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  • br The tight regulation between cell junctions and

    2022-09-14


    The tight regulation between cell junctions and migration is fun-damental during homeostasis and in diseases including metastatic cancers [31]. Regulator mechanisms linking cell junctions to cell mi-gration are not yet completely understood, but it is known that during EMT, the junctional complex is ruptured followed by changes in actin-based membrane dynamics, resulting in increased cell motility [4]. Consistently, we demonstrated that cofilin-1 regulation of PEG300 dy-namics can control malignant behaviors, modulating junctional com-plex organization during EMT in colon cancer cells. Although instability of F-actin was observed in TGF-β/siCofilin-1 cells, E-cadherin and claudin-3 returned to cell–cell adhesions, and the protein levels of claudin -3 was restored but not of the E-cadherin. Moreover, EMT progression is related as a nonlinear process involved cell plasticity and transitional states where cells may oscillate between a spectrum of in-termediary phases, a partial EMT program [4]. In fact, siCofilin-1/TGF-
    β cells exhibited wide spectra of epithelial/mesenchymal phases with 
    some cells displaying a partial restoration of E-cadherin and claudin-3 at cell-cell contact, but still with increased cell size indicating a partial reversion of TGF-β effects, while other cells exhibited restoration of the junctional proteins at cell-cell contact and decreased cell size, reflecting a total reversion of TGF-β effects.
    Furthermore, phosphorylation of cofilin-1 could be a critical event during EMT, since our results with S3E-cofilin-1 mutants showed a si-milar pattern to TGF-β-treated cells, displaying loss of E-cadherin and claudin-3 at cell–cell junctions. Although the phosphorylation of co-filin-1 is required for EMT behavior, it is important to consider that the non-phosphorylated cofilin-1 has also a crucial role. The fine balance between expression and subcellular localization of cofilin-1 (phos-phorylated or non-phosphorylated) and its regulator LIMKs is pivotal for small changes in the dynamics of the actin cytoskeleton [9]. Moreover, LIMK2 may have indirect participation but significant in junctional disassembly during EMT by increasing an active cofilin-1 at cell-cell contact enabling increasing depolymerization/severing of the cortical actin. LIMKs e cofilin-1 plays critical roles in the deceleration and acceleration of actin retrograde flow, respectively, in the regulation of actin dynamics during lamellipodium growth. Thus, cofilin-1 activity could play as a cycle between states of phosphorylation and depho-sphorylation in different subcellular regions [32]. Our findings are in agreement with studies that demonstrated that RhoA-ROCK signaling plays a key role in the rupture of junctional complexes by remodeling cortical actin, leading to E-cadherin redistribution [33,34]. Besides the regulation of epithelial proteins, cofilin-1 might directly or indirectly regulate mesenchymal proteins like vimentin. In a gastric cancer model, cofilin-1 suppression increased E-cadherin protein level and decreased mesenchymal biomarkers vimentin and N-cadherin, in accordance with our findings [10]. In intestinal cell line we have shown results involving the phosphorylated form of cofilin-1 and its phosphomimetic mutant S3E as well as effect of inhibitor SB431542 and siCofilin-1 cells that reversed the EMT-like effects. In line with these observations, some studies have correlated the cofilin-1 pathway with EMT features. For
    instance, in a cohort of CRC patient tumors, expression of non-phos-phorylated cofilin-1 and its regulators, LIMK1, LIMK2, and SSH1, was correlated with decreased E-cadherin expression [35]. Interestingly, analysis of bladder carcinoma in situ samples revealed an association between nuclear localization of cofilin-1 and progression to high-grade, invasive disease, and patients who had higher nuclear cofilin-1 ex-hibited lower and higher E-cadherin and N-cadherin, respectively [11]. Taken together, this evidence suggests a tight association between the EMT program and the actin cytoskeleton dynamics through cofilin-1 activity, but further investigation is required in future studies.