Extracellular Matrix Stiffness Promotes Malignant Progression Via PTEN-Reducing Effect of Micro-RNA

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Tissue mechanics are altered in tumor progression, although many of the mechanisms underlying the changes remain unclear. In a study reported in Nature Medicine, Mouw and colleagues found that increased tissue extracellular matrix stiffness modulated microRNA expression to promote tumor progression via integrin activation of beta-catenin and MYC. In human and mouse tissue, increased matrix stiffness was shown to induce increased expression of miR-18a; this resulted in a decrease in levels of the tumor suppressor PTEN both as a direct effect and as an indirect effect mediated by a reduction in homeobox A9 (HOXA9) levels.

In human breast tumor tissue, extracellular matrix stiffness was significantly correlated with miR-18a expression, with expression being highest in basal-like breast tumors with the lowest levels of PTEN and HOXA9. High levels of miR-18a expression were predictive of poor prognosis in patients with luminal breast cancers.

The instigators concluded, “Our findings identify a mechanically regulated microRNA circuit that can promote malignancy and suggest potential prognostic roles for HOXA9 and miR-18a levels in stratifying patients with luminal breast cancers.” ■

Mouw JK, et al: Nature Med 20:360-367, 2014.




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