The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes

Barreiro, Rodrigo; Guardia, Gabriela D. A.; Meliso, Fabiana Marcelino; Lei, Xiufen; Li, Weiqing; Sávio, André Luiz Ventura; Fellermeyer, Martin; Conceicao, Helena B; Mercuri, Rafael L. V.; Landry, Tesha; Qiao, Mu; Blázquez, Lorea; Ule, Jernej; Penalva, Luiz O. F.; Galante, Pedro A. F.

doi:10.1080/15476286.2023.2221511

Cited by 3 publications

(2 citation statements)

References 76 publications

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“…However, our understanding of the molecular mechanism of GC is still insufficient. MAGOH, a core protein involved in mRNA splicing, has been reported to be closely related to the occurrence and development of a variety of tumors [ 22 , 23 , 54 , 55 ]. For instance, Soederberg et al reported that the MAGOH and MAGOHB proteins were highly expressed in cutaneous melanoma cell lines and patient-derived tissue samples and that their knockdown significantly inhibited melanoma cell proliferation [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, this effect was enhanced by the downregulation of both MAGOH and MAGOHB [ 22 ]. Barreiro et al revealed that the expression of MAGOH/MAGOHB was upregulated in brain tumors, especially in glioblastoma and that the decreased expression of MAGOH/MAGOHB led to changes in the splicing spectrum [ 23 ]. Similarly, our research group revealed that MAGOH was highly expressed in GC cells, that its knockdown inhibited the occurrence of GC by mediating b-RAF/MEK/ERK signaling and that the double knockdown of MAGOH and MAGOHB exerted better antitumor effects than did the single knockdown of MAGOH and MAGOHB, thus providing a potential new strategy for the treatment of GC [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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MAGOH promotes gastric cancer progression via hnRNPA1 expression inhibition-mediated RONΔ160/PI3K/AKT signaling pathway activation

Yu,

Chen,

Chen

et al. 2024

J Exp Clin Cancer Res

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Background Gastric cancer (GC) is associated with high mortality and heterogeneity and poses a great threat to humans. Gene therapies for the receptor tyrosine kinase RON and its spliceosomes are attracting increasing amounts of attention due to their unique characteristics. However, little is known about the mechanism involved in the formation of the RON mRNA alternative spliceosome RONΔ160. Methods Fourteen human GC tissue samples and six normal gastric tissue samples were subjected to label-free relative quantitative proteomics analysis, and MAGOH was identified as a candidate protein for subsequent studies. The expression of MAGOH in clinical specimens was verified by quantitative real-time PCR and western blotting. We then determined the biological function of MAGOH in GC through in vitro and in vivo experiments. RNA pulldown, RNA sequencing and RNA immunoprecipitation (RIP) were subsequently conducted to uncover the underlying mechanism by which MAGOH regulated the formation of RONΔ160. Results Proteomic analysis revealed that MAGOH, which is located at key nodes and participates in RNA processing and mRNA splicing, was upregulated in GC tissue and GC cell lines and was associated with poor prognosis. Functional analysis showed that MAGOH promoted the proliferation, migration and invasion of GC cells in vitro and in vivo. Mechanistically, MAGOH inhibited the expression of hnRNPA1 and reduced the binding of hnRNPA1 to RON mRNA, thereby promoting the formation of RONΔ160 to activate the PI3K/AKT signaling pathway and consequently facilitating GC progression. Conclusions Our study revealed that MAGOH could promote the formation of RONΔ160 and activate the PI3K/AKT signaling pathway through the inhibition of hnRNPA1 expression. We elucidate a novel mechanism and potential therapeutic targets for the growth and metastasis of GC based on the MAGOH-RONΔ160 axis, and these findings have important guiding significance and clinical value for the future development of effective therapeutic strategies for GC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MAGOH promotes gastric cancer progression via hnRNPA1 expression inhibition-mediated RONΔ160/PI3K/AKT signaling pathway activation

Yu,

Chen,

Chen

et al. 2024

J Exp Clin Cancer Res

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FREDDIE: A comprehensive tool for detecting exonization of retrotransposable elements in short and long RNA sequencing data

Mercuri,

Miller,

dos Santos

et al. 2024

Preprint

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Background: Transposable elements (TEs) constitute a significant portion of mammalian genomes, accounting for about 50% of the total DNA. Intragenic TEs are of particular interest as they are co-transcribed with their host genes in pre-mRNA, potentially leading to the formation of novel chimeric transcripts and the exonization of TEs. The abundance of RNA sequencing data currently available offers a unique opportunity to explore transcriptomic variations. However, a significant limitation is the capability of existing computational tools. Here, we introduce FREDDIE, an innovative algorithm designed to detect the exonization of retrotransposable elements using RNA-seq data. FREDDIE can process short and long RNA sequencing data, assemble and quantify transcripts, evaluate coding potential, and identify protein domains in chimeric transcripts involving exonized TEs and retrocopies. Results: To demonstrate the efficacy of FREDDIE, we analyzed and validated TE exonization in two human cancer cell lines, K562 and U251. We have identified 322 chimeric transcripts, of which 126 were from K562, and 196 were from U251. Among these chimeric transcripts, there were 35 that showed similar exonization patterns and host genes. These transcripts involve protein-coding genes of the host and exonization of LINE-1 (L1), Alu elements, and retrocopies of coding genes. We have selected some candidates and validated them experimentally through RT-PCR. The validation rate for these candidates was 70%, later confirmed by long-read sequencing. Additionally, we applied FREDDIE to analyze TE exonization across 157 glioblastoma samples, identifying 1,010 chimeric transcripts. The majority of these transcripts involved the exonization of Alu elements (69.8%), followed by L1 (20.6%) and retrocopies (9.6%). Notably, we discovered a highly expressed L1 exonization within the ROS gene, resulting in a truncated open reading frame (ORF) with the deletion of two protein domains. Conclusions: FREDDIE is an efficient and user-friendly tool for identifying chimeric transcripts that involve exonization of intragenic TEs. Overall, FREDDIE enables comprehensive investigations into the contributions of TEs to transcriptome evolution, variation, and disease-associated abnormalities, and it operates effectively on standard computing systems. FREDDIE is publicly available: https://github.com/galantelab/freddie.

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Construction and analysis of a prognostic model for osteosarcoma based on lactate metabolism-related genes

Yang,

Kang,

Wen

et al. 2024

Preprint

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Background Lactic acid metabolism plays a significant role in tumor development, potentially resulting in alterations in the immune microenvironment. However, further research is necessary to investigate the link between lactic acid metabolism and osteosarcoma. Methods We obtained sequencing data and clinical information for osteosarcoma RNA from TCGA and GEO databases. Prognosis-related LMRGs were identified using Cox regression, enabling the construction of risk scores for patients. Model predictive ability was assessed using various methods. Drug sensitivity for high and low-risk groups was evaluated using the oncoPredict algorithm, and model genes were validated in a single-cell dataset. Besides, we verified the biological function of NHLRC2 using in vitro assays. Results We identified 256 differential LMRGs, of which 137 were associated with prognosis. After applying Lasso regression, we selected 5 LMRGs for our prognostic risk score model. The log-rank test showed significant survival differences between high-risk and low-risk groups. Multi-factor Cox analysis confirmed the independence of the prognostic risk score as a robust prognostic factor. In vitro experiments confirmed that NHLRC2 could promote the proliferation and invasion of OS. Conclusion We successfully developed and validated an osteosarcoma risk identification score using five LMRGs. Notably, one of these genes holds significant implications for the exploration of potential therapeutic targets in osteosarcoma research.

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The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes

Cited by 3 publications

References 76 publications

MAGOH promotes gastric cancer progression via hnRNPA1 expression inhibition-mediated RONΔ160/PI3K/AKT signaling pathway activation

MAGOH promotes gastric cancer progression via hnRNPA1 expression inhibition-mediated RONΔ160/PI3K/AKT signaling pathway activation

FREDDIE: A comprehensive tool for detecting exonization of retrotransposable elements in short and long RNA sequencing data

Construction and analysis of a prognostic model for osteosarcoma based on lactate metabolism-related genes

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