Publicação
Exploring the role of the JAK3/STAT3 pathway in colorectal cancer
| Resumo: | Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. Signal transducer and activator of transcription 3 (STAT3) is frequently dysregulated in various cancers, playing a pivotal role in tumour development and progression. Constitutive activation of STAT3 is observed in approximately 70% of solid tumours, highlighting its critical role in oncogenesis. Aberrant DNA methylation, a common epigenetic modification, occurs in nearly all CRC cases, prompting an investigation into the potential methylation of genes involved in the STAT3 pathway, particularly its upstream regulators. In this study, both in-house and publicly available CRC whole genome methylation databases were analysed to investigate STAT3 promoter methylation, but this was not detected. The analysis was extended to all genes of the STAT3 pathway. The upstream effector Janus kinase 3 (JAK3) was found to undergo promoter hypermethylation in a significant proportion of CRCs. The association between JAK3 promoter methylation with gene expression was studied in a panel of 5 CRC cell lines. All the studied cell lines exhibited JAK3 promoter methylation and low mRNA expression. Treatment with the inhibitor of methylation agent 5'-Aza-2′-deoxycytidine failed to restore gene transcription, indicating that promoter methylation is not the only factor underlying JAK3 silencing. Further analysis examined JAK3 protein expression alongside phosphorylated STAT3 (pSTAT3) and total STAT3. JAK3 protein was undetectable in the 5 CRC cell lines. These findings underscore the complexity of signalling pathways involved in CRC and emphasize the necessity of further research to fully elucidate the mechanisms underlying STAT3 regulation and its role in colorectal oncogenesis. |
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| Autores principais: | Violante, Catarina Sofia Ferreira |
| Assunto: | Cancro colorretal STAT3 JAK3 metilação do ADN linhas celulares de cancro Teses de mestrado - 2024 |
| Ano: | 2024 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. Signal transducer and activator of transcription 3 (STAT3) is frequently dysregulated in various cancers, playing a pivotal role in tumour development and progression. Constitutive activation of STAT3 is observed in approximately 70% of solid tumours, highlighting its critical role in oncogenesis. Aberrant DNA methylation, a common epigenetic modification, occurs in nearly all CRC cases, prompting an investigation into the potential methylation of genes involved in the STAT3 pathway, particularly its upstream regulators. In this study, both in-house and publicly available CRC whole genome methylation databases were analysed to investigate STAT3 promoter methylation, but this was not detected. The analysis was extended to all genes of the STAT3 pathway. The upstream effector Janus kinase 3 (JAK3) was found to undergo promoter hypermethylation in a significant proportion of CRCs. The association between JAK3 promoter methylation with gene expression was studied in a panel of 5 CRC cell lines. All the studied cell lines exhibited JAK3 promoter methylation and low mRNA expression. Treatment with the inhibitor of methylation agent 5'-Aza-2′-deoxycytidine failed to restore gene transcription, indicating that promoter methylation is not the only factor underlying JAK3 silencing. Further analysis examined JAK3 protein expression alongside phosphorylated STAT3 (pSTAT3) and total STAT3. JAK3 protein was undetectable in the 5 CRC cell lines. These findings underscore the complexity of signalling pathways involved in CRC and emphasize the necessity of further research to fully elucidate the mechanisms underlying STAT3 regulation and its role in colorectal oncogenesis. |
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