The tRNA-derived fragment 5026a inhibits the proliferation of gastric cancer cells by regulating the PTEN/PI3K/AKT signaling pathway

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Abstract

Background

Recently, tRNA-derived fragments (tRFs) have been shown to serve important biological functions. However, the role of tRFs in gastric cancer has not been fully elucidated. This study aimed to identify the tumor suppressor role of tRF-5026a (tRF-18-79MP9P04) in gastric cancer.

Methods

Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was first used to detect tRF-5026a expression levels in gastric cancer tissues and patient plasma. Next, the relationship between tRF-5026a levels and clinicopathological features in gastric cancer patients was assessed. Cell lines with varying tRF-5026a levels were assessed by measuring tRF-5026a using qRT-PCR. After transfecting cell lines with a tRF-5026a mimic or inhibitor, cell proliferation, colony formation, migration, apoptosis, and cell cycle were evaluated. The expression levels of related proteins in the PTEN/PI3K/AKT pathway were also analyzed by Western blotting. Finally, the effect of tRF-5026a on tumor growth was tested using subcutaneous tumor models in nude mice.

Results

tRF-5026a was downregulated in gastric cancer patient tissues and plasma samples. tRF-5026a levels were closely related to tumor size, had a certain diagnostic value, and could be used to predict overall survival. tRF-5026a was also downregulated in gastric cancer cell lines. tRF-5026a inhibited the proliferation, migration, and cell cycle progression of gastric cancer cells by regulating the PTEN/PI3K/AKT signaling pathway. Animal experiments showed that upregulation of tRF-5026a effectively inhibited tumor growth.

Conclusions

tRF-5026a (tRF-18-79MP9P04) is a promising biomarker for gastric cancer diagnostics and has tumor suppressor effects mediated through the PTEN/PI3K/AKT signaling pathway.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13287-021-02497-1.

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Most cited references 51

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Targeting PI3K in cancer: mechanisms and advances in clinical trials

Jing Yang, Ji Nie, Xuelei Ma … (2019)

Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways, which can be considered as a master regulator for cancer. Enormous efforts have been dedicated to the development of drugs targeting PI3K signaling, many of which are currently employed in clinical trials evaluation, and it is becoming increasingly clear that PI3K inhibitors are effective in inhibiting tumor progression. PI3K inhibitors are subdivided into dual PI3K/mTOR inhibitors, pan-PI3K inhibitors and isoform-specific inhibitors. In this review, we performed a critical review to summarize the role of the PI3K pathway in tumor development, recent PI3K inhibitors development based on clinical trials, and the mechanisms of resistance to PI3K inhibition.

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Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement.

Hani Goodarzi, Xuhang Liu, Hoang Nguyen … (2015)

Upon exposure to stress, tRNAs are enzymatically cleaved, yielding distinct classes of tRNA-derived fragments (tRFs), yielding distinct classes of tRFs. We identify a novel class of tRFs derived from tRNA(Glu), tRNA(Asp), tRNA(Gly), and tRNA(Tyr) that, upon induction, suppress the stability of multiple oncogenic transcripts in breast cancer cells by displacing their 3' untranslated regions (UTRs) from the RNA-binding protein YBX1. This mode of post-transcriptional silencing is sequence specific, as these fragments all share a common motif that matches the YBX1 recognition sequence. Loss-of-function and gain-of-function studies, using anti-sense locked-nucleic acids (LNAs) and synthetic RNA mimetics, respectively, revealed that these fragments suppress growth under serum-starvation, cancer cell invasion, and metastasis by breast cancer cells. Highly metastatic cells evade this tumor-suppressive pathway by attenuating the induction of these tRFs. Our findings reveal a tumor-suppressive role for specific tRNA-derived fragments and describe a molecular mechanism for their action. This transcript displacement-based mechanism may generalize to other tRNA, ribosomal-RNA, and sno-RNA fragments.

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Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets

Pankaj Kumar, Suresh Mudunuri, Anindya Dutta … (2014)

Background tRFs, 14 to 32 nt long single-stranded RNA derived from mature or precursor tRNAs, are a recently discovered class of small RNA that have been found to be present in diverse organisms at read counts comparable to miRNAs. Currently, there is a debate about their biogenesis and function. Results This is the first meta-analysis of tRFs. Analysis of more than 50 short RNA libraries has revealed that tRFs are precisely generated fragments present in all domains of life (bacteria to humans), and are not produced by the miRNA biogenesis pathway. Human PAR-CLIP data shows a striking preference for tRF-5s and tRF-3s to associate with AGO1, 3 and 4 rather than AGO2, and analysis of positional T to C mutational frequency indicates these tRFs associate with Argonautes in a manner similar to miRNAs. The reverse complements of canonical seed positions in these sequences match cross-link centered regions, suggesting these tRF-5s and tRF-3s interact with RNAs in the cell. Consistent with these results, human AGO1 CLASH data contains thousands of tRF-5 and tRF-3 reads chimeric with mRNAs. Conclusions tRFs are an abundant class of small RNA present in all domains of life whose biogenesis is distinct from miRNAs. In human HEK293 cells tRFs associate with Argonautes 1, 3 and 4 and not Argonaute 2 which is the main effector protein of miRNA function, but otherwise have very similar properties to miRNAs, indicating tRFs may play a major role in RNA silencing. Electronic supplementary material The online version of this article (doi:10.1186/s12915-014-0078-0) contains supplementary material, which is available to authorized users.

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Author and article information

Contributors

Junming Guo:

ORCID: http://orcid.org/0000-0003-2026-1075

guojunming@nbu.edu.cn

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 22 July 2021

Publication date PMC-release: 22 July 2021

Publication date Collection: 2021

Volume: 12

Electronic Location Identifier: 418

Affiliations

[1 ]GRID grid.460077.2, Department of Gastroenterology, , The Affiliated Hospital of Ningbo University School of Medicine, ; Ningbo, 315020 China

[2 ]GRID grid.203507.3, ISNI 0000 0000 8950 5267, Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, , Medical School of Ningbo University, ; Ningbo, 315211 China

[3 ]GRID grid.203507.3, ISNI 0000 0000 8950 5267, Affiliated Lihuili Hospital of Ningbo University, ; Ningbo, Zhejiang 315041 China

[4 ]GRID grid.203507.3, ISNI 0000 0000 8950 5267, Institute of Digestive Diseases of Ningbo University, ; Ningbo, 315020 China

Author information

Junming Guo http://orcid.org/0000-0003-2026-1075

Article

Publisher ID: 2497

DOI: 10.1186/s13287-021-02497-1

PMC ID: 8296675

PubMed ID: 34294122

SO-VID: c12256ff-3c23-41d9-847d-e4e69c262937

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 28 December 2020

Date accepted : 7 July 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81974316

Award Recipient : Junming Guo

Funded by: FundRef http://dx.doi.org/10.13039/501100004731, Natural Science Foundation of Zhejiang Province;

Award ID: LGF21H200004

Award Recipient : Junming Guo

Funded by: the K.C. Wong Magna Fund in Ningbo University

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ScienceOpen disciplines: Molecular medicine

Keywords: trna-derived small rnas,trf-5026a,trf-18-79mp9p04,gastric cancer,pten,pi3k

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ScienceOpen disciplines: Molecular medicine

Keywords: trna-derived small rnas, trf-5026a, trf-18-79mp9p04, gastric cancer, pten, pi3k

The tRNA-derived fragment 5026a inhibits the proliferation of gastric cancer cells by regulating the PTEN/PI3K/AKT signaling pathway

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Neuronal Signaling

Most cited references 51

Targeting PI3K in cancer: mechanisms and advances in clinical trials

Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement.

Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets

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