Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California San Francisco (UCSF), San Francisco, California, USA.
Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston-Medical School, Houston, Texas, USA.
Nat Med. 2014 Apr;20(4):360-7. doi: 10.1038/nm.3497. Epub 2014 Mar 16.
Tissue mechanics regulate development and homeostasis and are consistently modified in tumor progression. Nevertheless, the fundamental molecular mechanisms through which altered mechanics regulate tissue behavior and the clinical relevance of these changes remain unclear. We demonstrate that increased matrix stiffness modulates microRNA expression to drive tumor progression through integrin activation of β-catenin and MYC. Specifically, in human and mouse tissue, increased matrix stiffness induced miR-18a to reduce levels of the tumor suppressor phosphatase and tensin homolog (PTEN), both directly and indirectly by decreasing levels of homeobox A9 (HOXA9). Clinically, extracellular matrix stiffness correlated directly and significantly with miR-18a expression in human breast tumor biopsies. miR-18a expression was highest in basal-like breast cancers in which PTEN and HOXA9 levels were lowest, and high miR-18a expression predicted poor prognosis in patients with luminal breast cancers. 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.
组织力学调节发育和内稳态，并在肿瘤进展中持续改变。然而，改变力学调节组织行为的基本分子机制以及这些变化的临床相关性仍不清楚。我们证明，基质硬度的增加通过整合素激活β-catenin 和 MYC 来调节 microRNA 的表达，从而推动肿瘤进展。具体而言，在人和小鼠组织中，增加的基质硬度诱导 miR-18a 减少肿瘤抑制因子磷酸酶和张力蛋白同源物 (PTEN) 的水平，直接和间接通过降低同源盒 A9 (HOXA9) 的水平。临床上，细胞外基质硬度与人类乳腺癌活检中的 miR-18a 表达呈直接显著相关。miR-18a 在基底样乳腺癌中的表达最高，而在这些肿瘤中 PTEN 和 HOXA9 的水平最低，并且高 miR-18a 表达预示着 luminal 型乳腺癌患者的预后不良。我们的发现确定了一个机械调节的 microRNA 回路，它可以促进恶性肿瘤，并提示 HOXA9 和 miR-18a 水平在分层 luminal 型乳腺癌患者方面具有潜在的预后作用。
