title: Pro-metastatic splicing of Ron proto-oncogene mRNA can be reversed: therapeutic potential of bifunctional oligonucleotides and indole derivatives.
abstract: Alternative splicing is a key molecular mechanism for increasing the complexity of the human transcriptome. Nearly all human genes are regulated by alternative splicing and the deregulation of this process has a causative role in various human diseases, including cancer. The discovery that alternatively spliced isoforms of several genes are expressed selectively in tumor cells opened the exciting possibility that pharmacological treatment of aberrant splicing could lead to new anti-cancer therapeutic approaches. An alternatively spliced isoform of a scatter factor receptor and proto-oncogene, Ron, accumulates during tumor progression of epithelial tissues and is able to confer an invasive phenotype to the expressing cells. This isoform, called ΔRon, originates from skipping of exon 11, and this specific splicing event is controlled by the expression level of the splicing factor and proto-oncogene SF2/ASF. Over-expression of SF2/ASF, which occurs frequently in various human tumors, induces the production of ΔRon and activates the epithelial to mesenchymal transition (EMT), leading to increased cell motility. In this paper, we have used targeted oligonucleotide enhancers of splicing (TOES) to recruit positive splicing factors to Ron exon 11 and thereby stimulate its inclusion. As an alternative approach, we have used selected indole derivatives that target ASF/SF2 splicing activity. Both treatments correct aberrant ΔRon splicing, restoring the incorporation of Ron exon 11. Notably, indole derivatives are also able to affect the invasive phenotype of the cells. Thus, these treatments may have therapeutic applications for anti-cancer purposes.
authors.affiliation: Istituto di Genetica Molecolare-Consiglio Nazionale delle Ricerche (IGM-CNR), Pavia, Italy. arneri@igm.cnr.it
authors.forename: Claudia
authors.initials: C
authors.lastname: Ghigna
authors.forename: Marion
authors.initials: M
authors.lastname: De Toledo
authors.forename: Serena
authors.initials: S
authors.lastname: Bonomi
authors.forename: Cristina
authors.initials: C
authors.lastname: Valacca
authors.forename: Stefania
authors.initials: S
authors.lastname: Gallo
authors.forename: Maria
authors.initials: M
authors.lastname: Apicella
authors.forename: Ian
authors.initials: I
authors.lastname: Eperon
authors.forename: Jamal
authors.initials: J
authors.lastname: Tazi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Biamonti
mesh_terms: D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000628:therapy*; D009841:Oligonucleotides / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D012326:RNA Splicing / Q000187:drug effects*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: D007211:Indoles; C000715470:MAS1 protein, human; D009841:Oligonucleotides; D000090063:Proto-Oncogene Mas; C030374:indole; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases