RESUMO
To identify genetic alterations associated with tongue cancer recurrence in young adults, whole exome sequencing of the primary tumor, recurrence, and whole blood samples from young patients with tongue cancer was performed. A frameshift mutation in the TP53 gene was detected in the primary tumor and recurrence tumor tissue. A mutation in the EPHB6 gene was detected in the recurrence and was absent in the primary tumor. In addition, the primary tumor and recurrence tongue cancer tissue harbored amplification of the 20p13 region containing C20orf96, DEFB125, DEFB126, DEFB127, DEFB128, DEFB129, DEFB132, and ZCCHC3 genes. Thus, genetic alterations have been identified that are associated with tongue cancer recurrence in young adults.
RESUMO
Oral squamous cell carcinoma (OSCC) is one of the most important medical and socio-economic problems in many of the developed countries worldwide, due to the high mortality. The incidence of OSCC among individuals under 45 years of age is growing every year; however, the aetiological factors and pathogenetic mechanisms are poorly understood. This review summarizes the available information regarding clinicopathological features, extrinsic and intrinsic aetiological factors, and the molecular and immune landscape of early-onset OSCC. This cancer shows high recurrence rates and is not associated with the aetiological factors specific to adult-onset OSCC. Young adults with OSCC are not infected with human papillomavirus and rarely consume alcohol or tobacco, but more frequently use smokeless tobacco. Data from single studies indicate the hereditary nature of early-onset OSCC: the KIR2DL1+-HLA-C2+ genotype and MMP-1 2 G allele are frequently detected in young patients. Early-onset OSCC shows specific genetic, epigenetic, transcriptomic, and proteomic changes. The tumour microenvironment in early-onset OSCC is tolerogenic rather than immunogenic. All of the data suggest that OSCC in young patients is a separate clinical entity with a specific aetiology and pathogenesis. Further studies are needed to reveal the causes and molecular targets of early-onset OSCC for the development of preventive and therapeutic strategies.
Assuntos
Neoplasias Bucais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Neoplasias Bucais/genética , Proteômica , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Microambiente TumoralRESUMO
The biological aggressiveness of a tumor is determined by the ability of tumor cells to invade and metastasize which is a consequence of their acquisition of a number of phenotypic characteristics. Remodeling of the actin cytoskeleton occurs during cell migration which is carried out by various groups of actin binding proteins in the regulation of which proteasomes and calpains play an important role. Therefore the study of the relationship of proteins associated with cell motility with the processes of lymphogenous metastasis as well as the assessment of the regulatory role of intracellular proteases in these processes is extremely important for fundamental oncology. This study demonstrates the associations of actin-binding proteins with the activity of proteasomes and calpain, which are specific for tumors and metastases of the mammary gland. We proposed a possible scheme of the relationship of intracellular systems with the actin-binding proteins. The results obtained expand the fundamental understanding of the processes of tumor progression and can also be used in the search for proteins-targets for therapeutic action in molecular targeted cancer therapy.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Movimento Celular , Proteólise , Feminino , Humanos , Metástase LinfáticaRESUMO
Actin-binding proteins (ABPs) and various signaling systems are involved in the process of squamous cell carcinoma of the larynx and hypopharynx (SCCLH) metastasis. The clinical significance of these proteins has not yet been determined. We analyzed the relationship between the mRNA levels of cofilin 1 (CFL1), profilin 1 (PFN1), adenylyl cyclase-associated protein 1 (CAP1), SNAI1 and RND3 and SCCLH metastasis. The serum levels of the above ABPs were estimated and the relationship between them and their mRNA expressions was analyzed. The expression levels of ABP mRNAs were measured by real-time RT-PCR in paired tissue samples taken from 54 patients with SCCLH (T1-4N0-1M0). Expression analysis was performed using the 2-ΔΔCT method. The levels of ABPs in the blood serum were measured by ELISA. Statistical analysis was carried out using the SPSS Statistica 20.0 software package. No significant difference in the mRNA gene expression in tumor tissue of patients with T1-3N0M0 SCCLH and patients with T2-4N1-2M0 SCCLH was found. High expression of RND3 mRNA was accompanied by an increase in mRNA expression of all studied ABPs. In the blood serum of T2-4N1-2M0 patients, the level of PFN1 was lower by 21% and the level of CAP1 was higher by 75% than those observed in T1-4N0M0 patients. The data obtained showed that RND3 is involved in the regulation of molecular cascades of SCCLH metastasis. PFN1 and CAP1 serum levels can be good classifiers of metastases in patients with SCCLH.
Assuntos
Neoplasias Hipofaríngeas/metabolismo , Neoplasias Laríngeas/metabolismo , Proteínas dos Microfilamentos/genética , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Proteínas de Ciclo Celular/análise , Proteínas de Ciclo Celular/sangue , Proteínas de Ciclo Celular/genética , Cofilina 1/análise , Cofilina 1/sangue , Cofilina 1/genética , Proteínas do Citoesqueleto/análise , Proteínas do Citoesqueleto/sangue , Proteínas do Citoesqueleto/genética , Citoesqueleto/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Hipofaríngeas/sangue , Neoplasias Hipofaríngeas/genética , Neoplasias Laríngeas/sangue , Masculino , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Profilinas/análise , Profilinas/sangue , Profilinas/genética , RNA Mensageiro/genética , Federação Russa , Soro/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição da Família Snail/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Proteínas rho de Ligação ao GTP/genéticaRESUMO
The main cause of death in non-small-cell lung cancer (NSCLC) is tumor progression, in which metastasis and invasion play an important role. The metastatic cascade is marked by a change in morphological, biological, biochemical and functional characteristics, including the acquisition of cellular mobility. The migration activity of tumor cells determines the work of actin-binding proteins that cause their functional partners CAP1 and cofilin. Of interest is the study of the regulation of working tandem CAP1/cofilin in NSCLC. The mechanism that regulates the level of proteins in cells is proteolysis, carried out by proteasomes and calpains. Therefore, the aim of this study was to estimate the expression of CAP1/CFL1 mRNA and their protein level in NSCLC tissues, and to analyze the possible mechanisms of their regulation by the proteasome and calpain systems. Samples of NSCLC and histological unchanged lung tissue were used (n = 42). The CAP1 and CFL1 mRNA expressions were determined by real-time PCR, the contents of proteins encoded by them were determined by Western blotting, and the activity of proteasomes and calpains by the fluorimetric method. There was an increase in the expression of mRNA and protein levels of CAP1 and cofilin in the tumor tissue compared with the unchanged lung tissue. The expression of mRNA and the level of CAP1 in tumor tissue increased during growth of the primary tumor. The cofilin level in the tumor tissue decreases against the background of increased expression of its mRNA. At the same time, during tumor growth, the activity of proteasomes and calpains increased. A negative regression relationships between the activity of proteasomes and the levels of CAP1 and cofilin, as well as the activity of calpains and the level of cofilin, were found. It can be assumed that proteasomes and calpains are involved in the degradation of CAP1 and cofilin. The data obtained suggest the importance of CAP1, cofilin and proteolytic systems in the tumor transformation and lymphogenous metastasis.
Assuntos
Calpaína/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Ciclo Celular/metabolismo , Cofilina 1/metabolismo , Proteínas do Citoesqueleto/metabolismo , Neoplasias Pulmonares/genética , Calpaína/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/genética , Movimento Celular , Cofilina 1/genética , Proteínas do Citoesqueleto/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Proteólise , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de SinaisRESUMO
We analyzed the expression of genes encoding proteins involved in cytoskeleton remodeling (RND3, SNAI1, vimentin, cofilin, adenylate cyclase-associated protein 1, ezrin, and profilin) depending on the level of expression of protein phosphatase 1B (PPM1B) mRNA on the example of squamous cell carcinoma of the larynx and hypopharynx. Against the background of a high level of PPM1B expression, a significantly high level of profilin expression was noted. Metastasis correlated with the level of snai1 expression, while relapse after combination treatment was negatively associated with the level of vimentin expression. The obtained new data can reflect molecular peculiarities of the tumor growth in squamous cell carcinoma of the larynx and hypopharynx.
Assuntos
Citoesqueleto/genética , Neoplasias de Cabeça e Pescoço/genética , Recidiva Local de Neoplasia/genética , Profilinas/genética , Proteína Fosfatase 2C/genética , RNA Mensageiro/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Cofilina 1/genética , Cofilina 1/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Citoesqueleto/metabolismo , Citoesqueleto/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Hipofaringe/metabolismo , Hipofaringe/patologia , Laringe/metabolismo , Laringe/patologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Profilinas/metabolismo , Proteína Fosfatase 2C/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Vimentina/genética , Vimentina/metabolismo , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
Remodeling of the cytoskeleton underlies various cellular processes, including those associated with metastasis. The role of the proteases and proteins involved in cytoskeletal reorganization is being actively studied. However, there are no published data on the relationship between the mRNA expression levels of calpains 1/2 (CAPN 1/2) and the proteins associated with cytoskeleton remodeling. Therefore, the purpose of our study was to establish the relationship between the mRNA expression levels of CAPN 1/2 and the proteins involved in cytoskeletal reorganization, such as cell motility markers (SNAI1, VIM, and RND3) and actin-binding proteins (CFN1, PFN1, EZR, FSCN1, and CAP1) using the model of laryngeal/laryngopharyngeal squamous cell carcinoma (LC). The gene expression level was determined by reverse transcriptase real-time PCR and calculated using the 2-ΔΔCt method in paired tissue samples of 44 patients with LC (T1-4N0-2M0). The patients were divided into two groups: those with low and those with high CAPN 1/2 expression levels. It was found that metastasis in LC patients was associated with decreased expression levels of VIM and CAP1, and increased levels of CAPN1. A high level of CAPN2 was accompanied by a high expression level of EZR, indicating the activation of invasion processes. The results obtained need to be confirmed in further studies using a larger sample of patients and target genes. Our study is important in elucidating the mechanisms that underlie cancer progression and metastasis, a development that could subsequently open the way to a search for new prognostic and predictive markers of laryngeal/laryngopharyngeal cancer progression.
RESUMO
The actin-binding proteins profilin, fascin, and ezrin were tested for involvement in metastasis of non-small cell lung cancer (NSCLC). The levels of the PFN1, FSCN1, and EZR mRNAs and respective proteins were determined by real-time PCR and Western blotting; tumor and adjacent normal lung tissue samples were obtained from 46 NSCLC patients. Patients with lymphatic metastasis had higher expression levels of the profilin, fascin, and ezrin mRNAs and the profilin and fascin proteins. Both mRNA and protein expression levels increased in patients with distant metastasis. The molecules may serve as predictors to evaluate the prognosis in NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Transporte/metabolismo , Proteínas do Citoesqueleto/metabolismo , Neoplasias Pulmonares/patologia , Proteínas dos Microfilamentos/metabolismo , Profilinas/metabolismo , Linhagem Celular Tumoral , Humanos , Metástase Neoplásica , RNA MensageiroRESUMO
We analyzed the content of ß-catenin fractions and activity and content of proteasomes in the tissues of patients with non-small cells lung cancer. The content of ß-catenin fractions was elevated and proteasome-dependent proteolysis in the tumor tissue was enhanced in comparison with the corresponding unchanged lung tissue. A negative regression relationship of caspase-like activity of proteasomes and a positive correlation between the content of proteasomes and both fractions of ß-catenin were found. We hypothesize that proteasomes are involved in the degradation of ß-catenin due to caspase-like activity.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , beta Catenina/fisiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Caspases/metabolismo , Quimotripsina/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Via de Sinalização Wnt/fisiologia , beta Catenina/metabolismoRESUMO
We studied the expression of mRNA and the level of CAP1 (adenylate cyclase-associated protein 1) and cofilin proteins in the tissues of patients with non-small cell lung cancer. The expression of mRNA and the level of CAP1 in tumor tissue increased during growth of the primary tumor and its metastasis. It was shown that with the growth of the primary tumor, the content of cofilin in the tumor tissue decreases against the background of increased expression of its mRNA; in regional metastasis, the content of cofilin and expression of the corresponding mRNA increased. It was found that increased content of the studied proteins in the tumor tissue increased the risk of metastasis.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas de Ciclo Celular/genética , Cofilina 1/genética , Proteínas do Citoesqueleto/genética , Neoplasias Pulmonares/genética , RNA Mensageiro/biossíntese , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/metabolismo , Cofilina 1/metabolismo , Proteínas do Citoesqueleto/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Metástase Neoplásica/patologiaRESUMO
The model of head and neck squamous cell carcinoma (HNSCC) was used to study the expression of genes encoding actin-binding proteins depending on the type of cell motility. The expression of SNAIL1 and CAPN2 mRNA in HNSCC tissue was higher than in specimens of dysplastic epithelium of the larynx and hypopharynx, which can be explained by activation of mesenchymal and amoeboid types of cell motility. In biopsy material of HNSCC patients with T1-2N0M0, expression of genes responsible for actin-binding proteins differed from that of patients with pretumor pathology of the larynx and hypopharynx: expression of FSCN was lower, while expressions of EZR and CAP1 were higher. The data attest that progression of HNSCC is associated with activation of both types of cell motility and with the changes in the expression of mRNA encoding cell motility proteins.
Assuntos
Calpaína/genética , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Fatores de Transcrição da Família Snail/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Calpaína/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Cofilina 1/genética , Cofilina 1/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Progressão da Doença , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Hipofaringe/metabolismo , Hipofaringe/patologia , Laringe/metabolismo , Laringe/patologia , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Profilinas/genética , Profilinas/metabolismo , Transdução de Sinais , Fatores de Transcrição da Família Snail/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Vimentina/genética , Vimentina/metabolismo , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
Chymotrypsin- and caspase-like activities and expression of the total proteasome pool subunits (α1α2α3α5α6α7) were studied in patients with non-small-cell lung cancer. Proteasome activities were higher in the primary tumors and lymphogenic metastases than in corresponding adjacent lung tissue. The content of α1α2α3α5α6α7 subunits decreased in metastases and remained unchanged in primary tumor tissue. The development of metastatic process in non-small-cell lung cancer was associated with nonlinear changes in proteasome activities and content in primary tumor tissue and lymphogenic metastases.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Feminino , Humanos , Técnicas In Vitro , Metástase Linfática , Masculino , Pessoa de Meia-IdadeRESUMO
This review summarizes information available to date about the structural organization, regulation of functional activity of adenylyl cyclase-associated protein 1 (CAP1), and its participation in cellular processes. Numerous data are generalized on the role of CAP1 in the regulation of actin cytoskeleton and its interactions with many actin-binding proteins. Attention is drawn to the similarity of the structure of CAP1 and its contribution to the remodeling of actin filaments in prokaryotes and eukaryotes, as well as to the difference in the interaction of CAP1 with adenylyl cyclase in these cells. In addition, we discuss the participation of CAP1 in various pathological processes.
Assuntos
Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/metabolismo , Animais , HumanosRESUMO
To increase the sensitivity and specificity of the developed methods for diagnosis of oncological diseases using exosomes of blood, a stage of pre-selection of tumor exosomes from a common pool of circulating microvesicles is required. In the present work, universal proteins have been identified, their expression has been increased in the exosomes of patients with colorectal cancer, head and neck squamous cell carcinomas, and lung cancer. The use of antibodies against major exosomal proteins will further develop a simple and high-performance method of affinity isolation of tumor exosomes.
Assuntos
Micropartículas Derivadas de Células , Exossomos , Neoplasias Pulmonares , Humanos , ProteínasRESUMO
In patients with breast cancer and lung cancer, chymotrypsin-like and caspase-like activities of proteasomes and total activity of calpains in the primary tumor nodes and lymphogenic metastasis are elevated in comparison with the corresponding normal tissues. The development of lymphogenic metastases of breast cancer and lung cancer was associated with opposite change in caspase-like activity of proteasomes. These results can be useful for the development of methods for evaluation of aggressiveness of breast and lung cancer.
Assuntos
Neoplasias da Mama/metabolismo , Calpaína/metabolismo , Neoplasias Pulmonares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Adulto , Neoplasias da Mama/genética , Calpaína/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Complexo de Endopeptidases do Proteassoma/genéticaRESUMO
Here, we have investigated the participation of nuclear factors NF-kB, HIF-1 and HIF-2, VEGF, VEGFR2, and carboanhydrase IX in clear-cell renal cancer. We have determined the expression and protein level of transcription factors, VEGF, VEGFR2, and carboanhydrase IX in tumor and normal tissues of 30 patients with kidney cancer. The Real-Time PCR and ELISA were used in the study. The low levels of HIF-1 mRNA expression associated with high levels of HIF-1 protein were also associated with metastasis. The expression levels of VEGF, VEGFR2, and their protein levels are increased in primary tumors of patients with disseminated kidney cancer compared to nonmetastatic cancer. No correlation was revealed between the content of mRNA and encoded proteins in the kidney cancer tissues. The changes in the ratios of mRNA levels and the respective proteins (HIF-1α, HIF-2, NF-kB, VEGF, VEGFR2, and carboanhydrase IX) may contribute to kidney-cancer metastasis.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação Neoplásica da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/metabolismo , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Fator A de Crescimento do Endotélio Vascular/biossíntese , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , Metástase Neoplásica , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
It is necessary to maintain the safety of the cell proteome for the operation and adequate biological response of tumor cells to changing conditions, which is provided by chaperones and ATP-dependent proteases. Molecular chaperones, which include the small heat shock proteins, carry out folding, refolding and misfolding of proteins, support functional activity of intracellular proteins. Proteases, mainly proteasome, degrade abnormal, damaged and fulfilling its function proteins. The review presents modern data on the role of the proteasome and heat shock proteins in malignant tumors as well as the mechanism of interaction of these systems in the cell.
Assuntos
Proteínas de Choque Térmico Pequenas/genética , Chaperonas Moleculares/genética , Neoplasias/genética , Complexo de Endopeptidases do Proteassoma/genética , Movimento Celular/genética , Proteínas de Choque Térmico Pequenas/química , Humanos , Chaperonas Moleculares/química , Metástase Neoplásica , Neoplasias/patologia , Complexo de Endopeptidases do Proteassoma/química , Dobramento de Proteína , Ubiquitina/químicaRESUMO
Activation of AKT signaling pathway and mTOR substrates of kidney tumor tissue occurs by improving AKT, its phosphorylated form, the serine / threonine proteinkinase m-TOR, the exchange regulator glycogen GSK-3-beta and also the inhibitor of 4E-BP1transcription. Increasing the size of primary tumor is followed by increasing the content of therein c-Raf and decreasing the content of phospho-m-TOR. The development of disseminated forms of the disease was associated with a reduction PTEN and phospho-AKT in tumor.