A new regulatory loop in cancer-cell invasion.

A new regulatory loop in cancer-cell invasion the epithelial-to-mesenchymal transition (EMt) converts epithelial cells into mesenchymal cells that are able to invade and migrate. in the context of cancer pathogenesis, the EMt contributes to meta-static progression (thiery, 2002; acloque et al, 2008). one of the characteristics of EMt is the functional loss of E-cadherin, which is crucial for the progression to invasive carcinoma (perl et al, 1998). transcriptional repression has emerged as a fundamental mechanism for E-cadherin loss during EMt and several repressors have been characterized. these include zinc-finger E-box-binding homeo-box 1 (zEB1), zEB2/Sip1, Snail1, Snail2 and twist, which strongly repress E-cadherin transcription through their direct binding to the E-box motifs within the E-cadherin promoter (Barrallo-gimeno & nieto, 2005; peinado et al, 2007). During the past decade, it has emerged that micrornas (mirnas) are a fundamental mechanism of gene-expression regulation, and several recent reports have shown that these small molecules are involved in the control of E-cadherin expression in cancer cells and tumours (Hurteau et al, 2007; christoffersen et al, 2007; gregory et al, 2008; park et al, 2008). Furthermore, in this issue of EMBO reports, Burk and colleagues have provided a beautiful example of gene regulation in which mirnas and transcription factors are linked to one another in a gene-regulatory network to control E-cadherin expression and the invasive phenotype in cancer cells (Burk et al, 2008). Mirnas regulate gene expression through binding to mrna target sequences typically in their 3' untranslated regulatory regions (utrs), which results in the degradation of target mrnas and/or the inhibition of the translation process (Filipowicz et al, 2008). Several mirnas are deregulated or mutated in many human cancers, including lung, breast, brain, liver and colon cancers, making them attractive targets in biomedical research and anti-tumour therapies Mirnas can function as tumour promoters or as tumour suppressors. For example, mir-10b, mir-373 and mir-520c are highly expressed in metastatic breast cancer cells in which they positively regulate cell migration, invasion and metastatic properties (Ma et al, 2007; Huang et al, 2008). Similarly, mir-21 is increased in breast and colon carcinomas and is upregulated during the transforming growth factor-β (tgFβ)-induced EMt in cancer-derived cell lines (zavadil et al, 2007). conversely, tavazoie and colleagues showed that mir-126, mir-206 and mir-335 suppress breast cancer metastasis (tavazoie et al, 2007), and they were able to confirm clinical relevance for mir-126 and mir-335. Similarly, let-7 is a marker for differentiated cancers …