RESUMEN

Colorectal adenocarcinoma (COAD) has a poor prognosis. Cyclin-dependent kinase inhibitor 2A (CDKN2A) significantly affects the development and progression of various human tumors. However, the significance and pathological mechanisms of CDKN2A in COAD remain to be elucidated. We assessed expression levels, clinical significance, biological function, co-expressed genes, and enrichment of related pathways of CDKN2A in COAD using various databases, including The University of Alabama at Birmingham Cancer Data Analysis Portal, Gene Expression Profiling Interactive Analysis, Tumor Immune Estimation Resource, Human Protein Atlas, STRING, GeneMANIA, cBioPortal, and Linked Omics. Our investigation showed that CDKN2A was highly expressed in colon adenocarcinomas (P < .001). It is weakly expressed or not expressed in normal tissues. The survival time of patients with colon adenocarcinoma with high CDKN2A expression is significantly shorter than that of patients with low expression levels (P = .011). There was a significant positive correlation between the expression level of CDKN2A in colon adenocarcinoma tissues and the infiltration of CD4+ T cells, macrophages, and neutrophils. Moreover, there was a significant negative association between the expression level of CDKN2A in colon adenocarcinoma tissues and B cell infiltration. The ten hub genes included tumor protein 53, V-myc Avian Myelocytomatosis Viral Oncogene Homolog, AKT serine/threonine kinase 1, cyclin-dependent kinase 2, phosphatase and tensin homolog deleted on chromosome ten, cyclin D1, cyclin dependent kinase 4, cyclin dependent kinase inhibitor 1A, catenin beta 1, and B-Raf proto-oncogene, serine/threonine kinase. Mutations in the CDKN2A genome in colon adenocarcinoma reduce survival. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the differentially expressed genes were enriched in apoptotic signaling pathways and multiple pathways related to metabolic progression. Our results indicate that CDKN2A can be used as a marker of poor prognosis in patients with colon adenocarcinoma. CDKN2A may regulate the occurrence and development of colon adenocarcinomas by influencing immune cell infiltration and metabolic pathways.

Asunto(s)

Adenocarcinoma , Neoplasias del Colon , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Humanos , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Neoplasias del Colon/genética , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Regulación Neoplásica de la Expresión Génica , Proto-Oncogenes Mas , Perfilación de la Expresión Génica/métodos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico

RESUMEN

Prostate cancer (PCa) is the most common cancer diagnosed in men worldwide and was the second leading cause of cancer-related deaths in US males in 2022. Prostate cancer also represents the second highest cancer mortality disparity between non-Hispanic blacks and whites. However, there is a relatively small number of prostate normal and cancer cell lines compared to other cancers. To identify the molecular basis of PCa progression, it is important to have prostate epithelial cell (PrEC) lines as karyotypically normal as possible. Our lab recently developed a novel methodology for the rapid and efficient immortalization of normal human PrEC that combines simultaneous CRISPR-directed inactivation of CDKN2A exon 2 (which directs expression of p16INK4A and p14ARF) and ectopic expression of an hTERT transgene. To optimize this methodology to generate immortalized lines with minimal genetic alterations, we sought to target exon 1α of the CDKN2A locus so that p16INK4A expression is ablated while the exons encoding p14ARF remains unaltered. Here we describe the establishment of two cell lines: one with the above-mentioned p16INK4A only loss, and a second line targeting both products in the CDKN2A locus. We characterize the potential lineage origin of these new cell lines along with our previously obtained clones, revealing distinct gene expression signatures. Based on the analyses of protein markers and RNA expression signatures, these cell lines are most closely related to a subpopulation of basal prostatic cells. Given the simplicity of this one-step methodology and the fact that it uses only the minimal genetic alterations necessary for immortalization, it should also be suitable for the establishment of cell lines from primary prostate tumor samples, an urgent need given the limited number of available prostate cancer cell lines.

Asunto(s)

Inhibidor p16 de la Quinasa Dependiente de Ciclina , Células Epiteliales , Próstata , Neoplasias de la Próstata , Telomerasa , Humanos , Masculino , Telomerasa/genética , Telomerasa/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Células Epiteliales/metabolismo , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Exones/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Línea Celular

RESUMEN

PANoptosis induces programmed cell death (PCD) through extensive crosstalk and is associated with development of cancer. However, the functional mechanisms, clinical significance, and potential applications of PANoptosis-related genes (PRGs) in colorectal cancer (CRC) have not been fully elucidated. Functional enrichment of key PRGs was analyzed based on databases, and relationships between key PRGs and the immune microenvironment, immune cell infiltration, chemotherapy drug sensitivity, tumor progression genes, single-cell cellular subgroups, signal transduction pathways, transcription factor regulation, and miRNA regulatory networks were systematically explored. This study identified 5 key PRGs associated with CRC: BCL10, CDKN2A, DAPK1, PYGM and TIMP1. Then, RT-PCR was used to verify expression of these genes in CRC cells and tissues. Clinical significance and prognostic value of key genes were further verified by multiple datasets. Analyses of the immune microenvironment, immune cell infiltration, chemotherapy drug sensitivity, tumor progression genes, single-cell cellular subgroups, and signal transduction pathways suggest a close relationship between these key genes and development of CRC. In addition, a novel prognostic nomogram model for CRC was successfully constructed by combining important clinical indicators and the key genes. In conclusion, our findings offer new insights for understanding the pathogenesis of CRC, predicting CRC prognosis, and identifying multiple therapeutic targets for future CRC therapy.

Asunto(s)

Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Microambiente Tumoral , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Microambiente Tumoral/genética , Proteínas Quinasas Asociadas a Muerte Celular/genética , Proteínas Quinasas Asociadas a Muerte Celular/metabolismo , Pronóstico , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Carcinogénesis/genética , Redes Reguladoras de Genes , Transducción de Señal , Biomarcadores de Tumor/genética , MicroARNs/genética , Nomogramas

RESUMEN

Heterogeneous nuclear ribonucleoproteins (hnRNPs), a group of proteins that control gene expression, have been implicated in many post-transcriptional processes. SYNCRIP (also known as hnRNP Q), a subtype of hnRNPs, has been reported to be involved in mRNA splicing and translation. In addition, the deregulation of SYNCRIP was found in colorectal cancer (CRC). However, the role of SYNCRIP in regulating CRC growth remains largely unknown. Here, we found that SYNCRIP was highly expressed in colorectal cancer by analyzing TCGA and GEPIA database. Furthermore, we confirmed the expression of SYNCRIP expression in CRC tumor and CRC cell lines. Functionally, SYNCRIP depletion using shRNA in CRC cell lines (SW480 and HCT 116) resulted in increased caspase3/7 activity and decreased cell proliferation, as well as migration. Meanwhile, overexpression of SYNCRIP showed opposite results. Mechanistically, SYNCRIP regulated the expression of DNA methyltransferases (DNMT) 3A, but not DNMT1 or DNMT3B, which affected the expression of tumor suppressor, p16. More importantly, our in vivo experiments showed that SYNCRIP depletion significantly inhibited colorectal tumor growth. Taken all together, our results suggest SYNCRIP as a potent therapeutic target in colorectal cancer.

Asunto(s)

Carcinogénesis , Proliferación Celular , Neoplasias Colorrectales , ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3A , Regulación Neoplásica de la Expresión Génica , Regulación hacia Arriba , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , Proliferación Celular/genética , ADN Metiltransferasa 3A/metabolismo , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Ratones , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Ribonucleoproteínas Nucleares Heterogéneas/genética , Movimiento Celular/genética , Células HCT116 , Ratones Desnudos

RESUMEN

BACKGROUND: Dermatoporosis (DP) is a condition associated with thinning skin layers and resultant fragility. Much of the thinning is related to fibroblast dysfunction, production of destructive inflammatory cytokines, breakdown of the extracellular matrix (ECM), and weakening of the dermo-epidermal junction. A major contributor to this change in the ECM milieu, previously under-considered, is cellular senescence, particularly involving the papillary dermal fibroblasts. METHODS: A series of experiments were undertaken to explore the impact of a combination of known actives on senescent cell status. Human keratinocytes and fibroblasts were cultured, and cytotoxicity tests were performed to determine the ideal concentration to avoid cell toxicity. Microdoses of Centella asiatica (0.005%) and mandelic acid (0.05%) were found to be ideal in avoiding any cytotoxicity. However, the challenge was then to assess the efficacy of these actives in this microdosed form. After exposing the cells to the compounds, RNA was isolated and sequenced. Moreover, a well-described ex vivo model using photodamaged skin was subjected to immunofluorescence to identify senescent cells (via p16INK4a), particularly in the papillary dermis, using the microdose formulation compared to untreated skin. In addition, JAG/NOTCH expression in the epidermal basal cells was evaluated to further understand the cellular senescence signaling mechanism. RESULTS: Microdosing these two well-known agents had surprisingly significant synergistic effects in vitro, decreasing senescence-associated secretory phenotype (SASP) cytokines and the associated inflammation involved in the process. The ex vivo model revealed a significant (P<0.05) decrease in senescent cells in the papillary dermis and a significant increase (P<0.001) of JAG/NOTCH expression in the basal cells of the epidermis. CONCLUSION: Using microdoses of two known agents, a novel approach produced an unexpected effect of reversal of dermal senescent cells and promoting an anti-inflammatory milieu. A gene expression analysis of the individual and combined actives validated these observations, followed by full formulation testing in an ex vivo model. The approach of limiting cellular senescence in dermal fibroblasts for managing DP is novel and provides an exciting new direction to address dermatoporosis. Clinical studies will follow. J Drugs Dermatol. 2024;23(9):748-756. doi:10.36849/JDD.8388.

Asunto(s)

Senescencia Celular , Fibroblastos , Queratinocitos , Envejecimiento de la Piel , Humanos , Senescencia Celular/efectos de los fármacos , Envejecimiento de la Piel/efectos de los fármacos , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Triterpenos/farmacología , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Centella , Células Cultivadas , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo

RESUMEN

Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of octamer-binding transcription factor 4 (Oct4), sex-determining region Y-box 2 (Sox2), Kruppel-like factor 4 (Klf4), and cellular myelocytomatosis oncogene (cMyc) (OSKM) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring OSK under the control of the cyclin-dependent kinase inhibitor 2a (Cdkn2a) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell-specific OSK expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying Cdkn2a-OSK to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying Cdkn2a-OSK led to improved wound healing in aged wild-type mice. Expression of CDKN2A-OSK in aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle-related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.

Asunto(s)

Envejecimiento , Reprogramación Celular , Senescencia Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Modelos Animales de Enfermedad , Factor 4 Similar a Kruppel , Animales , Factor 4 Similar a Kruppel/metabolismo , Envejecimiento/metabolismo , Ratones , Humanos , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Biomarcadores/metabolismo , Progeria/metabolismo , Progeria/genética , Progeria/patología , Dependovirus/metabolismo , Regiones Promotoras Genéticas/genética

RESUMEN

OBJECTIVE: To establish the diagnostic utility of immunohistochemistry markers p16 along with MDM2 and CDK-4 in confirming the diagnosis of well-differentiated and de-differentiated liposarcoma while taking Fluorescent in situ Hybridisation (FISH) as a gold standard. STUDY DESIGN: A cross-sectional study. Place and Duration of the Study: Department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from 30th January 2022 to 30th June 2023. METHODOLOGY: A standard panel of three immunohistochemistry markers p16, MDM2, and CDK4 were applied to 36 cases of atypical lipomatous tumours, well-differentiated liposarcoma (WDLPS), and de-differentiated liposarcoma (DDLPS), on which the gold standard FISH was already performed. The sample size was calculated with the help of a WHO calculator taking prevalence 1-2% in Pakistani population. Qualitative variables such as gender and site of tumour were presented by calculating frequency and percentages and comparison of Immunohistochemistry results with FISH was done by using a 2x2 table. RESULTS: The sensitivity and specificity of this triple marker panel for detecting WDLPS/DDLPS were 43.47% and 15.38%, respectively. The sensitivity and specificity of CDK4 for detecting WDLPS / DDLPS were 82.6% and 15.4%, those of MDM2 were 73.9% and 61.5 %, and those of p16 were 60.9% and 53.8%, respectively. CONCLUSION: Among all three markers, CDK4 was the most sensitive and MDM2 was the most specific marker for detecting WDLPS-DDLPS. It also showed that a combination of these three markers improves the diagnostic credibility of the immunohistochemistry in diagnosing DDLPS and WDLPS but FISH is the most reliable and confirmatory method. KEY WORDS: De-differentiated liposarcoma, Well-differentiated liposarcoma, P16, CDK4, MDM2.

Asunto(s)

Biomarcadores de Tumor , Quinasa 4 Dependiente de la Ciclina , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Inmunohistoquímica , Hibridación Fluorescente in Situ , Liposarcoma , Proteínas Proto-Oncogénicas c-mdm2 , Humanos , Liposarcoma/diagnóstico , Liposarcoma/patología , Liposarcoma/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Femenino , Masculino , Biomarcadores de Tumor/metabolismo , Estudios Transversales , Persona de Mediana Edad , Adulto , Sensibilidad y Especificidad , Anciano

Asunto(s)

Inhibidor p16 de la Quinasa Dependiente de Ciclina , Tumor de Células de la Granulosa , Neoplasias Ováricas , Proteína p53 Supresora de Tumor , Humanos , Femenino , Tumor de Células de la Granulosa/genética , Tumor de Células de la Granulosa/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Adolescente , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Mutación , Recurrencia Local de Neoplasia

RESUMEN

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), particularly oropharyngeal squamous cell carcinoma (OPSCC), is an increasingly prevalent pathology worldwide, especially in developed countries. For diagnosing HPV in HNSCC, the combination of p16 immunohistochemistry (IHC) and polymerase chain reaction (PCR) offers high sensitivity and specificity, with p16 IHC being a reliable initial screen and PCR confirming HPV presence. Advanced techniques like next-generation sequencing (NGS) and RNA-based assays provide detailed insights but are primarily used in research settings. Regardless of HPV status, standard oncological treatments currently include surgery, radiation, and/or chemotherapy. This conventional approach does not account for the typically better prognosis of HPV-positive HNSCC patients, leading to increased chemo/radiation-induced secondary morbidities and reduced quality of life. Therefore, it is crucial to identify and detect HPV positivity and other molecular characteristics of HNSCC to personalize treatment strategies. This comprehensive review aims to summarize current knowledge on various HPV detection techniques and evaluate their advantages and disadvantages, with a focus on developing methodologies to identify new biomarkers in HPV-positive HNSCC. The review discusses direct and indirect HPV examination in tumor tissue, DNA- and RNA-based detection techniques, protein-based markers, liquid biopsy potentials, immune-related markers, epigenetic markers, novel biomarkers, and emerging technologies, providing an overall insight into the current state of knowledge.

Asunto(s)

Biomarcadores de Tumor , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Neoplasias de Cabeza y Cuello/virología , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/genética , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Inmunohistoquímica , ADN Viral/genética , ADN Viral/análisis , Reacción en Cadena de la Polimerasa/métodos , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética

RESUMEN

Hodgkin lymphoma (HL) is a rare lymphoid neoplasm in which Hodgkin/Reed-Stenberg (HRS) cells are admixed with a population of non-neoplastic inflammatory cells and fibrosis. Dysregulated expressions of cell cycle regulators and transcription factors have been proven as one of the hallmarks of HL. In that context, SATB1 and p16 have been reported as potential regulators of HL progression and survival. However, to date, no studies have assessed the expression levels of SATB1 and p16 in HL in Croatian patients or their prognostic values. Therefore, we investigated the expression pattern of SATB1 and p16 in paraffin-embedded lymph node biopsies using standard immunohistochemistry. We found that 21% of the patients stained positive for SATB1, while 15% of the patients displayed positive staining for p16. Furthermore, we aimed to understand the prognostic value of each protein through the analysis of the overall survival (OS) and progression-free survival (PFS). SATB1 showed a significantly positive correlation with better OS and PFS, while p16 expression had no impact. Interestingly, when patients were stratified by a combination of the two studied markers, we found that patients in the SATB1+/p16- group tended to have the best prognosis in HL, according to statistical significance. In conclusion, SATB1 and p16 might be potentially useful as diagnostic and prognostic markers for HL.

Asunto(s)

Inhibidor p16 de la Quinasa Dependiente de Ciclina , Enfermedad de Hodgkin , Proteínas de Unión a la Región de Fijación a la Matriz , Humanos , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/diagnóstico , Masculino , Femenino , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Adulto , Pronóstico , Persona de Mediana Edad , Croacia , Anciano , Adulto Joven , Adolescente , Biomarcadores de Tumor/metabolismo

RESUMEN

Kirsten Rat Sarcoma (KRAS) is the most commonly mutated oncogene in colorectal carcinoma (CRC). We have previously reported the interactions between microsatellite instability (MSI), DNA promoter methylation, and gene expression. In this study, we looked for associations between KRAS mutation, gene expression, and methylation that may help with precision medicine. Genome-wide gene expression and DNA methylation were done in paired CRC tumor and surrounding healthy tissues. The results suggested that (a) the magnitude of dysregulation of many major gene pathways in CRC was significantly greater in patients with the KRAS mutation, (b) the up- and down-regulation of these dysregulated gene pathways could be correlated with the corresponding hypo- and hyper-methylation, and (c) the up-regulation of CDKN2A was more pronounced in tumors with the KRAS mutation. A recent cell line study showed that there were higher CDKN2A levels in 5-FU-resistant CRC cells and that these could be down-regulated by Villosol. Our findings suggest the possibility of a better response to anti-CDKN2A therapy with Villosol in KRAS-mutant CRC. Also, the more marked up-regulation of genes in the proteasome pathway in CRC tissue, especially with the KRAS mutation and MSI, may suggest a potential role of a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) in selected CRC patients if necessary.

Asunto(s)

Neoplasias Colorrectales , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Mutación , Proteínas Proto-Oncogénicas p21(ras) , Transcriptoma , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Perfilación de la Expresión Génica , Inestabilidad de Microsatélites , Epigenoma , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo

RESUMEN

Structural variation heavily influences the molecular landscape of cancer, in part by impacting DNA methylation-mediated transcriptional regulation. Here, using multi-omic datasets involving >2400 pediatric brain and central nervous system tumors of diverse histologies from the Children's Brain Tumor Network, we report hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of somatic structural variant (SV) breakpoints is recurrently associated with altered expression or DNA methylation, respectively, including tumor suppressor genes ATRX and CDKN2A. Altered DNA methylation near enhancers associates with nearby somatic SV breakpoints, including MYC and MYCN. A subset of genes with SV-CGI methylation associations also have expression associations with patient survival, including BCOR, TERT, RCOR2, and PDLIM4. DNA methylation changes in recurrent or progressive tumors compared to the initial tumor within the same patient can predict survival in pediatric and adult cancers. Our comprehensive and pan-histology genomic analyses reveal mechanisms of noncoding alterations impacting cancer genes.

Asunto(s)

Neoplasias Encefálicas , Islas de CpG , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Humanos , Metilación de ADN/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Islas de CpG/genética , Niño , Proteína Nuclear Ligada al Cromosoma X/genética , Proteína Nuclear Ligada al Cromosoma X/metabolismo , Epigenoma , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Proteína Proto-Oncogénica N-Myc/genética , Proteína Proto-Oncogénica N-Myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Masculino , Telomerasa/genética , Femenino

RESUMEN

Various factors can affect the survival of patients with oropharyngeal cancer. We assessed the expression of protein p16INK4a, Flotillin2, epidermal growth factor receptor, and other clinicopathological features and their prognostic value for this type of cancer. We gathered patient data on demographics, clinicopathological characteristics, treatment patterns, and outcomes. Histologically and by immunochemistry staining we determined expression of prognostic factors and molecular biomarkers. The primary endpoints were overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). Survival was assessed using the Kaplan-Meier method and Cox regression model analyses of potential prognostic parameters. After a median follow-up of 78 months, the median OS was 41 months, with an event recorded in 77.8% of patients. Median DFS was 22 months, 37 patients (51.4%) had disease relapse. The DSS survival rate was 58.3% with a median survival of 68 months. In regards to molecular biomarkers previously mentioned, there was no statistical significance for survival categories. After conducting a multivariate analysis of significant variables, we found that only recurrence, vascular invasion, and surgical intervention remained as factors with independent effects on both OS and DFS. Recurrence and the N stage were identified as independent prognostic factors for DSS. Our analysis underscores the complexity of factors that collectively influence survival following the diagnosis of OPSCC. Several factors were found to be statistically significant. These factors included the type of surgical procedure, disease relapse, vascular invasion, lymphatic invasion, perineural invasion, advanced T stage of the disease, N stage of the disease, and smoking status. The significance of these factors may vary across different types of survival. This analysis did not find any significant impact on survival from the growth factors tested, namely epidermal growth factor receptor, Flotillin2, and p16INK4a, in the applied regression models.

Asunto(s)

Biomarcadores de Tumor , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Receptores ErbB , Proteínas de la Membrana , Neoplasias Orofaríngeas , Humanos , Masculino , Femenino , Neoplasias Orofaríngeas/mortalidad , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/metabolismo , Receptores ErbB/metabolismo , Persona de Mediana Edad , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Proteínas de la Membrana/metabolismo , Pronóstico , Anciano , Biomarcadores de Tumor/metabolismo , Adulto , Supervivencia sin Enfermedad , Estimación de Kaplan-Meier , Anciano de 80 o más Años , Estudios Retrospectivos

RESUMEN

Human papillomavirus (HPV) is an oncogenic DNA virus that plays a role in different cancer types. The aim of this study was to detect the prevalence and types of HPV and its relation with p16, EGFR and clinical findings in lung cancer. HPV and EGFR detection and genotyping of HPV were performed by polymerase chain reaction (PCR) and p16 by immunohistochemistry. Fifty lung cancer patients and seven patients with non-neoplastic lung disease were enrolled in this study. HPV was positive in 78% (39/50) of lung cancer cases. HPV 51 was the most frequent type, followed by HPV 16. Moreover, p16 was positive in 24% (12/50) of the cancer patients, and all of these patients were HPV-positive, while 27 HPV-positive patients showed no p16 expression. There was no relationship between HPV infection and p16 (p = 0.05), gender (p = 0.42), age (p = 0.38), or smoking history (p = 0.68). Although not statistically significant, the HPV prevalence was found to be higher in cancer patients compared to non-neoplastic patients. The prevalence of HPV in lung cancer varies across different studies, which may be due to differences in the detection methods, number of patients, geographic regions, and vaccination status. Further studies are necessary to understand the role of HPV in lung cancer pathogenesis.

Asunto(s)

Inhibidor p16 de la Quinasa Dependiente de Ciclina , Receptores ErbB , Neoplasias Pulmonares , Papillomaviridae , Infecciones por Papillomavirus , Humanos , Femenino , Masculino , Neoplasias Pulmonares/virología , Neoplasias Pulmonares/epidemiología , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/complicaciones , Persona de Mediana Edad , Anciano , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Turquía/epidemiología , Papillomaviridae/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Prevalencia , Región Mediterránea/epidemiología , Adulto , Genotipo , ADN Viral/genética , Anciano de 80 o más Años , Virus del Papiloma Humano

RESUMEN

BACKGROUND: Nail squamous cell carcinoma (NSCC) is the most frequent ungual malignant tumor, but its incidence remains low. The histopathological description is sparse. We aim to characterize NSCC histopathological aspects, search for a correlation with clinical subtypes, and investigate immunohistochemistry expression of p16, p53, and Ki67. METHODS: This retrospective study collected NSCC diagnosed in our dermatology department between 2007 and 2021. The histopathological features were correlated with the clinical signs and immunohistochemistry. RESULTS: A total of 48 patients were included, and immunohistochemistry was available for 36 of them. Two histopathological patterns became prominent: a blue-basaloid type characterized by koilocytosis (p < 0.001), and a pink-keratinizing type. Mean ages were similar when comparing basaloid and periungual versus keratinizing and subungual (p < 0.001). p16 was positive in 31 of 36 cases: 18 basaloid and 13 keratinizing (p = 0.167). p53 and Ki67 were all abnormal. CONCLUSIONS: Our study described two histopathological NSCC subtypes and associated them with the two clinical subtypes: the blue-basaloid type, HPV-induced, in situ, of periungual localization in younger males; and the pink-keratinizing type, non-HPV-induced, invasive, of subungual site, in elderly. Immunohistochemistry was not contributing on its own, but p16 positivity associated with basaloid histopathological profile helps support HPV etiology.

Asunto(s)

Carcinoma de Células Escamosas , Inmunohistoquímica , Antígeno Ki-67 , Enfermedades de la Uña , Neoplasias Cutáneas , Humanos , Masculino , Femenino , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Persona de Mediana Edad , Estudios Retrospectivos , Inmunohistoquímica/métodos , Anciano , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Enfermedades de la Uña/patología , Enfermedades de la Uña/metabolismo , Adulto , Anciano de 80 o más Años , Antígeno Ki-67/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Uñas/patología , Uñas/metabolismo , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisis

Asunto(s)

Inhibidor p16 de la Quinasa Dependiente de Ciclina , Antígeno Ki-67 , Neoplasias del Cuello Uterino , Femenino , Humanos , Cuello del Útero/patología , Cuello del Útero/metabolismo , Consenso , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Detección Precoz del Cáncer/métodos , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/virología , Coloración y Etiquetado/métodos , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/metabolismo , Displasia del Cuello del Útero/patología , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patología , Frotis Vaginal

RESUMEN

The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation.

Asunto(s)

Antígeno B7-H1 , Senescencia Celular , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Estabilidad Proteica , Senescencia Celular/inmunología , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Animales , Humanos , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/genética , Vigilancia Inmunológica , Ratones Endogámicos C57BL , Quinasa 6 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/genética , Ratones , Proteolisis , Receptores de IgG/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Inflamación/genética

RESUMEN

OBJECTIVE: Given the implications of concurrent human papilloma viral infection (HPV) in the prognostic course and implications on therapeutic approached of patients with oral squamous cell carcinoma (OSCC), we seek to investigate the implications that P16 expression has on the clinical course and pathological appearance of patients with OSCC and concurrent infection. METHODS: Using S-P immunohistochemistry, we examined the expression of P16 and Ki67 in 460 patients with OSCC. We compared the expression of the protein between the tumor cells and normal epithelial mucosa within the same patient. The clinical and pathological characteristics (including gender, age, histological grade, lymph node metastasis, clinical stage, clinical recurrence, tumor diameter, Ki67 proliferation index) were analyzed by stratification statistically. RESULTS: In total 460 cases of OSCC were identified and expression of P16 was significantly higher in the OSCC group compared to the normal mucosal epithelial group (X2 = 60.545, p = .000). There also appear to be a gender predilection as the expression was higher in females compared to males (0.218 vs. 0.144, X2 = 3.921, p = .048). Younger age also appears to be a predictive factor as those under 35 years old had higher expression of the protein compared to those over 35 years old (0.294 vs. 0.157, X2 = 4.230, p = .040). P16 positivity showed a significant positive correlation with histologic grade (X2 = 4.114, p = .043). In addition, the positive rate of P16 was higher in patients with ki67 over 85% (0.455 vs. 0.160, X2 = 6.667, p = .023). CONCLUSION: OSCC with HPV infection tends to occur more frequently in female patients and those under 35 years of age. HPV infection with expression of the P16 and ki67 protein may promote the proliferation and growth of OSCC at a higher frequency.

Asunto(s)

Carcinoma de Células Escamosas , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Antígeno Ki-67 , Neoplasias de la Boca , Infecciones por Papillomavirus , Humanos , Femenino , Masculino , Neoplasias de la Boca/patología , Neoplasias de la Boca/virología , Neoplasias de la Boca/metabolismo , Persona de Mediana Edad , Adulto , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Antígeno Ki-67/metabolismo , Carcinoma de Células Escamosas/virología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/virología , Anciano , Papillomaviridae/aislamiento & purificación , Inmunohistoquímica , Factores Sexuales , Metástasis Linfática , Anciano de 80 o más Años , Virus del Papiloma Humano

RESUMEN

Pulmonary hypertension (PH) is a severe cardiovascular disease characterised by pulmonary vascular remodelling. The pivotal role of cellular senescence in vascular remodelling has been acknowledged. Transglutaminase type 2 (TG2), a calcium-dependent enzyme, is intricately linked to both cellular senescence and PH. However, the precise mechanisms underlying the involvement of TG2 in PH remain unclear. In this study, we explored the expression of TG2 and the cellular senescence marker p16INK4a in the pulmonary vasculature of mice with PH induced by hypoxia combined with SU5416. Our findings revealed upregulation of both TG2 and p16INK4a expression in the pulmonary vasculature of PH mice. Additionally, a notable increase in TG2 expression was observed in senescent pulmonary artery smooth muscle cells (PASMC). To delve deeper, we employed proteomic sequencing to reveal seven genes associated with cellular senescence, with a subsequent focus on MAPK14. Our investigation revealed that TG2 regulates senescence in PASMC by modulating the phosphorylation levels of MAPK14. Additionally, in the context of hypoxia combined with SU5416, our observations revealed a noteworthy reduction in both pulmonary vascular remodelling and senescent manifestations in smooth muscle-specific TG2 knockout mice compared with their wild-type counterparts. In summary, our findings indicate that TG2 deficiency lowers the senescence levels of PASMC by inhibiting the activity of MAPK14. This inhibition of senescence in the pulmonary vasculature of PH mice helps to decelerate the progression of pulmonary vascular remodelling and consequently hinders the onset and development of PH.

Asunto(s)

Senescencia Celular , Hipertensión Pulmonar , Miocitos del Músculo Liso , Proteína Glutamina Gamma Glutamiltransferasa 2 , Arteria Pulmonar , Remodelación Vascular , Animales , Masculino , Ratones , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/genética , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/patología , Hipoxia/metabolismo , Indoles , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteína Glutamina Gamma Glutamiltransferasa 2/metabolismo , Arteria Pulmonar/metabolismo , Pirroles , Transglutaminasas/metabolismo , Transglutaminasas/genética

RESUMEN

The human tumor suppressor p16INK4a is a small monomeric protein that can form amyloid structures. Formation of p16INK4a amyloid fibrils is induced by oxidation which creates an intermolecular disulfide bond. The conversion into amyloid is associated with a change from an all α-helical structure into ß-sheet fibrils. Currently, structural insights into p16INK4a amyloid fibrils are lacking. Here, we investigate the amyloid-forming regions of this tumor suppressor using isotope-labeling limited-digestion mass spectrometry analysis. We discover two key regions that likely form the structured core of the amyloid. Further investigations using thioflavin-T fluorescence assays, electron microscopy, and solution nuclear magnetic resonance spectroscopy of shorter peptide regions confirm the self-assembly of the identified sequences that include methionine and leucine repeat regions. This work describes a simple approach for studying protein motifs involved in the conversion of monomeric species into aggregated fibril structures. It provides insight into the polypeptide sequence underlying the core structure of amyloid p16INK4a formed after a unique oxidation-driven structural transition.

Asunto(s)

Amiloide , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Proteolisis , Humanos , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/química , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Amiloide/química , Amiloide/metabolismo , Péptidos/química , Péptidos/metabolismo , Secuencia de Aminoácidos , Oxidación-Reducción , Espectrometría de Masas/métodos