The role of proteases in epithelial-to-mesenchymal cell transitions in cancer.

Changing the characteristics of cells from epithelial states to mesenchymal properties is a key process involved in developmental and physiological processes as well as in many diseases with cancer as the most prominent example. Nowadays, a great deal of work and literature concerns the understanding of the process of epithelial-to-mesenchymal transition (EMT) in terms of its molecular regulation and its implications for cancer. Similar statements can certainly be made regarding the investigation of the more than 500 proteases typically encoded by a mammalian genome. Specifically, the impact of proteases on tumor biology has been a long-standing topic of interest. However, although EMT actively regulates expression of many proteases and proteolytic enzymes are clearly involved in survival, division, differentiation, and movements of cells, information on the diverse roles of proteases in EMT has been rarely compiled. Here we aim to conceptually connect the scientific areas of "EMT" and "protease" research by describing how several important classes of proteolytic enzymes are regulated by EMT and how they are involved in initiation and execution of the EMT program. To do so, we briefly introduce the evolving key features of EMT and its regulation followed by discussion of protease involvement in this process.

Revisiting the miR-200 Family: A Clan of Five Siblings with Essential Roles in Development and Disease.

Over two decades of studies on small noncoding RNA molecules illustrate the significance of microRNAs (miRNAs/miRs) in controlling multiple physiological and pathological functions through post-transcriptional and spatiotemporal gene expression. Among the plethora of miRs that are essential during animal embryonic development, in this review, we elaborate the indispensable role of the miR-200 family (comprising miR-200a, -200b, 200c, -141, and -429) in governing the cellular functions associated with epithelial homeostasis, such as epithelial differentiation and neurogenesis. Additionally, in pathological contexts, miR-200 family members are primarily involved in tumor-suppressive roles, including the reversal of the cancer-associated epithelial-mesenchymal transition dedifferentiation process, and are dysregulated during organ fibrosis. Moreover, recent eminent studies have elucidated the crucial roles of miR-200s in the pathophysiology of multiple neurodegenerative diseases and tissue fibrosis. Lastly, we summarize the key studies that have recognized the potential use of miR-200 members as biomarkers for the diagnosis and prognosis of cancers, elaborating the application of these small biomolecules in aiding early cancer detection and intervention.

MicroRNAs coordinately regulate protein complexes.

BACKGROUND: In animals, microRNAs (miRNAs) regulate the protein synthesis of their target messenger RNAs (mRNAs) by either translational repression or deadenylation. miRNAs are frequently found to be co-expressed in different tissues and cell types, while some form polycistronic clusters on genomes. Interactions between targets of co-expressed miRNAs (including miRNA clusters) have not yet been systematically investigated. RESULTS: Here we integrated information from predicted and experimentally verified miRNA targets to characterize protein complex networks regulated by human miRNAs. We found striking evidence that individual miRNAs or co-expressed miRNAs frequently target several components of protein complexes. We experimentally verified that the miR-141-200c cluster targets different components of the CtBP/ZEB complex, suggesting a potential orchestrated regulation in epithelial to mesenchymal transition. CONCLUSIONS: Our findings indicate a coordinate posttranscriptional regulation of protein complexes by miRNAs. These provide a sound basis for designing experiments to study miRNA function at a systems level.

The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs.

Invasion and metastasis of carcinomas is promoted by the activation of the embryonic 'epithelial to mesenchymal transition' (EMT) program, which triggers cellular mobility and subsequent dissemination of tumour cells. We recently showed that the EMT-activator ZEB1 (zinc finger E-box binding homeobox 1) is a crucial promoter of metastasis and demonstrated that ZEB1 inhibits expression of the microRNA-200 (miR-200) family, whose members are strong inducers of epithelial differentiation. Here, we report that ZEB1 not only promotes tumour cell dissemination, but is also necessary for the tumour-initiating capacity of pancreatic and colorectal cancer cells. We show that ZEB1 represses expression of stemness-inhibiting miR-203 and that candidate targets of miR-200 family members are also stem cell factors, such as Sox2 and Klf4. Moreover, miR-200c, miR-203 and miR-183 cooperate to suppress expression of stem cell factors in cancer cells and mouse embryonic stem (ES) cells, as demonstrated for the polycomb repressor Bmi1. We propose that ZEB1 links EMT-activation and stemness-maintenance by suppressing stemness-inhibiting microRNAs (miRNAs) and thereby is a promoter of mobile, migrating cancer stem cells. Thus, targeting the ZEB1-miR-200 feedback loop might form the basis of a promising treatment for fatal tumours, such as pancreatic cancer.