RESUMO
Clear-cell renal-cell carcinoma (ccRCC) is a silent-development pathology with a high rate of metastasis in patients. The activity of coding genes in metastatic progression is well known. New studies evaluate the association with non-coding genes, such as competitive endogenous RNA (ceRNA). This study aims to build a ceRNA network and a gene signature for ccRCC associated with metastatic development and analyze their biological functions. Using data from The Cancer Genome Atlas (TCGA), we constructed the ceRNA network with differentially expressed genes, assembled nine preliminary gene signatures from eight feature selection techniques, and evaluated the classification metrics to choose a final signature. After that, we performed a genomic analysis, a risk analysis, and a functional annotation analysis. We present an 11-gene signature: SNHG15, AF117829.1, hsa-miR-130a-3p, hsa-mir-381-3p, BTBD11, INSR, HECW2, RFLNB, PTTG1, HMMR, and RASD1. It was possible to assess the generalization of the signature using an external dataset from the International Cancer Genome Consortium (ICGC-RECA), which showed an Area Under the Curve of 81.5%. The genomic analysis identified the signature participants on chromosomes with highly mutated regions. The hsa-miR-130a-3p, AF117829.1, hsa-miR-381-3p, and PTTG1 were significantly related to the patient's survival and metastatic development. Additionally, functional annotation resulted in relevant pathways for tumor development and cell cycle control, such as RNA polymerase II transcription regulation and cell control. The gene signature analysis within the ceRNA network, with literature evidence, suggests that the lncRNAs act as "sponges" upon the microRNAs (miRNAs). Therefore, this gene signature presents coding and non-coding genes and could act as potential biomarkers for a better understanding of ccRCC.
Assuntos
Carcinoma de Células Renais , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Neoplasias Renais , Aprendizado de Máquina , Humanos , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Biomarcadores Tumorais/genética , Metástase Neoplásica/genética , MicroRNAs/genética , Perfilação da Expressão Gênica/métodos , Transcriptoma , RNA Endógeno CompetitivoRESUMO
The Coatomer protein complex subunit beta 2 (COPB2) is involved in the formation of the COPI coatomer protein complex and is responsible for the transport of vesicles between the Golgi apparatus and the endoplasmic reticulum. It plays an important role in maintaining the integrity of these cellular organelles, as well as in maintaining cell homeostasis. More importantly, COPB2 plays key roles in embryonic development and tumor progression. COPB2 is regarded as a vital oncogene in several cancer types and has been implicated in tumor cell proliferation, survival, invasion, and metastasis. Here, we summarize the current knowledge on the roles of COPB2 in cancer development and progression in the context of the hallmarks of cancer.
Assuntos
Proteína Coatomer/fisiologia , Neoplasias/etiologia , Animais , Apoptose/genética , Apoptose/fisiologia , Morte Celular Autofágica/fisiologia , Ciclo Celular/fisiologia , Proliferação de Células/genética , Sobrevivência Celular/genética , Proteína Coatomer/genética , Modelos Animais de Doenças , Progressão da Doença , Desenvolvimento Embrionário , Retículo Endoplasmático/fisiologia , Complexo de Golgi/fisiologia , Homeostase , Humanos , Camundongos , Invasividade Neoplásica/genética , Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/genética , Metástase Neoplásica/fisiopatologia , Neoplasias/patologia , Vesículas Transportadoras/fisiologiaRESUMO
Despite advances in therapeutics, the progression of melanoma to metastasis still confers a poor outcome to patients. Nevertheless, there is a scarcity of biological models to understand cellular and molecular changes taking place along disease progression. Here, we characterized the transcriptome profiles of a multi-stage murine model of melanoma progression comprising a nontumorigenic melanocyte lineage (melan-a), premalignant melanocytes (4C), nonmetastatic (4C11-) and metastasis-prone (4C11+) melanoma cells. Clustering analyses have grouped the 4 cell lines according to their differentiated (melan-a and 4C11+) or undifferentiated/"mesenchymal-like" (4C and 4C11-) morphologies, suggesting dynamic gene expression patterns associated with the transition between these phenotypes. The cell plasticity observed in the murine melanoma progression model was corroborated by molecular markers described during stepwise human melanoma differentiation, as the differentiated cell lines in our model exhibit upregulation of transitory and melanocytic markers, whereas "mesenchymal-like" cells show increased expression of undifferentiated and neural crest-like markers. Sets of differentially expressed genes (DEGs) were detected at each transition step of tumor progression, and transcriptional signatures related to malignancy, metastasis and epithelial-to-mesenchymal transition were identified. Finally, DEGs were mapped to their human orthologs and evaluated in uni- and multivariate survival analyses using gene expression and clinical data of 703 drug-naïve primary melanoma patients, revealing several independent candidate prognostic markers. Altogether, these results provide novel insights into the molecular mechanisms underlying the phenotypic switch taking place during melanoma progression, reveal potential drug targets and prognostic biomarkers, and corroborate the translational relevance of this unique sequential model of melanoma progression.
Assuntos
Plasticidade Celular/genética , Progressão da Doença , Melanoma/genética , Melanoma/patologia , Transcriptoma/genética , Animais , Biomarcadores Tumorais/análise , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/fisiologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Melanócitos/patologia , Camundongos , Metástase Neoplásica/genética , Fenótipo , Prognóstico , RNA Mensageiro/genética , Análise de Sequência de RNARESUMO
El seminoma es la neoplasia testicular más frecuente alcanzando hasta el 50% de todos los casos de cancer del testículo. Dependiendo de su naturaleza, seminomatoso o no seminomatoso, las conductas de manejo y tratamiento médico quirúrgicas varían según los centros, los protocolos de manejo y la experiencia de los equipos de atención. Objetivos. Promover la discusión de adyuvancia o neoadyuvancia en caso de seminoma clásico. Paciente y Método. Presentar un caso de seminoma clásico tratado quirúrgicamente con orquidectomía y una década después se presenta con extensión metastásica mediastinal y retroperitoneal. Conclusiones. Para la etiología no seminomatosa, se establece la orquidectomía seguida de vigilancia; mientras que en caso de origen seminomatoso la discusión se basa en el momento del rol de la cirugía, radiación y quimioterapia, por lo tanto, se debe individualizar cada paciente según las características clínicas manifestadas. (AU)
Seminoma is the most common testicular neoplasm, reaching up to 50% of all cases of testicular cancer. Depending on its nature, seminomatous or non-seminomatous, the management behaviors and surgical medical treatment vary according to the centers, the management protocols and the experience of the care teams. Objective. Promote the discussion of adjuvant or neoadjuvant in case of classic seminoma. Patient and Method. To present a case of classic seminoma treated surgically with orchidectomy and a decade later it presents with mediastinal and retroperitoneal metastatic extension. Conclusions. For non-seminomatous etiology, orchidectomy followed by surveillance is established; while in the case of seminomatous origin, the discussion is based on the time of the role of surgery, radiation and chemotherapy, therefore, each patient must be individualized according to the clinical characteristics manifested. (AU)
Assuntos
Humanos , Masculino , Adulto , Neoplasias Testiculares/fisiopatologia , Seminoma/diagnóstico , Metástase Neoplásica/genética , Teratoma/classificação , Testículo/patologia , Radiografia/métodosRESUMO
BACKGROUND: We have previously developed a murine cellular system that models the transformation from melanocytes to metastatic melanoma cells. This model was established by cycles of anchorage impediment of melanocytes and consists of four cell lines: differentiated melanocytes (melan-a), pre-malignant melanocytes (4C), malignant (4C11-), and metastasis-prone (4C11+) melanoma cells. Here, we searched for transcriptional and epigenetic signatures associated with melanoma progression and metastasis by performing a gene co-expression analysis of transcriptome data and a mass-spectrometry-based profiling of histone modifications in this model. RESULTS: Eighteen modules of co-expressed genes were identified, and some of them were associated with melanoma progression, epithelial-to-mesenchymal transition (EMT), and metastasis. The genes in these modules participate in biological processes like focal adhesion, cell migration, extracellular matrix organization, endocytosis, cell cycle, DNA repair, protein ubiquitination, and autophagy. Modules and hub signatures related to EMT and metastasis (turquoise, green yellow, and yellow) were significantly enriched in genes associated to patient survival in two independent melanoma cohorts (TCGA and Leeds), suggesting they could be sources of novel prognostic biomarkers. Clusters of histone modifications were also linked to melanoma progression, EMT, and metastasis. Reduced levels of H4K5ac and H4K8ac marks were seen in the pre-malignant and tumorigenic cell lines, whereas the methylation patterns of H3K4, H3K56, and H4K20 were related to EMT. Moreover, the metastatic 4C11+ cell line showed higher H3K9me2 and H3K36me3 methylation, lower H3K18me1, H3K23me1, H3K79me2, and H3K36me2 marks and, in agreement, downregulation of the H3K36me2 methyltransferase Nsd1. CONCLUSIONS: We uncovered transcriptional and histone modification signatures that may be molecular events driving melanoma progression and metastasis, which can aid in the identification of novel prognostic genes and drug targets for treating the disease.
Assuntos
Transição Epitelial-Mesenquimal/genética , Expressão Gênica/genética , Código das Histonas/genética , Melanoma/genética , Melanoma/patologia , Metástase Neoplásica/genética , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Epigênese Genética , Humanos , CamundongosRESUMO
Los contenidos de este capítulo se basan en la 3a edición de las Clínicas Quirúrgicas de Cáncer Colorrectal. C. Vaccaro y N. Peralta. del hospital ediciones 2020 (en prensa)
Assuntos
Neoplasias Colorretais/genética , Biomarcadores Tumorais/genética , Medicina de Precisão/tendências , Farmacogenética/tendências , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/terapia , Epidemiologia Molecular/tendências , Mutação , Metástase Neoplásica/genética , Metástase Neoplásica/terapiaRESUMO
BACKGROUND AND OBJECTIVES: DNA repair is a new and important pathway that explains colorectal carcinogenesis. This study will evaluate the prognostic value of molecular modulation of double-strand break repair (XRCC2 and XRCC5); DNA damage tolerance/translesion synthesis (POLH, POLK, and POLQ), and interstrand crosslink repair (DCLRE1A) in sporadic colorectal cancer (CRC). METHODS: Tumor specimens and matched healthy mucosal tissues from 47 patients with CRC who underwent surgery were assessed for gene expression of XRCC2, XRCC5, POLH, POLK, POLQ, and DCLRE1A; protein expression of Polk, Ku80, p53, Ki67, and mismatch repair MLH1 and MSH2 components; CpG island promoter methylation of XRCC5, POLH, POLK, POLQ, and DCLRE1A was performed. RESULTS: Neoplastic tissues exhibited induction of POLK (P < .001) and DCLRE1A (P < .001) expression and low expression of POLH (P < .001) and POLQ (P < .001) in comparison to healthy paired mucosa. Low expression of POLH was associated with mucinous histology and T1-T2 tumors (P = .038); low tumor expression of POLK was associated with distant metastases (P = .042). CRC harboring POLK promoter methylation exhibited better disease-free survival (DFS) (P = .005). CONCLUSIONS: This study demonstrated that low expression or unmethylated POLH and POLK were related to worse biological behavior tumors. However, POLK methylation was associated with better DFS. POLK and POLH are potential prognostic biomarkers in CRC.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Idoso , Biomarcadores/metabolismo , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Neoplasias Colorretais/metabolismo , Ilhas de CpG , Dano ao DNA , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , DNA Polimerase Dirigida por DNA/genética , DNA Polimerase Dirigida por DNA/metabolismo , Intervalo Livre de Doença , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , Feminino , Expressão Gênica , Humanos , Autoantígeno Ku/genética , Autoantígeno Ku/metabolismo , Masculino , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Metástase Neoplásica/genética , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , DNA Polimerase tetaRESUMO
Endothelin-1 is a mitogenic peptide that activates several proliferation, survival, and invasiveness pathways. The effects of endothelin-1 rely on its activation by endothelin-converting enzyme-1 (ECE1), which is expressed as four isoforms with different cytoplasmic N termini. Recently, isoform ECE1c has been suggested to have a role in cancer aggressiveness. The N terminus of ECE1c is phosphorylated by protein kinase CK2 (also known as casein kinase 2), and this enhances its stability and promotes invasiveness in colorectal cancer cells. However, it is not known how phosphorylation improves stability and why this is correlated with increased aggressiveness. We hypothesized that CK2 phosphorylation protects ECE1c from N-terminal ubiquitination and, consequently, from proteasomal degradation. Here, we show that lysine 6 is the bona fide residue involved in ubiquitination of ECE1c and its mutation to arginine (ECE1cK6R ) significantly impairs proteasomal degradation, thereby augmenting ECE1c stability, even in the presence of the CK2 inhibitor silmitasertib. Furthermore, colorectal cancer cells overexpressing ECE1cK6R displayed enhanced cancer stem cell (CSC) traits, including increased stemness gene expression, chemoresistance, self-renewal, and colony formation and spheroid formation in vitro, as well as enhanced tumor growth and metastasis in vivo. These findings suggest that CK2-dependent phosphorylation enhances ECE1c stability, promoting an increase in CSC-like traits. Therefore, phospho-ECE1c may be a biomarker of poor prognosis and a potential therapeutic target for colorectal cancer.
Assuntos
Carcinogênese/metabolismo , Neoplasias Colorretais/metabolismo , Enzimas Conversoras de Endotelina/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Carcinogênese/genética , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/genética , Caseína Quinase II/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Enzimas Conversoras de Endotelina/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Naftiridinas/farmacologia , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Fenazinas/farmacologia , Fosforilação , Prognóstico , Estabilidade Proteica , Proteínas Recombinantes , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Caveolin-1 (CAV1) is a scaffolding protein with a controversial role in cancer. This review will initially discuss earlier studies focused on the role as a tumor suppressor before elaborating subsequently on those relating to function of the protein as a promoter of metastasis. Different mechanisms are summarized illustrating how CAV1 promotes such traits upon expression in cancer cells (intrinsic mechanisms). More recently, it has become apparent that CAV1 is also a secreted protein that can be included into exosomes where it plays a significant role in determining cargo composition. Thus, we will also discuss how CAV1 containing exosomes from metastatic cells promote malignant traits in more benign recipient cells (extrinsic mechanisms). This ability appears, at least in part, attributable to the transfer of specific cargos present due to CAV1 rather than the transfer of CAV1 itself. The evolution of how our perception of CAV1 function has changed since its discovery is summarized graphically in a time line figure.