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Michael P. Lisanti - One of the best experts on this subject based on the ideXlab platform.
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Caveolin 1 and cancer metabolism in the tumor microenvironment markers models and mechanisms
Annual Review of Pathology-mechanisms of Disease, 2012Co-Authors: Federica Sotgia, Ubaldo E Martinezoutschoorn, Anthony Howell, Richard G Pestell, Stephanos Pavlides, Michael P. LisantiAbstract:Caveolins are a family of membrane-bound scaffolding proteins that compartmentalize and negatively regulate signal transduction. Recent studies have implicated a loss of Caveolin-1 (Cav-1) expression in the pathogenesis of human cancers. Loss of Cav-1 expression in cancer-associated fibroblasts results in an activated tumor microenvironment, thereby driving early tumor recurrence, metastasis, and poor clinical outcome in breast and prostate cancers. We describe various paracrine signaling mechanism(s) by which the loss of stromal Cav-1 promotes tumor progression, including fibrosis, extracellular matrix remodeling, and the metabolic/catabolic reprogramming of cancer-associated fibroblast, to fuel the growth of adjacent tumor cells. It appears that oxidative stress is the root cause of initiation of the loss of stromal Cav-1 via autophagy, which provides further impetus for the use of antioxidants in anticancer therapy. Finally, we discuss the functional role of Cav-1 in epithelial cancer cells.
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lung remodeling and pulmonary hypertension after myocardial infarction pathogenic role of reduced Caveolin expression
Cardiovascular Research, 2004Co-Authors: Jean-francois Jasmin, Isabelle Mercier, Robert Hnasko, Michelle W C Cheung, Herbert B Tanowitz, Jocelyn Dupuis, Michael P. LisantiAbstract:Objectives: Pulmonary hypertension (PH) and lung structural remodeling are frequent complications of congestive heart failure (CHF). Yet, the molecular mechanisms involved in CHF-induced PH and lung remodeling remain unknown. Caveolins (Cav-1, -2 and -3) are the principal structural proteins of the vesicular invaginations of the plasma membrane, termed caveolae. Mice with homozygous deletion of the Caveolin-1 gene (Cav-1(−/−)) have been shown to develop dilated cardiomyopathy, PH and lung structural remodeling, characterized by hypercellularity and thickening of the alveolar septa. However, the physiological relevance of these observations for the pathogenesis of PH and lung remodeling remains to be determined. Methods and results: Here, we investigate the natural behavior of the endogenous Caveolin proteins during the development of PH and lung structural remodeling, using a rat model of myocardial infarction (MI). MI was induced in male Wistar rats by ligating the left anterior coronary artery. Two weeks post-MI, rats were anesthetized and hemodynamic and morphometric measurements were obtained. Rats subjected to MI developed marked PH, lung structural remodeling and right ventricular hypertrophy (RVH). Both immunoblot analysis and immunohistochemistry dramatically show that Cav-1 and Cav-2 expression is downregulated to almost undetectable levels in the lungs of post-MI rats. Mechanistically, the reduced expression of Caveolins was associated with the increased tyrosine-phosphorylation of the signal transducer and activator of transcription-3 (STAT3) and the upregulation of cyclin D1 and D3 expression. We also show that STAT3 is hyperphosphorylated, and cyclin D1 and D3 levels are dramatically upregulated, in lung tissue samples derived from Cav-1 (−/−)- and Cav-2 (−/−)-deficient mice. Conclusions: Thus, down-modulation of pulmonary Cav-1 and Cav-2 expression in rats subjected to MI may represent an initiating mechanism leading to the activation of the STAT3/Cyclins pathway and, ultimately, to the development of PH and lung structural remodeling.
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The Caveolin proteins
Genome Biology, 2004Co-Authors: Terence M Williams, Michael P. LisantiAbstract:The Caveolin gene family has three members in vertebrates: Caveolin-1, Caveolin-2, and Caveolin-3. So far, most Caveolin-related research has been conducted in mammals, but the proteins have also been found in other animals, including Xenopus laevis, Fugu rubripes , and Caenorhabditis elegans . Caveolins can serve as protein markers of caveolae ('little caves'), invaginations in the plasma membrane 50-100 nanometers in diameter. Caveolins are found predominantly at the plasma membrane but also in the Golgi, the endoplasmic reticulum, in vesicles, and at cytosolic locations. They are expressed ubiquitously in mammals, but their expression levels vary considerably between tissues. The highest levels of Caveolin-1 (also called Caveolin, Cav-1 and VIP2I) are found in terminally-differentiated cell types, such as adipocytes, endothelia, smooth muscle cells, and type I pneumocytes. Caveolin-2 (Cav-2) is colocalized and coexpressed with Cav-1 and requires Cav-1 for proper membrane targeting; the Cav-2 gene also maps to the same chromosomal region as Cav-1 (7q31.1 in humans). Caveolin-3 (Cav-3) has greater protein-sequence similarity to Cav-1 than to Cav-2, but it is expressed mainly in muscle cells, including smooth, skeletal, and cardiac myocytes. Caveolins participate in many important cellular processes, including vesicular transport, cholesterol homeostasis, signal transduction, and tumor suppression.
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the Caveolin genes from cell biology to medicine
Annals of Medicine, 2004Co-Authors: Terence M Williams, Michael P. LisantiAbstract:Caveolae are vesicular organelles (50-100-nm in diameter) that are particularly abundant in cells of the cardiovascular system, including endothelial cells, smooth muscle cells, macrophages, cardiac myocytes and fibroblasts. In these cell types, caveolae function both in protein trafficking and signal transduction, as well as in cholesterol homeostasis. Caveolins are the structural proteins that are both necessary and sufficient for the formation of caveolae membrane domains. Caveolins 1 and 2 are co-expressed in most cell types, while the expression of Caveolin-3 is muscle-specific. Thus, endothelial cells and fibroblasts are rich in Caveolins 1 and 2, while cardiac myocytes and skeletal muscle fibers express Caveolin-3. In contrast, smooth muscle cells express all three Caveolins (Cav-1, -2, and -3). Mechanistically, Caveolins interact with a variety of downstream signaling molecules, including Src-family tyrosine kinases, p42/44 mitogen activated protein (MAP) kinase, and endothelial nitric oxide synthase (eNOS), and hold these signal transducers in the inactive conformation until activation by an appropriate stimulus. In many ways, Caveolins serve both to compartmentalize and regulate signaling. Recent studies using Caveolin-deficient mouse models dramatically show that caveolae and Caveolins play a prominent role in various human patho-biological conditions, especially those related to the cardiovascular system. These disease phenotypes include: atherosclerosis, cardiac hypertrophy, cardiomyopathy, pulmonary hypertension, and neointimal hyperplasia (smooth muscle cell proliferation). In addition, Caveolins play a significant role in other disease phenotypes, such as cancer, diabetes, bladder dysfunction, and muscular dystrophy, as we discuss in this review. Thus, Caveolin-deficient mice will serve as important new animal models to dissect the intricate role of caveolae and Caveolins in the pathogenesis of human diseases.
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Transgenic overexpression of Caveolin-3 in the heart induces a cardiomyopathic phenotype
Human molecular genetics, 2003Co-Authors: Bharathi Aravamudan, Daniela Volonte, Michael P. Lisanti, Ravi Ramani, Erdal Gursoy, Barry London, Ferruccio GalbiatiAbstract:Caveolins are structural protein components of caveolar membrane domains. Caveolin-3, a muscle-specific member of the Caveolin family, is expressed in skeletal muscle tissue and in the heart. The multiple roles that Caveolin-3 plays in cellular physiology are becoming more apparent. We have shown that lack of Caveolin-3 expression in skeletal muscle resembles limb-girdle muscular dystrophy-1C. In contrast, we have demonstrated that overexpression of Caveolin-3 in skeletal muscle tissue promotes defects similar to those seen in Duchenne muscular dystrophy (DMD). Thus, a tight regulation of Caveolin-3 expression is fundamental for normal muscle functions. Since Caveolin-3 is also endogenously expressed in cardiac myocytes, and cardiomyopathies are observed in DMD patients, we looked at the effects of overexpression of Caveolin-3 on cardiac structure and function by characterizing Caveolin-3 transgenic mice. Our results indicate that overexpression of Caveolin-3 causes severe cardiac tissue degeneration, fibrosis and a reduction in cardiac functions. We also show that dystrophin and its associated glycoproteins are down-regulated in Caveolin-3 transgenic heart. In addition, we demonstrate that the activity of nitric oxide synthase (NOS) is down-regulated by high levels of Caveolin-3 in the heart. Taken together, these results indicate that overexpression of Caveolin-3 is sufficient to induce severe cardiomyopathy. In addition, these findings suggest that Caveolin-3 transgenic mice may represent a valid mouse model for studying the molecular mechanisms underlying cardiomyopathies associated with Duchenne muscular dystrophy.
Robert G. Parton - One of the best experts on this subject based on the ideXlab platform.
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Caveolin regulates endocytosis of the muscle repair protein dysferlin
Journal of Biological Chemistry, 2008Co-Authors: Delia J Hernandezdeviez, Mark T. Howes, John F. Hancock, Steven H Laval, Kate Bushby, Robert G. PartonAbstract:Dysferlin and Caveolin-3 are plasma membrane proteins associated with muscular dystrophy. Patients with mutations in the CAV3 gene show dysferlin mislocalization in muscle cells. By utilizing Caveolin-null cells, expression of Caveolin mutants, and different mutants of dysferlin, we have dissected the site of action of Caveolin with respect to dysferlin trafficking pathways. We now show that Caveolin-1 or -3 can facilitate exit of a dysferlin mutant that accumulates in the Golgi complex of Cav1-/- cells. In contrast, wild type dysferlin reaches the plasma membrane but is rapidly endocytosed in Cav1-/- cells. We demonstrate that the primary effect of Caveolin is to cause surface retention of dysferlin. Caveolin-1 or Caveolin-3, but not specific Caveolin mutants, inhibit endocytosis of dysferlin through a clathrin-independent pathway colocalizing with internalized glycosylphosphatidylinositol-anchored proteins. Our results provide new insights into the role of this endocytic pathway in surface remodeling of specific surface components. In addition, they highlight a novel mechanism of action of Caveolins relevant to the pathogenic mechanisms underlying Caveolin-associated disease.
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biogenesis of caveolae a structural model for Caveolin induced domain formation
Journal of Cell Science, 2006Co-Authors: Robert G. Parton, Michael Hanzalbayer, John F. HancockAbstract:Caveolae are striking morphological features of the plasma membrane of mammalian cells. Caveolins, the major proteins of caveolae, play a crucial role in the formation of these invaginations of the plasma membrane; however, the precise mechanisms involved are only just starting to be unravelled. Recent studies suggest that caveolae are stable structures first generated in the Golgi complex. Their formation and exit from the Golgi complex is associated with Caveolin oligomerisation, acquisition of detergent insolubility, and association with cholesterol. Modelling of Caveolin-membrane interactions together with in vitro studies of Caveolin peptides are providing new insights into how Caveolin-lipid interactions could generate the unique architecture of the caveolar domain.
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aberrant dysferlin trafficking in cells lacking Caveolin or expressing dystrophy mutants of Caveolin 3
Human Molecular Genetics, 2006Co-Authors: Delia J Hernandezdeviez, Steven H Laval, Kathryn N North, Sandra T Cooper, Kate Bushby, Sally Martin, Robert G. PartonAbstract:Mutations in the dysferlin (DYSF) and Caveolin-3 (CAV3) genes are associated with muscle disease. Dysferlin is mislocalized, by an unknown mechanism, in muscle from patients with mutations in Caveolin-3 (Cav-3). To examine the link between Cav-3 mutations and dysferlin mistargeting, we studied their localization at high resolution in muscle fibers, in a model muscle cell line, and upon heterologous expression of dysferlin in muscle cell lines and in wild-type or Caveolin-null fibroblasts. Dysferlin shows only partial overlap with Cav-3 on the surface of isolated muscle fibers but co-localizes with Cav-3 in developing transverse (T)-tubules in muscle cell lines. Heterologously expressed dystrophy-associated mutant Cav3R26Q accumulates in the Golgi complex of muscle cell lines or fibroblasts. Cav3R26Q and other Golgi-associated mutants of both Cav-3 (Cav3P104L) and Cav-1 (Cav1P132L) caused a dramatic redistribution of dysferlin to the Golgi complex. Heterologously expressed epitope-tagged dysferlin associates with the plasma membrane in primary fibroblasts and muscle cells. Transport to the cell surface is impaired in the absence of Cav-1 or Cav-3 showing that Caveolins are essential for dysferlin association with the PM. These results suggest a functional role for Caveolins in a novel post-Golgi trafficking pathway followed by dysferlin.
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cholesterol and fatty acids regulate dynamic Caveolin trafficking through the golgi complex and between the cell surface and lipid bodies
Molecular Biology of the Cell, 2005Co-Authors: Albert Pol, Sally Martin, Manuel A Fernandez, Charles Ferguson, Carlos Enrich, Mercedes Ingelmotorres, Robert G. PartonAbstract:Caveolins are a crucial component of plasma membrane (PM) caveolae but have also been localized to intracellular compartments, including the Golgi complex and lipid bodies. Mutant Caveolins associated with human disease show aberrant trafficking to the PM and Golgi accumulation. We now show that the Golgi pool of mainly newly synthesized protein is detergent-soluble and predominantly in a monomeric state, in contrast to the surface pool. Caveolin at the PM is not recognized by specific Caveolin antibodies unless PM cholesterol is depleted. Exit from the Golgi complex of wild-type Caveolin-1 or -3, but not vesicular stomatitis virus-G protein, is modulated by changing cellular cholesterol levels. In contrast, a muscular dystrophy-associated mutant of Caveolin-3, Cav3P104L, showed increased accumulation in the Golgi complex upon cholesterol treatment. In addition, we demonstrate that in response to fatty acid treatment Caveolin can follow a previously undescribed pathway from the PM to lipid bodies and can move from lipid bodies to the PM in response to removal of fatty acids. The results suggest that cholesterol is a rate-limiting component for Caveolin trafficking. Changes in Caveolin flux through the exocytic pathway can therefore be an indicator of cellular cholesterol and fatty acid levels.
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dynamic and regulated association of Caveolin with lipid bodies modulation of lipid body motility and function by a dominant negative mutant
Molecular Biology of the Cell, 2003Co-Authors: Albert Pol, A. J. Carozzi, Sally Martin, Manuel A Fernandez, Charles Ferguson, Robert Luetterforst, Carlos Enrich, Robert G. PartonAbstract:Caveolins are a crucial component of caveolae but have also been localized to the Golgi complex, and, under some experimental conditions, to lipid bodies (LBs). The physiological relevance and dynamics of LB association remain unclear. We now show that endogenous Caveolin-1 and Caveolin-2 redistribute to LBs in lipid loaded A431 and FRT cells. Association with LBs is regulated and reversible; removal of fatty acids causes Caveolin to rapidly leave the lipid body. We also show by subcellular fractionation, light and electron microscopy that during the first hours of liver regeneration, Caveolins show a dramatic redistribution from the cell surface to the newly formed LBs. At later stages of the regeneration process (when LBs are still abundant), the levels of Caveolins in LBs decrease dramatically. As a model system to study association of Caveolins with LBs we have used brefeldin A (BFA). BFA causes rapid redistribution of endogenous Caveolins to LBs and this association was reversed upon BFA washout. Finally, we have used a dominant negative LB-associated Caveolin mutant (cav(DGV)) to study LB formation and to examine its effect on LB function. We now show that the cav(DGV) mutant inhibits microtubule-dependent LB motility and blocks the reversal of lipid accumulation in LBs.
Aliana Egeo - One of the best experts on this subject based on the ideXlab platform.
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mutations in the Caveolin 3 gene cause autosomal dominant limb girdle muscular dystrophy
Nature Genetics, 1998Co-Authors: Carlo Minetti, Federica Sotgia, Claudio Bruno, M. Bado, Paolo Broda, Emiliana Masetti, Paolo Scartezzini, Michela Mazzocco, Aliana EgeoAbstract:Limb-girdle muscular dystrophy (LGMD) is a clinically and genetically heterogeneous group of myopathies, including autosomal dominant and recessive forms1–3. To date, two autosomal dominant forms have been recognized2,3: LGMD1A, linked to chromosome 5q, and LGMD1B, associated with cardiac defects and linked to chromosome 1q11–21. Here we describe eight patients from two different families with a new form of autosomal dominant LGMD, which we propose to call LGMD1C, associated with a severe deficiency of Caveolin-3 in muscle fibres. Caveolin-3 (or M-Caveolin) is the muscle-specific form of the Caveolin protein family, which also includes cave-olin-1 and -2 (refs 4–9). Caveolins are the principal protein components of caveolae (50–100 nm invaginations found in most cell types) which represent appendages or sub-compartments of plasma membranes10,11. We localized the human Caveolin-3 gene (CAV3) to chromosome 3p25 and identified two mutations in the gene: a missense mutation in the membrane-spanning region and a micro-deletion in the scaffolding domain. These mutations may interfere with Caveolin-3 oligomerization and disrupt caveolae formation at the muscle cell plasma membrane.
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mutations in the Caveolin 3 gene cause autosomal dominant limb girdle muscular dystrophy
Nature Genetics, 1998Co-Authors: Carlo Minetti, Federica Sotgia, Claudio Bruno, M. Bado, Paolo Broda, Emiliana Masetti, Paolo Scartezzini, Michela Mazzocco, Aliana EgeoAbstract:Limb-girdle muscular dystrophy (LGMD) is a clinically and genetically heterogeneous group of myopathies, including autosomal dominant and recessive forms. To date, two autosomal dominant forms have been recognized: LGMD1A, linked to chromosome 5q, and LGMD1B, associated with cardiac defects and linked to chromosome 1q11-21. Here we describe eight patients from two different families with a new form of autosomal dominant LGMD, which we propose to call LGMD1C, associated with a severe deficiency of Caveolin-3 in muscle fibres. Caveolin-3 (or M-Caveolin) is the muscle-specific form of the Caveolin protein family, which also includes Caveolin-1 and -2. Caveolins are the principal protein components of caveolae (50-100 nm invaginations found in most cell types) which represent appendages or sub-compartments of plasma membranes. We localized the human Caveolin-3 gene (CAV3) to chromosome 3p25 and identified two mutations in the gene: a missense mutation in the membrane-spanning region and a micro-deletion in the scaffolding domain. These mutations may interfere with Caveolin-3 oligomerization and disrupt caveolae formation at the muscle cell plasma membrane.
Claudio Bruno - One of the best experts on this subject based on the ideXlab platform.
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mutations in the Caveolin 3 gene cause autosomal dominant limb girdle muscular dystrophy
Nature Genetics, 1998Co-Authors: Carlo Minetti, Federica Sotgia, Claudio Bruno, M. Bado, Paolo Broda, Emiliana Masetti, Paolo Scartezzini, Michela Mazzocco, Aliana EgeoAbstract:Limb-girdle muscular dystrophy (LGMD) is a clinically and genetically heterogeneous group of myopathies, including autosomal dominant and recessive forms1–3. To date, two autosomal dominant forms have been recognized2,3: LGMD1A, linked to chromosome 5q, and LGMD1B, associated with cardiac defects and linked to chromosome 1q11–21. Here we describe eight patients from two different families with a new form of autosomal dominant LGMD, which we propose to call LGMD1C, associated with a severe deficiency of Caveolin-3 in muscle fibres. Caveolin-3 (or M-Caveolin) is the muscle-specific form of the Caveolin protein family, which also includes cave-olin-1 and -2 (refs 4–9). Caveolins are the principal protein components of caveolae (50–100 nm invaginations found in most cell types) which represent appendages or sub-compartments of plasma membranes10,11. We localized the human Caveolin-3 gene (CAV3) to chromosome 3p25 and identified two mutations in the gene: a missense mutation in the membrane-spanning region and a micro-deletion in the scaffolding domain. These mutations may interfere with Caveolin-3 oligomerization and disrupt caveolae formation at the muscle cell plasma membrane.
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mutations in the Caveolin 3 gene cause autosomal dominant limb girdle muscular dystrophy
Nature Genetics, 1998Co-Authors: Carlo Minetti, Federica Sotgia, Claudio Bruno, M. Bado, Paolo Broda, Emiliana Masetti, Paolo Scartezzini, Michela Mazzocco, Aliana EgeoAbstract:Limb-girdle muscular dystrophy (LGMD) is a clinically and genetically heterogeneous group of myopathies, including autosomal dominant and recessive forms. To date, two autosomal dominant forms have been recognized: LGMD1A, linked to chromosome 5q, and LGMD1B, associated with cardiac defects and linked to chromosome 1q11-21. Here we describe eight patients from two different families with a new form of autosomal dominant LGMD, which we propose to call LGMD1C, associated with a severe deficiency of Caveolin-3 in muscle fibres. Caveolin-3 (or M-Caveolin) is the muscle-specific form of the Caveolin protein family, which also includes Caveolin-1 and -2. Caveolins are the principal protein components of caveolae (50-100 nm invaginations found in most cell types) which represent appendages or sub-compartments of plasma membranes. We localized the human Caveolin-3 gene (CAV3) to chromosome 3p25 and identified two mutations in the gene: a missense mutation in the membrane-spanning region and a micro-deletion in the scaffolding domain. These mutations may interfere with Caveolin-3 oligomerization and disrupt caveolae formation at the muscle cell plasma membrane.
I B Zborovskaya - One of the best experts on this subject based on the ideXlab platform.
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simultaneous expression of flotillin 1 flotillin 2 stomatin and Caveolin 1 in non small cell lung cancer and soft tissue sarcomas
BMC Cancer, 2014Co-Authors: Ksenia Arkhipova, Anastasia N Sheyderman, K K Laktionov, Valeria V Mochalnikova, I B ZborovskayaAbstract:Background At the present time, there is a lack of data about the involvement of flotillins and stomatin in the development of non-small cell lung cancer (NSCLC) and soft tissue sarcomas (STS). Moreover, changes in expression of members of different families of the microdomain-forming proteins (Caveolins and SPFH-domain containing family) are usually investigated independently of each other. In this study we performed a combined analysis of flotillins, stomatin, and Caveolin-1 expression in these pathologies and evaluated correlations between generated data and clinicopathological characteristics of the specimens.
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simultaneous expression of flotillin 1 flotillin 2 stomatin and Caveolin 1 in non small cell lung cancer and soft tissue sarcomas
BMC Cancer, 2014Co-Authors: Ksenia Arkhipova, Anastasia N Sheyderman, K K Laktionov, Valeria V Mochalnikova, I B ZborovskayaAbstract:At the present time, there is a lack of data about the involvement of flotillins and stomatin in the development of non-small cell lung cancer (NSCLC) and soft tissue sarcomas (STS). Moreover, changes in expression of members of different families of the microdomain-forming proteins (Caveolins and SPFH-domain containing family) are usually investigated independently of each other. In this study we performed a combined analysis of flotillins, stomatin, and Caveolin-1 expression in these pathologies and evaluated correlations between generated data and clinicopathological characteristics of the specimens. The protein and mRNA expression was analyzed by Western blotting and real-time PCR, respectively, in tissue specimens of patients undergoing surgery for non-small cell lung cancer and soft tissue sarcomas. Association between expression of studied proteins and patient clinicopathological characteristics or outcome was evaluated. Stomatin protein expression was down-regulated in 80% of NSCLC samples and this decrease significantly associated with presence of lymph node metastases. Flotillin-2 protein expression was up-regulated in the majority of NSCLC samples whereas Caveolin-1α expression was decreased. We revealed a strong correlation between STOM and FLOT-1 mRNA expression in both pathologies, although the gene expression changes were diverse. Our data demonstrate for the first time that expression of stomatin, a poorly studied microdomain-forming protein, significantly changes in human tumors, thus pointing to its importance in the progression of NSCLC. We also suggest the existence of some relationship between the expression of these proteins.