Hypoxia regulates tumour characteristic RNA modifications in ovarian cancers

Yuya Monoe1, Shunsuke Miyamoto2,3, Kentaro Jingushi1

  • 1Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.

The FEBS Journal
|November 23, 2022
PubMed

Insights

Ovarian cancer exhibits distinct RNA modifications, with hypoxia and the tumor microenvironment driving these changes. Understanding these RNA alterations offers new insights into cancer development and potential therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Ovarian cancer tissue shows significant differences in RNA modifications compared to normal tissue.
  • Specific RNA modifications, N6-isopentenyladenosine (Im) and 5-hydroxymethyluridine (chm5U), characterize advanced and platinum-resistant ovarian cancers, respectively.

Purpose of the Study:

  • To investigate the role of the intra-tumour microenvironment, particularly hypoxia, in driving characteristic RNA modifications in ovarian cancer.
  • To identify specific RNA modifications associated with tumorigenesis and their correlation with gene expression pathways.

Main Methods:

  • Comparative analysis of RNA modifications in ovarian cancer and normal ovarian tissues.
  • Xenograft model using the RMG-1 ovarian cancer cell line to study tumorigenesis.
  • RNA sequencing (RNAseq) to analyze gene expression and its correlation with RNA modifications.
  • Assessment of RNA modifications under hypoxic conditions.

Main Results:

  • 31 RNA modifications differed significantly between ovarian cancer and normal tissues.
  • 14 RNA modifications varied during tumorigenesis in the xenograft model.
  • Eight specific RNA modifications (m2,2G, t6A, m7G, m5U, m1G, i6A, m6t6A, and m1A) were upregulated in cancer tissues, xenografts, and under hypoxic conditions.
  • RNAseq revealed 2137 highly expressed genes in ovarian cancer, with 134 genes enriched in the hypoxia signaling pathway and positively correlated with the eight upregulated RNA modifications.

Conclusions:

  • The tumor microenvironment, including hypoxia, significantly influences characteristic RNA modifications in ovarian cancer.
  • These findings highlight the importance of hypoxia-driven RNA modifications in ovarian cancer development.
  • The identified RNA modifications and associated genes may serve as potential biomarkers or therapeutic targets.

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