Publications by authors named "Sara Huerta-Yepez"

89 Publications

High expression of Myosin 1g in pediatric acute lymphoblastic leukemia.

Oncotarget 2021 Sep 14;12(19):1937-1945. Epub 2021 Sep 14.

Immunology and Proteomics Laboratory, Hospital Infantil de México Federico Gómez, México City, México.

Acute Lymphoblastic Leukemia (ALL) is the most frequent cancer in pediatric population. Although the treatment has improved and almost 85% of the children are cured about 20% suffer relapse, therefore finding molecules that participate in the pathogenesis of the disease for the identification of relapse and patients at risk is an urgent unmet need. Class I myosins are molecular motors involved in membrane tension, endocytosis, phagocytosis and cell migration and recently they have been shown important for development and aggressiveness of diverse cancer types, however Myo1g an hematopoietic specific myosin has not been studied in cancer so far. We evaluated the expression of Myo1g by qRT-PCR, Immunocytochemistry and Immunofluorescence in a cohort of 133 ALL patients and correlated the expression at diagnosis and after treatment with clinical features and treatment outcomes. We found high expression levels of Myo1g in Peripheral Blood Mononuclear Cells (PBMCs) from patients with ALL at diagnosis and those levels decreased after complete remission; furthermore, we found an increase in Myo1g expression on patients with 9:22 translocation and those who relapse. This study show that Myo1g is over expressed in ALL and that may participate in the pathogenesis of the disease specially in high-risk patients.
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http://dx.doi.org/10.18632/oncotarget.28055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448507PMC
September 2021

Bioelectric, tissue, and molecular characteristics of the gastric mucosa at different times of ischemia.

Exp Biol Med (Maywood) 2021 Sep 15;246(18):1968-1980. Epub 2021 Jun 15.

Departamento de Procesos y Tecnologia, Unidad Cuajimalpa, Universidad Autonoma Metropolitana, CDMX 05340, Mexico.

Gastrointestinal ischemia may be presented as a complication associated with late shock detection in patients in critical condition. Prolonged ischemia can cause mucosal integrity to lose its barrier function, triggering alterations that can induce organ dysfunction and lead to death. Electrical impedance spectroscopy has been proposed to identify early alteration in ischemia-induced gastric mucosa in this type of patients. This work analyzed changes in impedance parameters, and tissue and molecular alterations that allow us to identify the time of ischemia in which the gastric mucosa still maintains its barrier function. The animals were randomly distributed in four groups: Control, Ischemia 60, 90, and 120 min. Impedance parameters were measured and predictive values were determined to categorize the degree of injury using a receiver operating characteristic curve. Markers of inflammatory process and apoptosis (iNOS, TNFα, COX-2, and Caspase-3) were analyzed. The largest increase in impedance parameters occurred in the ischemia 90 and 120 min groups, with resistance at low frequencies (R) and reactance at high frequencies (X) being the most related to damage, allowing prediction of the occurrence of reversible and irreversible tissue damage. Histological analysis and apoptosis assay showed progressive mucosal deterioration with irreversible damage ( < 0.001) starting from 90 min of ischemia. Furthermore, a significant increase in the expression of iNOS, TNFα, and COX-2 was identified in addition to apoptosis in the gastric mucosa starting from 90 min of ischemia. Tissue damage generated by an ischemia time greater than 60 min induces loss of barrier function in the gastric mucosa.
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http://dx.doi.org/10.1177/15353702211021601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474982PMC
September 2021

Differential mast cell numbers and characteristics in human tuberculosis pulmonary lesions.

Sci Rep 2021 05 21;11(1):10687. Epub 2021 May 21.

Seccion de Patologia Experimental, Instituto Nacional de Ciencias Medicas y Nutricion "Salvador Zubiran", Mexico City, Mexico.

Tuberculosis (TB) is still a major worldwide health threat and primarily a lung disease. The innate immune response against Mycobacterium tuberculosis (Mtb) is orchestrated by dendritic cells, macrophages, neutrophils, natural killer cells and apparently mast cells (MCs). MCs are located at mucosal sites including the lungs and contribute in host-defence against pathogens, but little is known about their role during Mtb infection. This study investigates the location and characteristics of MCs in TB lesions to assess their contribution to TB pathology. To this purpose, number, location and phenotype of MCs was studied in 11 necropsies of pulmonary TB and 3 necropsies of non-TB infected lungs that were used as controls. MCs were localised at pneumonic areas, in the granuloma periphery and particularly abundant in fibrotic tissue. Furthermore, MCs displayed intracellular Mtb and IL-17A and TGF-β immunostaining. These findings were validated by analysing, post-mortem lung tissue microarrays from 44 individuals with pulmonary TB and 25 control subjects. In affected lungs, increased numbers of MCs expressing intracellularly both tryptase and chymase were found at fibrotic sites. Altogether, our data suggest that MCs are recruited at the inflammatory site and that actively produce immune mediators such as proteases and TGF-β that may be contributing to late fibrosis in TB lesions.
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http://dx.doi.org/10.1038/s41598-021-89659-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140073PMC
May 2021

Expression of YY1 in pro-B and T phenotypes correlation with poor survival in pediatric acute lymphoblastic leukemia.

Pediatr Hematol Oncol 2021 Aug 26;38(5):456-470. Epub 2021 Apr 26.

Oncology Disease Research Unit, Children's Hospital of Mexico, Federico Gomez, Mexico City, Mexico.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, constituting 80% of all acute leukemias in minors. Despite the increase in the success of therapies, disease-free survival is over 80% in most cases. For the remaining 20% of patients, new strategies are needed to allow us to know and select those at greatest risk of relapse. We evaluated by immunohistochemistry the expression of the transcription factor YY1 and found that it is overexpressed in peripheral blood leukemia cells of pediatric patients with ALL with Pro-B and T phenotype compared to control samples. Over expression of YY1 was associated with a significantly lower chance of survival. We also evaluated by RT-PCR in bone marrow samples from ALL pediatric patients the association of YY1 expression with the percentage of blasts. High levels of YY1 were present in samples with higher percent of blasts in these patients. In addition, ALL pediatric patients with a poor response to therapy had higher levels at the nuclear level of YY1 than those who responded well to chemotherapy. In conclusion, our data suggest that YY1 could serve in pediatric ALL as markers of evolution and response for this disease, mainly in patients with pro-B and T immunophenotype. It is also suggested that YY1 is implicated in the expanse of blast in these patients.
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http://dx.doi.org/10.1080/08880018.2020.1871139DOI Listing
August 2021

16α-Bromoepiandrosterone as a new candidate for experimental diabetes-tuberculosis co-morbidity treatment.

Clin Exp Immunol 2021 Aug 1;205(2):232-245. Epub 2021 Jun 1.

Experimental Pathology Section, Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.

Tuberculosis (TB) is the leading cause of death from a single bacterial infectious agent and is one of the most relevant issues of public health. Another pandemic disease is type II diabetes mellitus (T2D) that is estimated to affect half a billion people in the world. T2D is directly associated with obesity and a sedentary lifestyle and is frequently associated with immunosuppression. Immune dysfunction induced by hyperglycemia increases infection frequency and severity. Thus, in developing countries the T2D/TB co-morbidity is frequent and represents one of the most significant challenges for the health-care systems. Several immunoendocrine abnormalities are occurring during the chronic phase of both diseases, such as high extra-adrenal production of active glucocorticoids (GCs) by the activity of 11-β-hydroxysteroid dehydrogenase type 1 (11-βHSD1). 11-βHSD1 catalyzes the conversion of inactive cortisone to active cortisol or corticosterone in lungs and liver, while 11-β-hydroxysteroid dehydrogenase type 2 (11-βHSD2) has the opposite effect. Active GCs have been related to insulin resistance and suppression of Th1 responses, which are deleterious factors in both T2D and TB. The anabolic adrenal hormone dehydroepiandrosterone (DHEA) exerts antagonistic effects on GC signaling in immune cells and metabolic tissues; however, its anabolic effects prohibit its use to treat immunoendocrine diseases. 16α-bromoepiandrosterone (BEA) is a water miscible synthetic sterol related to DHEA that lacks an anabolic effect while amplifying the immune and metabolic properties with important potential therapeutic uses. In this work, we compared the expression of 11-βHSD1 and the therapeutic efficacy of BEA in diabetic mice infected with tuberculosis (TB) (T2D/TB) with respect to non-diabetic TB-infected mice (TB). T2D was induced by feeding mice with a high-fat diet and administering a single low-dose of streptozotocin. After 4 weeks of T2D establishment, mice were infected intratracheally with a high-dose of Mycobacterium tuberculosis strain H37Rv. Then, mice were treated with BEA three times a week by subcutaneous and intratracheal routes. Infection with TB increased the expression of 11-βHSD1 and corticosterone in the lungs and liver of both T2D/TB and TB mice; however, T2D/TB mice developed a more severe lung disease than TB mice. In comparison with untreated animals, BEA decreased GC and 11-βHSD1 expression while increasing 11-βHSD2 expression. These molecular effects of BEA were associated with a reduction in hyperglycemia and liver steatosis, lower lung bacillary loads and pneumonia. These results uphold BEA as a promising effective therapy for the T2D/TB co-morbidity.
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http://dx.doi.org/10.1111/cei.13603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274213PMC
August 2021

KLF4 inhibition by Kenpaullone induces cytotoxicity and chemo sensitization in B-NHL cell lines via YY1 independent.

Leuk Lymphoma 2021 06 7;62(6):1422-1431. Epub 2021 Jan 7.

Molecular Signal Pathway in Cancer Laboratory, UIMEO, Oncology Hospital, Siglo XXI National Medical Center, IMSS, México City, México.

Krüppel-like factor 4 (KLF4) is a member of the KLF transcription factor family containing zinc-fingers, and is involved in the regulation of apoptosis, proliferation and differentiation of B cells and B-cell malignancies. KLF4 can act like an oncogene, we shown that KLF4 overexpression correlated with poor prognostic and chemoresistance in B-NHL. In addition, we shown that KLF4 is regulated by YY1. In this study, we demonstrate that chemical inhibition of KLF4 by Kenpaullone, results in suppression of proliferation, cell survival, downregulation of Bcl-2 and increases apoptosis in B-NHL cell lines through YY1 independent pathway. Combination of Kenpaullone and Doxorubicin, increased apoptosis. The co-expressions of KLF4/YY1 or KLF4/Bcl-2 in NHL was analyzed using Oncomine Database, exhibiting a positive correlation of expression. The present findings suggest that the chemical inhibition of KLF4 by Kenpaullone treatment could be a potential therapeutic alternatively in KLF4 lymphomas.
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http://dx.doi.org/10.1080/10428194.2020.1869960DOI Listing
June 2021

MicroRNA-7 Regulates Migration and Chemoresistance in Non-Hodgkin Lymphoma Cells Through Regulation of KLF4 and YY1.

Front Oncol 2020 27;10:588893. Epub 2020 Oct 27.

Molecular Signal Pathway in Cancer Laboratory, Unidad de Investigación Medica en Enfermedades Oncologicas (UIMEO), Oncology Hospital, Siglo XXI National Medical Center, Instituto Méxicano del Seguro Social (IMSS), Mexico City, Mexico.

The discovery and description of the role of microRNAs has become very important, specifically due to their participation in the regulation of proteins and transcription factors involved in the development of cancer. microRNA-7 (miR-7) has been described as a negative regulator of several proteins involved in cancer, such as YY1 and KLF4. We have recently reported that YY1 and KLF4 play a role in non-Hodgkin lymphoma (NHL) and that the expression of KLF4 is regulated by YY1. Therefore, in this study we analyzed the role of miR-7 in NHL through the negative regulation of YY1 and KLF4. qRT-PCR showed that there is an inverse expression of miR-7 in relation to the expression of YY1 and KLF4 in B-NHL cell lines. The possible regulation of YY1 and KLF4 by miR-7 was analyzed using the constitutive expression or inhibition of miR-7, as well as using reporter plasmids containing the 3 'UTR region of YY1 or KLF4. The role of miR-7 in NHL, through the negative regulation of YY1 and KLF4 was determined by chemoresistance and migration assays. We corroborated our results in cell lines, in a TMA from NHL patients including DLBCL and follicular lymphoma subtypes, in where we analyzed miR-7 by ISH and YY1 and KLF4 using IHC. All tumors expressing miR-7 showed a negative correlation with YY1 and KLF4 expression. In addition, expression of miR-7 was analyzed using the GEO Database; miR-7 downregulated expression was associated with pour overall-survival. Our results show for the first time that miR-7 is implicate in the cell migration and chemoresistance in NHL, through the negative regulation of YY1 and KLF4. That also support the evidence that YY1 and KLF4 can be a potential therapeutic target in NHL.
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http://dx.doi.org/10.3389/fonc.2020.588893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654286PMC
October 2020

Yin-Yang-1 decreases Fas-induced apoptosis in acute lymphoblastic leukemia under hypoxic conditions: its implications in immune evasion.

Bol Med Hosp Infant Mex 2020 ;77(4):186-194

Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México Federico Gómez, Mexico City, Mexico.

Background: Acute lymphoblastic leukemia (ALL) is an aggressive malignant disease with high prevalence in pediatric patients. It has been shown that the downregulation of Fas expression is correlated with an inadequate response in ALL, although these mechanisms are still not well understood. Several reports demonstrated that hypoxia is involved in dysfunctional apoptosis. Yin-Yang-1 (YY1) transcription factor is involved in resistance to apoptosis, tumor progression, and it is increased in different types of cancer, including leukemia. The regulatory mechanism underlying YY1 expression in leukemia is still not understood, but it is known that YY1 negatively regulates Fas expression. The study aimed to evaluate the effect of YY1 on Fas expression under hypoxic conditions in ALL.

Methods: Leukemia cell line RS4; 11 was cultured under normoxic and hypoxic conditions. YY1, Fas receptor, and hypoxia-inducible factor (HIF-1α) expression were analyzed. After treatment with a Fas agonist (DX2), apoptosis was analyzed through the detection of active caspase 3. Data were analyzed using Pearson's correlation.

Results: Leukemia cells co-expressed both HIF-1α and YY1 under hypoxia, which correlated with a downregulation of Fas expression. During hypoxia, the levels of apoptosis diminished after DX2 treatment. The analysis revealed that patients with high levels of HIF-1α also express high levels of YY1 and low levels of Fas.

Conclusions: These results suggest that YY1 negatively regulates the expression of the Fas receptor, which could be involved in the escape of leukemic cells from the immune response contributing to the ALL pathogenesis.
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http://dx.doi.org/10.24875/BMHIM.19000187DOI Listing
October 2021

Importance of the Role of ω-3 and ω-6 Polyunsaturated Fatty Acids in the Progression of Brain Cancer.

Brain Sci 2020 Jun 17;10(6). Epub 2020 Jun 17.

Hospital Infantil de Mexico, Federico Gomez, Unidad de Investigacion en Enfermedades Oncologicas, Mexico City 06720, Mexico.

Brain cancer is one of the most malignant types of cancer in both children and adults. Brain cancer patients tend to have a poor prognosis and a high rate of mortality. Additionally, 20-40% of all other types of cancer can develop brain metastasis. Numerous pieces of evidence suggest that omega-3-polyunsaturated fatty acids (ω-PUFAs) could potentially be used in the prevention and therapy of several types of cancer. PUFAs and oxylipins are fundamental in preserving physiological events in the nervous system; it is, therefore, necessary to maintain a certain ratio of ω-3 to ω-6 for normal nervous system function. Alterations in PUFAs signaling are involved in the development of various pathologies of the nervous system, including cancer. It is well established that an omega-6-polyunsaturated fatty acid (ω-6 PUFA)-rich diet has a pro-tumoral effect, whereas the consumption of an ω-3 rich diet has an anti-tumoral effect. This review aims to offer a better understanding of brain cancer and PUFAs and to discuss the role and impact of PUFAs on the development of different types of brain cancer. Considering the difficulty of antitumor drugs in crossing the blood-brain barrier, the therapeutic role of ω-3/ω-6 PUFAs against brain cancer would be a good alternative to consider. We highlight our current understanding of the role of PUFAs and its metabolites (oxylipins) in different brain tumors, proliferation, apoptosis, invasion, angiogenesis, and immunosuppression by focusing on recent research in vitro and in vivo.
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http://dx.doi.org/10.3390/brainsci10060381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349634PMC
June 2020

Aryl Hydrocarbon Receptor-Dependent inductions of omega-3 and omega-6 polyunsaturated fatty acid metabolism act inversely on tumor progression.

Sci Rep 2020 05 12;10(1):7843. Epub 2020 May 12.

Department of Pathology & Laboratory Medicine, University of California, Los Angeles, CA, 90095, USA.

The Western diet contains a high ratio of omega-6 (ω6) to omega-3 (ω3) polyunsaturated fatty acids (PUFA). The prototypical aryl hydrocarbon receptor (AHR) ligand, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), induces CYP1 family enzymes, which can metabolize PUFA to epoxides. Mice fed ω3-rich or ω6-rich diets were treated with TCDD and injected subcutaneously with AHR-competent Hepa1-GFP hepatoma cells or AHR-deficient LLC lung cancer cells. TCDD reduced the growth rates of the resulting tumors in ω3-fed mice and inhibited their metastasis to the liver and/or lung, but had the opposite effects in mice fed ω6 PUFA. These responses were likely attributable to the corresponding PUFA epoxides generated in tumor cells and/or host, since many depended upon co-administration of a soluble epoxide hydrolase (EPHX2) inhibitor in males, and/or were associated with increases in epoxide levels in tumors and sites of metastasis. Equivalent effects occurred in females in the absence of EPHX2 inhibition, probably because this sex expressed reduced levels of EPHX2. The responses elicited by TCDD were associated with effects on tumor vascularity, tumor cell proliferation and/or apoptosis. Thus environmental AHR agonists, and potentially also endogenous, nutritional, and microbiome-derived agonists, may reduce or enhance cancer progression depending on the composition of dietary PUFA, particularly in females.
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http://dx.doi.org/10.1038/s41598-020-64146-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217871PMC
May 2020

Omega-3 Polyunsaturated Fatty Acids and Lung Cancer: nutrition or Pharmacology?

Nutr Cancer 2021 12;73(4):541-561. Epub 2020 May 12.

Pathology and Laboratory Medicine, University of California, Los Angeles, USA.

Omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplements for chemoprevention of different types of cancer including lung cancer has been investigated in recent years. ω-3 PUFAs are considered immunonutrients, commonly used in the nutritional therapy of cancer patients. ω-3 PUFAs play essential roles in cell signaling and in cell structure and fluidity of membranes. They participate in the resolution of inflammation and have anti-inflammatory effects. Lung cancer patients suffer complications, such as anorexia-cachexia syndrome, pain and depression. The European Society for Clinical Nutrition and Metabolism (ESPEN) 2017 guidelines for cancer patients only discuss the use of ω-3 PUFAs for cancer-cachexia treatment, leaving aside other cancer-related complications that could potentially be managed by ω-3 PUFAs. This review aims to elucidate whether the effects of ω-3 PUFAs in lung cancer is supplementary, pharmacological or both. In addition, clinical studies, evidence in cell lines and animal models suggest how ω-3 PUFAs induce anticancer effects. ω-3 PUFAs and their metabolites are suggested to modulate pivotal pathways underlying the progression or complications of lung cancer, indicating that this is a promising field to be explored. Further investigation is still required to analyze the benefits of ω-3 PUFAs as supplementation or pharmacological treatment in lung cancer.
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http://dx.doi.org/10.1080/01635581.2020.1761408DOI Listing
August 2021

A Novel Therapeutic Induces DEPTOR Degradation in Multiple Myeloma Cells with Resulting Tumor Cytotoxicity.

Mol Cancer Ther 2019 10 8;18(10):1822-1831. Epub 2019 Aug 8.

Hematology-Oncology, VA West LA-UCLA Medical Center, Los Angeles, California.

Prior work indicates DEPTOR expression in multiple myeloma cells could be a therapeutic target. DEPTOR binds to mTOR via its PDZ domain and inhibits mTOR kinase activity. We previously identified a drug, which prevented mTOR-DEPTOR binding (NSC126405) and induced multiple myeloma cytotoxicity. We now report on a related therapeutic, drug 3g, which induces proteasomal degradation of DEPTOR. DEPTOR degradation followed drug 3g binding to its PDZ domain and was not due to caspase activation or enhanced mTOR phosphorylation of DEPTOR. Drug 3g enhanced mTOR activity, and engaged the IRS-1/PI3K/AKT feedback loop with reduced phosphorylation of AKT on T308. Activation of TORC1, in part, mediated multiple myeloma cytotoxicity. Drug 3g was more effective than NSC126405 in preventing binding of recombinant DEPTOR to mTOR, preventing binding of DEPTOR to mTOR inside multiple myeloma cells, in activating mTOR and inducing apoptosis in multiple myeloma cells. , drug 3g injected daily abrogated DEPTOR expression in xenograft tumors and induced an antitumor effect although modest weight loss was seen. Every-other-day treatment, however, was equally effective without weight loss. Drug 3g also reduced DEPTOR expression in normal tissues. Although no potential toxicity was identified in hematopoietic or hepatic function, moderate cardiac enlargement and glomerular mesangial hypertrophy was seen. DEPTOR protected multiple myeloma cells against bortezomib suggesting anti-DEPTOR drugs could synergize with proteasome inhibitors (PI). Indeed, combinations of drug NSC126405 + bortezomib were synergistic. In contrast, drug 3g was not and was even antagonistic. This antagonism was probably due to prevention of proteasomal DEPTOR degradation.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774835PMC
October 2019

Regulation of Krüppel-Like Factor 4 (KLF4) expression through the transcription factor Yin-Yang 1 (YY1) in non-Hodgkin B-cell lymphoma.

Oncotarget 2019 Mar 15;10(22):2173-2188. Epub 2019 Mar 15.

Molecular Signal Pathway in Cancer Laboratory, UIMEO, Oncology Hospital, Siglo XXI National Medical Center, IMSS, México City, México.

Krüppel-Like Factor 4 (KLF4) is a member of the KLF transcription factor family, and evidence suggests that KLF4 is either an oncogene or a tumor suppressor. The regulatory mechanism underlying KLF4 expression in cancer, and specifically in lymphoma, is still not understood. Bioinformatics analysis revealed two YY1 putative binding sites in the KLF4 promoter region (-950 bp and -105 bp). Here, the potential regulation of KLF4 by YY1 in NHL was analyzed. Mutation of the putative YY1 binding sites in a previously reported system containing the KLF4 promoter region and CHIP analysis confirmed that these binding sites are important for KLF4 regulation. B-NHL cell lines showed that both KLF4 and YY1 are co-expressed, and transfection with siRNA-YY1 resulted in significant inhibition of KLF4. The clinical implications of YY1 in the transcriptional regulation of KLF4 were investigated by IHC in a TMA with 43 samples of subtypes DLBCL and FL, and all tumor tissues expressing YY1 demonstrated a correlation with KLF4 expression, which was consistent with bioinformatics analyses in several databases. Our findings demonstrated that KLF4 can be transcriptionally regulated by YY1 in B-NHL, and a correlation between YY1 expression and KLF4 was found in clinical samples. Hence, both YY1 and KLF4 may be possible therapeutic biomarkers of NHL.
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http://dx.doi.org/10.18632/oncotarget.26745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481341PMC
March 2019

Expression of YY1 in Wilms tumors with favorable histology is a risk factor for adverse outcomes.

Future Oncol 2019 Apr 27;15(11):1231-1241. Epub 2019 Feb 27.

Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México, Federico Gómez, Mexico City, Mexico.

Aim: To investigate the role of the transcription factor YY1 in Wilms tumor (WT).

Patients & Methods: We measured YY1 expression using tissue microarray from patients with pediatric renal tumors, mainly WT and evaluated correlations with the predicted clinical evolution. YY1 expression was measured using immunohistochemical and protein expression was determined by digital pathology.

Results & Conclusion: YY1 significantly increased in WT patients. In addition, an increase in YY1 expression had a greater risk of adverse outcomes in WT patients with favorable histology. YY1 expression was higher in the blastemal component of tumors, and high nuclear expression positively correlated with metastasis. YY1 may be considered as a metastasis risk factor in WT.
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http://dx.doi.org/10.2217/fon-2018-0764DOI Listing
April 2019

Lysine methyltransferase 2D regulates pancreatic carcinogenesis through metabolic reprogramming.

Gut 2019 07 18;68(7):1271-1286. Epub 2018 Oct 18.

Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.

Objective: Despite advances in the identification of epigenetic alterations in pancreatic cancer, their biological roles in the pathobiology of this dismal neoplasm remain elusive. Here, we aimed to characterise the functional significance of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in pancreatic tumourigenesis.

Design: DNA methylation sequencing and gene expression microarrays were employed to investigate CpG methylation and expression patterns of KMTs and KDMs in pancreatic cancer tissues versus normal tissues. Gene expression was assessed in five cohorts of patients by reverse transcription quantitative-PCR. Molecular analysis and functional assays were conducted in genetically modified cell lines. Cellular metabolic rates were measured using an XF24-3 Analyzer, while quantitative evaluation of lipids was performed by liquid chromatography-mass spectrometry (LC-MS) analysis. Subcutaneous xenograft mouse models were used to evaluate pancreatic tumour growth in vivo.

Results: We define a new antitumorous function of the histone lysine (K)-specific methyltransferase 2D (KMT2D) in pancreatic cancer. is transcriptionally repressed in human pancreatic tumours through DNA methylation. Clinically, lower levels of this methyltransferase associate with poor prognosis and significant weight alterations. RNAi-based genetic inactivation of KMT2D promotes tumour growth and results in loss of H3K4me3 mark. In addition, KMT2D inhibition increases aerobic glycolysis and alters the lipidomic profiles of pancreatic cancer cells. Further analysis of this phenomenon identified the glucose transporter SLC2A3 as a mediator of KMT2D-induced changes in cellular, metabolic and proliferative rates.

Conclusion: Together our findings define a new tumour suppressor function of KMT2D through the regulation of glucose/fatty acid metabolism in pancreatic cancer.
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http://dx.doi.org/10.1136/gutjnl-2017-315690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697184PMC
July 2019

Hypoxia increases chemoresistance in human medulloblastoma DAOY cells via hypoxia‑inducible factor 1α‑mediated downregulation of the CYP2B6, CYP3A4 and CYP3A5 enzymes and inhibition of cell proliferation.

Oncol Rep 2019 Jan 12;41(1):178-190. Epub 2018 Oct 12.

Laboratory of Experimental Oncology, National Institute of Pediatrics, Mexico City 04530, Mexico.

Medulloblastomas are among the most frequently diagnosed pediatric solid tumors, and drug resistance remains as the principal cause of treatment failure. Hypoxia and the subsequent activation of hypoxia‑inducible factor 1α (HIF‑1α) are considered key factors in modulating drug antitumor effectiveness, but the underlying mechanisms in medulloblastomas have not yet been clearly understood. The aim of the present study was to determine whether hypoxia induces resistance to cyclophosphamide (CPA) and ifosfamide (IFA) in DAOY medulloblastoma cells, whether the mechanism is dependent on HIF‑1α, and whether involves the modulation of the expression of cytochromes P450 (CYP)2B6, 3A4 and 3A5 and the control of cell proliferation. Monolayer cultures of DAOY medulloblastoma cells were exposed for 24 h to moderate (1% O2) or severe (0.1% O2) hypoxia, and protein expression was evaluated by immunoblotting. Cytotoxicity was studied with the MTT assay and by Annexin V/PI staining and flow cytometry. Cell proliferation was determined by the trypan‑blue exclusion assay and cell cycle by propidium iodide staining and flow cytometry. Hypoxia decreased CPA and IFA cytotoxicity in medulloblastoma cells, which correlated with a reduction in the protein levels of CYP2B6, CYP3A4 and CYP3A5 and inhibition of cell proliferation. These responses were dependent on hypoxia‑induced HIF‑1α activation, as evidenced by chemical inhibition of its transcriptional activity with 2‑methoxyestradiol (2‑ME), which enhanced the cytotoxic activity of CPA and IFA and increased apoptosis. Our results indicate that by stimulating HIF‑1α activity, hypoxia downregulates the expression of CYP2B6, CYP3A4 and CYP3A5, that in turn leads to decreased conversion of CPA and IFA into their active forms and thus to diminished cytotoxicity. These results support that the combination of HIF‑1α inhibitors and canonical antineoplastic agents provides a potential therapeutic alternative against medulloblastoma.
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http://dx.doi.org/10.3892/or.2018.6790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278548PMC
January 2019

Dual role of hypoxia-inducible factor 1 α in experimental pulmonary tuberculosis: its implication as a new therapeutic target.

Future Microbiol 2018 06 31;13:785-798. Epub 2018 May 31.

Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico, Federico Gomez, Mexico City, Mexico.

Aim: Investigate the role of hypoxia-inducible factor-1α (HIF-1α) in pulmonary tuberculosis (TB).

Methods & Results: A model of progressive pulmonary TB in BALB/c mice, immunohistochemistry and digital pathology were used. High HIF-1α expression was observed during early TB in activated macrophages. During late TB, even higher HIF-1α expression was observed in foamy macrophages, which are resistant to apoptosis. Blocking HIF-1α during early infection with 2-methoxyestradiol worsened the disease, while during late TB, it induced macrophage apoptosis and decreased bacillary loads.

Conclusion: HIF-1α has a dual role in experimental TB. This finding could have therapeutic implications because combined treatment with 2-methoxyestradiol and antibiotics appeared to eliminate mycobacteria more efficiently than conventional chemotherapy during advanced disease.
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http://dx.doi.org/10.2217/fmb-2017-0168DOI Listing
June 2018

Role of Yin Yang-1 (YY1) in the transcription regulation of the multi-drug resistance () gene.

Leuk Lymphoma 2018 11 4;59(11):2628-2638. Epub 2018 Apr 4.

a Unidad de Investigación en Enfermedades Oncológicas , Hospital Infantil de México, Federico Gómez , Mexico City , Mexico.

Resistance to chemotherapy hinders the successful treatment of acute lymphoblastic leukemia (ALL). The multi-drug resistance-1 (/ABCB1) gene encodes P-glycoprotein (P-gp), which plays an important role in chemoresistance; however, its transcriptional regulation remains unclear. We investigated the role of YY1 in the regulation of and its relation to ALL outcomes. Analysis of the promoter revealed four putative YY1-binding sites, which we analyzed using a reporter system and ChIP analysis. YY1 silencing resulted in the inhibition of expression and function. The clinical roles of YY1 and expression were evaluated in children with ALL. Expression of both proteins was increased in ALL patients compared to controls. We identified a positive correlation between YY1 and expression. High levels of YY1 were associated with decreased overall survival. Our results demonstrated that YY1 regulates the transcription of . Therefore, YY1 may serve as a useful prognostic and/or therapeutic target.
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http://dx.doi.org/10.1080/10428194.2018.1448083DOI Listing
November 2018

[Corrigendum] Death receptor 5 expression is inversely correlated with prostate cancer progression.

Mol Med Rep 2017 10 11;16(4):5738. Epub 2017 Aug 11.

Oncology Disease Research Unit, Children Hospital of Mexico 'Federico Gomez', Mexico City 06720, Mexico.

During the preparation of the figures in the above article, the authors inadvertently duplicated in Fig. 1B, a and b (high and low magnification images) the images that had already appeared as Figs. 5A, a and c (high and low magnification images), respectively, of the following paper: Huerta-Yepez S, Baritaki S, Baay-Guzman G, Hernandez-Luna MA, Hernandez-Cueto A, Vega MI and Bonavida B: Contribution of either YY1 or BclXL-induced inhibition by the NO-donor DETANONOate in the reversal of drug resistance, both in vitro and in vivo. Nitric Oxide 29: 17-24, 2013. The revised version of Fig. 1 containing the corrected data for Fig. 1B, a and b (high and low magnification images; the YY1 data) is shown opposite protein expression. All those authors whom the corresponding author was able to contact have agreed to this Corrigendum. The authors regret this error, and apologize for any confusion that it may have caused. [the original article was published in the Molecular Medicine Reports 10: 2279-2286, 2014; DOI: 10.3892/mmr.2014.2504 ].
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http://dx.doi.org/10.3892/mmr.2017.7234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647094PMC
October 2017

Correlation of the expression of YY1 and Fas cell surface death receptor with apoptosis of peripheral blood mononuclear cells, and the development of multiple organ dysfunction in children with sepsis.

Mol Med Rep 2017 May 9;15(5):2433-2442. Epub 2017 Mar 9.

Oncology Research Unit, Oncology Hospital, Siglo XXI National Medical Center, IMSS, 06720 Mexico City, Mexico.

Multiple organ dysfunction (MOD) is a lethal complication in children with sepsis. Apoptosis of several cell types is involved in this process, and it is associated with increased Fas cell surface death receptor (Fas) expression. As YY1 transcription factor (YY1) negatively regulates the expression of Fas in cancer models, and is associated with the clinical outcome, it may be important in MOD. The present study aimed to determine the association between the expression of Fas, YY1 and apoptosis in children with sepsis, and its association with MOD, these factors were analyzed in 30 pediatric patients that had been diagnosed with sepsis. Peripheral blood mononuclear cells were purified from patients, and YY1 and Fas protein expression was assessed by immunocytochemistry. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick‑end labeling. Sepsis was monitored using clinical parameters, pediatric logistic organ dysfunction (PELOD) score and the pediatric mortality index. The results demonstrated that Fas expression was directly correlated with apoptosis levels and the expression of YY1 was inversely correlated with apoptosis levels. Patients with high levels of apoptosis exhibited increased disease severity and poor clinical outcome. Notably, the findings of the present study demonstrated that there were higher survival rates in patients with high YY1 expression, compared with those with low YY1 expression. Additionally, patients with MOD exhibited lower proportions of apoptotic cells compared with sepsis patients without MOD. Furthermore, the PELOD score was positively correlated with Fas and inversely correlated with YY1 expression. Finally, high apoptosis and low YY1 expression were prognostic factors associated with poor survival rates. These data suggested that YY1 may be important for apoptosis induction via the regulation of Fas during sepsis. Therefore, Fas may be a potential therapeutic target to prevent MOD through regulation of YY1 expression. Furthermore, YY1 and Fas expression in PBMCs may be used to as prognostic markers.
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http://dx.doi.org/10.3892/mmr.2017.6310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428261PMC
May 2017

Sulforaphane induces differential modulation of mitochondrial biogenesis and dynamics in normal cells and tumor cells.

Food Chem Toxicol 2017 Feb 18;100:90-102. Epub 2016 Dec 18.

Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico. Electronic address:

Antioxidant-based chemotherapy has been intensely debated. Herein, we show that sulforaphane (SFN) induced mitochondrial biogenesis followed by mitochondrial fusion in a kidney cell line commonly used in nephroprotective models. At the same concentration and exposure time, SFN induced cell death in prostate cancer cells accompanied by mitochondrial biogenesis and fragmentation. Stabilization of the nuclear factor E2-related factor-2 (Nrf2) could be associated with these effects in the tumor cell line. An increase in the peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) level and a decrease in the hypoxia-inducible factor-1α (HIF1α) level would suggest a possible metabolic shift. The knockdown in the nuclear respiratory factor-1 (NRF1) attenuated the SFN-induced effect on prostate cancer cells demonstrating that mitochondrial biogenesis plays an important role in cell death for this kind of tumor cells. This evidence supports SFN as a potential antineoplastic agent that could inhibit tumor development and could protect normal tissues by modulating common processes.
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http://dx.doi.org/10.1016/j.fct.2016.12.020DOI Listing
February 2017

Association between nuclear expression of retinoic acid receptor alpha and beta and clinicopathological features and prognosis of advanced non-small cell lung cancer.

Int J Clin Oncol 2016 Dec 15;21(6):1051-1061. Epub 2016 Jun 15.

Laboratory of Personalized Medicine, Instituto Nacional de Cancerología, Mexico City, Mexico.

Background: Transcription factors such as retinoic acid receptor alpha (RARα) and beta (RARβ) and Yin Yang 1 (YY1) are associated with the progression of non-small cell lung cancer (NSCLC). In particular, a lack of RARβ expression is associated with NSCLC development. The aim of this study was to analyze the expression of RARα, RARβ and YY1 and their relationship with prognosis in patients with advanced NSCLC.

Methods: The expression of RARα, RARβ and YY1 was assessed by immunohistochemistry and quantitative computerized image software.

Results: Eighty-five patients treated with platinum-based chemotherapy were included in the analysis. The mean and standard deviation of the nuclear expression of RARα, RARβ and YY1 were 184.5 ± 124.4, 18 ± 27 and 16.6 ± 20.5, respectively. The nuclear expression of RARβ was associated with the nuclear expression of YY1 (R  = 0.28; p value < 0.0001). Patients with high nuclear expression of YY1 were likely to be non-smokers (61.9 vs 40.5 %). Median progression-free survival (PFS) was 5.9 months (3.48-8.28). Low expression of RARα was independently associated with worse PFS following chemotherapy (10.3 vs 5.46 months p = 0.040). Median overall survival (OS) was 15.6 months (4.5-26.7), and lower nuclear expression of RARβ was independently associated with shorter OS (27.5 vs 8.7 months; p = 0.037).

Conclusion: Our study suggests that the loss of RARs is associated with a worse prognosis and these receptors could be a potential molecular target for NSCLC.
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http://dx.doi.org/10.1007/s10147-016-1002-0DOI Listing
December 2016

A novel role of Yin-Yang-1 in pulmonary tuberculosis through the regulation of the chemokine CCL4.

Tuberculosis (Edinb) 2016 Jan 30;96:87-95. Epub 2015 Nov 30.

Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico "Federico Gomez", Mexico City, Mexico. Electronic address:

Mycobacterium tuberculosis (M. tb) is the etiological agent of pulmonary tuberculosis (TB); this disease remains a worldwide health problem. Yin-Yang-1 (YY1) plays a major role in the maintenance and progression of some pulmonary diseases, including pulmonary fibrosis. However, the role of YY1 in TB remains unknown. The aim of this study was to elucidate the role of YY1 in the regulation of CCL4 and its implication in TB. We determined whether YY1 regulates CCL4 using reporter plasmids, ChIP and siRNA assays. Immunohistochemistry and digital pathology were used to measure the expression of YY1 and CCL4 in a mouse model of TB. A retrospective comparison of patients with TB and control subjects was used to measure the expression of YY1 and CCL4 using tissue microarrays. Our results showed that YY1 regulates the transcription of CCL4; moreover, YY1, CCL4 and TGF-β were overexpressed in the lung tissues of mice with TB during the late stages of the disease and the tissues of TB patients. The expression of CCL4 and TGF-β correlated with YY1 expression. In conclusion, YY1 regulates CCL4 transcription; moreover, YY1 is overexpressed in experimental and human TB and is positively correlated with CCL4 and TGF-β expression. Therefore, treatments that decrease YY1 expression may be a new therapeutic strategy against TB.
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http://dx.doi.org/10.1016/j.tube.2015.10.013DOI Listing
January 2016

Role of diets rich in omega-3 and omega-6 in the development of cancer.

Bol Med Hosp Infant Mex 2016 Nov - Dec;73(6):446-456. Epub 2016 Nov 30.

Department of Pathology & Laboratory Medicine, UCLA Medical Center, Center for the Health Sciences, Los Angeles, United States. Electronic address:

Over the past decade, some studies have addressed the therapeutic effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and the opposite effects of omega-6 (ω-6) PUFAs on several diseases, including cardiovascular disorders, diabetes, neurodegenerative diseases, and cancer. Research demonstrates the safety of these naturally occurring ingredients. Of particular interest, several studies have shown that ω-3 PUFAs possess a therapeutic role against certain types of cancer. It is also known that ω-3 PUFAs can improve the efficacy and tolerability of chemotherapy. Previous reports have indicated that suppression of nuclear factor-κB, activation of AMPK/SIRT1, modulation of cyclooxygenase (COX) activity, and up-regulation of novel anti-inflammatory lipid mediators such as protectins, maresins, and resolvins, are the main mechanisms of the antineoplastic effect of ω-3 PUFAs. In contrast, several studies have demonstrated that ω-6 PUFAs induce progression in certain types of cancer. In this review, we discuss epidemiological and experimental studies addressing the relationship between the development of some types of cancer, including colon and colorectal carcinoma, breast cancer, prostate cancer, lung cancer and neuroblastoma, and the ingestion to ω-3 and ω-6 (PUFAs). We also discuss the clinical data, addressing the therapeutic role of omega-3 PUFA against different types of cancer.
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http://dx.doi.org/10.1016/j.bmhimx.2016.11.001DOI Listing
November 2016

Allergies: diseases closely related to cancer.

Bol Med Hosp Infant Mex 2016 Nov - Dec;73(6):432-445. Epub 2016 Dec 20.

Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México Federico Gómez, Mexico City, Mexico.

Allergies are hypersensitivity reactions that occur through specific type Th2 immunological mechanisms characterized by different soluble mediators, as well as specific cells of the immune system. In recent decades, evidence has emerged relating this disease with cancer development. However, most of the results of epidemiology studies have been controversial and contradictory. There are mainly two trends. While the first indicates that allergies can reduce the risk of cancer, the other indicates that they may increase this risk. The first trend can be explained by the immunosurveillance hypothesis, which states that the increased immune surveillance after the immune hyper-responsiveness can inhibit or exert a protective effect against the development of cancer. Similarly, the prophylaxis hypothesis suggests that the physical effects of allergy symptoms can prevent cancer by removing potential carcinogens. In contrast, the opposing hypothesis propose that there is a deviation of the immune response toward Th2, which favors the development of cancer, or that the process of chronic inflammation favors the generation of mutations, and therefore the development of cancer. With the purpose of understanding more about these two hypotheses, the main soluble and cellular factors of allergic diseases that could be playing a key role in the development or inhibition of cancer were considered in this review.
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http://dx.doi.org/10.1016/j.bmhimx.2016.11.006DOI Listing
December 2016

Application of computational methods for anticancer drug discovery, design, and optimization.

Bol Med Hosp Infant Mex 2016 Nov - Dec;73(6):411-423. Epub 2016 Nov 30.

Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México Federico Gómez, Mexico City, Mexico. Electronic address:

Developing a novel drug is a complex, risky, expensive and time-consuming venture. It is estimated that the conventional drug discovery process ending with a new medicine ready for the market can take up to 15 years and more than a billion USD. Fortunately, this scenario has recently changed with the arrival of new approaches. Many novel technologies and methodologies have been developed to increase the efficiency of the drug discovery process, and computational methodologies have become a crucial component of many drug discovery programs. From hit identification to lead optimization, techniques such as ligand- or structure-based virtual screening are widely used in many discovery efforts. It is the case for designing potential anticancer drugs and drug candidates, where these computational approaches have had a major impact over the years and have provided fruitful insights into the field of cancer. In this paper, we review the concept of rational design presenting some of the most representative examples of molecules identified by means of it. Key principles are illustrated through case studies including specifically successful achievements in the field of anticancer drug design to demonstrate that research advances, with the aid of in silico drug design, have the potential to create novel anticancer drugs.
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http://dx.doi.org/10.1016/j.bmhimx.2016.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7110968PMC
November 2016

Bactofection of sequences encoding a Bax protein peptide chemosensitizes prostate cancer tumor cells.

Bol Med Hosp Infant Mex 2016 Nov - Dec;73(6):388-396. Epub 2016 Dec 1.

Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México Federico Gómez, Mexico City, Mexico. Electronic address:

Background: Tumor cell resistance to chemotherapy agents is one of the main problems in the eradication of different neoplasias. One of the mechanisms of this process is the overexpression of anti-apoptotic proteins such as Bcl-2 and Bcl-; blocking the activity of these proteins may contribute to the sensitization of tumor cells and allow the adequate effects of chemotherapeutic drugs.

Methods And Results: This study adressed the transfection of prostate cancer cells (PC3) with a plasmid encoding a recombinant protein with an antagonist peptide from the BH3 region of the Bax protein fused to the GFP reporter protein (BaxGFP). This protein induced apoptosis of these tumor cells; further, selective transport of this plasmid to the tumor cell with Salmonella enterica serovar Typhimurium (strain SL3261), a live-attenuated bacterial vector, can induce sensitization of the tumor cell to the action of drugs such as cisplatin, through a process known as bactofection.

Conclusions: These results suggest that Salmonella enterica can be used as a carrier vector of nucleotide sequences encoding heterologous molecules used in antitumor therapy.
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http://dx.doi.org/10.1016/j.bmhimx.2016.10.002DOI Listing
December 2016

Perspectives in cancer: molecular findings, computational-designed drugs, and patient care.

Bol Med Hosp Infant Mex 2016 Nov - Dec;73(6):361-362. Epub 2016 Nov 30.

Hospital Infantil de México Federico Gómez, Mexico City, Mexico. Electronic address:

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http://dx.doi.org/10.1016/j.bmhimx.2016.11.002DOI Listing
November 2016

Diminished expression of CRHR2 in human colon cancer promotes tumor growth and EMT via persistent IL-6/Stat3 signaling.

Cell Mol Gastroenterol Hepatol 2015 Nov;1(6):610-630

IBD Center, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA ; Unidad de Investigacion en Enfermedades Oncologicas, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico ; Division of Surgery, School of Medicine, University of Crete, Heraklion, Crete, Greece.

Background & Aims: Chronic inflammation promotes development and progression of colorectal cancer (CRC). We explored the distribution of Corticotropin-Releasing-Hormone (CRH)-family of receptors and ligands in CRC and their contribution in tumor growth and oncogenic EMT.

Methods: mRNA expression of CRH-family members was analyzed in CRC (N=56) and control (N=46) samples, 7 CRC cell lines and normal NCM460 cells. Immunohistochemical detection of CRHR2 was performed in 20 CRC and 5 normal tissues. Cell proliferation, migration and invasion were compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing (CRHR2+) cells in absence or presence of IL-6. CRHR2/Ucn2-targeted effects on tumor growth and EMT were validated in SW620-xenograft mouse models.

Results: CRC tissues and cell lines showed decreased mRNA and protein CRHR2 expression compared to controls and NCM460, respectively. The opposite trend was shown for Ucn2. CRHR2/Ucn2 signaling inhibited cell proliferation, migration, invasion and colony formation in CRC-CRHR2+ cells. , SW620-CRHR2+ xenografts showed decreased growth, reduced expression of EMT-inducers and elevated levels of EMT-suppressors. IL-1b, IL-6 and IL-6R mRNAs where diminished in CRC-CRHR2+ cells, while CRHR2/Ucn2 signaling inhibited IL-6-mediated Stat3 activation, invasion, migration and expression of downstream targets acting as cell cycle- and EMT-inducers. Expression of cell cycle- and EMT-suppressors was augmented in IL-6/Ucn2-stimulated CRHR2+ cells. In patients, CRHR2 mRNA expression was inversely correlated with IL-6R and vimentin levels and metastasis occurrence, while positively associated with E-cadherin expression and overall survival.

Conclusions: CRHR2 downregulation in CRC supports tumor expansion and spread through maintaining persistent inflammation and constitutive Stat3 activation. CRHR2 CRC phenotypes are associated with higher risk for distant metastases and poor clinical outcomes.
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http://dx.doi.org/10.1016/j.jcmgh.2015.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610032PMC
November 2015

P38 MAPK expression and activation predicts failure of response to CHOP in patients with Diffuse Large B-Cell Lymphoma.

BMC Cancer 2015 Oct 16;15:722. Epub 2015 Oct 16.

Oncology Research Unit, Oncology Hospital, Siglo XXI National Medical Center, IMSS, Mexico City, Mexico.

Background: The p38 MAPK is constitutively activated in B-NHL cell lines and regulates chemoresistance. Accordingly, we hypothesized that activated p38 MAPK may be associated with the in vivo unresponsiveness to chemotherapy in B-NHL patients.

Methods: Tissue microarrays generated from eighty untreated patients with Diffused Large B Cell Lymphoma (DLBCL) were examined by immunohistochemistry for the expression of p38 and phospho p38 (p-p38) MAPK. In addition, both Bcl-2 and NF-κB expressions were determined. Kaplan Meier analysis was assessed.

Results: Tumor tissues expressed p38 MAPK (82 %) and p-p38 MAPK (30 %). Both p38 and p-p38 MAPK expressions correlated with the high score performance status. A significant correlation was found between the expression p-p38 and poor response to CHOP. The five year median follow-up FFS was 81 % for p38(-) and 34 % for p38(+) and for OS was 83 % for p38(-) and 47 % for p38(+). The p-p38(+) tissues expressed Bcl-2 and 90 % of p-p38(-) where Bcl-2(-). The coexpression of p-p38 and Bcl-2 correlated with pool EFS and OS. There was no correlation between the expression of p-p38 and the expression of NF-κB.

Conclusion: The findings revealed, for the first time, that a subset of patients with DLBCL and whose tumors expressed high p-p38 MAPK responded poorly to CHOP therapy and had poor EFS and OS. The expression of p38, p-p38, Bcl2 and the ABC subtype are significant risk factors both p38 and p-p38 expressions remain independent prognostic factors.
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http://dx.doi.org/10.1186/s12885-015-1778-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609122PMC
October 2015
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