-2; STAT3, signal transducer and activator of transcription 3; UTR, untranslated region.

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Fig. 1: The generation of tRF-33-P4R8YP9LON4VDP.
Fig. 2: tRF-33 expression levels in various groups and its clinical values in gastric cancer.
Fig. 3: The effects of tRF-33 on the tumor growth of HGC-27 xenografts.
Fig. 4: The subcellular location of tRF-33-P4R8YP9LON4VDP and bioinformation analysis of its target genes.
Fig. 5: tRF-33-P4R8YP9LON4VDP directly regulates STAT3 expression in gastric cancer cells.
Fig. 6: Attenuation of STAT3 expression rescues the targeting effects of tRF-33-P4R8YP9LON4VDP on tumor growth.

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Data availability

The datasets utilized and/or examined in the present investigation can be acquired from the author who provided them upon an acceptable request.

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Acknowledgements

The authors express their gratitude for the technical assistance provided by the Core Facilities of the Health Science Center of Ningbo University and Laboratory Animal Center of Ningbo University.

Funding

Funding

The current investigation received funding from National Natural Science Foundation of China (No. 81974316, 82372333, and 82302611), Zhejiang Provincial Natural Science Foundation of China (No. LGF21H200004 and LTGY24H200001), Ningbo Municipal Bureau of Science and Technology (No. 2021Z133, 2022Z130, and 2023J167), and the K.C. Wong Magna Fund of Ningbo University.

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Contributions

Jia G, and Ju G designed the investigation. SZ, Jie G, and Ju G drafted the manuscript. SZ, YG, Jia G, YX, XY, XW, D S, and XZ collected clinical data. Jie G revised the manuscript. For the final version of the paper, all authors provided their approval following active involvement in the revision process.

Corresponding authors

Correspondence to Jiaxin Ge or Junming Guo.

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The authors declare no competing interests.

Ethical approval

The investigation protocol granted approval from the Ethics Committee of Ningbo University (approval no. 2019022501) and was performed in adherence to the ethical principles outlined in the Declaration of Helsinki for medical research including human beings. Before being included in this study, all individuals were required to provide written informed consent. The protocol for the treatment of animals was approved by the Ningbo University Animal Ethics Committee (approval no. 2019-57) in accordance with the Declaration of Basel.

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Zhang, S., Gu, Y., Ge, J. et al. tRF-33-P4R8YP9LON4VDP inhibits gastric cancer progression via modulating STAT3 signaling pathway in an AGO2-dependent manner. Oncogene (2024). https://doi.org/10.1038/s41388-024-03062-9

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