Biology subjects

Nishimori, A.

Publications and source records attributed to Nishimori, A..

2 recordsLinked to original sources

bioRxiv2024

Effect of C-to-T transition at CpG sites on tumor suppressor genes in tumor development in cattle evaluated by somatic mutation analysis in enzootic bovine leukosis

Oncogenic transformation of normal cells is caused by mutations and chromosomal abnormalities in cancer-related genes. Enzootic bovine leukosis (EBL) is a malignant B-cell lymphoma caused by bovine leukemia virus (BLV) infection in cattle. Although a small fraction of BLV-infected cattle develops EBL after a long latent period, the mechanisms for oncogenesis in EBL cattle remain largely unknown. In this study, we analyzed the types and patterns of somatic mutations in cancer cells from 36 EBL cases, targeting 21 cancer-related genes. Various somatic mutations were identified in 8 genes, TP53, NOTCH1, KMT2D, CREBBP, KRAS, PTEN, CARD11, and MYD88. In addition, TP53 gene was found to be mutated in 69.4% of EBL cases, with most being biallelic mutations. In some cases, associations were observed between the ages at which cattle had developed EBL and somatic mutation patterns; young onset of EBL possibly occurs due to congenital mutations, high impact mutations affecting protein translation, and biallelic mutations. Furthermore, nucleotide substitution patterns indicated that cytosine at CpG sites tended to be converted to thymine in many EBL cases, which was considered to be the result of spontaneous deamination of 5-methylctosine. These results demonstrate how somatic mutations have occurred in cancer cells leading to EBL development, thereby explaining its pathogenic mechanism. These findings will contribute to a better understanding and future elucidation of disease progression in BLV infection. ImportanceEnzootic bovine leukosis (EBL) is a malignant and lethal disease in cattle. Currently, there are no effective vaccines or therapeutic methods against bovine leukemia virus (BLV) infection, resulting in severe economic losses in livestock industry. This study provides a renewed hypothesis to explain the general mechanisms of EBL onset by combining the previous finding that several integration sites of BLV provirus can affect the increase in survival and proliferation of infected cells. We demonstrate that two additional random events are necessary for oncogenic transformation in infected cell clones, elucidating the reason why only few infected cattle develop EBL. Further exploration of somatic mutation and BLV integration sites could support this hypothesis more firmly, potentially contributing to the development of novel control methods for EBL onset.

cancer biology↗

bioRxiv2023

Bovine leukemia virus-derived long-noncoding RNA, AS1-S, binds to bovine hnRNPM and alters interaction properties between hnRNPM and host mRNAs.

Viruses utilize several strategies to develop latent infection and evade host immune responses. Long non-coding RNA (lncRNA), a class of non-protein encoding RNA that regulates various cellular functions by interacting with RNA binding proteins, is a key factor for viral latency because of its lack of antigenicity. Bovine leukemia virus (BLV), which belongs to the family Retroviridae, encodes the BLV-derived lncRNA AS1-S, which is a major transcript expressed in latently infected cells. We herein identified bovine hnRNPM, an RNA-binding protein located in the nucleus, as the binding partner for AS1-S using an RNA-protein pull-down assay. The pull-down assay using recombinant hnRNPM mutants showed that RNA recognition motif 1 and 2, located in the N-terminal region of bovine hnRNPM, are responsible for binding AS1-S. Furthermore, an RNA immunoprecipitation assay showed that introduction of AS1-S increased the number of mRNA that co-immunoprecipitated with bovine hnRNPM in MDBK cells. These results suggested that AS1-S could alter the interaction between hnRNPM and host mRNAs, potentially interfering with cellular functions during the initial phase of mRNA maturation in the nucleus. Since most of the identified mRNAs that exhibited increased binding to hnRNPM were correlated with the KEGG term "Pathways in cancer", AS1-S may affect proliferation and expansion of BLV-infected cells and contribute to tumor progression. ImportanceBLV infects bovine B cells and causes malignant lymphoma, resulting in severe economic losses in the livestock industry. Due to its low incidence rate and long latent period, the molecular mechanisms underlying the progression to lymphoma remain enigmatic. Several non-coding RNAs, such as miRNA and lncRNA, have recently been discovered in the BLV genome and the relationship between BLV pathogenesis and these non-coding RNAs is attracting attention. However, most of the molecular functions of these transcripts remain un-identified. To the best of our knowledge, this is the first report describing a molecular function for the BLV-derived lncRNA AS1-S. The findings reported herein reveal a novel mechanism underlying BLV pathogenesis that could provide important insights for not only BLV research but also comparative studies of retroviruses.

microbiology↗