Concomitant suppression of three target genes can explain the impact of a microRNA on metastasis

Abstract

It remains unclear whether a microRNA (miRNA) affects a given phenotype via concomitant down-regulation of its entire repertoire of targets or instead by suppression of only a modest subset of effectors. We demonstrate that inhibition of breast cancer metastasis by miR-31-a miRNA predicted to modulate >200 mRNAs-can be entirely explained by miR-31's pleiotropic regulation of three targets. Thus, concurrent re-expression of integrina5, radixin, and RhoA abrogates miR-31-imposed metastasis suppression. These effectors influence distinct steps of the metastatic process. Our findings have implications concerning the importance of pleiotropy for the biological actions of miRNAs and provide mechanistic insights into metastasis.Supplemental material is available at http://www.genesdev.org.Received June 15, 2009; revised version accepted September 24, 2009. MicroRNAs (miRNAs) are an evolutionarily conserved family of regulatory RNAs that inhibit their mRNA targets post-transcriptionally, leading to modulation of diverse biological processes, including the development and progression of cancer (Ambros 2004;Bartel 2009;Ventura and Jacks 2009). An individual miRNA is capable of regulating dozens of distinct mRNAs (Baek et al. 2008;Selbach et al. 2008), and it is thought that pleiotropic suppression of multiple downstream effectors may underlie the phenotypic changes observed upon perturbing the levels of certain miRNAs (Rodriguez et al. 2007;Thai et al. 2007;van Rooij et al. 2007;Zhao et al. 2007;Johnnidis et al. 2008;Ventura et al. 2008). It remains unclear, however, whether these consequences depend on simultaneous deregulation of the entire repertoire of targets of a given miRNA or instead on the altered activity of only a small subset of effectors.Metastases, which are responsible for 90% of human cancer deaths, arise via a complex series of events, collectively termed the invasion-metastasis cascade (Fidler 2003;Gupta and Massagué 2006). In order to metastasize, cells in a primary tumor must become motile, degrade surrounding extracellular matrix (local invasion), intravasate into the vasculature, retain viability during transit through the circulation, extravasate into the parenchyma of a distant tissue, survive in this foreign microenvironment to form micrometastases, and, finally, thrive in their new milieu and establish macroscopic secondary tumors (colonization) (Fidler 2003). Colonization is the rate-limiting step of the invasion-metastasis cascade, yet the molecular underpinnings of this process are poorly understood (Gupta and Massagué 2006).We determined recently that expression of the miRNA miR-31 was both necessary and sufficient to inhibit the metastasis of human breast cancer xenografts, and that miR-31 levels correlated inversely with metastatic relapse in breast carcinoma patients ). We attributed these effects to miR-31's ability to pleiotropically suppress a cohort of prometastatic targets; however, we did not identify a minimal set of downstream effectors whose concomitant re-expression is suffic...

Roles for microRNAs in the regulation of cell adhesion molecules

“…For example, miR-31 (Valastyan et al, 2009a;Valastyan et al, 2009b), miR-133 (Cáre et al, 2007 and miR-155 (Kong et al, 2008) suppress the expression levels of RhoA in various different tissue types. Similarly, RhoC is a direct downstream effector of miR-138 (Jiang et al, 2010), as well as an indirect downstream target of miR-10b (Ma et al, 2007).…”

“…Certain miRNAs have been found to regulate the expression levels of specific integrins. For example, miR-31 (Valastyan et al, 2009a;Valastyan et al, 2009b) and miR-92a (Bonauer et al, 2009) can bind the 3Ј UTR of the mRNA encoding integrin 5, thereby mediating its suppression. Furthermore, integrin 3 can be targeted by the let-7a (Müller and Bosserhoff, 2008) and miR-30 miRNAs.…”

MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1

“…The miRNAs can regulate a wide range of cellular functions including proliferation, apoptosis, differentiation and development 1,2 . Some miRNAs exert only minor effects on target gene repression, however, increasing evidence suggests that miRNAs can confer robustness of biological processes via regulation of target networks 3,4 . For example, miR-126 impacts endothelial recruitment by modulating the IGF1/IGF1R and GAS6/MERK pathways 5 .…”

The Function of miR-31 Expression in Differentiation of Neural Stem Cells

“…So, miR-31 may be play an important role in maintaining NSCs in an undifferentiated state. [10] and so on; and down-regulated at breast cancer (Valastyan S et al, 2009) [11], prostatic cancer (Schaefer A et al, 2010) [12], gastric cancer (Guo J et al, 2009;Zhang Y et al, 2009) [13] [14]. Although there are a lot of research about miR-31, most of them are from the study of the process of disease.…”