Cancer Pages Volume 2, Issue 2, 2021

Review and Epithelial Mesenchymal Transition Susinjan Bhattacharya*

Department of Biotechnology, Jaypee Institute of Information Technology, Noida 201309, UP, India

Received: 18 March, 2021; Accepted: 23 March, 2021; Published: 26 March, 2021

*Corresponding author

© Susinjan Bhattacharya, Department of Biotechnology, Jaypee Institute of Copyright 2021 Susinjan Bhattacharya. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, Information Technology, A-10, Sector-62, Noida 201309, UP, India. and reproduction in any medium, provided the original work is properly cited. To view a E-mail: [email protected] copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Abstract

Epithelial-mesenchymal transition (EMT) is a developmental process that occurs not only in developmental processes but also in diseased states like cancer and metastases. The process includes changes in cytoskeleton and can be induced by several factors, one of them being TGF-β induced signaling. The cytoskeleton is made up of three components, fibres, microtubules, and intermediate filaments. This review provides insight into the influences of the cytoskeleton in EMT and cancer cell migration and invasion. The miRNAs are emerging as promising therapeutic targets and influence cytoskeleton gene functioning. A short note on the role of miRNAs influencing changes in cell architecture and functions in EMT has been also discussed.

Keywords: Metastasis, Cytoskeleton, Actin, Microtubules, Intermediate Filaments, EMT

Introduction Cortical organization of cytoskeletal elements is a characteristic feature of epithelial cells, whereas actin stress fibres are found in Metastasis, the movement of cancer cells from one to another mesenchymal cells. For cell migration, an essential process in cancer site needs cytoskeleton remodeling. The functions of cytoskeletal metastasis, actin cytoskeleton is remodeled by Rho GTPases [9]. are well interconnected within the cell; however, metastasis During EMT, cancer cells involve formation of various migratory also involves mutations of cytoskeletal proteins [1]. protrusions like lamellipodia, filopodia, etc which evolves from dynamic actin cytoskeleton remodeling. Reports indicated a direct Epithelial-mesenchymal transition (EMT), an essential process in link between EMT and actin dynamics showing a significant role of development also plays role in diseases like cancer and the process of the actin cytoskeleton in the development of tumors [8, 10]. wound healing [2]. As the cell transforms epithelial to mesenchymal phenotype, there are distinct changes that will be initiated, like The cytoskeletal elements play the role to maintain cell shape and conversion of cells from polar to apolar type, gain of invasive and structure and they are (actin), IFs, and microtubules metastatic potential, and altered biosynthesis of ECM components (MT). These three elements crosstalk amongst themselves and and remodeling of the cytoskeleton [1, 3 ,4]. The transcriptional there is interdependency amongst them [11]. Thus, a global view of networks of regulating EMT have been widely studied, however, the cytoskeleton in tumor cell metastases and EMT is of interest. the importance of cytoskeletal signaling in EMT initiation and This review will focus on cytoskeleton functions associated with progression has not been studied significantly [5]. metastases in EMT.

As a cell goes through EMT, cytoskeleton and signaling pathways Cytoskeletal Elements are altered. EMT is initiated with loss of tight junctions. Further, there is disassembling of gap and adherent junctions coupled with The cytoskeleton provides framework to the cell and helps to resist loss of basement membrane integrity [6]. Along with this, there is change in cell shape. Besides this, several functions can be done by cytoskeleton remodeling wherein actin allocation to stress fiber the cytoskeleton. It is made up of three different proteins: actin, IFs, formation and replacement of intermediate filaments (IFs) by and MTs. Though the cytoskeletal elements consist of three major vimentin takes place [7]. This allows formation of spindle-shaped cell elements, they can be still found as a single strand [12, 13]. morphology from cuboidal/columnar precursors with more ability to invade neighboring tissue [8]. A cell undergoes EMT when it loses Actin its epithelial marker and expresses mesenchymal marker. There is increased cell movement associated with actin cytoskeleton

Citation Bhattacharya S (2021) Cytoskeleton and Epithelial Mesenchymal Transition. Cancer Pages 2(2): 16. 1 Cancer Pages Bhattacharya S (2021) 2(2): 16 | Review

remodeling in EMT. Actin is assembled to stress fibres, regulated by expression is also upregulated in cell culture models used to study Rho family GTPases, and are with periodic cross-linking proteins wound healing [15]. VIFs also play important role in metastasis, by like alpha-actinin and II motor proteins. Inhibition of actin elongating and stabilizing invadopodia. These invadopodia are depolymerization maintains fiber stability [14]. Stress fibers are membranous protrusions rich in matrix metalloproteinases which subtyped further on basis of intracellular location: transverse arcs, can degrade the basement membrane and facilitating movement out perinuclear actin cap, ventral, and dorsal stress fibers. Further, motile of cancer cells [16]. mesenchymal cells have dorsal and ventral stress fibers that are linked to the extracellular matrix via focal adhesions. Focal adhesions are Microtubules unique to contain proteins like vinculin, focal adhesion kinase, and integrins, links cytoskeleton to the ECM, as well as sites of localized Microtubules (MTs) are another type of cytoskeletal element that events [15]. does many central cellular functions. These are polarized structures composed of α/β-tubulin heterodimers. With onset of EMT, there is Reorganization of the actin cytoskeleton gives rise to structures detyrosination of α-tubulin, and accumulation of this is necessary like invadopodia, lamellipodia, and filapodia that give migratory to form MT based protrusion, microtentacles (McTNs), and are properties to mesenchymal cells [12]. supported by vimentin, and detyrosinated α–tubulin [8]. However, it was observed in cells without EMT induction, MTs were mainly Actin also plays role in stabilization and regulation of cellular distributed uniformly in the cytoplasm and invasive protrusions junctions by interacting with adhesion proteins. Adhesion proteins were mainly MT based structures. The MT associated , tau are connected to cytoskeleton components and signaling molecules plays important role in tubulin assembly essential for formation due to the presence of cytoplasmic tails. Actin filaments are also of protrusions [17]. The MT stability is also determined by actin linked to cadherins and play role in the creation of adherens junction cytoskeleton regulators, like PI3K-Akt signal and Rho GTPases, [8]. and depolymerization of actin play role in cell Hepatocyte growth factor/Rac1/PAK1/stathmin signaling pathway migration, whereas the process of actin microfilaments creation and [8]. Stathmin, a 149 amino acid cytosoluble protein regulates depolymerization is regulated by actin-binding proteins (ABP). SATB1 microtubule polymerization by destabilizing MTs. In turn, activity of (special AT-rich sequence-binding protein-1) nuclear protein, an ABP stathmin is regulated by the interaction between stathmin and the plays important role in the EMT process. Its main role is to bind DNA α/β-tubulin hetrodimers [18]. sequences rich in AT pairs and coordinate gene expression control through changes in chromatin loop architecture [12]. During transport Cell migration of tumor cells in blood vessels, actin contributes to their survival, and protects tumor cells from degradation, and makes connections with Tumor metastasis occurs via a series of steps and EMT has been shown blood cells like erythrocytes or thrombocytes that prevent tumor to play a critical role in promoting metastasis in epithelium derived cells from immune action. Actin also plays role in extravasation carcinoma [19]. Tumor metastasis could be stopped by controlling of tumor cells. Actin-rich protrusions, namely invadopodia exert actin filament formation [12]. Tumor metastasis is involved with proteolytic function in ECM degradation and penetration. In the case motility and interactions with tumor microenvironment [10]. Cell of EMT increased cell contractility and actin stress fibre formation motility is orchestrated by specific four stages, namely Protrusion, can be seen [13]. adhesion, contraction and migration all of which requires cytoskeletal changes [20]. Motility is initiated in response to an external gradient In epithelial cells, actin filaments are organized as cortical thin of growth factors or chemokines [21, 22]. Cell motility can be either of bundles, whereas in mesenchymal cell these are bundled into thick mesenchymal motility or amoeboid motility. Mesenchymal motility is contractile fibers at the ventral cell surface [14]. involved with F-actin rich protrusions whereas amoeboid motility is associated with rounded bleb form of motility [10, 23]. Intermediate filaments Cytoskeletal communications Intermediate filaments (IFs) are composed of one or more members of a large family of cytoskeletal proteins and the expression of IFs are The fatty acids serve as sites wherein actin and microtubule elements fixed regarding cell and tissue type. They are important to influence crosstalk [24]. However, the molecular mechanisms involved in this cell physiology and cell shape. Vimentin, an communication is not well understood. Microtubules play role to protein is an important marker of EMT and increases in number in limit cytoskeletal activity to specific cellular locations [25]. Stathmin, cells undergoing EMT and plays role in cell migration [10]. a 19 kDa cytosolic microtubule destabilizing phosphoprotein provides more evidence of the cross communication in cytoskeleton. Stathmin When the cells undergo EMT, intermediate filaments undergo also overexpression also parallels with metastatic disease progression change in expression, wherein cell which expresses keratin IFs (KIFs) and survival, whereas stathmin suppression was found to effect switch over to expression of vimentin IFs (VIFs). Thus, VIF expression phosphorylation of actin regulatory proteins, cofilin and MLC via has become a marker of cells undergoing EMT. VIFs and KIFs do ROCK signaling [10]. not copolymerize in the same cell and form two distinct networks2 when expressed [8]. Reports observed that vimentin expression is The cytoskeleton plays a key role in cell adhesion and proliferation necessary for invasiveness of prostate and breast cancer cells. VIF and growth factor signaling is an important driver of tumor growth

Citation Bhattacharya S (2021) Cytoskeleton and Epithelial Mesenchymal Transition. Cancer Pages 2(2): 16. 2 Cancer Pages Bhattacharya S (2021) 2(2): 16 | Review

[26]. The cytoskeletal changes and EMT are also induced by growth transcript elongation [45, 46]. Cofilin increases number of actin factors like EGFR, FGFR and cytokine, TGFβ. Many epidermal growth free barbed ends [47] and increased levels of CFL1 expression are factor receptor family members, especially EGFR are aberrantly associated with tumor progression and presence of EMT markers [13]. expressed or deregulated in tumors resulting in aberrant signaling In the regulation of cofilin, it is phosphorylated at serine 3 position in transformed cells. This results in phenotypic changes associated by LIM kinase (LIMK) and testis specific kinase 1 and 2 (TESK1 and with several features including hallmarks of EMT [27]. Davidson et 2) [48, 49, 50], wherein LIMK mediated phosphorylation can block al in a study observed that cultured podocytes need FGF signaling ABP of cofilin leading to actin cytoskeleton stabilization [48]. Stress to undergo EMT like changes and concluded that FGF signaling is conditions can also lead to nuclear accumulation of cofilin as well as essential in regulating cell differentiation and formation of actin based actin [51, 52]. Furthermore, cofilin expression levels were correlated cellular processes during morphogenesis [28]. Further, physiological with filopodia formation suggesting its role in EMT as well as gene and pathological EMT can be induced by cytokines such as TGF-β expression regulation by controlling nuclear actin organization [53]. and HGF [29]. Additionally, Rac protein can stimulate lamellipodia formation and Moreover, EMT increases the invasiveness and migratory potential F-actin polymerization [54, 55] and increased expression of Cdc 42 of abnormal cells, which increases the risk of metastasis. This also leads to formation of invadopodia and matrix metalloproteinases involves change in phenotype of the cells involved in metastasis suggesting increased migration of cancer cells [56]. Another protein, and this stage can be also a potential target of drugs. The other SATB1 complexes with F-actin and plays role in the transcription phenomenon involved with EMT is presence of CSCs (cancer stem process [57]. Elevated expression of SATB1 results in downregulation cells) which can lead to secondary tumors and the transformation from of E-cadherin through upregulation of the repressors, Slug and Snail non-CSC to CSC requires EMT [13]. Metastasis involves movement suggesting its involvement in EMT [13]. of cells which involves intravasation, extravasation, and implantation of cell elsewhere followed by proliferation. Actin is involved in the The miRNA as master influencer of cellular processes influences steps of metastasis. Actin polymerization and depolymerization transcription factors involved in EMT and controls single or multiple facilitates cell migration which involves formation of lamellipodia steps of metastasis, like miR-200 family regulates ZEB and TGFβ or filopodia [30, 31]. Treatment with growth factor, EGF led to the transcription factors [58, 59, 60]. Many miRNAs also influences formation of lamellipodia within a short time [31]. However, abnormal functions of cytoskeleton [61], like knockdown of miR155 leads to tight growth factor expression can also lead to increased cell migration junction dissolution, cell migration and invasion, whereas miR155 and proliferation [32, 33]. Invadopodia can exert proteolytic function expression can lead to reduced RhoA expression. Upon treatment of in ECM degradation and invasion [34]. It may be possible that colon cancer cells with TGFβ, it was observed that there is induction myosin plays role in actin structure reorganization. However, actin of miR21 and miR31 expression resulting in increased cellular motility polymerization within intracellular junctions can be suppressed by and invasiveness [62]. Upregulation of miR-9 in human breast cancer α-catenin [35, 36]. The build up and breakdown of actin microfilaments cells reduces expression of cadherin-1 (CDH1) resulting in increased is controlled by actin-binding proteins (ABP) which can influence the cell motility and invasiveness [63]. Further, N-cadherin expression dynamics of polymerization, branching and blocking of can be negatively regulated by miR-194 [64]. Stimulation of EMT ends, as well as stabilization of actin networks [37]. Intracellular as well as cell proliferation, migration, and invasion abilities can be protein signaling cascades regulates ABP binding. The Rho GTPases enhanced by miR-490-3p [65] in HCC cells. These reports indicate are the main regulators of actin dynamics and controllers of actin functions of miRNA in EMT by influencing cell functions, can provide rearrangement during EMT, which in turn are activated by ABPs due candidate targets for cancer therapy and suggests about usage of to either osmotic pressure, Ca2+ concentration, or growth factors. miRNAs as therapeutic targets [66, 67]. The Rho proteins are known to create actomyosin-based structures and addition of Rho proteins in cell culture leads to the accumulation Future directions of stress fibres [38]. The Rho-associated kinase (ROCK) can lead to contraction of smooth muscle cells by phosphorylating light myosin The cytoskeletal network is a dynamic system in management of chains [39]. Additionally, Rho can also increase total amount of cell shape and structure. Its close relationship with EMT makes cellular F-actin. Rho activation can lead to interaction of ROCK with it a potential therapeutic target. As epithelial cells undergo DIAI [40]. Rho-GTPases controls functioning of actin cytoskeleton in transition to mesenchymal cells, there is dramatic reorganization epithelial as well as in mesenchymal cells thus playing important role of cytoskeleton mediated by changes in expression of a variety of in EMT [12]. Interestingly, Rho GTPases activity is controlled by GEFs cytoskeleton associated proteins and TGF-β induced intracellular (guanine nucleotide exchange factors), GAPs (GTPase–activating signaling pathways in EMT [4, 68]. The strong relationship between proteins), and GDIs (guanine nucleotide dissociation inhibitors) [41]. cytoskeleton changes and EMT provides opportunities to select cytoskeleton as therapeutic target. Combination therapies can be The actin monomeric form can bind with BRG1 (Brahma related gene used to treat drug resistances and signaling pathways associated 1) which in turn can affect gene availability. Actin also interacts with with the cytoskeleton and treat metastatic cancer. Further growth the three RNA polymerases and is part of the basal transcription factor signaling pathways can be considered as a therapeutic target machinery [42, 43, 44]. Cofilin, a nuclear ABP acts as the downstream3 to prevent cytoskeletal changes associated with EMT [69]. effectors for Rho GTPases and can influence gene expression and

Citation Bhattacharya S (2021) Cytoskeleton and Epithelial Mesenchymal Transition. Cancer Pages 2(2): 16. 3 Cancer Pages Bhattacharya S (2021) 2(2): 16 | Review

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