RESUMEN

Natural killer (NK) cells play a crucial role in antitumoral and antiviral responses. Yet, cancer cells can alter themselves or the microenvironment through the secretion of cytokines or other factors, hindering NK cell activation and promoting a less cytotoxic phenotype. These resistance mechanisms, often referred to as the "hallmarks of cancer" are significantly influenced by the activation of oncogenes, impacting most, if not all, of the described hallmarks. Along with oncogenes, other types of genes, the tumor suppressor genes are frequently mutated or modified during cancer. Traditionally, these genes have been associated with uncontrollable tumor growth and apoptosis resistance. Recent evidence suggests oncogenic mutations extend beyond modulating cell death/proliferation programs, influencing cancer immunosurveillance. While T cells have been more studied, the results obtained highlight NK cells as emerging key protagonists for enhancing tumor cell elimination by modulating oncogenic activity. A few recent studies highlight the crucial role of oncogenic mutations in NK cell-mediated cancer recognition, impacting angiogenesis, stress ligands, and signaling balance within the tumor microenvironment. This review will critically examine recent discoveries correlating oncogenic mutations to NK cell-mediated cancer immunosurveillance, a relatively underexplored area, particularly in the era dominated by immune checkpoint inhibitors and CAR-T cells. Building on these insights, we will explore opportunities to improve NK cell-based immunotherapies, which are increasingly recognized as promising alternatives for treating low-antigenic tumors, offering significant advantages in terms of safety and manufacturing suitability.

Asunto(s)

RESUMEN

Cancer, being the most formidable ailment, has had a profound impact on the human health. The disease is primarily associated with genetic mutations that impact oncogenes and tumor suppressor genes (TSGs). Recently, growing evidence have shown that X-linked TSGs have specific role in cancer progression and metastasis as well. Interestingly, our genome harbors around substantial portion of genes that function as tumor suppressors, and the X chromosome alone harbors a considerable number of TSGs. The scenario becomes even more compelling as X-linked TSGs are adaptive to key epigenetic processes such as X chromosome inactivation. Therefore, delineating the new paradigm related to X-linked TSGs, for instance, their crosstalk with autosome and involvement in cancer initiation, progression, and metastasis becomes utmost importance. Considering this, herein, we present a comprehensive discussion of X-linked TSG dysregulation in various cancers as a consequence of genetic variations and epigenetic alterations. In addition, the dynamic role of X-linked TSGs in sex chromosome-autosome crosstalk in cancer genome remodeling is being explored thoroughly. Besides, the functional roles of ncRNAs, role of X-linked TSG in immunomodulation and in gender-based cancer disparities has also been highlighted. Overall, the focal idea of the present article is to recapitulate the findings on X-linked TSG regulation in the cancer landscape and to redefine their role toward improving cancer treatment strategies.

RESUMEN

Acquired cystic disease associated renal cell carcinomas (ACD-RCC) are rare and their molecular and histopathological characteristics are still being explored. We therefore investigated the clinicopathologic and molecular characteristics of 31 tumors. The patients were predominantly male (n = 30), with tumors mainly left-sided (n = 17), unifocal (n = 19), and unilateral (n = 29) and a mean tumor size of 25 mm (range, 3-65 mm). Microscopically, several histologic patterns were present, including pure classic sieve-like (n = 4), and varied proportions of mixed classic sieve-like with papillary (n = 23), tubulocystic (n = 9), compact tubular (n = 4) and solid (n = 1) patterns. Calcium-oxalate crystals were seen in all tumors. Molecular analysis of 9 tumors using next generation sequencing showed alterations in SMARCB1 in 3 tumors (1 with frameshift deletion and 2 with copy number loss in chromosome 22 involving SMARCB1 region), however, INI1 stain was retained in all. Nonrecurrent genetic alterations in SETD2, NF1, NOTCH4, BRCA2 and CANT1 genes were also seen. Additionally, MTOR p.Pro351Ser was identified in one tumor. Copy number analysis showed gains in chromosome 16 (n = 5), 17 (n = 2) and 8 (n = 2) as well as loss in chromosome 22 (n = 2). In summary, ACD-RCC is a recognized subtype of kidney tumors, with several histological architectural patterns. Our molecular data identifies genetic alterations in chromatin modifying genes (SMARCB1 and SETD2), which may suggest a role of such genes in ACD-RCC development.

Asunto(s)

RESUMEN

Ovarian cancer (OC) represents the most prevalent malignancy of the female reproductive system. Its distinguishing features include a high aggressiveness, substantial morbidity and mortality, and a lack of apparent symptoms, which collectively pose significant challenges for early detection. Given that aberrant DNA methylation events leading to altered gene expression are characteristic of numerous tumor types, there has been extensive research into epigenetic mechanisms, particularly DNA methylation, in human cancers. In the context of OC, DNA methylation is often associated with the regulation of critical genes, such as BRCA1/2 and Ras­association domain family 1A. Methylation modifications within the promoter regions of these genes not only contribute to the pathogenesis of OC, but also induce medication resistance and influence the prognosis of patients with OC. As such, a more in­depth understanding of DNA methylation underpinning carcinogenesis could potentially facilitate the development of more effective therapeutic approaches for this intricate disease. The present review focuses on classical tumor suppressor genes, oncogenes, signaling pathways and associated microRNAs in an aim to elucidate the influence of DNA methylation on the development and progression of OC. The advantages and limitations of employing DNA methylation in the diagnosis, treatment and prevention of OC are also discussed. On the whole, the present literature review indicates that the DNA methylation of specific genes could potentially serve as a prognostic biomarker for OC and a therapeutic target for personalized treatment strategies. Further investigations in this field may yield more efficacious diagnostic and therapeutic alternatives for patients with OC.

Asunto(s)

RESUMEN

The impact of centrosome abnormalities on cancer cell proliferation has been recognized as early as 1914 (Boveri, Zur Frage der Entstehung maligner Tumoren. Jena: G. Fisher, 1914), but vigorous research on molecular levels has only recently started when it became fully apparent that centrosomes can be targeted for new cancer therapies. While best known for their microtubule-organizing capabilities as MTOC (microtubule organizing center) in interphase and mitosis, centrosomes are now further well known for a variety of different functions, some of which are related to microtubule organization and consequential activities such as cell division, migration, maintenance of cell shape, and vesicle transport powered by motor proteins, while other functions include essential roles in cell cycle regulation, metabolic activities, signal transduction, proteolytic activity, and several others that are now heavily being investigated for their role in diseases and disorders (reviewed in Schatten and Sun, Histochem Cell Biol 150:303-325, 2018; Schatten, Adv Anat Embryol Cell Biol 235:43-50, 2022a; Schatten, Adv Anat Embryol Cell Biol 235:17-35, 2022b).Cancer cell centrosomes differ from centrosomes in noncancer cells in displaying specific abnormalities that include phosphorylation abnormalities, overexpression of specific centrosomal proteins, abnormalities in centriole and centrosome duplication, formation of multipolar spindles that play a role in aneuploidy and genomic instability, and several others that are highlighted in the present review on ovarian cancer. Ovarian cancer cell centrosomes, like those in other cancers, display complex abnormalities that in part are based on the heterogeneity of cells in the cancer tissues resulting from different etiologies of individual cancer cells that will be discussed in more detail in this chapter.Because of the critical role of centrosomes in cancer cell proliferation, several lines of research are being pursued to target centrosomes for therapeutic intervention to inhibit abnormal cancer cell proliferation and control tumor progression. Specific centrosome abnormalities observed in ovarian cancer will be addressed in this chapter with a focus on targeting such aberrations for ovarian cancer-specific therapies.

Asunto(s)

RESUMEN

The present review demonstrates the major tumor suppressor genes, including TP53, CDKN2A and SMAD4, associated with pancreatic cancer. Each gene's role, prevalence and impact on tumor development and progression are analyzed, focusing on the intricate molecular landscape of pancreatic cancer. In addition, this review underscores the prognostic significance of specific mutations, such as loss of TP53, and explores some potential targeted therapies tailored to these molecular signatures. The findings highlight the importance of genomic analyses for risk assessment, early detection and the design of personalized treatment approaches in pancreatic cancer. Overall, this review provides a comprehensive analysis of the molecular intricacies of pancreatic tumors, paving the way for more effective and tailored therapeutic interventions.

RESUMEN

Glioblastoma is the most prevalent primary brain tumor. Because glioblastomas are very vascular, they may worsen the disease's neurologic symptoms by causing vasogenic brain edema and mass effects with a wide range of other symptoms. In this case report, a 42-year-old male complaining of severe headache, generalized weakness, and forgetfulness was brought to a territory care hospital, where a detailed neurological examination and investigations with magnetic resonance imaging (MRI) revealed a grade IV (high-grade) glioma at the right frontotemporal and capsuloganglionic regions of the brain, and was suggested for surgery. Postoperatively, the patient was referred for chemotherapy, but due to severe weakness, fatigue, and motor deficits, he was referred for physiotherapy. Follow-up was conducted to monitor the patient's progression using various outcome measures. These measures included the Functional Independence Measure (FIM), the Intensive Care Unit (ICU) Mobility Scale, the Glasgow Coma Scale (GCS), the modified Rankin Scale (mRS), and the Karnofsky Performance Status (KPS) Scale. Significant improvement was observed in the patient's symptoms, as tracked by these outcome measures. Therefore, it is important that a tailored rehabilitation protocol of six weeks was planned, focusing on palliative care and some symptoms of weakness, reduced strength, tone, and breathlessness to prevent secondary complications like deep vein thrombosis, irritability, anxiety, forgetfulness, decreased balance, and coordination in sitting. Since the prognosis of grade IV glioblastoma is poor, the goal-oriented rehabilitation program will help improve the palliative status and the overall quality of life of the patient.

RESUMEN

BACKGROUND: Oral microbial dysbiosis contributes to the development of oral squamous cell carcinoma (OSCC). Our previous study showed that Prevotella intermedia (P. intermedia) were enriched in the oral mucosal surface, plaque, and saliva of patients with OSCC. Intratumoral microbiome could reshape the immune system and influence the development of various tumors. However, the invasion status of human OSCC tissues by P. intermedia and the pathway through which intratumoral P. intermedia potentiates tumor progression remain unexplored. METHODS: P. intermedia in human OSCC or normal tissues was detected by FISH. A mouse OSCC cell line SCC7 was adopted to investigate the effects of heat-killed P. intermedia treatment on cell proliferation, invasion, and cytokine release by using CCK-8 assay, transwell invasion assay and ELISA. Moreover, we established a mouse transplanted tumor model by using SCC7 cells, injected heat-killed P. intermedia into tumor tissues, and investigated the effects of heat-killed P. intermedia on tumor growth, invasion, cytokine levels, immune cell infiltrations, and expression levels by using gross observation, H&E staining, ELISA, immunohistochemistry, mRNA sequencing, and transcriptomic analysis. RESULTS: Our results indicated that P. intermedia were abundant in OSCC and surrounding muscle tissues. Heat-killed P. intermedia promoted SCC7 cell proliferation, invasion and proinflammatory cytokine secretions, accelerated transplanted tumor growth in mice, exacerbate muscle and perineural invasion of OSCC, elevated the serum levels of IL-17A, IL-6, TNF-α, IFN-γ, and PD-L1, induced Treg cells M2 type macrophages in mouse transplanted tumors. The data of transcriptomic analysis revealed that heat-killed P. intermedia increased the expression levels of inflammatory cytokines and chemokines while reduced the expression levels of some tumor suppressor genes in mouse transplanted tumors. Additionally, IL-17 signaling pathway was upregulated whereas GABAergic system was downregulated by heat-killed P. intermedia treatment. CONCLUSIONS: Taken together, our results suggest that P. intermedia could inhibit the expression of tumor suppressors, alter the tumor microenvironment, and promote the progression of OSCC.

RESUMEN

BACKGROUND: Androgen deprivation therapy (ADT) with docetaxel (D) and/or antiandrogen receptor therapies (ARTs) are the standard therapies in metastatic hormone-sensitive prostate cancer (mHSPC). Alterations in the tumor suppressor genes (TSGs) RB1, PTEN, and TP53 are associated with an aggressive evolution and treatment resistance in castration-resistant prostate cancer (CRPC). OBJECTIVE: To study the clinical implications of TSG mRNA expression in mHSPC patients. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective biomarker study in mHSPC patients. TSGlow status was defined when two or more out of the three TSGs presented low RNA expression by nCounter in formalin-fixed paraffin-embedded samples and TSGwt for the remaining cases. The microarray data from the CHAARTED trial were analyzed as an independent validation cohort. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Molecular data were correlated with CRPC-free survival (CRPC-FS) and overall survival (OS) by the Kaplan-Meier method and multivariate Cox analysis. RESULTS AND LIMITATIONS: A total of 226 patients were included, of whom 218 were eligible: 93 were treated with ADT and 125 with ADT + D; 75.7% presented de novo stage IV and 67.9% high-volume disease. TSGlow (19.2%) was independently correlated with shorter CRPC-FS (hazard ratio [HR] 1.8, p = 0.002) and OS (HR 2, p = 0.002). In the CHAARTED trial, TSGlow was independently correlated with lower CRPC-FS (HR 2.2, p = 0.02); no differences in clinical outcomes according to treatment were observed in TSGlow patients, while a significant benefit was observed for ADT + D in the TSGwt group for CRPC-FS (HR 0.4, p < 0.001) and OS (HR 0.4, p = 0.001). However, no interaction was observed between TSG signature and treatment in either series. Study limitations are the retrospective design, small sample size, and lack of inclusion of patients treated with ADT + ART. CONCLUSIONS: TSGlow expression correlates with adverse outcomes in patients with mHSPC. The investigation of new therapeutic strategies in these patients is warranted. PATIENT SUMMARY: The low RNA expression of tumor suppressor genes in the tumors is correlated with adverse outcomes in patients with metastatic hormone-sensitive prostate cancer.

Asunto(s)

RESUMEN

Oral cancer is a significant global health concern, with a high mortality rate mainly due to late-stage diagnosis. Early detection plays a critical role in improving patient outcomes, highlighting the need for non-invasive and accessible screening methods. Salivary biomarkers have emerged as a promising avenue for oral cancer detection, leveraging advancements in human DNA and RNA analysis. Several DNA-based biomarkers, such as genetic mutations, chromosomal aberrations, and epigenetic alterations, have shown promise in detecting oral cancer at various stages. Likewise, RNA-based biomarkers, including microRNAs, long non-coding RNAs, and messenger RNAs, have demonstrated potential for diagnosing oral cancer and predicting treatment outcomes. The integration of high-throughput sequencing technologies, such as next-generation sequencing and transcriptomic profiling, has enabled the identification of novel biomarkers and provided deeper insights into the molecular mechanisms underlying oral cancer development and progression. Despite the promising results, challenges remain in standardizing sample collection, establishing robust biomarker panels, and validating their clinical utility. Nevertheless, salivary biomarkers hold great promise as a non-invasive, cost-effective, and accessible approach for oral cancer detection, ultimately leading to improved patient outcomes through early diagnosis and intervention. The analysis of genetic material obtained from saliva offers several advantages, including ease of collection, non-invasiveness, and the potential for repeated sampling. Furthermore, saliva reflects the physiological and pathological status of the oral cavity, making it an ideal source for biomarker discovery and validation. This article presents a comprehensive review of the current research on salivary biomarkers for oral cancer detection, focusing on insights gained from human DNA and RNA analysis.

RESUMEN

Despite efforts to ban asbestos mining and manufacturing, mesothelioma deaths in the United States have remained stable at approximately 2500 cases annually. This trend is not unique to the United States but is also a global phenomenon, associated with increased aging of populations worldwide. Although geoeconomic factors such as lack of regulations and continued asbestos manufacturing in resource-poor countries play a role, it is essential to consider biological factors such as immune senescence and increased genetic instability associated with aging. Recognizing that mesothelioma shares genetic instability and immune system effects with other age-related cancers is crucial because the impact of aging on mesothelioma is frequently assessed in the context of disease latency after asbestos exposure. Nevertheless, the long latency period, often cited as a reason for mesothelioma's elderly predominance, should not overshadow the shared mechanisms. This communication focuses on the role of immune surveillance in mesothelioma, particularly exploring the impact of immune escape resulting from altered TSG function during aging, contributing to the phylogenetic development of gene mutations and mesothelioma oncogenesis. The interplay between the immune system, TSGs, and aging not only shapes the immune landscape in mesothelioma but also contributes to the development of heterogeneous tumor microenvironments, significantly influencing responses to immunotherapy approaches and survival rates. By understanding the complex interplay between aging, TSG decline, and immune senescence, health care professionals can pave the way for more effective and personalized immunotherapies, ultimately offering hope for better outcomes in the fight against mesothelioma.

Asunto(s)

RESUMEN

INTRODUCTION: Patients with metastatic EGFR-mutant NSCLC inevitably have disease progression while on tyrosine kinase inhibitor (TKI) therapy. Co-occurring tumor suppressor gene (TSG) alterations have been associated with poor outcomes, however, detailed analyses of their impact on patient outcomes are limited. METHODS: Patients with EGFR-mutant NSCLC treated with EGFR TKIs who had tumor genomic profiling were included. Alterations in TP53 and five additional TSGs (RB1, NF1, ARID1A, BRCA1, and PTEN) were used to stratify the cohort into the following three subgroups: patients with tumors harboring a TP53 mutation plus a mutation in at least one additional TSG (TP53mut/TSGmut), those having a TP53 mutation without additional TSG mutations (TP53mut/TSGwt), and those with TP53wt. Patient characteristics and clinical outcomes were assessed in two independent cohorts. RESULTS: A total of 101 patients from the Yale Cancer Center and 182 patients from the American Association for Cancer Research Project GENIE database were included. In the Yale cohort, TP53 mutations were identified in 65 cases (64%), of which 23 were TP53mut/TSGmut and 42 were TP53mut/TSGwt. Although the presence of a TP53 mutation was associated with worse outcomes, the additional TSG alteration in TP53mut tumors identified a subset of patients associated with particularly aggressive disease and inferior clinical outcome in both the Yale and the GENIE cohorts. Specifically, in the Yale cohort for patients receiving first-line TKIs, those with TP53mut/TSGmut tumors had shorter progression-free survival (PFS) and overall survival (OS) than TP53mut/TSGwt (PFS: hazard ratio [HR] = 2.03, confidence interval [CI]: 1.12-3.69, p < 0.01, OS: HR = 1.58, CI: 0.82-3.04, p = 0.12) or TP53wt cases (PFS: HR 2.4, CI: 1.28-4.47, p < 0.001, OS: HR = 2.54, CI: 1.21-5.34, p < 0.005). Inferior outcomes in patients with TP53mut/TSGmut tumors were also found in those receiving osimertinib as second-line therapy. Similar findings were seen in patients in the GENIE cohort. CONCLUSIONS: Patients with TP53mut/TSGmut tumors represent a patient subgroup characterized by an aggressive disease phenotype and inferior outcomes on EGFR TKIs. This information is important for understanding the biological underpinnings of differential outcomes with TKI treatment and has implications for identifying patients who may benefit from additional therapeutic interventions beyond osimertinib monotherapy.

Asunto(s)

RESUMEN

Objective: To investigate the role of Human Papilloma Virus (HPV) (16/18) in relation to the molecular genetic mechanisms of Cyclin D1, p53, p16, and Epidermal growth factor receptor (EGFR) in Laryngeal Squamous Cell Carcinoma (LSSC). Methods: A cross-sectional study of 88 (Formalin-fixed Paraffin Embedded) FFPE laryngeal biopsies were done at Basic Medical Sciences Institute, Jinnah Postgraduate Centre, Karachi from 2010 to 2019 with the application of Polymerase chain reaction (PCR) for HPV 16/18and Immuno-histochemical staining for molecular genetic expression of proteins, Cyclin D1, p53, p16, and EGFR. Results: Out of 88 cases of Laryngeal Squamous Cell Carcinoma (LSSC) there was female preponderance. Mean age of the participants was found as 50.7±12.8 years. High risk HPV 16/18 was positive in 28 cases (31.8%), largely related to Grade-II and Grade-III. Immunohistochemically, Cyclin D1 (87.5%) appeared as the most important driver mutation followed by p16 (86.4%), EGFR (65.9%), and, p53 was positive in (61.4%) of cases. Conclusion: The role of high-risk HPV 16/18 is concurred in the present study strongly in correlation to p16 as a surrogate marker. Moreover, the other driver mutations of Cyclin D1, p53, and EGFR are also implicated as cumulative molecular events in tumor progression as mostly seen in higher Grades.

RESUMEN

Cervical cancer is a huge worldwide health burden, impacting women in impoverished nations in particular. Traditional therapeutic approaches, such as surgery, radiation therapy, and chemotherapy, frequently result in systemic toxicity and ineffectiveness. Nanomedicine has emerged as a viable strategy for targeted delivery of therapeutic drugs to cancer cells while decreasing off-target effects and increasing treatment success in recent years. Nanomedicine for cervical cancer introduces several novel aspects that distinguish it from previous treatment options such as tailored delivery system, precision targeting, combination therapies, real-time monitoring and diverse nanocarriers to overcome the limitations of one another. This abstract presents recent advances in nanomedicine-based tailored delivery systems for the treatment of cervical cancer. Liposomes, polymeric nanoparticles, dendrimers, and carbon nanotubes have all been intensively studied for their ability to transport chemotherapeutic medicines, nucleic acids, and imaging agents to cervical cancer cells. Because of the way these nanocarriers are designed, they may cross biological barriers and preferentially aggregate at the tumor site, boosting medicine concentration and lowering negative effects on healthy tissues. Surface modification of nanocarriers with targeting ligands like antibodies, peptides, or aptamers improves specificity for cancer cells by identifying overexpressed receptors or antigens on the tumor surface. Furthermore, nanomedicine-based techniques have made it possible to co-deliver numerous therapeutic drugs, allowing for synergistic effects and overcoming drug resistance. In preclinical and clinical investigations, combination treatments comprising chemotherapeutic medicines, gene therapy, immunotherapy, and photodynamic therapy have showed encouraging results, opening up new avenues for individualized and multimodal treatment regimens. Furthermore, the inclusion of contrast agents and imaging probes into nanocarrier systems has enabled real-time monitoring and imaging of treatment response. This enables the assessment of therapy efficacy, the early diagnosis of recurrence, and the optimization of treatment regimens.

Asunto(s)

RESUMEN

De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5-10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since 2015, the prognosis of mHSPC has slightly improved thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. This review describes the current therapeutic opportunities for de novo mHSPC, focusing on potential molecular biomarkers identified in the main clinical trials that have modified the standard of care, the genomic features of de novo mHSPC, and the principal ongoing trials that are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment in this setting. The road toward personalized treatment for de novo mHSPC is still long, considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that did not necessarily reflect the biological rationale of the chosen therapy. The role of transcriptomic profiling of mHSPC as a predictive biomarker requires further validation, and it remains to be ascertained how the genomic variants detected in mHSPC, which are regarded as predictive in the castration-resistant disease, can be exploited in the mHSPC setting.

RESUMEN

Lung cancer is indeed a major cause of cancer-related deaths worldwide. The development of tumors involves a complex interplay of genetic, epigenetic, and environmental factors. Epigenetic mechanisms, including DNA methylation (DNAm), histone modifications, and microRNA expression, play a crucial role in this process. Changes in DNAm patterns can lead to the silencing of important genes involved in cellular functions, contributing to the development and progression of lung cancer. MicroRNAs and exosomes have also emerged as reliable biomarkers for lung cancer. They can provide valuable information about early diagnosis and treatment assessment. In particular, abnormal hypermethylation of gene promoters and its effects on tumorigenesis, as well as its roles in the Wnt signaling pathway, have been extensively studied. Epigenetic drugs have shown promise in the treatment of lung cancer. These drugs target the aberrant epigenetic modifications that are involved in the development and progression of the disease. Several factors have been identified as drug targets in non-small cell lung cancer. Recently, combination therapy has been discussed as a successful strategy for overcoming drug resistance. Overall, understanding the role of epigenetic mechanisms and their targeting through drugs is an important area of research in lung cancer treatment.

RESUMEN

Los MicroARNs (miARNs) son moléculas reguladoras de la expresión de genes y como tales colaboran para determinar cuántas proteínas se producen en las células de un determinador gen. Como su nombre indican son moléculas funcionales pese a su pequeño tamaño (micro) y están constituidas por ácido ribonucleico (ARN), en contraste con los reguladores de la expresión génica más extensamente estudiados, que son de naturaleza proteica. Debido a su pequeño tamaño y su naturaleza peculiar, la presencia de los genes que codifican a los microARNs fue descubierta en el genoma humano en etapas posteriores a la de su secuenciación, ya en el siglo XXI. Los microARNs juegan un papel fundamental en el establecimiento de la identidad y el funcionamiento celular. Por lo que componentes de la maquinaria de síntesis de microARNs o microARNs per se, han sido asociados con diversas patologías humanas, incluyendo el cáncer. Se ha descubierto que los microARNs juegan un papel importante en muchos procesos celulares que están alterados en cáncer como: diferenciación, proliferación y apoptosis. Los genes que codifican para los microARNs se han encontrado en regiones cromosómicas frecuentemente ganadas o perdidas en cáncer. Algunos microARNs presentan niveles de expresión alterados en cáncer y han demostrado su capacidad para afectar la transformación celular, carcinogénesis y metástasis actuando como oncogenes o genes supresores de tumores. Así, la presencia de determinados microARNs se ha visto con utilidad clínica diagnóstica y pronóstica y se están intentando validar terapias basadas en la actividad de microARNs relevantes en cáncer. La familia de microARNs let-7 fue la primera descubierta en humanos. Muchos de sus miembros están en regiones cromosómicas frecuentemente delecionadas en tumores de cáncer de pulmón. Además, se ha correlacionado una expresión reducida de estos genes con un peor pronóstico cáncer de pulmón.(AU)

MicroRNAs (miRNAs) are molecules that regulate gene expression and as such they collaborate to determine how many proteins are produced in the cells of a given gene. As their name indicates, they are functional molecules despite their small size (micro) and are made up of ribonucleic acid (RNA), in contrast to the most extensively studied regulators of gene expression, which are protein in nature. Due to its small size and peculiar nature, the presence of the genes that encode microRNAs was discovered in the human genome in stages after its sequencing, already in the 21st century.MicroRNAs play a fundamental role in establishing cellular identity and function. Therefore, components of the microRNA synthesis machinery, or microRNAs per se, have been associated with various human pathologies, including cancer.It has been discovered that microRNAs play an important role in many cellular processes that are altered in cancer such as: differentiation, proliferation, and apoptosis. The genes that code for microRNAs have been found in chromosomal regions frequently gained or lost in cancer. Some microRNAs have altered expression levels in cancer and have demonstrated their ability to affect cellular transformation, carcinogenesis, and metastasis by acting as oncogenes or tumor suppressor genes. Thus, the presence of certain microRNAs has been seen to have clinical diagnostic and prognostic utility and attempts are being made to validate therapies based on the activity of relevant microRNAs in cancer.The let-7 family of microRNAs was the first discovered in humans. Many of its members are in chromosomal regions frequently deleted in lung cancer tumors.(AU)

Asunto(s)

RESUMEN

The identification of cancer predisposition syndromes (CPSs) plays a crucial role in understanding the etiology of pediatric cancers. CPSs are genetic mutations that increase the risk of developing cancer at an earlier age compared to the risk for the general population. This article aims to provide a comprehensive analysis of three unique cases involving pediatric patients with CPS who were diagnosed with multiple simultaneous or metachronous cancers. The first case involves a child with embryonal rhabdomyosarcoma, nephroblastoma, glioma, and subsequent medulloblastoma. Genetic analysis identified two pathogenic variants in the BRCA2 gene. The second case involves a child with alveolar rhabdomyosarcoma, juvenile xanthogranuloma, gliomas, and subsequent JMML/MDS/MPS. A pathogenic variant in the NF1 gene was identified. The third case involves a child with pleuropulmonary blastoma and pediatric cystic nephroma/nephroblastoma, in whom a pathogenic variant in the DICER1 gene was identified. Multiple simultaneous and metachronous cancers in pediatric patients with CPSs are a rare but significant phenomenon. Comprehensive analysis and genetic testing play significant roles in understanding the underlying mechanisms and guiding treatment strategies for these unique cases. Early detection and targeted interventions are important for improving outcomes in these individuals.

RESUMEN

BACKGROUND: Proteins containing the Jumonji C (JmjC) domain participated in tumorigenesis and cancer progression. However, the mechanisms underlying this effect are still poorly understood. Our objective was to investigate the role of Jumonji and the AT-rich interaction domain-containing 2 (JARID2) - a JmjC family protein - in breast cancer, as well as its latent association with obesity. METHODS: Immunohistochemistry, The Cancer Genome Atlas, Gene Expression Omnibus, and other databases were used to analyze the expression of JARID2 in breast cancer cells. Growth curve, 5-ethynyl-2-deoxyuridine (EdU), colony formation, and cell invasion experiments were used to detect whether JARID2 affected breast cancer cell proliferation and invasion. Spheroidization-based experiments and xenotumor transplantation in NOD/SCID mice were used to examine the association between JARID2 and breast cancer stemness. RNA-sequencing, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis were used to identify the cell processes in which JARID2 participates. Immunoaffinity purification and silver staining mass spectrometry were conducted to search for proteins that might interact with JARID2. The results were further verified using co-immunoprecipitation and glutathione S-transferase (GST) pull-down experiments. Using chromatin immunoprecipitation (ChIP) sequencing, we sought the target genes that JARID2 and metastasis-associated protein 1 (MTA1) jointly regulated; the results were validated by ChIP-PCR, quantitative ChIP (qChIP) and ChIP-reChIP assays. A coculture experiment was used to explore the interactions between breast cancer cells and adipocytes. RESULTS: In this study, we found that JARID2 was highly expressed in multiple types of cancer including breast cancer. JARID2 promoted glycolysis, lipid metabolism, proliferation, invasion, and stemness of breast cancer cells. Furthermore, JARID2 physically interacted with the nucleosome remodeling and deacetylase (NuRD) complex, transcriptionally repressing a series of tumor suppressor genes such as BRCA2 DNA repair associated (BRCA2), RB transcriptional corepressor 1 (RB1), and inositol polyphosphate-4-phosphatase type II B (INPP4B). Additionally, JARID2 expression was regulated by the obesity-associated adipokine leptin via Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in the breast cancer microenvironment. Analysis of various online databases also indicated that JARID2/MTA1 was associated with a poor prognosis of breast cancer. CONCLUSION: Our data indicated that JARID2 promoted breast tumorigenesis and development, confirming JARID2 as a target for cancer treatment.

RESUMEN

Tumor suppressor genes (TSGs) are commonly downregulated in colon cancer and play a negative role in tumorigenesis and cancer progression by affecting genomic integrity, the cell cycle, and cell proliferation. Curcumin (CUR), a Chinese herb-derived phytochemical, exerts antitumor effects on colon cancer. However, it remains unclear whether CUR exerts its antitumor effects by reactivating TSGs in colon cancer. Here, we demonstrated that CUR inhibited HT29 and HCT116 proliferation and migration by cell-counting kit-8, colony-formation, and wound-healing assays. Furthermore, the comprehensive bioinformatics analysis of mRNA sequencing revealed that 3,505 genes were significantly upregulated in response to CUR in HCT116 cells. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses showed that the most upregulated genes were enriched in cancer pathways containing 37 TSGs. Five (ARHGEF12, APAF1, VHL, CEBPA, and CASP8) of the 37 upregulated TSGs were randomly selected for real-time fluorescence polymerase chain reaction and the verification results showed that these five genes were significantly reactivated after CUR treatment, suggesting that TSGs are related to CUR-mediated colon cancer inhibition. ARHGEF12 is a newly identified TSG and a potential therapeutic target for colon cancer. Furthermore, molecular docking was performed to predict the binding sites of CUR and ARHGEF12, suggesting that CUR can prevent colon cancer cell invasion and metastasis by inhibiting ARHGEF12 and RhoA binding. In conclusion, the present study reveals that CUR inhibits colon cancer cell proliferation and migration by reactivating TSGs, revealing a new mechanism and potential target for colon cancer treatment.