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1.
Int J Mol Sci ; 25(12)2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38928200

RESUMEN

Hypoxia-inducible factor 1-alpha (HIF1A) is a key transcription factor aiding tumor cells' adaptation to hypoxia, regulated by the prolyl hydroxylase family (EGLN1-3) by directing toward degradation pathways. DNA methylation potentially influences EGLN and HIF1A levels, impacting cellular responses to hypoxia. We examined 96 HNSCC patients and three cell lines, analyzing gene expression of EGLN1-3, HIF1A, CA9, VEGF, and GLUT1 at the mRNA level and EGLN1 protein levels. Methylation levels of EGLNs and HIF1A were assessed through high-resolution melting analysis. Bioinformatics tools were employed to characterize associations between EGLN1-3 and HIF1A expression and methylation. We found significantly higher mRNA levels of EGLN3, HIF1A, GLUT1, VEGF, and CA9 (p = 0.021; p < 0.0001; p < 0.0001; p = 0.004, and p < 0.0001, respectively) genes in tumor tissues compared to normal ones and downregulation of the EGLN1 mRNA level in tumor tissues (p = 0.0013). In HNSCC patients with hypermethylation of HIF1A in normal tissue, we noted a reduction in HIF1A mRNA levels compared to tumor tissue (p = 0.04). In conclusion, the differential expression of EGLN and HIF1A genes in HNSCC tumors compared to normal tissues influences patients' overall survival, highlighting their role in tumor development. Moreover, DNA methylation could be responsible for HIF1A suppression in the normal tissues of HNSCC patients.


Asunto(s)
Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello , Subunidad alfa del Factor 1 Inducible por Hipoxia , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Femenino , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Masculino , Línea Celular Tumoral , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Persona de Mediana Edad , Prolil Hidroxilasas/metabolismo , Prolil Hidroxilasas/genética , Anciano , Carcinogénesis/genética , Adulto
2.
Rep Pract Oncol Radiother ; 29(2): 148-154, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39143964

RESUMEN

Background: Head and neck squamous carcinoma (HNSC) is the sixth most common neoplasm, with a 40-50% overall survival rate. HNSC standard treatment depends on tumor size, metastasis or human papillomavirus (HPV) status including surgery, chemotherapy, and radiotherapy. The last two may lead to defects in the tumor microenvironment and cancer cell biology as disorders in DNA damage repair systems. Here, we evaluate the correlation between single nucleotide polymorphism (SNP) rs2228001 in the XPC gene with the early and late adverse effects of radiotherapy, determine the distribution of the SNP and post-treatment follow-up in HNSC patients. Materials and methods: Head and neck cancer tissues and clinical data were obtained from 79 patients. The SNP of the XPC gene (rs2228001) was evaluated with polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP). The chi-square test was used to determine the correlation between mutation and adverse effects occurrence. Results/Conclusion: Single nucleotide polymorphism rs2228001 in the XPC gene is correlated with the early adverse effect of skin reaction and the late adverse effect of elevated C-reactive protein (CRP) levels in the HNSC patients.

3.
Rep Pract Oncol Radiother ; 29(2): 245-257, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39143966

RESUMEN

Cellular information about "life instruction" is stored, transferred, and modified using different types of RNA molecules. During the last decades, a growing number of RNA data has been generated thanks to the development of microarray chips and next-generation sequencing (NGS) methods. Improvement of bioinformatics contributed to the discovery of many types of new non-coding RNAs (ncRNAs), mostly with regulatory functions that supplemented the knowledge about the world of RNA. All of it, as well as the Human Genome Project (HGP) and the Cancer Genome Atlas (TCGA) project, has resulted in the formation of data storage and analysis portals which are widely used in cancer research and moved science from in vitro to in silico research. In this review we presented and discussed the data storage and analysis portals used by us, such as cBioPortal, UALCAN, ENCORI, and others. During the revision of these sites, we paid attention to data integration, simplicity of analysis, and results visualization, which are important for users without bioinformatic or statistical skills. In our opinion, the RNA analysis online tools will rapidly develop during the next decade and it seems to be a way for personalization of cancer treatment.

4.
Int J Cancer ; 150(11): 1838-1849, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35049055

RESUMEN

Cancer stemness, which covers the stem cell-like molecular traits of cancer cells, is essential for tumor development, progression and relapse. Both transcriptional and epigenetic aberrations are essentially connected with cancer stemness. The engagement of bromodomain (BrD) proteins-a family of epigenetic factors-has been presented in the pathogenesis of several tumor types, although their association with cancer stemness remains largely unknown. Here, we harnessed TCGA and GEO databases and used several bioinformatic tools (ie, Oncomine, PrognoScan, GEPIA2, TIMER2.0, TISIDB, GSEA, R2 platform) to characterize the association between the BrD family members' expression and cancer stemness in solid tumors. Our results demonstrate that significant upregulation of ATAD2 and SMARCA4, and downregulation of SMARCA2 is consistently associated with enriched cancer stem cell-like phenotype, respectively. Especially, higher-grade tumors that display stem cell-like properties overexpress ATAD2. In contrast to most BrD members, the gene expression profiles of ATAD2HIGH expressing tumors are strongly enriched with known markers of stem cells and with specific targets for c-Myc transcription factor. For other BrD proteins, the association with cancer de-differentiation status is rather tumor-specific. Our results demonstrate for the first time the relation between distinct BrD family proteins and cancer stemness across 27 solid tumor types. Specifically, our approach allowed us to discover a robust association of high ATAD2 expression with cancer stemness and reveal its' versatility in tumors. As bromodomains are attractive targets from a chemical and structural perspective, we propose ATAD2 as a novel druggable target for de-differentiated tumors, especially those overexpressing MYC.


Asunto(s)
Neoplasias , ATPasas Asociadas con Actividades Celulares Diversas/genética , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Neoplasias/genética , Neoplasias/patología , Proteínas Nucleares/genética , Dominios Proteicos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Activación Transcripcional
5.
Int J Mol Sci ; 24(1)2022 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-36614001

RESUMEN

Cells and immune cells in the extracellular matrix: Depending on the tumor type and variety of TAAs (tumor-associated antigens), immune infiltrates are composed of many different subpopulations of immune cells. Epigenetic changes are also considered to be characteristic of cancer. Epigenetic factors taking part in the regulation of gene expression include the VII group of bromodomain proteins (BrD)-SP-family proteins. Here, we used transcriptomic data from the TCGA database, as well as immunological evidence from ESTIMATE, TIP, and TIMER2.0 databases for various solid tumor types and harnessed several publicly available bioinformatic tools (such as GSEA and GSCA) to demonstrate mechanisms and interactions between BrD proteins and immune infiltrates in cancer. We present a consistently positive correlation between the SP-family genes and immune score regardless of the tumor type. The SP-family proteins correlate positively with T cells' trafficking and infiltration into tumor. Our results also show an association between the high expression of SP family genes and enriched transcriptome profiles of inflammatory response and TNF-α signaling via NF-κß. We also show that the SP-family proteins could be considered good predictors of high immune infiltration phenotypes.


Asunto(s)
Neoplasias , Proteínas , Humanos , Proteínas/genética , Neoplasias/genética , Inmunidad , Perfilación de la Expresión Génica , Transcriptoma
6.
Adv Med Sci ; 69(2): 368-376, 2024 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-39047970

RESUMEN

Hypoxia in the tumor core negatively affects the outcome of patients with head and neck squamous cell carcinoma (HNSCC). Nevertheless, its role in predicting treatment response requires further exploration. Typically, reduced oxygen levels in the tumor core correlate with diminished efficacy of radiotherapy, chemotherapy, and immunotherapy, which are commonly used for HNSCC patients' treatment. Understanding the mechanistic underpinnings of these varied treatment responses in HNSCC is crucial for enhancing therapeutic outcomes and extending patients' overall survival (OS) rates. Standard monolayer cell culture conditions have major limitations in mimicking tumor physiological features and the complexity of the tumor microenvironment. Three-dimensional (3D) cell cultures enable the recreation of the in vivo tumor attributes, encompassing oxygen and nutrient gradients, cellular morphology, and intracellular connections. It is vital to use the 3D model in treatment response studies to mimic the tumor microenvironment, as evidenced by the decreased sensitivity of 3D structures to anticancer therapy. Accordingly, the aim of the study was to delineate the utility of the 3D models of hypoxic head and neck tumors in drug screening and treatment response studies.

7.
Front Oncol ; 14: 1402126, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38966069

RESUMEN

Background: RNA methyltransferase-like 3 (METTL3) is responsible for methyl group transfer in the progression of N 6-methyladenosine (m6A) modification. This epigenetic feature contributes to the structural and functional regulation of RNA and consequently may promote tumorigenesis, tumor progression, and cellular response to anticancer treatment (chemo-, radio-, and immunotherapy). In head and neck squamous cell carcinoma (HNSCC), the commonly used chemotherapy is cisplatin. Unfortunately, cisplatin resistance is still a major cause of tumor relapse and patients' death. Thus, this study aimed to investigate the role of METTL3 on cellular response to cisplatin in HNSCC in vitro models. Materials and methods: HNSCC cell lines (H103, FaDu, and Detroit-562) with stable METTL3 knockdown (sgMETTL3) established with CRISPR-Cas9 system were treated with 0.5 tolerable plasma level (TPL) and 1 TPL of cisplatin. Further, cell cycle distribution, apoptosis, CD44/CD133 surface marker expression, and cell's ability to colony formation were analyzed in comparison to controls (cells transduced with control sgRNA). Results: The analyses of cell cycle distribution and apoptosis indicated a significantly higher percentage of cells with METTL3 knockdown 1) arrested in the G2/S phase and 2) characterized as a late apoptotic or death in comparison to control. The colony formation assay showed intensified inhibition of a single cell's ability to grow into a colony in FaDu and Detroit-562 METTL3-deficient cells, while a higher colony number was observed in H103 METTL3 knockdown cells after cisplatin treatment. Also, METTL3 deficiency significantly increased cancer stem cell markers' surface expression in all studied cell lines. Conclusion: Our findings highlight the significant influence of METTL3 on the cellular response to cisplatin, suggesting its potential as a promising therapeutic target for addressing cisplatin resistance in certain cases of HNSCC.

8.
Clin Transl Oncol ; 26(4): 1022-1032, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38175424

RESUMEN

BACKGROUND: Cellular senescence is a state characterized by cell-cycle arrest and apoptotic resistance. Senescence in cancer may be induced by oncogenes or therapy. While cellular senescence might play an important role in protection against cancer development, elevated and uncontrolled senescent cells accumulation may promote carcinogenesis by secreting a collection of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP). MATERIAL AND METHODS: We determined the gene expression at mRNA level of selected cellular senescence markers (p16 and LMNB1) and SASP factors (IL-6, IL-1b, CXCL-1 and TNF-α) in 72 cancerous tissues and 64 normal tissues obtained from patients with head and neck squamous cell carcinoma (HNSCC) and correlated this data with patients' clinical follow-up. RESULTS: Our results indicate higher levels of selected SASP factors in cancerous compared to normal tissues. We presented the relationship between SASP factors expression at the transcript level and the progression of the disease. Moreover, we proposed CXCL1 as a candidate biomarker differentiating normal tissues from cancerous ones and IL1b expression as a molecular factor related to increased TNM stage. CONCLUSION: Our primary study indicates that SASP expression may be associated with some clinicopathological features. However, a more detailed study is needed to present specific role of senescence-related mechanism and SASPs especially in tumor therapy response and in relation to the patient's immune system condition.


Asunto(s)
Neoplasias de Cabeza y Cuello , Fenotipo Secretor Asociado a la Senescencia , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Senescencia Celular/genética , Carcinogénesis , Neoplasias de Cabeza y Cuello/genética , Fenotipo
9.
Clin. transl. oncol. (Print) ; 26(4): 1022-1032, Abr. 2024. graf
Artículo en Inglés | IBECS (España) | ID: ibc-VR-65

RESUMEN

Background: Cellular senescence is a state characterized by cell-cycle arrest and apoptotic resistance. Senescence in cancer may be induced by oncogenes or therapy. While cellular senescence might play an important role in protection against cancer development, elevated and uncontrolled senescent cells accumulation may promote carcinogenesis by secreting a collection of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP). Material and methods: We determined the gene expression at mRNA level of selected cellular senescence markers (p16 and LMNB1) and SASP factors (IL-6, IL-1b, CXCL-1 and TNF-α) in 72 cancerous tissues and 64 normal tissues obtained from patients with head and neck squamous cell carcinoma (HNSCC) and correlated this data with patients’ clinical follow-up. Results: Our results indicate higher levels of selected SASP factors in cancerous compared to normal tissues. We presented the relationship between SASP factors expression at the transcript level and the progression of the disease. Moreover, we proposed CXCL1 as a candidate biomarker differentiating normal tissues from cancerous ones and IL1b expression as a molecular factor related to increased TNM stage. Conclusion: Our primary study indicates that SASP expression may be associated with some clinicopathological features. However, a more detailed study is needed to present specific role of senescence-related mechanism and SASPs especially in tumor therapy response and in relation to the patient’s immune system condition.(AU)


Asunto(s)
Humanos , Masculino , Femenino , Carcinoma de Células Escamosas de Cabeza y Cuello , Senescencia Celular/genética , Senescencia Celular , Neoplasias de Cabeza y Cuello/genética , Fenotipo
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