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tsRNA-GlyGCC promotes colorectal cancer progression and 5-FU resistance by regulating SPIB

Rong Xu1, Ashuai Du2, Xinpei Deng3

  • 1Department of Pathology, Changde Hospital, Xiangya School of Medicine, Central South University (The first people's hospital of Changde city), Changde, Hunan, 415000, China.

Journal of Experimental & Clinical Cancer Research : CR
|August 17, 2024
PubMed
Abstract

Insights

A novel tRNA-derived small RNA (tsRNA-GlyGCC) promotes colorectal cancer (CRC) and 5-fluorouracil (5-FU) resistance by targeting the JAK1/STAT6 pathway. Targeting tsRNA-GlyGCC with 5-FU offers a potential nanotherapeutic strategy for CRC.

Area of Science:

  • Molecular Biology
  • Oncology
  • RNA Biology

Background:

  • tRNA-derived small RNAs (tsRNAs) are emerging regulators in biological processes and diseases, including cancer.
  • The specific role and mechanisms of tsRNAs in colorectal cancer (CRC) and their influence on 5-fluorouracil (5-FU) resistance remain largely undefined.

Purpose of the Study:

  • To investigate the role of tsRNAs in CRC and their impact on 5-FU resistance.
  • To identify specific tsRNAs involved in CRC progression and drug resistance.
  • To elucidate the molecular mechanisms underlying tsRNA function in CRC and 5-FU resistance.

Main Methods:

  • RNA sequencing to identify differentially expressed tsRNAs in CRC tissues.
  • In vitro and in vivo assays (CCK8, colony formation, transwell, tumor sphere) to assess the function of tsRNA-GlyGCC in 5-FU resistance.
  • Bioinformatic analysis (TargetScan, miRanda) and molecular experiments (biotin pull-down, luciferase assay, ChIP, western blotting, MeRIP) to determine target genes and mechanisms, including N(7)-methylguanosine modification.

Main Results:

  • A specific tsRNA, 5'tiRNA-Gly-GCC (tsRNA-GlyGCC), was found to be upregulated in CRC tissues and linked to METTL1-mediated N(7)-methylguanosine tRNA modification.
  • tsRNA-GlyGCC exhibits an oncogenic role, promoting 5-FU drug resistance in CRC through in vitro and in vivo studies.
  • tsRNA-GlyGCC targets SPIB, modulating the JAK1/STAT6 signaling pathway; a synthesized inhibitor combined with 5-FU effectively suppressed tumor growth and enhanced 5-FU sensitivity in vivo.

Conclusions:

  • A distinct tsRNA-GlyGCC-mediated pathway contributes to CRC progression and 5-FU resistance.
  • Targeting tsRNA-GlyGCC in combination with 5-FU presents a promising nanotherapeutic strategy for overcoming 5-FU resistance in CRC.
Keywords:
5-FU resistanceCRCJAK1/STAT6METTL1SPIBm7GtsRNA

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