Alternative Splicing (AS) of precursor messenger RNA (pre-mRNA) is a process by which introns are excised from pre-mRNA and exons are joined together to generate different mature mRNA splicing variants prior to translation. This process is a crucial step in eukaryotic gene expression, which increases the coding potential of a genome. Moreover, AS allows a single gene to generate various distinct mRNA isoforms to subsequently code for numerous proteins that contribute to proteome diversification. This vital process can explain why there are more than 100,000 annotated human transcripts (transcriptome) and around 500,000 distinct human proteins (proteome) encoded by only around 20,000-25,000 human genes (genome). Intriguingly, many such splicing variants are expressed at a specific developmental stage, in a specific tissue or cell type, or even in a disease-specific manner. In addition, splicing is executed by the molecular complex known as the spliceosome, which consists of five uridine-rich small nuclear RNAs (snRNAs) - U1, U2, U4, U5, and U6 (RNU1, RNU2, RNU4, RNU5, and RNU6) and aided by more than 150 associated proteins known as Serine and arginine-rich (SR) proteins, forming small nuclear ribonucleoproteins (snRNPs) and additional non-snRNP-associated proteins (such as SF1, U2AF, and the Prp19 complex (NTC) to remove introns from a transcribed pre-mRNA. Nonetheless, spliceosome assembly is a complicated procedure not yet fully understood, which involves RNA–RNA, RNA–protein, and protein-protein interactions to excise introns from precursor mRNA and join the flanking exons back together to create mature mRNA splicing variants. It is speculated that 90-95% of human multi-exonic genes are alternatively spliced based on high throughput sequencing and any dysregulation/misregulation of AS, either due to mis-splicing of a single gene affecting the exon inclusion/exclusion or mis-regulation of the whole spliceosome complex, such as mutations in splicing factors may lead to the disruption of normal cellular function which has been reported to be associated with various human diseases, carcinogenesis, and tumor progression.
Many cancer-associated genes, in every hallmark of cancer, are regulated through alternative splicing to generate splicing variants to function as proto-oncogenes, tumor suppressors, or even splicing variants that are needed for the transformation process. Although the molecular function of the various cancer splicing variants is not fully understood or even interpretable, the proper approach to unravel these splicing aberrations and their impact on cancer seems to be of paramount importance. Thus, identifying splice variants differentially expressed in human cancer compared to matched healthy tissues represent promising diagnostic markers with therapeutic potential.
This Research Topic aims to publish research articles identifying the cancer-specific splicing variants and/or aberrations in the core components of the spliceosome and elucidate their molecular mechanisms during the tumorigenesis and metastasis of different cancer types. Considering that the majority of the current cancer drugs target the constitutive or longer gene isoform instead of a specific splicing variant, therapeutic targeting of mis-splicing or those specific splicing variants during tumorigenesis genetically or pharmacologically would offer new horizons for the cancer therapies and treatment.
Alternative Splicing (AS) of precursor messenger RNA (pre-mRNA) is a process by which introns are excised from pre-mRNA and exons are joined together to generate different mature mRNA splicing variants prior to translation. This process is a crucial step in eukaryotic gene expression, which increases the coding potential of a genome. Moreover, AS allows a single gene to generate various distinct mRNA isoforms to subsequently code for numerous proteins that contribute to proteome diversification. This vital process can explain why there are more than 100,000 annotated human transcripts (transcriptome) and around 500,000 distinct human proteins (proteome) encoded by only around 20,000-25,000 human genes (genome). Intriguingly, many such splicing variants are expressed at a specific developmental stage, in a specific tissue or cell type, or even in a disease-specific manner. In addition, splicing is executed by the molecular complex known as the spliceosome, which consists of five uridine-rich small nuclear RNAs (snRNAs) - U1, U2, U4, U5, and U6 (RNU1, RNU2, RNU4, RNU5, and RNU6) and aided by more than 150 associated proteins known as Serine and arginine-rich (SR) proteins, forming small nuclear ribonucleoproteins (snRNPs) and additional non-snRNP-associated proteins (such as SF1, U2AF, and the Prp19 complex (NTC) to remove introns from a transcribed pre-mRNA. Nonetheless, spliceosome assembly is a complicated procedure not yet fully understood, which involves RNA–RNA, RNA–protein, and protein-protein interactions to excise introns from precursor mRNA and join the flanking exons back together to create mature mRNA splicing variants. It is speculated that 90-95% of human multi-exonic genes are alternatively spliced based on high throughput sequencing and any dysregulation/misregulation of AS, either due to mis-splicing of a single gene affecting the exon inclusion/exclusion or mis-regulation of the whole spliceosome complex, such as mutations in splicing factors may lead to the disruption of normal cellular function which has been reported to be associated with various human diseases, carcinogenesis, and tumor progression.
Many cancer-associated genes, in every hallmark of cancer, are regulated through alternative splicing to generate splicing variants to function as proto-oncogenes, tumor suppressors, or even splicing variants that are needed for the transformation process. Although the molecular function of the various cancer splicing variants is not fully understood or even interpretable, the proper approach to unravel these splicing aberrations and their impact on cancer seems to be of paramount importance. Thus, identifying splice variants differentially expressed in human cancer compared to matched healthy tissues represent promising diagnostic markers with therapeutic potential.
This Research Topic aims to publish research articles identifying the cancer-specific splicing variants and/or aberrations in the core components of the spliceosome and elucidate their molecular mechanisms during the tumorigenesis and metastasis of different cancer types. Considering that the majority of the current cancer drugs target the constitutive or longer gene isoform instead of a specific splicing variant, therapeutic targeting of mis-splicing or those specific splicing variants during tumorigenesis genetically or pharmacologically would offer new horizons for the cancer therapies and treatment.
