Abstract
The MICAL (Molecules Interacting with CasL) proteins catalyze actin oxidation-reduction reactions destabilizing F-actin in cytoskeletal dynamics. Here we show for the first time that MICAL2 mRNA is significantly over-expressed in aggressive, poorly differentiated/undifferentiated, primary human epithelial cancers (gastric and renal). Immunohistochemistry showed MICAL2-positive cells on the cancer invasive front and in metastasizing cancer cells inside emboli, but not at sites of metastasis, suggesting MICAL2 expression was 'on' in a subpopulation of primary cancer cells seemingly detaching from the tissue of origin, enter emboli and travel to distant sites, and was turned 'off' upon homing at metastatic sites. In vitro, MICAL2 knock-down resulted in mesenchymal to epithelial transition, reduction of viability, and loss of motility and invasion properties of human cancer cells. Moreover, expression of MICAL2 cDNA in MICAL2-depleted cells induced epithelial to mesenchymal transition. Altogether our data indicate that MICAL2 over-expression is associated with cancer progression and metastatic disease. MICAL2 might be an important regulator of epithelial to mesenchymal transition and therefore a promising target for anti-metastatic therapy.
Highlights
The cure of most cancers will depend on the capability to eradicate disseminated secondary tumors that do not respond to therapy
To search for novel genes involved in metastasis, we investigated the possible role of MICAL2 in cancer
Interrogating web-based, expression databases we found MICAL2 mRNA variably and almost ubiquitously expressed in normal tissues, including stomach, lung and kidney (UniGene: http://www.ncbi.nlm.nih.gov/ UniGene/ESTProfileViewer.cgi?uglist = Hs.501928), with noticeable expression variations in several types of human cancer (IST Online: http://ist.medisapiens. com/#ENSG00000133816), together with several outliers, in lung and gastric cancer (GC), indicating possible patient subpopulations within each cancer type
Summary
The cure of most cancers will depend on the capability to eradicate disseminated secondary tumors that do not respond to therapy. We reasoned that the striking capability of MICAL to directly and mechanistically connect oxygen availability with F-actin depolimerization and cytoskeleton dynamics might be extremely important for metastatic cancer cells whose motility is increased as part of epithelial to mesenchymal transition (EMT). Lead by a regulated genetic/epigenetic program, epithelial cells loose epithelial markers, cell-cell and cell-extracellular matrix (ECM) interactions, undergo cytoskeleton reorganization, gain gene expression profile, morphological and functional characteristics of mesenchymal cells, and leave the primary tumor site [10]. Both EMT and its opposite, mesenchymal to epithelial transition (MET), are implicated in developmental and pathological contexts [10]. During MET, mesenchymal markers are downregulated, cell motility decreases and cells adopt epithelial characteristics [10]
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