Regulatory role of lncH19 in RAC1 alternative splicing: implication for RAC1B expression in colorectal cancer.
Humans
Colorectal Neoplasms
/ genetics
Alternative Splicing
RNA, Long Noncoding
/ genetics
rac1 GTP-Binding Protein
/ genetics
RNA Splicing Factors
/ genetics
Gene Expression Regulation, Neoplastic
Cell Line, Tumor
Heterogeneous-Nuclear Ribonucleoprotein Group M
/ metabolism
Repressor Proteins
/ genetics
Alternative splicing
Colorectal cancer
RAC1
RBFOX2
RNA-binding proteins
lncH19
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
05 Aug 2024
05 Aug 2024
Historique:
received:
19
04
2024
accepted:
26
07
2024
medline:
5
8
2024
pubmed:
5
8
2024
entrez:
4
8
2024
Statut:
epublish
Résumé
Aberrant alternative splicing events play a critical role in cancer biology, contributing to tumor invasion, metastasis, epithelial-mesenchymal transition, and drug resistance. Recent studies have shown that alternative splicing is a key feature for transcriptomic variations in colorectal cancer, which ranks third among malignant tumors worldwide in both incidence and mortality. Long non-coding RNAs can modulate this process by acting as trans-regulatory agents, recruiting splicing factors, or driving them to specific targeted genes. LncH19 is a lncRNA dis-regulated in several tumor types and, in colorectal cancer, it plays a critical role in tumor onset, progression, and metastasis. In this paper, we found, that in colorectal cancer cells, the long non-coding RNA H19 can bind immature RNAs and splicing factors as hnRNPM and RBFOX2. Through bioinformatic analysis, we identified 57 transcripts associated with lncH19 and containing binding sites for both splicing factors, hnRNPM, and RBFOX2. Among these transcripts, we identified the mRNA of the GTPase-RAC1, whose alternatively spliced isoform, RAC1B, has been ascribed several roles in the malignant transformation. We confirmed, in vitro, the binding of the splicing factors to both the transcripts RAC1 and lncH19. Loss and gain of expression experiments in two colorectal cancer cell lines (SW620 and HCT116) demonstrated that lncH19 is required for RAC1B expression and, through RAC1B, it induces c-Myc and Cyclin-D increase. In vivo, investigation from biopsies of colorectal cancer patients showed higher levels of all the explored genes (lncH19, RAC1B, c-Myc and Cyclin-D) concerning the healthy counterpart, thus supporting our in vitro model. In addition, we identified a positive correlation between lncH19 and RAC1B in colorectal cancer patients. Finally, we demonstrated that lncH19, as a shuttle, drives the splicing factors RBFOX2 and hnRNPM to RAC1 allowing exon retention and RAC1B expression. The data shown in this paper represent the first evidence of a new mechanism of action by which lncH19 carries out its functions as an oncogene by prompting colorectal cancer through the modulation of alternative splicing.
Identifiants
pubmed: 39098911
doi: 10.1186/s13046-024-03139-z
pii: 10.1186/s13046-024-03139-z
doi:
Substances chimiques
RNA, Long Noncoding
0
rac1 GTP-Binding Protein
EC 3.6.5.2
RNA Splicing Factors
0
RAC1 protein, human
0
Heterogeneous-Nuclear Ribonucleoprotein Group M
0
RBFOX2 protein, human
0
HNRNPM protein, human
0
Repressor Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
217Subventions
Organisme : Fondazione AIRC
ID : 19982
Informations de copyright
© 2024. The Author(s).
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