Integrin ?3?1 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 ?3?1 in breast cancer cells can promote tumor progression. We have used RNAi to suppress ?3?1 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 ?3?1-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 ?3?1-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 ?3?1-deficient cells, which is partially reversed by knockdown of the essential NMD factor UPF1. Our study identifies ?3?1-mediated AEU as a novel paradigm of integrin-dependent gene regulation that has potential for exploitation as a therapeutic target.

SUBMITTER: Subbaram S 

PROVIDER: S-EPMC3953813 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature