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In addition to the phosphorylation/dephosphorylation regulation patterns of Src, the activity of Src can also be monitored by intracellular ROS

In addition to the phosphorylation/dephosphorylation regulation patterns of Src, the activity of Src can also be monitored by intracellular ROS. early 1980s, Elizabeth Hay observed a phenotypic transition of epithelial cells to acquire mesenchymal characteristics.1 This differentiation process is now widely known as epithelialCmesenchymal transition (EMT), which is involved in embryonic development, wound healing and cancer progression.2,3,4,5 Epithelial and mesenchymal cells can be discriminated by distinct morphologic features: epithelial cells are laterally conjoined to form layers or polarized sheets, whereas mesenchymal cells rarely show conjunctions with adjacent cells.6 Epithelial cells can be identified by so-called epithelial markers, including claudins, E-cadherin, Crumbs3 and PALS1, all of which are critical for keeping cellCcell junctions and cell polarity. By contrast, mesenchymal cells are characterized by key migration-promoting genes, such as N-cadherin, vimentin, -clean muscle mass actin (-SMA) and fibroblast activation protein (FAP).7 The major changes of epithelial cells undergoing EMT include the following: (1) diminished cellular conjunctions (including adherens junctions, limited junctions, gap junctions and desmosomes); (2) decreased focal adhesion; (3) downregulated epithelial markers and upregulated mesenchymal markers; (4) improved cell mobility; (5) remodeled cytoskeleton; (6) and degraded ECM.8,9 Several transcription factors, such as Snail, Slug, Twist, ZEB1 and ZEB2, are responsible for repressing epithelial markers and upregulating genes associated with the mesenchymal phenotype.10,11 These transcription factors are tightly regulated from the nuclear factor-B (NF-B), hypoxia-inducible element 1 (HIF-1) and transforming growth element beta (TGF-) signaling pathways. In addition, the transcription element forkhead box class O (FoxO) can modulate ECM turnover and cell mobility by advertising the manifestation of matrix metalloproteinases (MMPs).12 Rock2 Importantly, the subcellular localization of -catenin is also critical for regulating the EMT process. Within the cytomembrane, -catenin tightly interacts with E-cadherin to keep up cell adhesion. When Wnt signaling is definitely triggered, -catenin dissociates from SRPIN340 E-cadherin, SRPIN340 translocates to the nucleus and binds with TCF/LEF to activate the transcription of Snail, Twist and MMP-7. 13 Although numerous transcription factors and modulators of EMT have been extensively analyzed, the precise mechanisms underlying EMT progression remain unclear. Importantly, a number of important EMT regulators were recently found to be redox-sensitive, enabling the elucidation of the molecular basis underlying the EMT process from a redox perspective.14,15,16 ROS are defined as oxygen-containing varieties that have highly reactive properties, and include free radicals such as hydroxyl free radicals (HO?), superoxide (O2??) and non-radical molecules such as hydrogen peroxide (H2O2).17,18 ROS are important second messengers that regulate multifarious signaling pathways involved in cell proliferation, apoptosis, autophagy, migration, DNA damage, inflammation and drug resistance.19,20,21 Recently, the reversible and irreversible oxidative modifications of redox-sensitive proteins that possess SRPIN340 free thiols (-SH) on cysteine residues, which are susceptible to ROS, have been found to play a crucial part in regulating signaling pathways. Several patterns of oxidative modifications have been reported, including sulfenylation (-SOH), sulfinylation (-SO2H), sulfonylation (-SO3H), S-glutathionylation (PrS-SG) and disulfide bonds (intramolecular, intermolecular and combined types).22 Through these redox modifications, ROS can alter the biological functions of redox-sensitive proteins involved in ECM remodeling (for example, integrin, Hu antigen R), cytoskeleton remodeling (for example, actin, cofilin), cellCcell junctions (for example, NF-B, HIF-1, TGF-) and cell mobility (for example, Src, FAK, PTEN), thereby regulating EMT initiation and malignancy cell progression.9 With this review, we will highlight recent progress in understanding the molecular basis of redox-regulated EMT in cancer cells and discuss the opportunities and challenges for focusing on redox-regulated EMT like a potential therapeutic strategy SRPIN340 for cancer. Redox rules of ECM redesigning During EMT, ECM proteins undergo degradation to confer cells with invasive potential. ECM stabilization is definitely closely correlated with the manifestation of MMPs. The urokinase plasminogen activator (uPA) pathway has been reported to participate in ECM turnover and could be regulated by ROS. Integrins are believed to be important transmembrane proteins that link intracellular signaling mediators and ECM proteins. When EMT is initiated, the original integrins will be downregulated, and other types of integrin will be indicated, leading to fresh SRPIN340 relationships with different ECM parts to promote cell invasion.23 Recent studies have.