miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis

Abstract

MicroRNAs (miRNAs) are increasingly implicated in regulating the malignant progression of cancer. Here we show that miR-9, the level of which is upregulated in breast cancer cells, directly targets CDH1, the E-cadherin-encoding mRNA, leading to increased cell motility and invasiveness. miR-9-mediated E-cadherin downregulation results in the activation of β-catenin signaling, which contributes to upregulated expression of the gene encoding vascular endothelial growth factor (VEGF); this leads, in turn, to increased tumor angiogenesis. Overexpression of miR-9 in otherwise-non-metastatic breast tumor cells enables these cells to form pulmonary micrometastases in mice. Conversely, inhibiting miR-9 using a ‘miRNA sponge’ in highly malignant cells inhibits metastasis formation. Expression of miR-9 is activated by MYC and MYCN, both of which directly bind to the mir-9-3 locus. Significantly, in human cancers, miR-9 levels correlate with MYCN amplification, tumor grade, and metastatic status. These findings uncover a regulatory and signaling pathway involving a metastasis-promoting miRNA that is predicted to directly target expression of the key metastasis-suppressing protein E-cadherin.

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

“…miR‐9 can inhibit cell proliferation and migration in the context of cancer (Selcuklu et al ., 2012; Yu et al ., 2013), although its effects can be both cell type and context dependent (Ma et al ., 2010). miR‐9 may also have a role during aging.…”

“…The regulation of CXCR4 by miR‐9 has also been invoked to explain the effect of miR‐9 on cell growth (Yu et al ., 2013). In addition, miR‐9 can regulate NF‐KB1 , affecting cell migration (Liu et al ., 2012), and E–cadherin (Ma et al ., 2010), explaining its role in regulating metastatic growth. It would clearly be interesting to determine how the regulatory module involving CBX7 and miR‐9 contributes to these physiological processes and whether it influences aging.…”

“…Besides its role in the brain, miR‐9 also influences normal physiology and tumour development in other tissues. For example, miR‐9 is highly expressed in primary breast cancers, where it promotes angiogenesis and metastasis (Ma et al ., 2010). In contrast, downregulation of miR‐9 has been reported in other cancer types, such as leukaemias (Emmrich et al ., 2014), suggesting cell‐ and tumour‐specific effects that might be explained by different expression levels of its targets.…”

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

“…Among other c-myc-induced miRNAs are miR-221 and miR-222, which target proteins involved in cell cycle arrest [128], and miR-9, which suppresses E-cadherin expression and promotes metastasis. MiR-9 has also been found to sensitize cells to EMT-inducing signals arising from the TME [129]. Overall, the c-myc-induced miRNA network is reported to be directly related to tumor aggressiveness in various types of cancers [130].…”

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…The function of miRNAs may be deregulated in cancer in several manners, including miRNA gene mutation, deletion or promoter hypermethylation, but also as a consequence of mutations in their target sequences (Esquela‐Kerscher and Slack, 2006; Nana‐Sinkam and Croce, 2011; Palmero et al., 2011). Although attenuated expression of the miRNA transcriptome is frequently observed (Kumar et al., 2007; Lu et al., 2005), various miRNAs are overexpressed in specific tumors compared to their healthy tissue of origin (Ma et al., 2010a,b; Volinia et al., 2006), and thus are termed “oncomiRs”. Furthermore, the predicted targets for several cancer‐associated miRNAs include protein‐coding tumor suppressors and oncogenes, supporting a role for miRNAs in cancer pathogenesis (Esquela‐Kerscher and Slack, 2006; Nana‐Sinkam and Croce, 2011; Palmero et al., 2011).…”