title: Iro/IRX transcription factors negatively regulate Dpp/TGF-β pathway activity during intestinal tumorigenesis.
abstract: Activating mutations in Wnt and EGFR/Ras signaling pathways are common in colorectal cancer (CRC). Remarkably, clonal co-activation of these pathways in the adult Drosophila midgut induces "tumor-like" overgrowths. Here, we show that, in these clones and in CRC cell lines, Dpp/TGF-β acts as a tumor suppressor. Moreover, we discover that the Iroquois/IRX-family-protein Mirror downregulates the transcription of core components of the Dpp pathway, reducing its tumor suppressor activity. We also show that this genetic interaction is conserved in human CRC cells, where the Iro/IRX proteins IRX3 and IRX5 diminish the response to TGF-β. IRX3 and IRX5 are upregulated in human adenomas, and their levels correlate inversely with the gene expression signature of response to TGF-β. In addition, Irx5 expression confers a growth advantage in the presence of TGF-β, but is selected against in its absence. Together, our results identify a set of Iro/IRX proteins as conserved negative regulators of Dpp/TGF-β activity. We propose that during the characteristic adenoma-to-carcinoma transition of human CRC, the activity of IRX proteins could reduce the sensitivity to the cytostatic effect of TGF-β, conferring a growth advantage to tumor cells prior to the acquisition of mutations in TGF-β pathway components.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Barcelona, Spain.
authors.forename: Òscar
authors.initials: Ò
authors.lastname: Martorell
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Barriga
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Merlos-Suárez
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Camille
authors.initials: C
authors.lastname: Stephan-Otto Attolini
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Casanova
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Batlle
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Sancho
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain andreu.casali@irbbarcelona.org.
authors.forename: Andreu
authors.initials: A
authors.lastname: Casali
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D029721:Drosophila Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; C501598:IRX3 protein, human; C501600:IRX5 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C064196:dpp protein, Drosophila; C105790:mirr protein, Drosophila
keywords: Dpp; EGFR/Ras; TGF‐β; Wnt