title: Integrin α3β1 controls mRNA splicing that determines Cox-2 mRNA stability in breast cancer cells.
abstract: It is unknown how cues from the tumor microenvironment can regulate post-transcriptional mechanisms, such as alternative splicing, that control genes that drive malignant growth. The induction of cyclooxygenase 2 (Cox-2) by integrin α3β1 in breast cancer cells can promote tumor progression. We have used RNAi to suppress α3β1 in human MDA-MB-231 breast cancer cells and then investigated changes in global gene expression. Numerous mRNAs, including Cox-2, show altered expression and/or alternative exon usage (AEU) in α3β1-deficient cells. AEU included patterns predicted to render an mRNA susceptible to degradation, such as 3'-UTR variations or retention of elements that target an mRNA for nonsense-mediated decay (NMD). PCR-based analysis of α3β1-deficient cells confirmed changes in Cox-2 mRNA that might target it for NMD, including retention of an intron that harbors premature termination codons and changes within the 3'-UTR. Moreover, Cox-2 mRNA has reduced stability in α3β1-deficient cells, which is partially reversed by knockdown of the essential NMD factor UPF1. Our study identifies α3β1-mediated AEU as a novel paradigm of integrin-dependent gene regulation that has potential for exploitation as a therapeutic target.
authors.affiliation: Center for Cell Biology and Cancer Research, Albany Medical College, MC-165, 47 New Scotland Avenue, Albany, NY 12208, USA.
authors.forename: Sita
authors.initials: S
authors.lastname: Subbaram
authors.forename: Scott P
authors.initials: SP
authors.lastname: Lyons
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Svenson
authors.forename: Sean L
authors.initials: SL
authors.lastname: Hammond
authors.forename: Lorena G
authors.initials: LG
authors.lastname: McCabe
authors.forename: Sridar V
authors.initials: SV
authors.lastname: Chittur
authors.forename: C Michael
authors.initials: CM
authors.lastname: DiPersio
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039201:Integrin alpha3beta1 / Q000502:physiology*; D007438:Introns; D007797:Laminin / Q000378:metabolism; D008969:Molecular Sequence Data; D059365:Nonsense Mediated mRNA Decay; D011485:Protein Binding; D020365:RNA Helicases; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D039201:Integrin alpha3beta1; D007797:Laminin; D012333:RNA, Messenger; D015534:Trans-Activators; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020365:RNA Helicases; C101828:UPF1 protein, human
keywords: Alternative splicing; Breast cancer; Cox-2; Nonsense-mediated mRNA decay; α3β1 integrin