title: HnRNP A1 controls a splicing regulatory circuit promoting mesenchymal-to-epithelial transition.
abstract: Epithelial-to-mesenchymal transition (EMT) is an embryonic program used by cancer cells to acquire invasive capabilities becoming metastatic. ΔRon, a constitutively active isoform of the Ron tyrosine kinase receptor, arises from skipping of Ron exon 11 and provided the first example of an alternative splicing variant causatively linked to the activation of tumor EMT. Splicing of exon 11 is controlled by two adjacent regulatory elements, a silencer and an enhancer of splicing located in exon 12. The alternative splicing factor and oncoprotein SRSF1 directly binds to the enhancer, induces the production of ΔRon and activates EMT leading to cell locomotion. Interestingly, we now find an important role for hnRNP A1 in controlling the activity of the Ron silencer. HnRNP A1 is able to antagonize the binding of SRSF1 and prevent exon skipping. Notably, hnRNP A1, by inhibiting the production of ΔRon, activates the reversal program, namely the mesenchymal-to-epithelial transition, which instead occurs at the final metastasis sites. Also, hnRNP A1 affects Ron splicing by regulating the expression level of hnRNP A2/B1, which similarly to SRSF1 can promote ΔRon production. These results shed light on how splicing regulation contributes to the tumor progression and provide potential targets to develop anticancer therapies.
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), 27100 Pavia, Italy, International Centre for Genetic Engineering and Biotechnology, 34012 Trieste, Italy and Division of Regenerative Medicine, Stem Cells, and Gene Therapy, Dulbecco Telethon Institute at San Raffaele Scientiﬁc Institute, 20132 Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Bonomi
authors.forename: Anna
authors.initials: A
authors.lastname: di Matteo
authors.forename: Emanuele
authors.initials: E
authors.lastname: Buratti
authors.forename: Daphne S
authors.initials: DS
authors.lastname: Cabianca
authors.forename: Francisco E
authors.initials: FE
authors.lastname: Baralle
authors.forename: Claudia
authors.initials: C
authors.lastname: Ghigna
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Biamonti
mesh_terms: D017398:Alternative Splicing; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005091:Exons; D057809:HEK293 Cells; D006367:HeLa Cells; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D059365:Nonsense Mediated mRNA Decay; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D038621:Regulatory Sequences, Ribonucleic Acid
chemical_list: D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D038621:Regulatory Sequences, Ribonucleic Acid; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases