Factor inducible por hipoxia en cáncer

El oxígeno y dióxido de carbono son vitales en la respiración, sus variaciones fuera del rango fisiológico son una amenaza para la supervivencia de las células. La hipoxia es una condición común en la mayoría de los tumores malignos, la cual promueve angiogénesis y vascularización disfuncional, mayor proliferación celular y la adquisición de un fenotipo de transición epitelial a mesenquimatoso, que contribuye con la metástasis; asimismo, altera el metabolismo de las células cancerosas y genera resistencia a la terapia, ya que induce a la inactividad celular. Por tanto, la hipoxia es un factor negativo, asociado a resultados adversos en la mayoría de los tratamientos de los distintos tipos de cáncer. El factor inducible por hipoxia (HIF) es el factor de transcripción relacionado con la hipoxia en cáncer, que produce la activación de más de una centena de genes reguladores de la actividad celular, que generan funciones cruciales para el desarrollo del cáncer. El objetivo principal de la presente revisión es puntualizar la importancia de la hipoxia en la génesis del cáncer, conocer las principales moléculas que interactúan en la expresión del HIF, explicar los mecanismos moleculares de las vías involucradas en la inducción del HIF, las consecuencias celulares por su alteración y las potenciales terapias dirigidas contra este factor. Se consultaron PubMed, Scopus y SciELO, del año 1990 hasta el año 2022, y se buscaron las referencias bibliográficas en relación con las palabras clave asociadas al factor inducible por hipoxia y cáncer. En conclusión, la sobreexpresión de HIF-1α en biopsias tumorales se asocia con una mayor mortalidad de pacientes en cánceres humanos. Los posibles genes diana regulados por HIF-1α que pueden desempeñar un papel en la progresión tumoral están empezando a descubrirse. A pesar de que se han estudiado cientos de compuestos en relación con el HIF en cáncer, en la actualidad existen pocos inhibidores del HIF aprobados en el mercado mundial; asimismo, muchos estudios clínicos, en sus distintas fases en desarrollo, no muestran resultados alentadores. Probablemente, en el futuro, cuando se tenga una mejor comprensión de la estructura, funcionamiento molecular y biológico de este factor, se desarrollarán fármacos más específicos para la inhibición del HIF.

Oxygen and carbon dioxide are essential for breathing; variations in these gases outside of the normal range are a threat to cell survival. Hypoxia is a common condition that occurs in most malignant tumors, increases angiogenesis and defective vascularization, promotes cell proliferation and acquires an epithelial-mesenchymal transition phenotype, which causes metastasis. It also affects cancer cell metabolism and makes patients resistant to treatment by causing cell quiescence. As a result, hypoxia is a detrimental component that is linked to unfavorable outcomes in most cancer treatments. Through the activation of more than a hundred genes that control cell activity, which produce key functions for cancer development, the transcription factor known as hypoxia-inducible factor (HIF) is linked to hypoxia in cancer. This review's main goals are to highlight the role of hypoxia in the development of cancer, identify the key molecules that interact to promote HIF expression, explain the molecular mechanisms of the pathways that lead to HIF induction, describe the cellular effects of HIF alteration, and discuss potential HIF-targeted therapies. Articles from 1990 to 2022 were reviewed in PubMed, Scopus and SciELO databases. Keywords related to cancer and HIF were searched in bibliographical references. In conclusion, HIF-1α overexpression in tumor biopsies is associated with increased patient mortality in human cancers. Potential HIF-1α-regulated target genes that may play a role in tumor progression are starting to be identified. Although hundreds of chemicals have been studied in relation to HIF in cancer, there are currently few approved HIF inhibitors available on the global market; moreover, many clinical trials, in their various stages of development, do not show encouraging results. It is likely that in the future, when there is a better understanding of the structure, molecular and biological functioning of this factor, more specific drugs for HIF inhibition will be developed.

Research progress of p53 protein in the development mechanism of triple negative breast cancer / 中国医师杂志

Tumor suppressor gene p53 plays an important role in regulating cell cycle, controlling apoptosis and repairing damaged DNA. Mutation of this gene is closely related to the occurrence, development and drug resistance of various tumors. The mutant p53 protein is closely related to the growth and metastasis of triple negative breast cancer (TNBC) with higher malignancy and higher risk of metastasis. This paper expounds the mechanism of p53 protein participating in the occurrence, development and metastasis of TNBC, introduces the effect of interfering with mouse dual-microbody gene 2 (MDM2), activated T cell nuclear factor 1 (NFAT1) and other proteins on p53, as well as small molecular targeted drugs closely related to p53 protein, and provides a new direction and theoretical basis for targeted treatment of TNBC.

The mechanism of p53 signaling pathway regulating ferroptosis in hepatocellular carcinoma / 临床肝胆病杂志

Hepatocellular carcinoma (HCC) is the most common type of liver cancer in China, and the development and progression of HCC is a complex pathological process. As a new way of cell death, ferroptosis has huge potential in the treatment of HCC. This article introduces the mechanism of action of the tumor suppressor p53 in regulating ferroptosis and briefly describes its role in the development and progression of HCC. The tumor suppressor p53 can promote or inhibit ferroptosis by affecting solute carrier family 7 member 11, spermidine/spermine N1-acety-ltransferase 1, glutaminase 2, dipeptidyl peptidase 4, and cyclin-dependent kinase inhibitor 1A, which in turn affects the progression of HCC. The treatment of HCC by regulating the ferroptosis pathway has great application prospects.

Autopsy findings of acute erythroid leukemia

ABSTRACT Acute erythroid leukemia (AEL) is an exceedingly uncommon but distinct hematological malignancy that shows neoplastic proliferation of erythroid precursors with maturation arrest and no significant myeloblasts. We describe an autopsy case of this rare entity in a 62-year-old man with co-morbidities. He underwent a bone marrow (BM) examination for pancytopenia during the first outpatient department visit, which revealed an increased number of erythroid precursors with dysmegakaryopoiesis suggesting the possibility of Myelodysplastic syndromes (MDS). Thereafter, his cytopenia got worsened, warranting blood and platelet transfusions. Four weeks later on the second BM examination, AEL was diagnosed based on morphology and immunophenotyping. Targeted resequencing for myeloid mutations revealed TP53 and DNMT3A mutations. He was initially managed along febrile neutropenia with the stepwise escalation of antibiotics. He developed hypoxia attributed to anemic heart failure. Subsequently, he had hypotension and respiratory fatigue pre-terminally and succumbed to his Illness. A complete autopsy showed infiltration of various organs by AEL and leukostasis. Besides, there was extramedullary hematopoiesis, arterionephrosclerosis, diabetic nephropathy (ISN-RPS class II), mixed dust pneumoconiosis, and pulmonary arteriopathy. The histomorphology of AEL was challenging, and the differential diagnoses were many. Thus, this case highlights the autopsy pathology of AEL, an uncommon entity with a strict definition, and its relevant differentials.

Expressions of survivin, p53 and human epidermal growth factor receptor 2 in breast cancer tissues and their prognostic value / 肿瘤研究与临床

Objective:To investigate the expressions of apoptosis-related factors survivin, p53 and human epidermal growth factor receptor 2 (HER2) in breast cancer tissues and their prognostic value.Methods:A total of 131 patients undergoing radical mastectomy for breast cancer who were admitted to Tangshan Maternal and Child Health Care Hospital from February 2015 to January 2019 were selected as the research subjects. During the operation, the cancer tissues and adjacent tissues (normal tissues >3 cm from the tumor margin) were collected from the patients. Expressions of survivin, p53 and HER2 in cancer tissues and adjacent tissues of patients were detected by using immunohistochemistry. The prognoses of patients were recorded after the follow-up for 3 years; the recurrence, metastasis and death treated as the poor prognosis, the rest prognoses of patients were treated as the good prognosis group. The difference of clinicopathological characteristics between the poor prognosis group and the good prognosis group was compared. Multivariate logistic regression was used to analyze risk factors for prognosis of breast cancer patients. The result of prognosis of breast cancer was taken as the golden standard. The receiver operating characteristic (ROC) curve was used to analyze the value of survivin pasitive, p53 pasitive, HER2 pasitive alone, the combination of both and the combination of the there in the judgement of poor prognosis of breast cancer.Results:The positive expression rates of survivin [49.6% (65/131) vs. 7.6% (10/131)], p53 [60.3% (79/131) vs. 13.0% (17/131)] and HER2 [79.4% (104/131) vs. 16.8% (22/131)] in cancer tissues were higher than those in adjacent tissues (all P<0.001). A total of 131 breast cancer patients were followed up for 3 years without any loss of follow-up, and the follow-up rate was 100%. Within the follow-up for 3 years, there were 15 (11.5%) cases of recurrence, 8 (6.1%) cases of metastasis, and 10 (7.6%) cases of death, the incidence of poor prognosis was 25.2% (33/131); and the remaining 98 cases had good prognosis. The proportions of patients with TNM stage Ⅲ, lymph node metastasis, poorly differentiated histology, tumor diameter ≥3 cm, survivin, p53, and HER2 positive expressions in the poor prognosis group were higher than those in the good prognosis group (all P<0.05). Multivariate logistic regression analysis showed that TNM stage Ⅲ [ OR = 5.323 (95% CI 2.190-12.936)], lymph node metastasis [ OR = 4.773 (95% CI 1.964-11.600)], tumor diameter ≥3 cm [ OR = 3.582(95% CI 1.474-8.706)], positive survivin [ OR = 2.740 (95% CI 1.127-6.659)], positive p53 [ OR = 3.271 (95% CI 1.346-7.949)], and positive HER2 [ OR = 3.873 (95% CI 1.594-9.412)] were independent risk factors for prognosis of breast cancer (all P<0.001). The ROC curve results showed that the area under the curve (AUC) values of survivin positive, p53 positive,HER2 positive, and the combination of any two were more than 0.80 (all P<0.001); the AUC of the combination of the three was 0.944 (95% CI 0.890-0.977) ( P<0.001). Conclusions:The expressions of survivin, p53, and HER2 are highly expressed in breast cancer tissues. The expressions of the three can be used to judge the prognosis of breast cancer patients, and the combination of the three has a higher judgement value.

Nueva mutación en el gen TSC2 protege contra el cáncer colorrectal en población mexicana / A novel mutation in the TSC2 gene protects against colorectal cancer in the Mexican population

Resumen Introducción: El cáncer colorrectal (CCR) es una enfermedad compleja debido al gran número de factores que influyen en su desarrollo, incluyendo variantes en genes supresores de tumores. Objetivo: Estimar las frecuencias alélicas y genotípicas de las variantes c.3915G>A y c.5371G>A del gen TSC2 en una población mexicana con CCR, así como analizar la asociación con el desarrollo de CCR. Métodos: Se incluyeron 126 muestras de sangre periférica de pacientes con diagnóstico de CCR esporádico y 134 de individuos sanos, considerados como grupo de control. La identificación de los genotipos se llevó a cabo mediante PCR tradicional y digestión enzimática. Todos los individuos firmaron una carta de consentimiento informado. Resultados: El alelo A de la variante c.3915G>A (RM = 0.31, IC 95 % = 0.15-0.69, p = 0.004), así como el haplotipo A/G de las variantes c.3915G>A y c.5371G>A (RM = 0.28, IC 95 % = 0.12-0.68, p = 0.005) mostraron un posible efecto protector contra CCR esporádico. El análisis in silico indicó que ambas variantes generan modificaciones en el proceso de corte y empalme. Conclusión: La presencia de la variante c.3915G>A del gen TSC2 sugiere un posible efecto protector contra CCR esporádico en población mexicana; sin embargo, no se observó esta asociación con la variante c.5371G>A.

Abstract Introduction: Colorectal cancer (CRC) is a complex disease due to the large number of factors that influence its development, including variants in tumor suppressor genes. Objective: To estimate allelic and genotypic frequencies of c.3915G>A and c.5371G>A variants of the TSC2 gene in a Mexican population with CRC, as well as to analyze their association with the development of CRC. Methods: 126 peripheral blood samples from patients diagnosed with sporadic CRC and 134 from healthy individuals, regarded as the control group, were included. Identification of genotypes was carried out using traditional PCR and enzymatic digestion. All individuals signed an informed consent letter. Results: The A allele of the c.3915G>A variant (OR = 0.31, 95% CI = 0.15-0.69, p = 0.004), as well as A/G haplotype of the c.3915G>A and c.5371G>A variants (OR = 0.28, 95% CI = 0.12-0.68, p = 0.005) showed a possible protective effect against sporadic CRC. In silico analysis indicated that both variants generate modifications in the splicing process. Conclusion: The presence of TSC2 gene c.3915G>A variant suggests a possible protective effect against sporadic CRC in the Mexican population; however, no association was observed with the c.5371G>A variant.

DIFFERENTIAL EXPRESSION OF MICRORNAs IN LUNG CANCER: A REVIEW ARTICLE

MicroRNAs (miRNAs) are small non-coding RNA molecules of approximately 16-24 nucleotide length. The miRNA biogenesis is a 2 step cleavage process mediated by Dorsha and Dicer. The nuclear cleavage by Dorsha / DiGeorge syndrome critical region 8 (DGCR8) generates 60-70 nucleotide long precursor microRNA (pre-miRNA). Furthermore, the pre-miRNA is exported to the cytoplasm by exportin 5 to be cleaved by Dicer. This resultant miRNA is further processed to generate a mature miRNA and get assembled into a RNA-induced silencing complex (RISC). Hence leading to transcriptional repression of the target mRNAs. It has been reported that one miRNA may target many genes accounting from a few to as many as thousands. Lung cancer (LC) ranks third worldwide and is marked by poor prognosis. The early staged LC patients usually exhibit no symptoms and the condition worsens till the time of first diagnosis. Therefore, studies are required to outline good early detecting and surveillance biomarkers for LC. Several evidences support the role of miRNAs in the pathogenesis of LC. They show differential expression pattern i.e. may be either upregulated or downregulated. The oncogenic miRNAs remain upregulated while the tummor suppressive miRNAs remain downregulated. In LC miRNAs are the important factors for tumour initiation, differentiation, apoptosis, proliferation as well as tumor progression. Thus, this review article focuses on the diagnostic significance of miRNAs in LC

Versatility of berberine as an effective immunomodulator and chemo sensitizer against p53 mutant cell

Cancer is the leading cause of death among individuals due to its poor prognosis. Various therapeutics treatments are available in form radiation therapy, chemotherapy, or immunotherapy but major point of concern is the treatment of cancer resistant cell lines. Homozygous loss of the p53 gene is virtually present in every type of cancer. Mutation in DNA binding domain of p53 leads to formation of mutant forms having altered amino acid sequence which lacks DNA binding activity. Berberine is chemo-sensitizing isoquinoline quaternary alkaloid molecule obtained from Berberis vulgaris. Berberine has the capability to suppress the growth of broad range of tumors. It exhibits pharmacological, biochemical and anticancer properties which can potentiate the activities of the existing therapeutics available in a way that it can re-sensitize the cancer resistant clones. Berberine has an immanent potential to bind with DNA and can communicate with several cellular targets, further it also shows hormetic effect which refers to biphasic dose response curve in order to determine dose dependent stimulatory and inhibitory effect. Mode of action involved is yet not well understood but mechanistic pathway involved are autophagy, up-regulation of tumor-suppressor gene (p53) and epigenetic alterations in the viral DNA. In this review, versatility of berberine can be utilized ideally or in combination with chemotherapeutics drugs to potentiate chemo sensitization of the resistant cancer cell line. Further, cancer cell specific receptor targeting can also be employed in combination with berberine for therapeutic treatment of metastasizing cancer cells.

Caracterización molecular de pacientes con cáncer colorrectal / Molecular characterization of colorectal cancer patients

Introducción. El cáncer colorrectal tiene una alta incidencia en la población mundial. Diversas vías moleculares están involucradas en su desarrollo, entre ellas, la inestabilidad cromosómica, la inestabilidad microsatelital y la epigenética. Objetivo. Hacer la caracterización molecular de 44 individuos con cáncer colorrectal esporádico. Materiales y métodos. El análisis de mutaciones en los genes APC, KRAS, TP53 y BRAF se hizo mediante secuenciación de Sanger; la inestabilidad microsatelital se determinó mediante electroforesis capilar utilizando cinco marcadores de repetición corta en tándem (Short Tandem Repeat) y el estado de metilación del promotor del gen MLH1 se hizo con la técnica MS-PCR (Methylation-Specific PCR). Resultados. La frecuencia de mutación de los genes APC, KRAS y TP53 fue del 18,1, 25 y 4,5 %, respectivamente; las mutaciones detectadas se localizaron con mayor frecuencia en el colon derecho. La frecuencia de inestabilidad microsatelital fue del 27,2 % y el 73,1 % en los tumores con metilación en el gen MHL1, y el 91,6 % de los tumores con inestabilidad microsatelital presentaba metilación en el gen MLH1. En el grupo de tumores con estabilidad microsatelital, las mutaciones en los genes APC, KRAS y TP53 fueron más frecuentes que en el grupo de tumores con inestabilidad microsatelital. La metilación del gen MLH1 fue la alteración más predominante. Conclusiones. En los pacientes con cáncer colorrectal evaluados se demostró la presencia de alteraciones moleculares en las diferentes vías genéticas, las cuales son comunes en su carcinogénesis. Los pacientes presentaron un perfil de mutaciones diferente al de otras poblaciones. Los hallazgos obtenidos en este estudio confirman la heterogeneidad molecular descrita en el desarrollo del cáncer colorrectal.

Introduction: Colorectal cancer has a high incidence in the world population. Different molecular pathways, such as chromosomal instability, microsatellite instability, and epigenetics are involved in its development. Objective: To perform molecular characterization in 44 individuals with sporadic colorectal cancer. Materials and methods: We conducted mutation analyses of the APC, KRAS, TP53 y BRAF genes using Sanger sequencing techniques; microsatellite instability was determined by capillary electrophoresis with five STR genetic markers while the methylation status of the MHL1 promotor gene was analyzed using methylation-specific PCR. Results: APC, KRAS, and TP53 genes mutation frequency was 18.1%, 25%, and 4.5%, respectively; the somatic mutations detected were located more frequently in the right colon. The frequency of microsatellite instability was 27.2% and 73.1% of the tumors had the MHL1 gene methylated while 91.6% of microsatellite instability-positive tumors had the methylated MLH1 gene. The mutation profile of microsatellite stability tumors APC, KRAS, and TP53 genes was more frequent than in the microsatellite instability-positive tumors. The methylation of the MLH1 gene was the most predominant molecular alteration. Conclusions: We identified molecular alterations in different genetic pathways of the colorectal cancer patients evaluated, which are common in the carcinogenesis of this cancer. These patients showed a different mutational profile compared to other populations. Our findings confirm the molecular heterogeneity described in the development of colorectal cancer.

Basaloid follicular hamartoma associated with follicular mucinosis and inflammation

Abstract Basaloid follicular hamartoma is a benign, superficial malformation of hair follicles that can be mistaken both clinical and histopathologically for basal cell carcinoma. Basaloid follicular hamartoma has been linked to a mutation in the PTCH-1 gene, which is part of the same pathway involved in Gorlin-Goltz syndrome. Here we present a 9-year-old patient with an asymptomatic congenital lesion on the forehead, which increased in size over the years. Histopathology showed a basaloid follicular hamartoma associated with follicular mucinosis and inflammation. Gorlin-Goltz syndrome was ruled out by clinical examination.

Hamartoma folicular basaloide / Basaloid follicular hamartoma

O hamartoma folicular basaloide (HFB) é um tumor anexial raro e benigno, que se assemelha ao carcinoma basocelular (CBC), e pode apresentar manifestações clínicas diversas. Uma mutação no gene PTCH, envolvido na síndrome de Gorlin-Goltz, poderia estar associada à patogênese dessa neoplasia. Descreve-se caso de menina, sete anos, apresentando múltiplas pápulas na face.

Basaloid follicular hamartoma (BFH) is a rare and benign adnexal tumor that resembles basal cell carcinoma (BCC) and may present with different clinical manifestations. A mutation in the PTCH gene, involved in Gorlin-Goltz syndrome, could be associated with the pathogenesis of this neoplasm. We describe the case of a 7-year-old girl with multiple papules on her face.

Evaluation of a new detection method for microsatellite instability and its relationship with the expression of human epidermal growth factor receptor 2 and P53 in gastric cancer tissues / 中华老年医学杂志

Objective:To investigate the expression of human epidermal growth factor receptor 2(HER2)and P53 and their relationship with microsatellite instability(MSI)in gastric cancer tissues.Methods:A total of 103 patients diagnosed with gastric cancer between January 2018 and October 2020 at Yueyang Hospital were enrolled in this study.HER2, P53 and mismatch repair proteins in gastric cancer tissues were detected with immunohistochemical(IHC)methods, and MSI screening was conducted at 7 sites with a new Idylla MSI(multiple fluorescent PCR)method.Results:Of 103 gastric cancer patients in this study, 77(74.8%)showed microsatellite stability(MSS)and 26(25.2%)showed MIS via IHC, and PCR also detected 77 MSS cases and 26 MSI cases.In MSI, there was more low HER2 expression than high HER2 expression, and the rate of low HER2 expression in MSI was higher than the rate of high HER2 expression in MSI( P<0.05).Also in MSI, there was more low P53 expression than high P53 expression, and the rate of low P53 expression in MSI was higher than the rate of high expression in MSI( P<0.05). Conclusions:MSS may exist in the process of gastric carcinogenesis and in gastric cancer it may be accompanied by low expression of HER2 and p53 in cancer tissues.There may be a mutually exclusive relationship between MSI and expressions of HER2 and p53, suggesting that carcinogenic mechanisms involving MSI may be very different from those involving HER2 and p53.MSI detection is very valuable in guiding treatment drug selection and prognosis assessment.

DNA damage-related proteins in smokers and non-smokers with oral cancer

Abstract: Tobacco smoking involves a high risk of human malignancies, including oral cancer, because it contains multiple carcinogens that cause genetic instability. Thus, a worse prognosis would be expected for cancer patients who are smokers. The aim of this study was to assess the DNA damage response through the expression of checkpoint kinase 2 (CHK2), H2A histone family member X (H2AX), and P53 among smokers and non-smokers with oral squamous cell carcinoma (OSCC). Associations between immunoexpression of proteins and clinicopathological data and histopathological grading were also analyzed. A total of 35 individuals (18 non-smokers and 17 smokers) with OSCC of the tongue and/or floor of the mouth were included. Immunohistochemistry for H2AX was conducted for the identification of double-strand breaks, CHK2, and P53 to evaluate the expression of this protein in cell cycle regulation. The sample consisted of 22 males and 13 females, with a mean age of 63.9±11.8 years. OSCC of non-smokers were well-differentiated tumors in 50% of the cases, and those of smokers were equally distributed into moderately differentiated and poorly differentiated tumors (35.3% each). Overall, 31 (88.6%) cases were CHK2-positive, 27 (77.1%) were H2AX-positive, and 23 (65.7%) were P53-positive, with no difference between smokers and non-smokers (p > 0.05). No association was found between proteins and clinicopathologic data (p > 0.05). Similarities in CHK2, H2AX, and P53 immunohistochemical staining patterns were observed between smokers and non-smokers, and immunoexpression was not associated with clinicopathological parameters. However, the findings indicated consistent expression of these proteins in OSCC.

p53 & Cyclin D1 expression in surgically resected clear margins of oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is one of the most well-known malignancies that affect the human population worldwide. The early diagnosis and early intervention of OSCC help improve the survival rate of the patients. The tumour free surgical margins are a positive prognostic factor for recurrence-free survival. The molecular markers can be used to detect the tumour free surgical margins. Aim: The aim of the study is to evaluate the expression of p53 & Cyclin D1 marker in resected surgical apparently clear margins and to correlate the p53 & Cyclin D1 expression with clinicopathological characteristics and patient outcome. Methods: The study population included retrospective cases of OSCC with apparently clear margins (2017-18) n=10 and Clinicopathological variables relevant to survival analysis were recorded. Finally, two margins were selected from each case, a total of 20 margins were included in this study. Paraffin-embedded wax blocks retrieved and tissue sections were made. Expression of cyclin D1 and p 53 was assessed by the immunohistochemical staining procedure Results: Positive expressions Cyclin D1 in 40% of mild dysplasia margins and 60% in clearance adequate margins were present. p53 expression was seen in 16% of mild dysplasia margins and 84% in clearance adequate margins. The expression of p53 and Cyclin D1 molecular markers are noted in the basal & parabasal layer of epithelium. Conclusion: Molecular markers could play a more reliable method for the assessment of dysplasia at the margins

Speckle type POZ adaptor protein (SPOP) and its role in cancer / La proteína adaptadora Speckle-type POZ (SPOP) y su papel en cáncer

Abstract Proteasomal degradation is an essential regulatory mechanism for cellular homeostasis maintenance. The speckle-type POZ adaptor protein (SPOP) is part of the ubiquitin ligase E3 cullin-3 RING-box1 complex, responsible for the ubiquitination and proteasomal degradation of biomolecules involved in cell cycle control, proliferation, response to DNA damage, epigenetic control, and hormone signaling, among others. Changes in SPOP have been associated with the development of different types of cancer, since it can act as a tumor suppressor mainly in prostate, breast, colorectal, lung cancer and liver cancer, due to point mutations and/or reduced expression, or as an oncogene in kidney cancer by protein overexpression. In endometrial cancer it has a dual role, since it can act as a tumor suppressor or as an oncogene. SPOP is a potential prognostic biomarker and a promising therapeutic target.

Resumen La degradación proteosómica es un mecanismo de regulación esencial para el mantenimiento de la homeostasis celular. La proteína adaptadora Speckle-type POZ (SPOP) hace parte del complejo ubiquitin ligasa E3 cullin-3 RING-box1, encargado de la ubiquitinación y degradación proteosomal de biomoléculas involucradas en el control del ciclo celular, proliferación, respuesta al daño de ADN, control epigenético, señalización hormonal, entre otros. Las alteraciones en SPOP han sido asociadas al desarrollo de diferentes tipos de cáncer, ya que puede actuar como supresor tumoral principalmente en cáncer de próstata, mama, colorrectal y pulmón, debido a mutaciones puntuales y/o expresión reducida o como oncogén en cáncer riñón por sobreexpresión de la proteína. En cáncer endometrial tiene un rol dual, ya que puede actuar como supresor tumoral o como oncogén. SPOP es considerado como un potencial biomarcador pronóstico y un objetivo terapéutico prometedor.

Genes involucrados en el cáncer pulmonar / Genes involved in lung cancer

Introducción: El cáncer pulmonar constituye un serio problema de salud mundial por su elevada prevalencia y mortalidad. En la carcinogénesis pulmonar están implicados oncogenes y genes supresores tumorales, que en una compleja interacción con factores ambientales favorecen la transformación cancerosa. Objetivo: Describir los principales genes implicados en el cáncer pulmonar. Métodos: Se buscaron referencias en las bases de datos PubMed Central, Annual Reviews y SciELO. Se revisaron preferentemente los artículos originales, las revisiones bibliográficas, las revisiones sistemáticas y los metaanálisis de los últimos cinco años. Análisis e integración de la información: En la carcinogénesis pulmonar se involucran los oncogenes JUN, FOS, ABL1, BRAF, RAF1, GNAS, KRAS, NRAS, HRAS, CSF 1R, MYC, EGFR, MET, ALK, CCNE1, DDR2, ERBB3, FGFR1, MDM2, ROS1, SOX2 y TP63 y los genes supresores tumorales TP53, CDKN2A, CDKN1A, RB1, CDK2AP1, ATM, ERCC2, BRCA1, CCND1, STK11, PDLIM2, PTEN, ARID1A, ASCL4, CUL3, EP300, KEAP1, KMT2D, NF1, NOTCH1, RASA1, ETD2 y SMARCA4. El conocimiento de la genética molecular del cáncer pulmonar es importante para la identificación de biomarcadores diagnósticos y pronósticos más eficaces y para el diseño de fármacos diana sobre genes específicos(AU)

Introduction: Lung cancer is a serious global health problem due to its high prevalence and mortality. Lung carcinogenesis involves oncogenes and tumor suppressor genes which interact in complex manners with environmental factors, paving the way for the cancerous transformation. Objective: Describe the main genes involved in lung cancer. Methods: References were searched for in the databases PubMed Central, Annual Reviews and SciELO. Particular attention was paid to original papers, bibliographic reviews, systematic reviews and meta-analyses published in the last five years. Data analysis and integration: Lung carcinogenesis involves the oncogenes JUN, FOS, ABL1, BRAF, RAF1, GNAS, KRAS, NRAS, HRAS, CSF 1R, MYC, EGFR, MET, ALK, CCNE1, DDR2, ERBB3, FGFR1, MDM2, ROS1, SOX2 and TP63, and the tumor suppressor genes TP53, CDKN2A, CDKN1A, RB1, CDK2AP1, ATM, ERCC2, BRCA1, CCND1, STK11, PDLIM2, PTEN, ARID1A, ASCL4, CUL3, EP300, KEAP1, KMT2D, NF1, NOTCH1, RASA1, ETD2 and SMARCA4. Knowledge about the molecular genetics of lung cancer is important to identify more efficient diagnostic and prognostic biomarkers and to design targeted drugs for specific genes(AU)

Mechanism of action of forkhead box transcription factors in hepatocellular carcinoma and their prospects as treatment targets / 临床肝胆病杂志

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers and has high incidence and mortality rates and poor prognosis. Forkhead box (FOX) transcription factor family can regulate cell growth, differentiation, and tissue development and plays an important role in tumor. This article reviews the association of the molecular expression of the FOX family with the development, progression, and prognosis of HCC and analyzes the mechanism of action of FOX in the progression of HCC. It is pointed out that FOX family is expected to become a new target for HCC treatment.

A single-centre observational study of 124 surgically managed glioma patients: molecular subtyping and its correlation with clinico-radiological profile

Background: The World Health Organization (WHO) 2016 classification incorporated molecular subtyping in glioma, highlighting the diagnostic and prognostic significance. The study aims to determine the isocitrate dehydrogenase (IDH-1) gene, α-thalassemia/mental retardation syndrome X-linked (ATRX) gene, and tumor suppressor gene-53 (p53) mutation in glioma and their correlation with various clinical and radiological parameters.Methods: In this prospective observational study, histopathological slides of glioma (2017-2018), were analyzed for IDH-1, ATRX and p53 mutations and their correlation with various clinical and radiological parameters.Results: IDH-1 mutation was found in 48 (38.7%), ATRX loss in 38 (30.6%) and p53 mutation in 40 (32.5%) patients. The expression of IDH-1 was significantly higher (43.7%) in adults; however, no significant difference was seen with gender. Also 51.2% of patients, who presented with seizures, showed IDH-1 expression; and 27.7% of patients, who had neurological deficit also showed IDH-1 expression. IDH-1 expression was high in glioma located at insula (73.3%) and parietal lobe (71.4%); while ATRX loss was seen in glioma located at insula (80%). Intraventricular glioma characteristically lacks all three markers: IDH-1 expression, p53 overexpression and ATRX loss. IDH-1 expression and p53 overexpression was seen mainly in diffuse fibrillary astrocytoma, oligodendroglioma, anaplastic astrocytoma and glioblastoma.Conclusions: Molecular subtyping is of paramount importance in glioma management. IDH-1 mutation is commonly observed in adults and patients presenting with seizures. The duration of symptoms correlates with IDH-1 and ATRX mutations. Hypothalamic tumors lack all three mutations.

Expression of Sirtuin 4 in Oral Squamous Cell Carcinoma and its Correlation with Clinicopathological Parameters

Introduction: SIRTs (Sirtuins) are class III histone deacetylase enzymes that use NAD+ as a co-substrate for their enzymaticactivities. In mammals, there are seven sirtuin proteins (SIRT1–SIRT7) among which SIRT4, SIRT3 and SIRT5 are mitochondrialsirtuins that regulate enzymes and other mitochondrial proteins to coordinate oxidative production of ATP with the availability ofenergy in the diet. SIRT4 is known to have tumor suppression activity in many human cancers. However, the role of SIRT4 inoral squamous cell carcinoma is not known. It is present at higher levels under nutrient-rich conditions, and inhibits glutaminecatabolism through ADP-ribosylation and hence repression of glutamate dehydrogenase (GDH) activity, a rate-limiting enzymein glutamine catabolism. Due to higher requirement of energy and bio-molecules for proliferation, cancer cell often resort tovarious metabolic pathways that are otherwise uncommon in normal cells. One of such mechanism is switching to Glutaminemetabolism. SIRT4 acts as a tumor suppressor by repressing glutamine utilisation by cells.Purpose: Study the role of SIRT4 in oral squamous cell carcinoma and evaluate its tumor suppressor role.Method: Here we studied expression of SIRT4 in oral cancer tissues by immuohistochemistry and compared it with that ofnormal tissue.Results: SIRT 4 was seen to significantly down regulated in oral squamous carcinoma.Conclusion: The present study suggests SIRT4 as a marker of tumor aggressiveness and as a therapeutic target for OSCC.

Hereditary pituitary tumor syndromes: genetic and clinical aspects

ABSTRACT The pituitary gland is responsible for the synthesis and secretion of various hormones that play a key role in regulating endocrine function and homeostasis. Pituitary adenomas (PA) are benign epithelial tumors arising from the endocrine cells of the anterior pituitary gland. Clinically relevant PA are relatively common and they occur in 0.1% of the general population. They are mostly benign monoclonal neoplasms that arise from any of the five hormone-secreting cell types of the anterior pituitary gland. PA are categorized as either functioning or non-functioning, depending on whether or not they produce a hormonal hypersecretion syndrome. Both functioning and non-functioning adenomas can produce symptoms or signs resulting from compression of the optic chiasm or invasion of cavernous sinuses. Only 5% of PA occur within the context of hereditary syndromes with reasonably well-defined oncogenic mechanisms. The vast majority of PA are sporadic, and their etiopathogenesis remains largely unknown. Pituitary tumor oncogenesis involves several mechanisms that eventually lead to abnormal cell proliferation and dysregulated hormone production. Among these factors, we found inactivating mutations of tumor suppressor genes, activating mutation of oncogenes and the participation of hormonal signals coming from the hypothalamus, all resulting in cell-cycle regulation abnormalities. In this review, we summarize the clinical and pathophysiological aspects of the different hereditary pituitary tumor syndromes.