Cellular retinol-binding protein 1: a therapeutic and diagnostic tumor marker.

Cellular Retinol Binding Protein 1 (CRBP1) gene is a protein coding gene located on human chromosome 3q21, which codifies a protein named CRBP1. CRBP1 is widely expressed in many tissues as a chaperone protein to regulate the uptake, subsequent esterification and bioavailability of retinol. CRBP1 combines retinol and retinaldehyde with high affinity to protect retinoids from non-specific oxidation, and transports retinoids to specific enzymes to promote the biosynthesis of retinoic acid. The vital role of CRBP1 in retinoids metabolism has been gradually discovered, which has been implicated in tumorigenesis. However, the precise functions of CRBP1 in different diseases are still poorly understood. The purpose of this review is to provide an overview of the role of CRBP1 in various diseases, especially in both the promotion and inhibition of cancers, which may also offer a novel biomarker and potential therapeutic target for human diseases.

Disruption of retinoid homeostasis induces RBP4 overproduction in diabetes: O-GlcNAcylation involved.

BACKGROUND: Retinol-binding protein 4 (RBP4) is elevated and associated with inflammation in metabolic diseases. Disruption of the retinol cascade and O-GlcNAcylation of the RBP4 receptor (STRA6) are found in diabetic kidneys. OBJECTIVES: We investigated whether the disruption of the retinol cascade induces RBP4 overproduction and if O-linked GlcNAc modification targets RBPR2 and contributes to the disruption of retinol cascades in diabetic livers. METHODS: Western blot or immunohistochemistry for RBPR2, CRBP1, LRAT, RALDH, RARα, RARγ, RXRα, RBP4, GFAT, OGT, OGA and inflammatory markers, as well as ELISA for RBP4, were performed in livers of db/db and ob/ob mice and high glucose-cultured hepatocytes. Immunoprecipitation and dual fluorescence staining were used to explore O-GlcNAc-modified RBPR2 and RBP4 binding activity on RBPR2. Transfection of the CRBP1 gene was done to verify whether a disrupted retinol cascade induces RBP4 overproduction. OGT silencing was done to investigate the association of O-GlcNAcylation with the disruption of retinol cascade. RESULTS: Disruption of retinol cascade, RBP4 overproduction, O-GlcNAcylation of RBPR2, decreased RBP4 binding activity on RBPR2 and inflammation were found in livers of db/db and ob/ob mice and high glucose-cultured hepatocytes. CRBP1 gene transfection reversed the suppression of the cellular retinol cascade and simultaneously attenuated the RBP4 overproduction and inflammation in high glucose-treated hepatocytes. The silencing of OGT reversed the disruption of the cellular retinol cascade, RBP4 overproduction and inflammation induced by high glucose in hepatocytes. CONCLUSIONS: This study indicates that the disruption of cellular retinol cascade is strongly associated with RBP4 overproduction and inflammation in diabetic livers. RBPR2 is one target for high glucose-mediated O-linked GlcNAc modification, which causes liver retinol dyshomeostasis.

Cellular retinol binding protein 1 transfection reduces proliferation and AKT-related gene expression in H460 non-small lung cancer cells.

In recent years, new treatments with novel action mechanisms have been explored for advanced non-small cell lung cancer (NSCLC). Retinoids promote cancer cell differentiation and death and their trafficking and action is mediated from specific cytoplasmic and nuclear receptors, respectively. The purpose of this study was to investigate the effect of Cellular retinol binding protein-1 (CRBP-1) transfection in H460 human NSCLC cell line, normally not expressing CRBP-1. H460 cells were transfected by using a vector pTargeT Mammalian expression system carrying the whole sequence of CRBP-1 gene. For proliferation and apoptosis studies, cells were treated with different concentrations of all-trans Retinoic Acid (atRA) and retinol. AKT-related gene expression was analyzed by using western blot and Signosis array and results analysed by one-way analysis of variance (ANOVA) or by t-student test. CRBP-1+ showed reduced proliferation and viability in basal condition and after atRA treatment when compared to empty-transfected H460 cells. Reduced proliferation in CRBP-1+ H460 cells associated to the down-regulation of pAKT/pERK/pEGFR-related genes. In particular, gene array documented the down-regulation of AKT and Stat-3-related genes, including M-Tor, Akt1, Akt2, Akt3, Foxo1, p27, Jun. Restoration of CRBP-1 expression in H460 cells reduced proliferation and viability in both basal condition and after atRA treatment, likely by down-regulating AKT-related gene level. Further studies are needed to better clarify how those CRBP-1-related intracellular pathways contribute to counteract NSCLC progression in order to suggest a potential tool to improve efficacy of retinoid anti lung cancer adjuvant therapy.

Vitamin D receptor and cellular retinol-binding protein-1 immunohistochemical expression in normal, hyperplastic and neoplastic endometrium: Possible diagnostic and therapeutic implications.

BACKGROUND: We conducted this study to assess the effect of VDR and CRBP-1 immunohistochemical expression on the endometrium and to explore their role in endometrial cancer carcinogenesis. METHODS: This study comprised two hundred paraffin-embedded endometrial tissue samples diagnosed as 42 and 63 proliferative and secretory endometrium respectively, 45 endometrial hyperplasias with atypia and 50 endometrial carcinomas (25 low-grade and 25 high-grade endometrial carcinomas). The immunohistochemical method was done to determine the expression of VDR and CRBP-1. RESULTS: VDR was strongly expressed in 8 (17.8%) cases with endometrial hyperplasia, 15 (60%) cases with low-grade endometrial carcinoma, and 22 (88%) cases with high-grade endometrial carcinoma. While CRPB1 overexpression was noted in cases with proliferative endometrium, secretory endometrium and endometrial hyperplasia with atypia, 37 (88.1%), 56 (88.9%) and 3 (6.7%) cases respectively and all malignant cases showed negative expression. CONCLUSIONS: Increased VDR expression and reduced CRBP-1 expression are associated with malignant features of the endometrium with a significant statistical difference of immunoreactivity between groups of normal endometrium, hyperplastic changes & carcinoma. Our data suggested that increased VDR expression is partly associated with endometrial cancers through a premalignant phase. Also, increased VDR and reduced CRBP-1 expression are associated with the progression of endometrial carcinoma with higher grades.

Vitamin A deficiency causes islet dysfunction by inducing islet stellate cell activation via cellular retinol binding protein 1.

Background: Vitamin A (VA) plays an essential role in pancreatic homeostasis. Islet stellate cells (ISCs) are VA-storing cells in pancreatic islets. Herein, we have investigated the effect of VA on glucose homeostasis trough regulation of ISCs function in dietary VA deficiency model mice. Methods: Male C57BL/6 mice were randomly fed a VA-sufficient, a VA-deficient (VAD) or a VAD-rescued diet. Glucose metabolism was assessed by glucose tolerance tests and immunohistochemistry. ISCs activation degree was evaluated by immunofluorescence, quantitative PCR and western blotting in both, retinol-treated cultured ISCs and model mice. Changes in ISCs phenotype and their effect on islets were assessed by lentiviral transduction and enzyme-linked immunosorbent assays in a co-culture system. Results: VAD mice showed irregular shaped islet, glucose intolerance, islet size distribution excursions, and upregulated expression of α-smooth muscle actin (α-SMA, marker of ISCs activation). Reintroduction of dietary VA restored pancreatic VA levels, endocrine hormone profiles, and inhibited ISCs activation. Incubation with retinol increased the expression of VA signaling factors in ISCs, including cellular retinol binding protein 1 (CRBP1). The knockdown of CRBP1 maintained the quiescent ISCs phenotype and reduced the damage of activated ISCs on islet function. Conclusions: VA deficiency reduced islet function by activating ISCs in VAD mice. Restoring ISCs quiescence via CRBP1 inhibition could reverse the impairment of islet function caused by activated ISCs exposure.

Cellular retinol-binding protein-1 expression increases with increasing clinical severity of alopecia areata.

BACKGROUND: Alopecia areata (AA) is multifactorial disease mostly autoimmune affecting anagen hair follicles. Many researchers hypothesize that adequate retinoic acid (RA) levels are important for proper hair follicle behavior. Previous animal studies revealed increase in RA synthesis proteins and decrease in RA degradation proteins in AA patients when compared with controls. OBJECTIVE: To evaluate cellular retinol-binding protein-1 expression in lesional skin of alopecia areata in comparison with controls, in an attempt to know its role in the pathogenesis of alopecia areata . METHODS: Immunohistochemical expression of cellular retinol-binding protein-1 CRBP1 was evaluated in skin biopsies taken from lesions of alopecia areata in 30 patients and 10 normal biopsy specimens taken from skin of healthy controls (HC) who were within the same age and sex. RESULTS: CRBP1 expression was significantly increased in lesional alopecia areata skin in comparison with normal skin of controls (P < 0.001*). Significant positive correlation was found between expression of CRBP-1 and percentage of hair loss in the scalp (SALT score; r = 0.840, P = <0.001). CONCLUSION: These results may enhance the idea of the possible role of CRBP1 in the pathogenesis of AA, and ensuring the importance of its level in AA treatment.

CRBP-1 over-expression is associated with poor prognosis in tongue squamous cell carcinoma.

BACKGROUND: Tongue squamous cell carcinoma (TSCC) is one of the most common malignancies of oral squamous cell carcinomas. Cellular retinol binding protein-1 (CRBP-1) as a carrier protein transports retinol from the liver storage site to peripheral tissue. Up-regulated expression of CRBP-1 is associated with some tumor types such as prostate cancer, breast cancer and ovarian cancer as reported, but its role in TSCC remains uncertain. METHODS: In this study, an integrated bioinformatics analysis based on the multiple cancer microarray data sets available from Oncomine database was conducted to view the differential expression of CRBP-1 between TSCC and the adjacent non-tumorous tissues. Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting (WB) and immunohistochemical (IHC) assays were performed to investigate CRBP-1 expression in 101 paraffin-embeded TSCC tissues and 48 pairs of freshly frozen tissues. Kaplan-Meier curve and univariate and multivariate Cox-regression analysis were used to estimate the association between CRBP-1 expression and patients' prognosis. Then western blotting, MTT, transwell migration and invasion assays were performed in TSCC cell lines to investigate the effects of CRBP-1 on cellular proliferation and invasion. RESULTS: Compared with the matched adjacent non-tumorous tissues, the expression of CRBP-1 was significantly up-regulated in TSCC tissues, which correlated with the differentiation state (P = 0.003), N classification (P = 0.048), the clinical stage (P = 0.048) and death (P = 0.001). The Kaplan-Meier curve showed that TSCC patients with higher CRBP-1 expression levels had lower overall survival rates than those with lower CRBP-1 expression levels. A univariate and multivariate analysis demonstrated that CRBP-1 was an independent prognostic factor (P < 0.05). Furthermore, we knocked down CRBP-1 expression and observed that TSCC cell proliferation and invasion in vitro were significantly blocked, as determined by MTT and transwell assays. CONCLUSIONS: Up-regulated expression of CRBP-1 is associated with poor prognosis in TSCC, so it might potentially serve as an additional prognostic marker, and the inhibition of CRBP-1 might provide new therapeutic approaches for TSCC.

Lung and liver growth and retinoic acid status in human fetuses with congenital diaphragmatic hernia.

BACKGROUND: Abnormal retinoic acid (RA) signalling is considered a major cause of congenital diaphragmatic hernia (CDH). Pulmonary hypoplasia and pulmonary hypertension are the major causes of morbidity and mortality in infants born with CDH. Experimental studies in animals have found that RA signalling is involved in lung and liver development, but animal models of CDH do not directly correlate with CDH in human fetuses. This study investigated if RA status is also linked to lung and liver growth in human fetuses with CDH. STUDY DESIGN AND PATIENTS: Hepatic stellate cells (HSC) in autopsy human fetal liver tissue were identified using cRBP-1 immunohistochemistry and the numbers of HSC manually counted. In mammals, RA is principally stored in HSC complexed to cRBP-1 and therefore cRBP-1+ HSC numbers were used as an indicator of fetal RA status. The number of HSCs was correlated with liver and lung weights, calculated relative to either normal biometric values or fetal body weight. RESULTS: The number of cRBP-1+ HSCs correlated with lung weight contralateral to the side of the diaphragmatic hernia (r=0.82, p=0.025) and combined lung weight (r=0.78, p=0.039) but not with ipsilateral lung weight (r=0.43, p=0.33), in fetuses with right and left CDH and a case of giant omphalocoele. Liver growth was influenced by contact with diaphragm but not significantly correlated with cRBP-1 expression (r=0.52, p=0.056). CONCLUSION: Fetal RA stores, reflected in the number of cRBP-1+ HSCs, influence lung growth as well as diaphragm development in human fetuses with CDH. Contact with diaphragm influenced liver growth.

Identification of molecular markers distinguishing adult neural stem cells in the subventricular and subcallosal zones.

Neural stem cells (NSCs) in the adult subventricular zone (SVZ) are regionally specified and have distinct molecular gene expression signatures. Recently, we identified the subcallosal zone (SCZ) as a novel brain region where adult NSCs maintain and spontaneously produce neuroblasts. In an attempt to isolate genes specifically expressed in the SCZ or SVZ, microarray analyses of their differentially expressing transcripts were done. The comparison between neurospheres generated from SVZ and SCZ revealed differential expression >1.5-fold in two groups in only 83 genes, representing <0.03% of the genes examined, suggesting that these two populations are largely similar. The differential expression patterns SCZ and SVZ genes were confirmed by RT-PCR and Western blots. The selective expressions of two genes (CRBP1, HMGA1) in SVZ-NSCs were further confirmed by immunohistochemistry. These molecular markers could be useful for further molecular and cellular characterization of NSCs.

Retinoic Acid Synthesis and Degradation.

Retinoic acid (RA) was identified as the biologically active form of vitamin A almost 70 years ago and work on its function and mechanism of action is still of major interest both from a scientific and a clinical perspective. The currently accepted model postulates that RA is produced in two sequential oxidative steps: first, retinol is oxidized reversibly to retinaldehyde, and then retinaldehyde is oxidized irreversibly to RA. Excess RA is inactivated by conversion to hydroxylated derivatives. Much is left to learn, especially about retinoid binding proteins and the trafficking of the hydrophobic retinoid substrates between membrane bound and cytosolic enzymes. Here, background on development of the field and an update on recent advances in our understanding of the enzymatic pathways and mechanisms that control the rate of RA production and degradation are presented with a focus on the many questions that remain unanswered.

[Genes associated to cancer]. / Los genes del cáncer.

In 2010, in a cancer genes census, 291 genes were enumerated. These represent near to the 1 % of the total genes, for which there is enough biological evidence that they belong to a new genes classification, known as the cancer genes. These have been defined as the causal genes for sporadic or familiar cancer, when they mutate. The mutation types for these genes includes amplifications, point mutations, deletions, genomic rearranges, amongst others, which lead to a protein over-expression, muting, production of chimeric proteins or a de novo expression. In conjunction these genomic alterations or those of the genetic expression, when they affect specific genes which contribute to the development of cancer, are denominated as cancer genes. It is possible that the list of these alterations will grow longer due to new strategies being developed, for example, the genomic analysis.

En el año 2010, en un censo de genes del cáncer, se enumeraron 291 genes humanos que representan cerca del 1 % de los genes totales, para los cuales existe suficiente evidencia biológica de que pertenecen a una nueva clasificación de genes: los genes del cáncer. Estos se han definido como los genes causales de cáncer esporádico o cáncer familiar, cuando mutan. El tipo de mutaciones para estos genes del cáncer incluye las amplificaciones, las mutaciones puntuales, las deleciones, los rearreglos genómicos, entre otros, los cuales conducen a una sobreexpresión proteica, silenciamiento, producción de proteínas quiméricas o una expresión de novo. Cuando afectan genes específicos que contribuyen al desarrollo de un cáncer, estas alteraciones genómicas o de la expresión génica son denominadas en conjunto como genes del cáncer. Es posible que esta lista crezca más debido a las nuevas estrategias que se están desarrollando, como, por ejemplo, las de análisis genómico.

The development of hepatic stellate cells in normal and abnormal human fetuses - an immunohistochemical study.

The precise embryological origin and development of hepatic stellate cells is not established. Animal studies and observations on human fetuses suggest that they derive from posterior mesodermal cells that migrate via the septum transversum and developing diaphragm to form submesothelial cells beneath the liver capsule, which give rise to mesenchymal cells including hepatic stellate cells. However, it is unclear if these are similar to hepatic stellate cells in adults or if this is the only source of stellate cells. We have studied hepatic stellate cells by immunohistochemistry, in developing human liver from autopsies of fetuses with and without malformations and growth restriction, using cellular Retinol Binding Protein-1 (cRBP-1), Glial Fibrillary Acidic Protein (GFAP), and α-Smooth Muscle Actin (αSMA) antibodies, to identify factors that influence their development. We found that hepatic stellate cells expressing cRBP-1 are present from the end of the first trimester of gestation and reduce in density throughout gestation. They appear abnormally formed and variably reduced in number in fetuses with abnormal mesothelial Wilms Tumor 1 (WT1) function, diaphragmatic hernia and in ectopic liver nodules without mesothelium. Stellate cells showed similarities to intravascular cells and their presence in a fetus with diaphragm agenesis suggests they may be derived from circulating stem cells. Our observations suggest circulating stem cells as well as mesothelium can give rise to hepatic stellate cells, and that they require normal mesothelial function for their development.

High expression of cellular retinol binding protein-1 in lung adenocarcinoma is associated with poor prognosis.

PURPOSE: Adenocarcinoma, the most common non-small cell lung cancer is a leading cause of death worldwide, with a low overall survival (OS) despite increasing attempts to achieve an early diagnosis and accomplish surgical and multimodality treatment strategies. Cellular retinol binding protein-1 (CRBP-1) regulates retinol bioavailability and cell differentiation, but its role in lung cancerogenesis remains uncertain. EXPERIMENTAL DESIGN: CRBP-1 expression, clinical outcome and other prognostic factors were investigated in 167 lung adenocarcinoma patients. CRBP-1 expression was evaluated by immunohistochemistry of tissue microarray sections, gene copy number analysis and tumor methylation specific PCR. Effects of CRBP-1 expression on proliferation/apoptosis gene array, protein and transcripts were investigated in transfected A549 lung adenocarcinoma cells. RESULTS: CRBP-1(High) expression was observed in 62.3% of adenocarcinomas and correlated with increased tumor grade and reduced OS as an independent prognostic factor. CRBP-1 gene copy gain also associated with tumor CRBP-1(High) status and dedifferentiation. CRBP-1-transfected (CRBP-1(+)) A549 grew more than CRBP-1(-) A549 cells. At >1µM concentrations, all trans-retinoic acid and retinol reduced viability more in CRBP-1(+) than in CRBP-1(-) A549 cells. CRBP-1(+) A549 cells showed up-regulated RARα/ RXRα and proliferative and transcriptional genes including pAkt, pEGFR, pErk1/2, creb1 and c-jun, whereas RARß and p53 were strongly down-regulated; pAkt/pErk/ pEGFR inhibitors counteracted proliferative advantage and increased RARα/RXRα, c-jun and CD44 expression in CRBP-1(+) A549 cells. CONCLUSION: CRBP-1(High) expression in lung adenocarcinoma correlated with increased tumor grade and reduced OS, likely through increased Akt/Erk/EGFR-mediated cell proliferation and differentiation. CRBP-1(High) expression can be considered an additional marker of poor prognosis in lung adenocarcinoma patients.

Identification of SNPs in Cellular Retinol Binding Protein 1 and Cellular Retinol Binding Protein 3 Genes and Their Associations with Laying Performance Traits in Erlang Mountainous Chicken.

CRBP1 (cellular retinol binding protein 1) and CRBP3 (cellular retinol binding protein 3), are important components of the retinoid signaling pathway and take part in vitamin A absorption, transport and metabolism. Based on the role of vitamin A in chicken laying performance, we investigated the polymorphism of CRBP1 and CRBP3 genes in 349 chickens using single strand conformation polymorphism and DNA sequencing methods. Only one polymorphism was identified in the third intron of CRBP1, two polymorphisms were detected in CRBP3; they were located in the second intron and the third intron respectively. The association studies between these three SNPs and laying performance traits were performed in Erlang mountainous chicken. Notably, the SNP g.14604G>T of CRBP1 was shown to be significantly associated with body weight at first egg (BWFE), age at first egg (AFE), weight at first egg (WFE) and total number of eggs with 300 age (EN). The CRBP3 polymorphism g.934C>G was associated with AFE, and the g.1324A>G was associated with AFE and BWFE, but none of these polymorphisms were associated with egg quality traits. Haplotype combinations constructed on these two SNPs of CRBP3 gene were associated with BWFE and AFE. In particular, diplotype H2H2 had positive effect on AFE, BWFE, EN, and average egg-laying interval. We herein describe for the first time basic research on the polymorphism of chicken CRBP1 and CRBP3 genes that is predictive of genetic potential for laying performance in chicken.

Hepatic stellate cells that coexpress LRAT and CRBP-1 partially contribute to portal fibrogenesis in patients with human viral hepatitis.

BACKGROUND & AIMS: Precisely what type of cells mainly contributes to portal fibrosis, especially in chronic viral hepatitis, such as hepatic stellate cells (HSCs) in the parenchyma or myofibroblasts in the portal area, still remains unclear. It is necessary to clarify the characteristics of cells that contribute to portal fibrosis in order to determine the mechanism of portal fibrogenesis and to develop a therapeutic target for portal fibrosis. This study was undertaken to examine whether LRAT+/CRBP-1+ HSCs contribute to portal fibrosis on viral hepatitis. METHODS: Antibodies to lecithin:retinol acyltransferase (LRAT), cellular retinol-binding protein-1 (CRBP-1) and widely ascertained antibodies to HSCs (alpha-smooth muscle actin, neurotrophin-3) and endothelial cells (CD31) were used for immunohistochemical studies to assess the distribution of cells that contribute to the development of portal fibrosis with the aid of fluorescence microscopy. A quantitative analysis of LRAT+/CRBP-1+ HSCs was performed. RESULTS: The number of LRAT+/CRBP-1+ HSCs was increased in fibrotic liver in comparison with normal liver in the portal area and fibrous septa. The number of double positive cells was less than 20% of all cells/field in maximum. CONCLUSION: This study provides evidence that functional HSCs coexpressing both LRAT and CRBP-1 that continue to maintain the ability to store vitamin A contribute in part to the development of portal fibrogenesis in addition to parenchymal fibrogenesis in patients with viral hepatitis.

Cellular retinol binding protein 1 could be a tumor suppressor gene in cervical cancer.

AIMS: Cervical Cancer (CC) is one of the most important health problems in women. It frequently presents genetic changes at chromosome region 3q21. This region contains the Cellular Retinol Binding Protein 1 gene (CRBP1) which has been implicated as an important element in the development of other types of cancer. The main goal of the present work was to determine the molecular alterations of CRBP1 and its relationship to CC. METHODS: To determine the molecular alterations of CRBP1 gene in CC; twenty-six CC and twenty-six healthy cervix samples were evaluated for: 1) Copy number gain by real-time PCR analysis, 2) expression levels by an immunohistochemistry assay on tissue microarray, and 3) the methylation status of the CRBP1 promoter region. RESULTS: The increase in CRBP1 copy number was observed in 10 out of the 26 CC samples analyzed, while healthy cervices samples showed no changes in the copy number. In addition, there was a lack of expression of the CRBP1 gene in an important number of the CC samples (17/26), and the CRBP1 gene promoter was methylated in 15/26 of the CC samples. Interestingly, there was a significant association between the lack of expression of the CRBP1 gene and its methylation status. CONCLUSIONS: The data indicates that, both activating and inactivating changes in the CRBP1 gene could be significant events in the development and progression of CC, and the lack of expression of the CRBP1 protein could be related with to the development of CC. We believe that there is enough evidence to consider to CRBP1 gene as a tumor suppressor gene for CC.

Gene methylation in gastric cancer.

Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.

Retinoides (RARβ y CRBP1) en carcinoma de pulmón a células no pequeñas / Retinoid expression (RARβ and CRBP1) in non-small-cell lung carcinoma

Aunque los pacientes con cáncer de pulmón a células no pequeñas en estadios tempranos (NSCLC) tienen buen pronóstico, el 20-30% recae, siendo relevante la identificación de biomarcadores pronósticos. Los retinoides regulan crecimiento y diferenciación, y pueden antagonizar la progresión tumoral. Su efecto depende del transporte citosólico mediado por moléculas como CRBP1, y de la unión a receptores específicos (RARβ). Alteraciones en esta vía se asociaron con cáncer. Nuestro objetivo fue estudiar la expresión, mediante inmunohistoquímica, de RARβ y CRBP1 en el tejido tumoral de 49 pacientes NSCLC Estadio I/II, obtenido durante la cirugía. La supervivencia se analizó mediante los test Log Rank y multivariado de Cox. El 44.9% de los tumores fueron positivos para RARβ con expresión a nivel citoplasmático, mientras que el 34.7% lo expresó a nivel nuclear. La tinción para CRBP1 se observó en el 61.2% de los tumores. No se encontró asociación entre la expresión de ambas moléculas y las características clinicopatológicas (sexo, tamaño tumoral, nódulos línfáticos comprometidos, histopatología y p53). Tampoco se encontró asociación con el hábito de fu-mar. La presencia de células tumorales en el lavado pleural se asoció significativamente con la expresión de CRBP1. Por otro lado, se demostró asociación entre la expresión elevada de RARβ citoplasmático y menor supervivencia global (LR 4.17, p=0.0412). El análisis multivariado no mostró asociación con otras variables de pronóstico en NSCLC. En conclusión, en este grupo de pacientes NSCLC Estadio I/II, RARβ pareciera predecir la supervivencia global en forma independiente.

Although early-stage non-small-cell lung carcinoma (NSCLC) patients have a relative by favorable prognosis, the risk of a bad outcome remains substantial. Identification of reliable prognostic markers for disease recurrence and death has meaningful clinical application. Retinoids are involved in cell growth and differentiation and may antagonize cancer progression. Their effects are mediated through nuclear receptors called Retinoic Acid Receptor (RAR) and regulated by molecules such as Cellular Retinol-Binding Protein 1 (CRBP1) that function in retinol storage. The aim of this work was to analyze by immunohistochemistry the expression patterns of RARβ and CRBP1, involved in retinoid-mediated signaling, in the tumoral tissue of a cohort of stage I/II NSCLC patients (n=49) who underwent a successful surgical resection. Prognostic evaluation was performed with the multivariate Cox proportional hazard model: 44.9% of tumors were positive for RARβ staining at cytoplasmic level, while 34.7% showed nuclear staining. CRBP1 staining was observed in 61.2% of the lung tumors. No relationship was found between the number of cells expressing the studied molecules and clinical pathological features, including sex, T and N (stage), histopathology and p53 expression. Univariate analysis showed a significant association between positive cytoplasmatic expression of RARβ with shorter overall survival (Log-rank test 4.17, p=0.0412). Multivariate studies indicated that RARβ expression was not influenced by other clinical pathological parameters. In conclusion, in this cohort of stage I and II NSCLC, only the expression of RARβ at cytoplasmatic level is a significant independent unfavorable prognostic factor.