Vimentin in Oral Cancers: History
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Subjects: Cell Biology
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crismita dmello

Oral carcinogenesis is a multistep process. As much as 5% to 85% of oral tumors can develop from potentially malignant disorders (PMD). Although the oral cavity is accessible for visual examination, the ability of current clinical or histological methods to predict the lesions that can progress to malignancy is limited.

  • vimentin
  • biomarker
  • oral cancer

1. Introduction

The cytoskeleton comprises microfilaments, intermediate filaments (IF), and microtubules. Together, the three filament systems operate as an integrated, dynamic network that is functionally regulated through their associated proteins to mediate cytoskeletal scaffolding [1]. Of the three types of cytoskeletal proteins, intermediate filaments are involved in an assortment of cellular functions, such as cell division and plasticity, motility, mechanical stress resistance, and organelle transport [2]. At least 65 genes encode the six major categories of intermediate filaments [3][4]. Type I and II intermediate filaments include acidic and basic keratins that are predominantly found in the epithelial cells. Vimentin and desmins are the Type III intermediate filaments that are primarily found in cells of mesenchymal origin and muscle cells, respectively; however, vimentin expression is also observed in other cell types, such as endothelial cells, macrophages, neutrophils, and lymphocytes as the only form of intermediate filaments [5]. Type III IF glial fibrillary acidic protein (GFAP) and peripherin are found solely in astrocytes and peripheral neurons. Type IV neurofilaments and α-internexin are present in neurons, whereas Type V IF neurofilaments include nuclear lamins. Nestins are the type VI IF and are detected in neuronal epithelial cells and in embryonic neurons [3]. IF-associated proteins (or IFAPs) organize intermediate filaments in bundles and networks. These include plectin, ankyrin, desmoplakin, and filaggrin [1].
Structurally, intermediate filament proteins share a central α-helical rod domain flanked by the non-α-helical N- and C-terminal end domains known as the head and the tail [6]. The central α-coiled rod domain of the individual molecules is further divided into the coil segments 1A, 1B, 2A, 2B1, and 2B2. The L1 linker segment links coil 1A and 1B, while the L12 links coil 1 and 2 [7]. A pre-coil domain (PCD) that does not engage in the coiled-coil formation precedes coil 1A. As a dimer, the vimentin rod is flanked by the flexible head domain on the left and the tail domain on the right [8]. Rod 1B assembles into A11 tetramer in an anti-parallel alignment of two parallel coiled-coil structures formed by the segments of rod 1. A vimentin monomer thus assembles itself into a homodimer that can later form tetramers and octamers [9].
Intermediate filaments, including vimentin, have functions distinct from those of the microfilaments and microtubules. Early research indicated that vimentin provides structural support to maintain cellular integrity and resistance to stress [10]. The structural and physiological functions of IFs are interconnected [6]. They are involved in wound healing by controlling fibroblast proliferation, TGFβ1-Slug signaling, collagen accumulation and EMT, proliferation [11], adhesion [12], migration and invasion [13][14], and as a positive regulator of stemness [15]. A survey of the Human Protein Atlas database showed vimentin expression in the majority of the tissues analyzed [16][17], wherein the multiple roles of vimentin in physiological and pathophysiological stress conditions are well established [18]. Homozygous deletion of vimentin (Vim−/−) in mice impaired the normal development of the mammary gland [15], glia [19], angiogenesis [20], and myelination of peripheral nerves [21]. In normal cells, vimentin synthesis occurs during embryogenesis in the primary streak stage, albeit restricted to the primary mesenchymal cells at this time, and it is associated with cell migration [22]. Vimentin is known to be involved in regulating actomyosin contractile force and can interact with the extracellular matrix to promote cell motility [23][24]. There is also evidence that interaction with vimentin may affect the function of chaperones [5]. One study reported that vimentin plays a role in the protection against misfolded proteins in the cells [17].
Although a majority of studies have described an intracellular role of vimentin, it is also noted to be present on the surface of the cells and in the extracellular matrix when secreted via the Golgi apparatus [25][26]. Additionally, vimentin controls cell proliferation, apoptosis, and differentiation. It promotes cell plasticity either by forming new cells through proliferation or by differentiating into new types of cells [17][27][28]. Furthermore, vimentin is also known to contribute to the aging process. Increased mRNA and protein expression are observed in senescent cells, suggesting a potential application of a vimentin variant as a marker for oxidative stress and aging [29]. Finally, vimentin-expressing cells possess a higher capacity to adapt to pathological conditions than those lacking vimentin. Thus, vimentin upregulation presents as an important drug target and a clinical biomarker [17].

2. Regulators of Vimentin

A complex transcriptional machinery regulates vimentin. In a comprehensive review, Satelli and Li [30] have described the various regulatory elements within its promoter region. These include TATA boxes, GC-boxes [31][32], and binding sites for transcription factors such as NF-ĸB, AP-1 containing the TGFβ1-response elements [31][33][34], PEA3 [35], Sp/XKLF [36], β-catenin/TCF4 [37][38][39], and ZBP-89 [36][40]. In addition to direct transcriptional regulation, epigenetic modification of vimentin expression has also been reported. Knockdown of SIRT1 (Sirtuin 1 histone deacetylase) decreased ZEB1 expression and subsequently of vimentin to suppress EMT in HNSCC [34]. Likewise, preventing DNA methylation by 5-aza-deoxycytidine in colon cancer cells dramatically increased vimentin mRNA expression [31]. These studies suggest various cell- and tissue-specific activators or repressors of vimentin expression.
Recent reports suggest that the post-transcriptional regulation of vimentin can also play a crucial role in cancer progression. For example, in a non-small cell lung carcinoma cell line, binding of NANOS3 protein to vimentin mRNA regulated the length of the poly(A) tail and prevented microRNA-mediated repression of vimentin, causing an increase in the invasive potential of these cells [35]. Furthermore, exosomes derived from hypoxic OSCC cells showed high levels of miR-21, which caused significantly enhanced Snail and vimentin expression in these cells [36]. However, further studies are required to adequately understand the role of microRNAs in the regulation of vimentin expression.
Vimentin is an excellent substrate for post-translational modifications (PTM) on account of its multiple domains and residues [6][7][8][9][30][41]. A thorough review by Snider and Omary has described several PTMs of vimentin, including but not limited to, phosphorylation, SUMOylation, and ADP-ribosylation, which were discovered by LC-MS-based analyses [42]. Interestingly, partial phosphorylation of vimentin by 14-3-3 can soften the filament to facilitate increased mobility of cancer cells [43]. Moreover, phosphorylation of vimentin on distinctive serine residues plays a role in a range of biological activities, such as cell motility, cytokinesis, IF assembly, and disassembly [44]. Nonetheless, while phosphorylation by several tyrosine kinases and SUMO 2/3 modifications of vimentin plays a key role in promoting cell growth and migration, mechanisms and pathophysiological consequences of SUMOylation, O-linked glycosylation, and other PTMs in cancers remain poorly understood [42][45][46][47].

3. Aberrant Expression of Vimentin in Premalignant Oral Lesions

Various studies have reported that the expression pattern of vimentin changes markedly between normal and cancerous epithelial tissues of the prostate, gastrointestinal tract, breast, central nervous system, and lung. While mechanisms of transcriptional and translational regulation of vimentin during cellular events leading to cancer progression are diverse [30][42], overexpression of vimentin is associated with a more metastatic and invasive phenotype in these cancers.
Vimentin expression was observed in the basal epithelial cells of benign oral buccal mucosa lesions showing lymphocyte infiltration, suggesting an association between inflammation and vimentin in the non-dysplastic lesions of the oral cavity [48]. Our group has also reported aberrant vimentin expression in premalignant oral lesions, such as leukoplakia and submucous fibrotic (SMF) tissues, as well as primary keratinocyte cultures isolated from these tissues. Interestingly, the percentage of vimentin-positive lesions was higher in clinically non-homogenous leukoplakia than in homogeneous leukoplakia [49]. Furthermore, increased vimentin protein and mRNA levels statistically correlated with the degree of disease progression from dysplasia to invasive carcinomas [49][50].

4. Role of Vimentin in Oral Cancer Progression

Immunohistochemical analysis of 227 oral tumors suggested a significant correlation of vimentin expression with various prognostic factors of OSCC, such as the tumor size, clinical stage, regional lymph node metastasis, local recurrence, and poor survival [49]. In addition, analysis of leukoplakia and OSCC epithelial tissue samples also revealed high vimentin and low E-cadherin expression [51][52].
Based on published studies, authors may hypothesize that the increased vimentin levels can lead to a higher grade of oral malignancy; however, the mechanisms by which vimentin plays a role in tumor progression remain unclear. Our lab has previously shown that exogenous expression of vimentin alone is insufficient but requires an additional carcinogenic trigger to transform premalignant lesion-derived cells. However, overexpression of vimentin alone caused the acquisition of EMT and stemness-related changes [52]. Furthermore, overexpression of vimentin led to decreased expression of E-cadherin, while knockdown resulted in an increased level of a differentiation-specific marker involucrin, suggesting a role of vimentin in maintaining the dedifferentiated state of cells during cancer progression [53][52]. Additional studies with the vimentin knockdown OSCC-derived cells suggested a role of vimentin in modulating the expression of K5/K14, mediated partly through ΔNp63 to favor a dedifferentiated phenotype that can promote tumor progression [53]. Another study reported an inverse expression pattern of vimentin and β4 integrin to modulate cell motility by destabilizing β4 integrin-mediated adhesions in OSCC [54].

5. Vimentin in Late Stages of Oral Cancer

As a driver towards acquiring stemness-related signatures in premalignant oral cancer lesions, our lab has shown a critical role of vimentin in the development and progression of oral cancers [53][52]. Vimentin has been associated with poor prognosis in patients with higher histological degrees of OSCC malignancies [55]. While studies have documented statistical associations between higher vimentin expression and cancer progression through tumor stages and increased metastasis [49][55][56][57], its expression was not limited to the invasive front of tumor cells or other histological measures of invasiveness [58]. Nonetheless, Lazarevic and colleagues reported higher expression of EMT markers, including vimentin, in primary cell cultures derived from surgically resected margins compared to those from the tumor tissues obtained from six patients with OSCC [59]. The states wherein the lesions expressed altered E-cadherin and vimentin were referred to as undergone partial EMT by Wangmo and colleagues. These were clinicopathologically associated with poor survival for patients presented with primary OSCC, as determined by univariate Cox regression [60]. Similarly, Liu et al. have shown that among five EMT markers, Snail, Twist, E-cadherin, N-cadherin, and vimentin, vimentin is the most promising prognostic marker. This study was done in tongue squamous cell carcinoma patients using tissue microarray immunohistochemistry [61].
In addition, cell membrane β-catenin expression was significantly associated with vimentin in HPV-associated oropharyngeal squamous cell carcinoma [62]. In an OSCC-derived cell line Tca8113, treatment of exogenous TGFβ1 upregulated vimentin expression at both mRNA and protein levels. TGFβ1-dependent upregulation of vimentin was associated with increased migration and invasion of the OSCC cells; inhibiting TGFβ1 abrogated the migratory potential of these cells, suggesting a role of vimentin in driving TGFβ1-induced EMT in these cells [63]. Together, these studies suggest a role of elevated vimentin expression in the late stages of OSCC.

This entry is adapted from the peer-reviewed paper 10.3390/life12020150

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