Hypoxia regulates tumour characteristic RNA modifications in ovarian cancers

• Published in: The FEBS journal 2023-04, Vol.290 (8), p.2085-2096
• Main Authors: Monoe, Yuya, Miyamoto, Shunsuke, Jingushi, Kentaro, Tanimoto, Masaya, Tanaka, Tomohito, Taniguchi, Kohei, Komura, Kazumasa, Ohmichi, Masahide, Tsujikawa, Kazutake
• Format: Article
• Language: English
• Subjects: Cancer; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Genes; Humans; Hypoxia; Hypoxia - genetics; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Platinum; Ribonucleic acid; RNA; RNA modification; Signal transduction; Tissues; Tumor microenvironment; Tumor Microenvironment - genetics; Tumorigenesis; Tumors; tumour microenvironment; Xenografts
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.16688

Analysis of ovarian cancer tissue and normal ovarian tissue revealed 31 RNA modifications with significant differences observed in cancer tissue compared with normal tissue. Moreover, we found Im and chm5U as characteristic RNA modifications in advanced and platinum‐resistant ovarian cancers, respectively. Considering that these differences in RNA modifications may be due to the intra‐tumour microenvironment, we xenografted the ovarian cancer cell line RMG‐1 to create RMG‐1 tumours and compared them with original RMG‐1 cells. As a result, 14 of the 31 RNA modifications showed marked variations during tumorigenesis. Eight RNA modifications (m2,2G, t6A, m7G, m5U, m1G, i6A, m6t6A and m1A), which were upregulated in ovarian cancer tissues and in RMG‐1‐xenografted tumour, were also upregulated under hypoxic conditions. RNAseq analysis, using the matched RNA samples analysed for RNA modifications, showed that 2137 genes were highly expressed in ovarian cancer tissues compared with those in normal ovarian tissues. Of these, 134 genes, which were enriched in a gene set belonging to the hypoxia signalling pathway, were positively correlated with the above eight RNA modifications. These results suggest that the tumour microenvironment, including hypoxia, is important for cancer characteristic RNA modifications. Analysis of ovarian cancer tissue and normal ovarian tissue revealed 31 RNA modifications with significant differences observed in cancer tissue compared with normal tissue. Eight RNA modifications (m2,2G, t6A, m7G, m5U, m1G, i6A, m6t6A and m1A), which were upregulated in ovarian cancer tissues were also upregulated under hypoxic conditions. These results suggest that the tumour microenvironment, including hypoxia, is important for cancer characteristic RNA modifications.