Browsing by Author "Riquelme Sánchez, Erick Marcelo"
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- ItemAberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis(American Association Cancer Research, 2004) Takahashi, Takao; Shivapurkar, Narayan; Riquelme Sánchez, Erick Marcelo; Shigematsu, Hisayuki; Reddy, Jyotsna; Suzuki, Makoto; Miyajima, Kuniharu; Zhou, Xian; Bekele, B. Nebiyou; Gazdar, Adi F.; Wistuba Oyarzún, IgnacioPurpose: Aberrant methylation of 5' gene promoter regions is an epigenetic phenomenon that is a major mechanism for silencing of tumor suppressor genes in many cancer types. There is limited information about the molecular changes involved in the pathogenesis of gallbladder carcinoma (GBC), including methylation status. Experimental Design: We investigated the aberrant promoter methylation profile of 24 known or suspected tumor suppressor genes in 50 GBCs and compared those results with the findings in 25 chronic cholecystitis (CC) specimens without cancer. The methylation-specific polymerase chain reaction and combined restriction analysis methods were used to detect methylation, and the results were confirmed by sequencing of cloned polymerase chain reaction products. Results: In GBC, gene methylation frequencies varied from 0% to 80%. Ten genes demonstrated relatively high frequencies of aberrant methylation: SHP1 (80%), 3-OST-2 (72%), CDH13 (44%), P-15(INK4B) (44%), CDH1 (38%), RUNX3 (32%), APC (30%), RIZ1 (26%), P16(INK4A) (24%), and HPP1 (20 %). Eight genes (P73, RARbeta2, SOCS-1, DAPK, DcR2, DcR1, HIN1, and CHFR) showed low frequencies (2-14%) of methylation, and no methylation of the remaining six genes (TIMP-3, P57, RASSF1A, CRBP1, SYK, and NORE1) was detected. In CC, methylation was detected for seven genes: SHP1 (88 %), P15(INK4B) (28 %), 3-OST-2 (12%), CDH1 (12 %), CDH13 (8 %), DcR2 (4 %), and P16(INK4A) (4%) Significantly higher frequencies of methylation in GBC compared with CC were detected for eight genes (3-OST-2, CDH13, CDH1, RUNX3, APC, RIZ1, P16(INK4A), and HPP1). Of those, four genes showed frequent methylation (>30%) in GBCs. The mean methylation index, an expression of the amount of methylated genes by case, was significantly higher in GBC (0.196 +/- 0.013) compared with CC (0.065 +/- 0.008; P < 0.001). Conclusions: Our study constitutes the most comprehensive methylation profile report available in GBC and demonstrates that this neoplasm has a distinct pattern of abnormal gene methylation. Whereas gallbladders from healthy individual were not available, our finding of methylation in CC cases without cancer suggests that this phenomenon represents an early event in the pathogenesis of GBC.
- ItemFragile histidine triad gene abnormalities in the pathogenesis of gallbladder carcinoma(2002) Wistuba Oyarzún, Ignacio; Ashfaq, Raheela; Maitra, Anirban; Álvarez Pando, Héctor Andrés; Riquelme Sánchez, Erick Marcelo; Gazdar, Adi F.There is limited information about the molecular changes involved in the pathogenesis of gallbladder carcinoma (GBC). Our recent allelotyping analyses have indicated that chromosome 3p loss of heterozygosity (LOH), including the fragile histidine triad (FHIT) candidate tumor-suppressor gene locus at 3p14.2, is frequently detected in this neoplasm. To investigate the role of the FHIT abnormalities in the multistage sequential development of GBC, 33 formalin-fixed paraffin-embedded invasive GBC specimens and 76 accompanying histologically normal (n = 43) and dysplastic (n = 33) epithelia were examined by nostaining for expression of Fhit protein. Allele loss at the FHIT gene locus (3p14.2) was studied in all GBCs and in a subset of accompanying gallbladder epithelia by polymerase chain reaction-based LOH analysis, using three 3p14.2 microsatellite markers. In addition, histologically normal epithelium from chronic cholecystitis (n = 19) and dysplasia (it = 13) from gallbladder specimens without cancer were examined for immunostaining and LOH. There was a progressive increase in both the frequency of loss of Fhit expression and LOH at FHIT with increasing severity of histopathological changes. FHIT abnormalities were occasionally demonstrated in histologically normal gallbladder epithelium. Dysplastic foci demonstrated frequent reduction or absence of Fhit immunostaining (38 to 55%) and FHIT allelic loss (33 to 46%). In invasive tumors, these abnormalities were even higher, with 79% reduction or absence of Fhit immunostaining and 76% FHIT allele loss. A high correlation (70%) was observed between Fhit immunostaining abnormalities and allele loss in GBC specimens (P < 0.05). Although a high frequency of FHIT locus breakpoints; were detected in both invasive and dysplastic gallbladder specimens, no intronic homozygous deletions on FHIT were detected in GBCs. FHIT gene abnormalities are nearly universal in GBC and these changes are detected early in the sequential development of this neoplasm. Our findings indicate that the FHIT gene is one of the chromosome 3p putative tumor suppressor genes involved in the pathogenesis of this highly malignant neoplasm.
- ItemGPR43 stimulation on TCRαβ+ intraepithelial colonic lymphocytes inhibits the recruitment of encephalitogenic T-cells into the central nervous system and attenuates the development of autoimmunity(2023) Prado, Carolina; Espinoza, Alexandra; Martínez-Hernández, J. E.; Petrosino, Joseph; Riquelme Sánchez, Erick Marcelo; Martin, Alberto J. M.; Pacheco, RodrigoAbstract Introduction Gut microbiota plays a critical role in the regulation of immune homeostasis. Accordingly, several autoimmune disorders have been associated with dysbiosis in the gut microbiota. Notably, the dysbiosis associated with central nervous system (CNS) autoimmunity involves a substantial reduction of bacteria belonging to Clostridia clusters IV and XIVa, which constitute major producers of short-chain fatty acids (SCFAs). Here we addressed the role of the surface receptor-mediated effects of SCFAs on mucosal T-cells in the development of CNS autoimmunity. Methods To induce CNS autoimmunity, we used the mouse model of experimental autoimmune encephalomyelitis (EAE) induced by immunization with the myelin oligodendrocyte glycoprotein (MOG)-derived peptide (MOG35-55 peptide). To address the effects of GPR43 stimulation on colonic TCRαβ+ T-cells upon CNS autoimmunity, mucosal lymphocytes were isolated and stimulated with a selective GPR43 agonist ex vivo and then transferred into congenic mice undergoing EAE. Several subsets of lymphocytes infiltrating the CNS or those present in the gut epithelium and gut lamina propria were analysed by flow cytometry. In vitro migration assays were conducted with mucosal T-cells using transwells. Results Our results show a sharp and selective reduction of intestinal propionate at the peak of EAE development, accompanied by increased IFN-γ and decreased IL-22 in the colonic mucosa. Further analyses indicated that GPR43 was the primary SCFAs receptor expressed on T-cells, which was downregulated on colonic TCRαβ+ T-cells upon CNS autoimmunity. The pharmacologic stimulation of GPR43 increased the anti-inflammatory function and reduced the pro-inflammatory features in several TCRαβ+ T-cell subsets in the colonic mucosa upon EAE development. Furthermore, GPR43 stimulation induced the arrest of CNS-autoreactive T-cells in the colonic lamina propria, thus avoiding their infiltration into the CNS and dampening the disease development. Mechanistic analyses revealed that GPR43-stimulation on mucosal TCRαβ+ T-cells inhibits their CXCR3-mediated migration towards CXCL11, which is released from the CNS upon neuroinflammation. Conclusions These findings provide a novel mechanism involved in the gut-brain axis by which bacterial-derived products secreted in the gut mucosa might control the CNS tropism of autoreactive T-cells. Moreover, this study shows GPR43 expressed on T-cells as a promising therapeutic target for CNS autoimmunity.
- ItemGut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation(2024) Chandra, Vidhi; Li, Le; Le Roux, Olivereen; Zhang, Yu; Howell, Rian M.; Rupani, Dhwani N.; Baydogan, Seyda; Miller, Haiyan D.; Riquelme Sánchez, Erick Marcelo; Petrosino, Joseph; Kim, Michael P.; Bhat, Krishna P. L.; White, James R.; Kolls, Jay K.; Pylayeva-Gupta, Yuliya; McAllister, FlorenciaMicrobes influence cancer initiation, progression and therapy responsiveness. IL -17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL -17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL -17 signaling increases DUOX2 signaling in tumor cells. Inefficacy of pharmacological inhibition of IL-17RA is overcome with targeted microbial ablation that blocks the compensatory loop. These findings demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and the relevance for accounting for its homeostatic host defense function during cancer therapy.
- ItemMitochondrial DNA mutation at the D310 (displacement loop) mononucleotide sequence in the pathogenesis of gallbladder carcinoma(2004) Tang, Moying; Baez, S; Pruyas Arieda, Martha; Diaz, A; Calvo, A; Riquelme Sánchez, Erick Marcelo; Wistuba, Oyarzún IgnacioPurpose: Mutations in the mitochondrial DNA (mtDNA) have been observed frequently in human neoplasia, in both coding and noncoding regions. A mononucleotide repeat (poly-C) between 303 and 315 nucleotides (D310) within the regulatory displacement loop has been identified recently as a frequent hot spot of deletion/insertion mutations in tumors. We investigated the frequency and pattern of D310 abnormalities in the pathogenesis of gallbladder carcinoma (GBC). Experimental Design: DNA extracted from neoplastic and nonneoplastic archival gallbladder tissue including 123 tumors, 53 dysplastic areas, and 90 histologically normal epithelia adjacent to GBC, chronic cholecystitis, and 15 normal gallbladders were examined by PCR-based assay for D310 mutations, followed by sequencing in a subset of cases. Results: D310 mutation was a relatively frequent (47 of 123; 38%) abnormality in GBC. A very high frequency of mutations were detected in dysplastic (8 of 14; 57%) and normal-appearing gallbladder epithelia (10 of 22; 46%) accompanying GBC, showing a clonal relationship compared with the corresponding tumors. D310 mutations were also detected in dysplastic (8 of 39; 21%) and normal (17 of 68; 25%) epithelia obtained from chronic cholecystitis. A single case of 15 normal gallbladders showed a D310 abnormality. Overall, deletions (67 of 91; 74%) at D310 were more frequent than insertions. Conclusions: D310 mutation at the mtDNA displacement loop is a relatively frequent and early event in the sequential pathogenesis of GBC, being detected in normalappearing epithelium from chronic cholecystitis. Our findReceived 4/28/03; revised 11/3/03; accepted 11/4/03. Grant support: Grant FONDECYT (Fondo Nacional de Desarrollo Cientifico y Tecnologico) #1020960. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Ignacio I. Wistuba, Department of Pathology, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 85, Houston, TX 77030-4009. Phone: (713) 563-1659; Fax: (713) 7923184; E-mail: iiwistuba@mdanderson.org. ings suggest that mtDNA mutations should be additionally investigated in GBC pathogenesis, and D310 mononucleotide abnormalities could be included in a panel of molecular biomarkers for GBC early detection strategy.
- ItemRol patogénico del gen supresor de tumores PTEN en cáncer ovárico asociado a endometriosis(2006) Castiblanco Galvis, Adriana; Pires, Yumay; Wistuba Oyarzún, Ignacio; Riquelme Sánchez, Erick Marcelo; Andrade M., Leonardo; Corvalán R., AlejandroBackground: Endomeotrioid carcinoma and clear cell carcinoma of the ovary are associated to endometriosis. Somatic mutations of PTEN (10q23.3) are present in endothelial endometrioid carcinoma. Therefore, these mutations could be also present in ovarian tumors Molecular studies show that solitary endometriotic cysts are monoclonal, have aneuploid DNA, have a loss of 9p, 11q and 22q heterozygosity (LOH) and a higher cellular proliferation index of the epithelial component. Aim: To determine the cellular proliferation index using Ki 67, the immunohistochemical expression of PTEN and LOH in patients with ovarian endometriosis without atypia (EN), ovarian endometriosis with atypia (P-A) and endometriosis with adjacent ovarian carcinoma (0). Material and methods: Paraffin embedded samples of 37 endometrioid and clear cell carcinomas of the ovary (CC/CE), 15 solitary ovarian EN and 15 ovarian EA, were studied. Expression of Ki 67 and PTEN was measured by immunohistochemistry. LOH of 10q23-3 locus was measured by polymerase chain reaction. Results: Ki 67 was 5.5 and 23% in EA and EN, respectively (p < 0.005). There was a histological correlation between LA and a higher cellular proliferation index. PTEN was negative in 5 of 15 EN, 9 of 15 EA and 30 of 37 CE/CC. There was a correlation between LOH and loss of PTEN protein in EN, EA and ET(60%), Conclusions: Negative expression on PTEN in EN; EA; ET and CE/CC is a manifestation of the inactivation of this gene. The mechanisms that cause this inactivation, must be elucidated.
- ItemThe duration of TCR/pMHC interactions regulates CTL effector function and tumor-killing capacity(2009) Riquelme Sánchez, Erick Marcelo; Carreño Márquez, Leandro Javier; Kalergis Parra, Alexis Mikes