RESUMO
Colorectal cancer (CRC) remains the second most lethal cancer worldwide, with incidence rates expected to rise substantially by 2040. Although biomarker-driven therapies have improved treatment, responses to standard chemotherapeutics, such as 5-fluorouracil (5-FU), oxaliplatin, and irinotecan, vary considerably. This clinical heterogeneity emphasizes the urgent need for novel biomarkers that can guide therapeutic decisions and overcome chemoresistance. microRNAs (miRNAs) have emerged as key post-transcriptional regulators that critically influence chemotherapy responses. miRNAs orchestrate post-transcriptional gene regulation and modulate diverse pathways linked to chemoresistance. They influence drug transport by regulating ABC transporters and affect metabolic enzymes like thymidylate synthase (TYMS). These activities shape responses to standard CRC chemotherapy agents. Furthermore, miRNAs can regulate the epithelial-mesenchymal transition (EMT). The miR-200 family (e.g., miR-200c and miR-141) can reverse EMT phenotypes, restoring chemosensitivity. Additionally, miRNAs like miR-19a and miR-625-3p show predictive value for chemotherapy outcomes. Despite these promising findings, the clinical translation of miRNA-based biomarkers faces challenges, including methodological inconsistencies and the dynamic nature of miRNA expression, influenced by the tumor microenvironment. This review highlights the critical role of miRNAs in elucidating chemoresistance mechanisms and their promise as biomarkers and therapeutic targets in CRC, paving the way for a new era of precision oncology.
Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Humanos , MicroRNAs/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Animais , Microambiente Tumoral/genética , Microambiente Tumoral/efeitos dos fármacosRESUMO
Oral squamous cell carcinoma (OSCC) is the main form of head and neck cancer. Gap junctions (GJs) are communication channels involved in cell proliferation control; they consist of hemichannels formed by connexin (Cx) proteins. The abnormal expression/function of Cx43 has been associated with tumor progression. Also, some human papillomaviruses (HPVs) have been linked to squamous cell cancer. Therefore, this study aimed at assessing Cx43 as a potential OSCC biomarker and exploring its association with histopathological differentiation and HPV infection. OSCC samples were inspected using hematoxylin and eosin staining, and Cx43 expression and HPV 16/18 were tested by immunofluorescence. Pearson correlation tests, ANOVA, and Kaplan-Meier curves were used in the analysis. Samples from 39 patients with OSCC were studied. Most had well-differentiated histology and 61.5% were HPV+. Cx43 expression was significantly associated with HPV infection (p = 0.047), differentiation (p < 0.001), and survival (p = 0.009), and HPV positivity was also associated with the degree of differentiation (p = 0.012). Cx43 shows potential as a prognostic biomarker for OSCC. Lower Cx43 expression, correlated with poorer differentiation, is associated with an unfavorable prognosis. Further studies are needed to confirm its clinical utility.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas , Conexina 43 , Papillomavirus Humano 16 , Papillomavirus Humano 18 , Neoplasias Bucais , Infecções por Papillomavirus , Humanos , Conexina 43/metabolismo , Conexina 43/genética , Papillomavirus Humano 16/genética , Feminino , Biomarcadores Tumorais/metabolismo , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Carcinoma de Células Escamosas/virologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias Bucais/virologia , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Idoso , Papillomavirus Humano 18/genética , Prognóstico , Adulto , Estimativa de Kaplan-MeierRESUMO
PURPOSE: Oral squamous cell carcinoma (OSCC) is a significant public health challenge associated with high mortality rates primarily due to its invasive and metastatic behavior. This study aimed to evaluate the expression patterns of five critical biomarkers: ß-catenin, E-cadherin, podoplanin (PDPN), CXCR4, and p53 in OSCC tissues and to investigate their correlations with clinicopathologic features and patient outcomes. METHODS: We conducted an immunohistochemical analysis utilizing tissue microarrays (TMAs) from 95 patients diagnosed with primary OSCC. The expression levels of the five biomarkers were quantified using H-scores. Statistical analyses, including Kruskal-Wallis tests, Dunn's post-hoc tests, and correlation analyses, were performed to explore the associations between biomarker expression, clinicopathologic parameters, and overall patient survival. RESULTS: The study found that loss of E-cadherin and ß-catenin expression was significantly associated with increased tumor depth and lymphatic invasion, corroborating their role in the process of epithelial-mesenchymal transition (EMT). High levels of PDPN were noted in both early and late-stage OSCC, indicating its potential involvement in initiating invasive behaviors. Notably, CXCR4 expression exhibited positive correlations with E-cadherin and ß-catenin, suggesting a hybrid invasion phenotype incorporating both EMT and collective invasion strategies. Although Cox regression analysis did not reveal significant associations between biomarker expression and overall survival (OS) or disease-specific survival (DSS), factors such as alcohol consumption, tumor size, lymph node involvement, and advanced clinical stage emerged as significant negative predictors of both OS and DSS. CONCLUSION: The expression profiles of ß-catenin, E-cadherin, PDPN, CXCR4, and p53 in OSCC tissues provide valuable insights into a hybrid model of invasion that integrates mechanisms of EMT with an important rule in the tumor invasion. This nuanced understanding of OSCC progression highlights the potential of PDPN and CXCR4 as novel therapeutic targets, emphasizing the need for further investigation into their roles in OSCC biology and the development of targeted treatments that could improve patient outcomes and survival rates.
Assuntos
Biomarcadores Tumorais , Caderinas , Imuno-Histoquímica , Glicoproteínas de Membrana , Neoplasias Bucais , Receptores CXCR4 , Análise Serial de Tecidos , Proteína Supressora de Tumor p53 , beta Catenina , Humanos , Neoplasias Bucais/patologia , Neoplasias Bucais/metabolismo , Caderinas/metabolismo , Caderinas/biossíntese , Receptores CXCR4/metabolismo , Receptores CXCR4/biossíntese , Masculino , beta Catenina/biossíntese , beta Catenina/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Feminino , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/biossíntese , Idoso , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/metabolismo , Adulto , Invasividade Neoplásica , Antígenos CD/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Idoso de 80 Anos ou maisRESUMO
Adult-type diffuse gliomas arise from glial or progenitor cells. These tumors are currently classified as astrocytoma isocitrate dehydrogenase (IDH)-mutant or IDH-mutant oligodendroglioma with co-deletion of chromosomal arms 1p and 19q, both of which could be either slow-growing tumors, or glioblastoma (GBM), which is a more aggressive tumor. Despite advances in diagnosis and treatment, the median survival time after GBM diagnosis remains low at approximately 15 months, with a 5-year overall survival (OS) rate of 6.8 %. Therefore, new biomarker and therapeutic target discoveries are required to improve prognosis. Mucin 1 (MUC1) and MUC4 are membrane-bound mucins and potential biomarkers of several tumors. However, the role of these mucins in adult gliomas has not been well explored. In this retrospective study, in silico analysis of data from patients with adult-type diffuse glioma revealed differential methylation and expression patterns of MUC1 and MUC4 between GBM and non-GBM groups. In the GBM group, decreased methylation and elevated expression of MUC1 were observed (r = -0.25, p < 0.0001), whereas increased methylation and decreased expression of MUC4 were observed (r = -0.13, p = 0.1344). Conversely, in the non-GBM group, MUC1 exhibited higher methylation and lower expression (r = -0.27, p < 0.0001), whereas MUC4 showed lower methylation and higher expression (r = -0.32, p < 0.0001). The expression of these genes influenced OS in adult patients with glioma (p = 0.0344), with high MUC1 and low MUC4 expression associated with worse OS. MUC1 and MUC4 expression correlated with that of MUC20 in both GBM (r = 0.54) and non-GBM (r = 0.53) groups (p < 0.0001). Functional enrichment analysis identified the biological roles of MUC1-co-expressed genes as involvement in innate immunity, antigen processing, and proinflammatory responses in both the non-GBM and GBM groups, and integrin-based signaling pathways in the GBM group. MUC4-co-expressed genes are involved in ion transport in GBM patients. Using molecular docking, we observed that MUC1 domains physically interact with immune response-related proteins, such as receptors for advanced glycation end products (RAGE), major histocompatibility complex II (MHC-II), and extracellular matrix receptor integrin alpha 2 (ITGA2). To our knowledge, this is the first retrospective study and in silico analysis demonstrating the relevance and correlation of MUC1 and MUC4 in adult gliomas. These findings elucidate the molecular mechanisms underlying adult-type diffuse glioma progression and highlight MUC1 and MUC4 as potential prognostic markers and therapeutic targets for glioma management.
Assuntos
Glioma , Mucina-1 , Mucina-4 , Humanos , Mucina-1/genética , Mucina-1/metabolismo , Mucina-4/genética , Mucina-4/metabolismo , Glioma/metabolismo , Glioma/genética , Glioma/imunologia , Adulto , Masculino , Regulação Neoplásica da Expressão Gênica , Feminino , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Metilação de DNARESUMO
OBJECTIVE: TRIB3 has been confirmed to participate in and regulate biological metabolic activities in head and neck tumors such as nasopharyngeal carcinoma and oropharyngeal carcinoma, so the purpose of this study was to explore whether there is a correlation between TRIB3 and Laryngeal Squamous Cell Carcinoma (LSCC) and to preliminarily explore the biological characteristics of TRIB3 in LSCC. METHODS: TRIB3 expression in the LSCC was analyzed based on The Cancer Genome Atlas (TCGA) database. CCK-8 assay, Colony Formation Assay, wound healing assay, and Transwell assay were performed to investigate the roles of TRIB3 in the proliferation, invasion and metastasis of LSCC. The Protein-Protein Interaction (PPI) network of TRIB3 was analyzed based on the STRING database. Western blotting and qRT-PCR were employed to detect the protein and mRNA expression of TRIB3. RESULTS: TRIB3 over-expressed in the LSCC, which was related to the poor prognosis of LSCC. Patients with methylation related to high TRIB3 expression had a poorer prognosis. Knock-down of TRIB3 expression suppresses the growth, invasion and migration of LSCCs via PI3K / AKT / mTOR. TIME analysis, surface checkpoint analysis, and prediction model indicated that TRIB3 related risk model displayed a poor prognosis. CONCLUSION: This study investigates the role of TRIB3 in the biological characteristics of LSCC, and preliminarily concludes that TRIB3 may be a potentially promising prognostic biomarker for LSCC. TRIB3 may facilitate the growing, invasive and migrating LSCC, leading to a poor prognosis.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas , Proteínas de Ciclo Celular , Neoplasias Laríngeas , Fosfatidilinositol 3-Quinases , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Humanos , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/metabolismo , Prognóstico , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proliferação de Células/genética , Transdução de Sinais , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Movimento Celular/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genéticaRESUMO
Acute lymphoblastic leukemia (ALL) is a malignant neoplasm with the highest incidence in the pediatric population. Although the 5-year overall survival is greater than 85%, in emerging countries such as Mexico, the mortality rate is high. In Mexico, B-ALL is the most common type of childhood cancer; different characteristics suggest the presence of the disease; however, the prognosis is dependent on clinical and laboratory features, and no adverse prognostic molecular marker for B-ALL has yet been identified. The present research aimed to identify the prognostic value of HMMR expression in pediatric patients with B-ALL. The differential expression profile of B-ALL cells was determined via in silico analysis, and HMMR expression was subsequently measured via qRT-PCR and immunocytochemistry. The results were statistically analyzed via the ROUT test, Kolmogorov-Smirnov Z test, and Mann-Whitney U test. ROC curves and the Youden index were constructed, and Kaplan-Meier curves were plotted. We found that HMMR expression was increased in B-ALL patients (p < 0.0001). We observed that high expression was related to poor prognosis (p < 0.05). We observed that high expression was related to poor prognosis (p < 0.05). The increase in HMMR expression could be a potential early molecular prognostic marker and/or a new target in childhood B-ALL patients.
Assuntos
Biomarcadores Tumorais , Receptores de Hialuronatos , Humanos , Feminino , Masculino , Criança , Prognóstico , Pré-Escolar , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Receptores de Hialuronatos/metabolismo , Receptores de Hialuronatos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Lactente , Estimativa de Kaplan-Meier , Adolescente , México/epidemiologia , Curva ROC , Proteínas da Matriz ExtracelularRESUMO
OBJECTIVE: This study aimed to investigate the influence of p16 immunohistochemical expression on the biochemical recurrence rate of pT2-pT3 prostate cancer. MATERIALS AND METHODS: A total of 488 pT2-pT3 stage prostate adenocarcinomas undergoing radical prostatectomy were included in this study. Following a review of Gleason classification and retrieval of sociodemographic and clinicopathological data, as well as the date of last consultation and biochemical recurrence, immunohistochemistry for p16 was performed. Data were associated using the chi-square test, Fisher's exact test, and multinomial logistic regression model. RESULTS: A total of 432(94.5%) cases showed positivity for p16 with an average of 37.38±27.32% positive cells and a mean histoscore of 2.70±2.24. A total of 117 (18.4%) patients experienced biochemical recurrence within three years, which was directly associated with high preoperative PSA (p=0.007), positive surgical margins (p<0.001), pT3 staging (p<0.001), nodal involvement (p<0.001), Gleason score > 3+4 (p<0.001), <50% positivity for p16 (p=0.035), and histoscore p16 =<3 (p=0.004). In multivariate analysis, Gleason score > 3+4 (HR = 3.08 (95% CI = 1.69-5.62), positive surgical margins (HR = 2.93 (95% CI = 1.70-5.04), and histoscore p16 =<3 (HR = 2.49 (95% CI = 1.17-5.32) were predictors of biochemical recurrence within three years. CONCLUSION: p16 immunostaining, along with classical features such as Gleason Score and surgical margin involvement, are significant predictors of biochemical recurrence in pT2-pT3 prostate tumors.
Assuntos
Biomarcadores Tumorais , Inibidor p16 de Quinase Dependente de Ciclina , Gradação de Tumores , Recidiva Local de Neoplasia , Prostatectomia , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/cirurgia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Biomarcadores Tumorais/metabolismo , Pessoa de Meia-Idade , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Prognóstico , Seguimentos , Idoso , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Antígeno Prostático Específico/metabolismo , Antígeno Prostático Específico/sangue , Imuno-Histoquímica , Estudos Retrospectivos , Fatores de RiscoRESUMO
OBJECTIVE: To determine the association of a metabolomic profile with the diagnosis of localized prostate cancer. METHODS: We conducted a search strategy in MEDLINE (OVID), EMBASE, LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL) from 2008 to the present. We included Clinical trials and analytical and descriptive observational studies that reported metabolite results and metabolite profiles in serum, tissue, urine, and seminal fluid. All studies used metabolomic techniques such as MS and MRI to identify patients with localized prostate cancer compared with patients without cancer. We used QUADAS 2 to assess the risk of bias. RESULTS: We found 1248 studies with the search strategy. Finally, 14 case-control studies were included. Serum was the primary sample to identify the metabolites. Low concern was found regarding applying the index test and the reference standard in assessing the risk of bias. The metabolites of interest associated with establishing a metabolomic profile in the diagnosis of localized prostate cancer were amino acids, lipids, androgens, estrogens, nucleotides, and histidine metabolism. CONCLUSION: Disturbances in the metabolism of fatty acids, amino acids, nucleotides, and steroid hormones were identified, suggesting the presence of localized prostate cancer. Importantly, serum samples showed an increase in amino acid levels. Glutamate and aspartic acid stand out among the amino acids that register high levels. In addition, glycine and serine were consistently decreased metabolites in the three kinds of biological samples analyzed.
Assuntos
Metabolômica , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/sangue , Metabolômica/métodos , Metaboloma , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Aminoácidos/metabolismo , Aminoácidos/sangueRESUMO
Objective: The average age of patients with vulvar squamous cell carcinoma (SCC) has been reported to have declined. Human papilloma virus (HPV)-related lesions have been shown to be associated with the expression of the immunohistochemical (IHC) marker p16. Non-HPV-related tumors have been characterized by p53 abnormal expression and PDL1 expression. We aimed to evaluate the correlation between these markers and vulvar SCC and to relate it to the clinical and pathological characteristics. Methods: Histopathologic assessments and IHC analyses of p16, p53, and PDL1 were performed in 41 samples of vulvar SCC collected between 2016 and 2021. The data were correlated with clinical and pathological characteristics of the patients. Results: The mean age of the patients was 72.1 years. Positive p16 and PDL1 staining was detected in 24.4% and 17.1% of the samples, respectively. p53 expression was negative in 19.5% of the samples, whereas it was overexpressed in 24.4%. p16-positive tumors showed a smaller depth of invasion (DOI) (p = 0.014), while tumors with p53 abnormal expression showed greater DOI (p = 0.041). PDL1 expression was correlated with increased number of inflammatory cells (p = 0.055). In addition, lesions with lymphovascular space invasion were p16-negative. Conclusion: In our sample, regarding to the SCC incidence the patients' mean age did not change. The expression of p16 was inversely correlated with p53 results. Tumors with p53 abnormal expression and absence of p16 showed a greater DOI. Our data suggest an association between PDL1 expression and increased inflammatory infiltrates in vulvar SCC.
Assuntos
Carcinoma de Células Escamosas , Inibidor p16 de Quinase Dependente de Ciclina , Imuno-Histoquímica , Neoplasias Vulvares , Humanos , Feminino , Neoplasias Vulvares/patologia , Neoplasias Vulvares/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/química , Idoso , Pessoa de Meia-Idade , Inibidor p16 de Quinase Dependente de Ciclina/análise , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/metabolismo , Antígeno B7-H1/análise , Antígeno B7-H1/metabolismo , AdultoRESUMO
Medullary thyroid carcinoma (MTC) is a rare and aggressive tumor, often requiring systemic treatment in advanced or metastatic stages, where drug resistance presents a significant challenge. Given the role of cancer stem cells (CSCs) in cancer recurrence and drug resistance, we aimed to identify CSC subpopulations within two MTC cell lines harboring pathogenic variants in the two most common MEN2-associated codons. We analyzed 15 stemness-associated markers, along with well-established thyroid stem cell markers (CD133, CD44, and ALDH1), a novel candidate (DLK1), and multidrug resistance proteins (MRP1 and MRP3). The ability to efflux the fluorescent dye Hoechst 3342 and form spheroids, representing CSC behavior, was also assessed. MZ-CRC-1 cells (p.M918T) displayed higher expressions of canonical markers, DLK1, and MRP proteins than TT cells (p.C634W). MZ-CRC-1 cells also formed more spheroids and showed less dye accumulation (p < 0.0001). Finally, we observed that DLK1+ cells (those expressing DLK1) in both cell lines exhibited significantly higher levels of stemness markers compared to DLK1- cells (those lacking DLK1 expression). These findings underscore DLK1's role in enhancing the stemness phenotype, providing valuable insights into MTC progression and resistance and suggesting potential therapeutic implications.
Assuntos
Proteínas de Ligação ao Cálcio , Carcinoma Neuroendócrino , Células-Tronco Neoplásicas , Neoplasias da Glândula Tireoide , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Linhagem Celular Tumoral , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/genética , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Fenótipo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Esferoides Celulares/metabolismo , Esferoides Celulares/patologiaRESUMO
OBJECTIVE: To evaluate the influence of MMR complex protein immunoexpression on disease-free survival in oropharyngeal SCC treated non-surgically. MATERIALS AND METHODS: 85 cases of oropharyngeal SCC diagnosed and treated at the Ceará Cancer Institute were surveyed, from which clinical-pathological data and paraffin blocks of incisional biopsies were retrieved for immunohistochemical reaction for MSH2, MSH6, PMS2, MLH1 and p16. Disease-free survival was calculated and Kruskal-Wallis and Friedman/Dunn tests, chi-square and Fisher's exact, Log-Rank Mantel Cox and Cox regression were performed. RESULTS: In p16- tumors, loss of MSH2 expression was associated with shorter disease-free survival (p = 0.035) and mean MSH6 expression was significantly higher than MSH2 (p = 0.001). Loss of MSH2 expression in p16 + tumors was associated with longer disease-free survival compared to p16- tumors. Imbalance in the MSH6/MSH2 ratio in p16 + tumors was associated with longer survival compared to p16- tumors. MLH1/PMS2 imbalance was significantly higher in p16 + with recurrence (p = 0.003). Low MSH2 immunoexpression increased the risk of relapse by 9.10 times (CI95% 1.99 to 83.06). CONCLUSION: Microsatellite instability in oropharyngeal SCC is demonstrated by the association between loss of protein expression and its heterodimer imbalance with disease-free survival. It was demonstrated that the imbalance of the MMR complex can consequently lead to resistance to treatment and a decrease in disease-free survival in p16 + oropharyngeal SCC tumors.
Assuntos
Biomarcadores Tumorais , Reparo de Erro de Pareamento de DNA , Neoplasias Orofaríngeas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/metabolismo , Intervalo Livre de Doença , Adulto , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/metabolismo , Proteína 2 Homóloga a MutS/análise , Proteína 2 Homóloga a MutS/metabolismo , Imuno-HistoquímicaRESUMO
BACKGROUND: Squamous cell carcinoma (SCC) is the most common histological type in the oropharynx with high incidence and mortality. The Pi3K-AKT signaling pathway is important for understanding prognostic factors such as metastasis, which is involved in the aetiopathogenesis of cancer and is associated with angiogenesis, progression, and cell survival. The aim of this study was to evaluate the correlation of the Pi3K/AKT pathway with prognostic factors associated with oropharyngeal SCC, including overall survival. MATERIALS AND METHODS: Patients diagnosed and treated for oropharyngeal SCC at the Haroldo Juaçaba Hospital were included in the study. Clinicopathological and socio-demographic data were collected by reviewing patient records and reports. Excisional biopsies were analyzed by immunohistochemical techniques using TMA for the detection of antibodies against ANTI-AKT, ANTI-Pi3K, ANTI-p16, ANTI-Ki67, and ANTI-p53. Immunoexpression was evaluated qualitatively and quantitatively using ImageJ software, and data were correlated with patient survival. RESULTS: There was a significant reduction in nuclear Pi3K immunoexpression in perilesional tissue compared to primary tumors and nodal metastases (p<0.001). Cytoplasmic Pi3K was increased in primary tumors and decreased in nodal metastases (p=0.001). pAKT expression in p16-negative tumors was associated with poorer overall survival. Further studies are needed to understand how this pathway may influence tumor progression and multimodal therapies. CONCLUSION: The PI3K/AKT pathway regulates cell survival and apoptosis and is associated with the malignant transformation of oropharyngeal tumors. AKT expression in p16-negative tumors is a strong predictor of poor prognosis.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas , Neoplasias Orofaríngeas , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Humanos , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/mortalidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Masculino , Prognóstico , Feminino , Fosfatidilinositol 3-Quinases/metabolismo , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Taxa de Sobrevida , Idoso , Seguimentos , Metástase Linfática , Adulto , Transdução de SinaisRESUMO
Urothelial bladder carcinoma (UBC) is a malignant neoplasm of the urinary tract that is highly prevalent worldwide and has a high rate of tumor recurrence. It is known that the BCL2 apoptosis regulator (BCL-2) gene encodes a mitochondrial protein that regulates programmed death cells by apoptosis. In contrast, the H2A.X histone variant (H2AX) gene encodes a histone responsible for regulating and signaling genomic instability processes. The present study aimed to analyze the immunostaining profiles of BCL-2 and γ-H2AX proteins in tissue samples (n=80) from UBC patients (muscle-invasive MI; and non-muscle invasive NMI) using indirect immunohistochemistry and to correlate the results with prognostic and clinical parameters. BCL-2 protein expression was cytoplasmic and absent in half of the samples, including the MI and NMI groups. Strong nuclear expression was observed for γ-H2AX, predominant in the MI samples. The immunostaining profile of both proteins was not associated with tumor recurrence or invasion, and no significant associations were found in relation to prognosis (tumor grade, pathological staging). No significant correlation was found between protein profiles in malignant tissue. All in all, BCL-2 and γ-H2AX did not prove to be candidate markers for UBC clinical management in the present sample, despite their expression in malignant bladder tissue.
Assuntos
Biomarcadores Tumorais , Histonas , Imuno-Histoquímica , Proteínas Proto-Oncogênicas c-bcl-2 , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Histonas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/análise , Masculino , Feminino , Prognóstico , Pessoa de Meia-Idade , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/metabolismo , AdultoRESUMO
Introduction: Forkhead box E1 (FOXE1) is a transcription factor with a crucial role in thyroid morphogenesis and differentiation. Promoter hypermethylation downregulates FOXE1 expression in different tumor types; nevertheless, its expression and relationship with methylation status in differentiated thyroid cancer (DTC) remain unclear. Methods: A total of 33 pairs of matched samples of PTC tumors and non-tumors were included. Tumor cell cultures were treated with either 5-Aza-2'-deoxycytidine demethylating agent or dimethyl sulfoxide (DMSO). A real-time polymerase chain reaction (RT-PCR) and Western blotting were performed to assess FOXE1 expression. The methylation status was quantified using bisulfite sequencing. A luciferase gene assay was used to determine CpG-island functionality. Gene expression and promoter methylation of FOXE1 and FOXE1-regulated genes were also analyzed with data from The Cancer Genome Atlas (TCGA) thyroid samples. Results: After demethylating treatment, increased FOXE1 mRNA was observed concomitantly with reduced promoter methylation of CpGisland2. A negative correlation between mRNA downregulation and an increased methylation level of CpGisland2 was observed in tumors. Diminished protein expression was also detected in some DTC cell lines and in some tumor samples, suggesting the involvement of post-transcriptional regulatory mechanisms. CPGisland2 was proved to be an enhancer. TCGA data analysis showed low FOXE1 mRNA expression in tumors with a negative correlation with methylation status and a positive correlation with the expression of most of its target genes. Reduced FOXE1 expression, accompanied by a high methylation level, was associated with PTC aggressiveness (tall cell variant, advanced extra thyroid extension, T4 American Joint Committee on Cancer (AJCC) classification), age at diagnosis (over 45 years old), and presence of a BRAFV600E mutation. Conclusion: FOXE1 mRNA was downregulated in DTC compared with non-tumors, followed by high CpGisland methylation. A coupling of low mRNA expression and high methylation status was related to characteristics of aggressiveness in DTC tumors.
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Ilhas de CpG , Metilação de DNA , Fatores de Transcrição Forkhead , Regulação Neoplásica da Expressão Gênica , Regiões Promotoras Genéticas , Neoplasias da Glândula Tireoide , Humanos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Feminino , Pessoa de Meia-Idade , Masculino , Adulto , Linhagem Celular Tumoral , Idoso , Regulação para Baixo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Relevância ClínicaRESUMO
BACKGROUND: Cancer is a significant public health problem, causing dozens of millions of deaths annually. New cancer screening programs are urgently needed for early cancer detection, as this approach can improve treatment outcomes and increase patient survival. The search for affordable, noninvasive, and highly accurate cancer detection methods revealed a valuable source of tumor-derived metabolites in the human metabolome through the exploration of volatile organic compounds (VOCs) in noninvasive biofluids. AIM OF REVIEW: This review discusses volatilomics-based approaches for cancer detection using noninvasive biomatrices (breath, saliva, skin secretions, urine, feces, and earwax). We presented the historical background, the latest approaches, and the required stages for clinical validation of volatilomics-based methods, which are still lacking in terms of making noninvasive methods available and widespread to the population. Furthermore, insights into the usefulness and challenges of volatilomics in clinical implementation steps for each biofluid are highlighted. KEY SCIENTIFIC CONCEPTS OF REVIEW: We outline the methodologies for using noninvasive biomatrices with up-and-coming clinical applications in cancer diagnostics. Several challenges and advantages associated with the use of each biomatrix are discussed, aiming at encouraging the scientific community to strengthen efforts toward the necessary steps to speed up the clinical translation of volatile-based cancer detection methods, as well as discussing in favor of (i) hybrid applications (i.e., using more than one biomatrix) to describe metabolite modulations that can be "cancer volatile fingerprints" and (ii) in multi-omics approaches integrating genomics, transcriptomics, and proteomics into the volatilomic data, which might be a breakthrough for diagnostic purposes, onco-pathway assessment, and biomarker validations.
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Neoplasias , Compostos Orgânicos Voláteis , Humanos , Neoplasias/diagnóstico , Neoplasias/metabolismo , Compostos Orgânicos Voláteis/metabolismo , Compostos Orgânicos Voláteis/análise , Metabolômica/métodos , Metaboloma , Biomarcadores Tumorais/metabolismo , Detecção Precoce de Câncer/métodos , Líquidos Corporais/metabolismo , Líquidos Corporais/químicaRESUMO
BACKGROUND: Cervical cancer has a high incidence and mortality rate, affecting more than half a million women in 2018. Its development is strongly related to high-risk HPV infection. After infection, several cellular molecules are affected, including microRNAs (miRNAs), which are the focus of our study. We aimed to investigate changes in microRNA expression associated with cervical cancer and analyze the biological significance of these changes induced by HPV proteins. METHODS: We analyzed transcriptome data retrieved from the NCBI website to investigate miRNA and gene expression in cervical cancer. We evaluated the alteration in expression of miRNAs and genes (between normal tissues and cervical cancer) using the GEO2R tool and selected those with significantly altered expression (p-value < 0.05). The target genes of miRNAs were predicted using the miRNA Pathway Dictionary Database. Subsequently, we created a network of biological pathways affected by miRNA deregulation using Cytoscape software and associated the altered miRNAs with the Hallmarks of Cancer using COSMIC v84. RESULTS: We identified 10 miRNAs and 82 target genes with significantly altered expression levels in cervical cancer that matched the predicted results. In addition, the deregulation of these genes causes changes in 52 biological pathways. These miRNAs affected pathways such as interferon signaling (miR-106b-5p and miR-1183), signaling by interleukins (miR-557, miR-106b-5p, miR-15a-5p, and miR-21-5p), oxidative stress-induced senescence (miR-557 and miR-15a-5p), cell cycle checkpoints (miR-557), transcriptional regulation by P53 (miR-557 and miR-15a-5p), and the exchange of oxygen and carbon dioxide in erythrocytes (miR-15a-5p). CONCLUSION: Alterations in miRNA expression play an important role in the pathogenesis of cervical cancer, affecting several biological pathways and Hallmarks of Cancer, such as immune system regulation, cell cycle regulation, and energy metabolism. Thus, their analysis can contribute to the development of diagnostic and prognostic biomarkers and more effective treatments for cervical cancer.
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Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/patologia , MicroRNAs/genética , Feminino , Redes Reguladoras de Genes , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/genética , Perfilação da Expressão Gênica , Transcriptoma , PrognósticoRESUMO
PI3K/AKT/mTOR pathway is implicated in breast cancer progression and recurrence. The identification of PIK3CA and AKT1 mutations and loss of PTEN serve as selection criterion for targeted therapies involving selective inhibitors. However, they do not consistently align with pathway activation, and high-cost determinations limit their routine application. PI3K-downstream epigenetic regulatory mechanisms broaden the alterations that amplify pathway activity and, consequently, sensitivity to selective inhibitors. In this retrospective observational study, conducted within a cohort of early-stage breast cancer patients, we determined phosphorylated ribosomal protein S6 (pS6) at Ser240/244 by immunohistochemistry as an indicator of PI3K pathway activation. Log-Rank test and Cox proportional hazards regression were used to analyze the clinical relevance of pS6, alone and together with clinicopathological variables, regarding recurrence-free survival. ROC curves and the area under the curves were used to evaluate the calibration and discrimination properties of uni- and multivariate models. Our results show that a high percentage of pS6 positive tumor cells was associated with an unfavorable prognosis in a cohort of 129 hormone receptor positive/HER2 negative breast cancer patients (Hazard Ratio = 5.92; Log-Rank p = 9.5e-08; median follow-up = 53 months). When assessed in combination with lymph node status, the predictive capacity was higher compared to both univariate models individually. In conclusion, pS6 could represent a novel independent marker for predicting recurrence risk in luminal breast cancer.
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Neoplasias da Mama , Recidiva Local de Neoplasia , Proteína S6 Ribossômica , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Feminino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Proteína S6 Ribossômica/metabolismo , Estudos Retrospectivos , Idoso , Estadiamento de Neoplasias , Adulto , Prognóstico , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , FosforilaçãoRESUMO
Introduction: Pituitary adenomas (PAs) are benign tumors with high prevalence and, occasionally, aggressive course. The tumorigenesis of these lesions is not completely understood at the molecular level. BAK1 and BAX proteins play fundamental roles in apoptosis and seem to interact with VDAC proteins, whose expressions have been markedly altered in cancer, impacting their prognosis. Objective: to evaluate the gene expression of VDAC1, VDAC2, BAK1 and BAX and their association with clinical and imaging characteristics in PA. Methods: Clinical-epidemiological data were collected from 117 tumor samples from patients affected by PA. Invasiveness was assessed by the Knosp scale. Gene expression was examined by real-time PCR. Relative expression analysis was performed by 2^(-DDCt) method. Results: The sample was mainly composed of women (69/117 - 57.2%). Tumor subtypes observed were Non-Functioning (NF) (73/117 - 62.4%), Acromegaly (24/117 - 20.5%) and Cushing's Disease (CD) (20/117 - 17.1%). Compared to normal tissue, there was a significant reduction in VDAC1 expression in the Acromegaly (p=0.029) and NF (p=0.002) groups. BAX expression was lower in all groups (p <0.001; p=0.007; P =0.005). No difference was found in VDAC2 and BAK1 expression, compared to normal pituitary. Overexpression of VDAC2 occurred in PAs with post-surgical regrowth (p=0.042). A strongly negative correlation was observed in BAX and BAK1 expression in CD. Conclusion: The results indicated that downregulations of VDAC1 and BAX may be related to resistance to apoptosis. In contrast, overexpression of VDAC2 in regrowing PAs suggests an antiapoptotic role for this gene. In summary, the genes evaluated might be involved in the biopathology of PAs.
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Adenoma , Neoplasias Hipofisárias , Canal de Ânion 1 Dependente de Voltagem , Proteína Killer-Antagonista Homóloga a bcl-2 , Humanos , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/patologia , Feminino , Adenoma/genética , Adenoma/metabolismo , Adenoma/cirurgia , Adenoma/patologia , Pessoa de Meia-Idade , Masculino , Adulto , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Canal de Ânion 1 Dependente de Voltagem/genética , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Canal de Ânion 2 Dependente de Voltagem/genética , Canal de Ânion 2 Dependente de Voltagem/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Prognóstico , Idoso , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
Gastric cancer (GC) is a complex and highly variable disease, ranking among the top five cancers diagnosed globally, and a leading cause of cancer-related deaths. Emerging from stomach lining cells amid chronic inflammation, it often advances to preneoplastic stages. Late-stage diagnoses and treatment challenges highlight the critical need for early detection and innovative biomarkers, motivating this study's focus on identifying theranostic markers through gene ontology analysis. By exploring deregulated biological processes, this study aims to uncover insights into cancer progression and associated markers, potentially identifying novel theranostic candidates in GC. Using public data from The Human Protein Atlas, this study pinpointed 299 prognostic genes, delineating 171 with unfavorable prognosis and 128 with favorable prognosis. Functional enrichment and protein-protein interaction analyses, supported by RNAseq results and conducted via Metascape and Cytoscape, highlighted five genes (vWF, FN1, THBS1, PCDH7, and F5) with promising theranostic potential. Notably, FN1 and THBS1 exhibited significant promise, with FN1 showing a 370% expression increase in cancerous tissue, and it is possible that FN1 can also indicate the stratification status in GC. While further validation is essential, these findings provide new insights into molecular alterations in GC and potential avenues for clinical application of theranostic markers.
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Biomarcadores Tumorais , Fibronectinas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Fibronectinas/metabolismo , Fibronectinas/genética , Regulação Neoplásica da Expressão Gênica , Prognóstico , Mapas de Interação de Proteínas , Trombospondina 1/genética , Trombospondina 1/metabolismo , Simulação por Computador , Ontologia Genética , Caderinas/genética , Caderinas/metabolismoRESUMO
BACKGROUND: Gastric cancer (GC) is a major global cause of cancer mortality, with a median overall survival of just 12 months. CLDN18.2, a specific isoform of Claudin18 normally expressed in the gastric mucosa, has emerged as a potential therapeutic target and prognostic biomarker due to its exposure on the surface of tumor cells following malignant transformation. This exposure allows CLDN18.2's extracellular loops to bind monoclonal antibodies, presenting new opportunities for targeted therapy and improved prognostic assessment. METHODS: A comprehensive search of PubMed, EMBASE, Cochrane Library, and Web of Science databases was conducted for studies that addressed the correlation of CLDN18.2 with: (1) Progression-free survival (PFS) and (2) Overall Survival (OS). Hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CIs) were calculated using a fixed-effects model. Heterogeneity was examined with I2 statistics. P values of ≤ 0.05 were considered statistically significant. Statistical analyses were performed using RStudio, version 4.2.3. RESULTS: A total of 15 studies encompassing a total of 4,085 patients were included. There were 2,691 (65.8%) male and 1,394 (34.2%) female patients. In the histologic GC analysis, there were 1,582 (38.7%) patients that had intestinal type and 1,280 (31.3%) with diffuse type. Patients with CLDN18.2 negative status exhibited a non-significant trend towards prolonged PFS (HR: 1.25; 95% CI: 0.98-1.61; p = 0.07; I2 = 18%) and a significant prolonged OS (HR: 1.20; 95% CI: 1.07-1.34; p < 0.01; I2 = 37%) when compared to CLDN18.2-positive patients. CONCLUSION: Our findings establish CLDN18.2 as a robust negative prognostic indicator for overall survival in GC patients. While its impact on PFS was not statistically significant, the association with OS suggests CLDN18.2 may serve as a marker for complex biological processes underlying tumor advancement.