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  • br Introduction br Colorectal cancer CRC is the third most


    1. Introduction
    Colorectal cancer (CRC) is the third most frequent malignant cause of cancer-related death worldwide. The incidence and mortality rates are closely correlated with the adoption of a western lifestyle and are still rising rapidly in many low and middle-income countries [1]. Ap-proximately 50% of patients will develop metastasis during the disease course, and the 5-year survival is usually only around 55% [2]. The tumor aggressiveness in each patient is strongly influenced by genetic heterogeneity and may reflect the activation of paracrine extracellular stimulus of the tumor microenvironment, triggering metastasis [3]. Cancer metastasis can be regulated by signaling of the epithelial–me-senchymal transition (EMT) program, which promotes cell detachment, migration, and invasion into the surrounding tissue and resistance to
    apoptosis and anticancer drugs [4].
    Intestinal epithelial cells have highly organized structures that regulate the intestinal barrier; these are known as apical junctional complex (AJCs), which are formed by tight junctions (TJs) and ad-herens junctions (AJs). TJs and AJs mediate cell-cell adhesion through interactions of their transmembrane proteins, such as occludin, clau-dins, and E-cadherin, with cytoplasmic proteins that directly or in-directly connect to the cortical actin, stabilizing cellular junctions [5]. During EMT, epithelial cells lose proteins of the junctional complex and acquire mesenchymal proteins, such as vimentin and N-cadherin, al-tering the apical-basal polarity to front-rear polarity, thereby re-modeling cell-matrix adhesions and allowing increased migratory and invasive capabilities of tumor cells [4]. This process is also mediated by the dynamics of the LY 294002 cytoskeleton in which the cortical actin is
    Abbreviations: AJCs, apical junctional complexes; AJs, adherens junctions; TJs, tight junctions; CRC, colorectal cancer; EMT, epithelial–mesenchymal transition; F-actin, filamentous actin; G-actin, globular actin; RFP, red fluorescent protein; siRNA, small interfering RNA; WT, wild type
    Corresponding author at: Cellular and Molecular Oncobiology Program, Brazilian National Cancer Institute (INCA), LY 294002 37 André Cavalcanti Street, 5th Floor, Rio de Janeiro, RJ 20230-051, Brazil. E-mail address: [email protected] (J.A. Morgado-Diaz).
    arranged, actin stress fibers are formed, and new actin-rich membrane projections such as lamellipodia are stimulated. The major regulators of the cytoskeleton, the Rho GTPases, can spatiotemporally regulate rapid polymerization/depolymerization of filamentous actin (F-actin) and formation of actin-based bundles and cellular protrusions [6]. In this context, cofilin-1 is one terminal effector protein of the Rho GTPase signaling cascades that is essential to regulating actin dynamics, se-vering F-actin, and increasing depolymerization of the filament. In addition, cofilin-1 can directly generate free actin barbed ends, which can be used for nucleation of the F-actin and provide a globular actin (G-actin) pool [7].
    The activity of cofilin-1 is regulated by phosphorylation of residue Ser3 by LIM kinases (LIMK1 and LIMK2), whereas upstream activity is regulated by Rho GTPase signaling, such as RhoA, Rac1, and Cdc42. Once phosphorylated, cofilin-1 loses its affinity for actin, and depoly-merization and severing are inhibited. Conversely, dephosphorylation of Ser3 by phosphatases leads to cofilin-1 activation [8]. Furthermore, the balance between synthesis of protein and subcellular localization of LIMKs/cofilin-1 and its activation/deactivation cycle is crucial to de-fining cellular response; thus, small changes in the dynamics of the actin cytoskeleton can increase or decrease the invasiveness of tumor cells [9]. Overexpression of cofilin-1 has been reported in human can-cers [10–13] and implicated in tumor progression events, including migration, invasion, and metastasis [9,14,15]. However, its regulation and role during EMT development in CRC is still unknown. Thus, considering that actin cytoskeleton rearrangement is downstream of EMT activation, we hypothesize that there is a direct association be-tween the loss of epithelial characteristics and gain of a migratory and mesenchymal phenotype with actin cytoskeleton reordering. Therefore, we believe that a better understanding of these dynamics may elucidate the role of cofilin-1 during EMT in CRC, facilitating the discovery of new therapeutic strategies for these metastases.