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1.
Nat Commun ; 15(1): 4514, 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38802491

RESUMEN

Knowledge on the distribution and dynamics of glycosylation enzymes in the Golgi is essential for better understanding this modification. Here, using a combination of CRISPR/Cas9 knockin technology and super-resolution microscopy, we show that the Golgi complex is assembled by a number of small 'Golgi units' that have 1-3 µm in diameter. Each Golgi unit contains small domains of glycosylation enzymes which we call 'zones'. The zones of N- and O-glycosylation enzymes are colocalised. However, they are less colocalised with the zones of a glycosaminoglycan synthesizing enzyme. Golgi units change shapes dynamically and the zones of glycosylation enzymes rapidly move near the rim of the unit. Photobleaching analysis indicates that a glycosaminoglycan synthesizing enzyme moves between units. Depletion of giantin dissociates units and prevents the movement of glycosaminoglycan synthesizing enzymes, which leads to insufficient glycosaminoglycan synthesis. Thus, we show the structure-function relationship of the Golgi and its implications in human pathogenesis.


Asunto(s)
Glicosaminoglicanos , Aparato de Golgi , Aparato de Golgi/metabolismo , Glicosilación , Humanos , Glicosaminoglicanos/metabolismo , Células HeLa , Sistemas CRISPR-Cas , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Matriz de Golgi
2.
Cancer Lett ; 582: 216509, 2024 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-38036042

RESUMEN

Lung cancer, primarily non-small-cell lung cancer (NSCLC), is a significant cause of cancer-related mortality worldwide. Cisplatin-based chemotherapy is a standard treatment for NSCLC; however, its effectiveness is often limited due to the development of resistance, leading to NSCLC recurrence. Thus, the identification of effective chemosensitizers for cisplatin is of paramount importance. The integrated stress response (ISR), activated by various cellular stresses and mediated by eIF2α kinases, has been implicated in drug sensitivity. ISR activation globally suppresses protein synthesis while selectively promoting the translation of ATF4 mRNA, which can induce pro-apoptotic proteins such as CHOP, ATF3, and TRIB3. To expedite and economize the development of chemosensitizers for cisplatin treatment in NSCLC, we employed a strategy to screen an FDA-approved drug library for ISR activators. In this study, we identified mifepristone as a potent ISR activator. Mifepristone activated the HRI/eIF2α/ATF4 axis, leading to the induction of pro-apoptotic factors, independent of its known role as a synthetic steroid. Our in vitro and in vivo models demonstrated mifepristone's potential to inhibit NSCLC re-proliferation following cisplatin treatment and tumor growth, respectively, via the ISR-mediated cell death pathway. These findings suggest that mifepristone, as an ISR activator, could enhance the efficacy of cisplatin-based therapy for NSCLC, highlighting the potential of drug repositioning in the search for effective chemosensitizers.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Cisplatino/farmacología , Cisplatino/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mifepristona/farmacología , Reposicionamiento de Medicamentos , Transducción de Señal , Línea Celular Tumoral , Resistencia a Antineoplásicos
3.
Cancer Sci ; 114(12): 4677-4690, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37781962

RESUMEN

To select the most suitable chelate for 225 Ac radiolabeling of the anti-FZD10 antibody OTSA101, we directly compared three chelates: S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2,2',2″-(10-(1-carboxy-4-((4-isothiocyanatobenzyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (p-SCN-Bn-DOTAGA), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DO3A-NHS-ester). We evaluated the binding affinity of the chelate-conjugated OTSA101 antibodies, as well as the labeling efficiency and stability in murine serum of 225 Ac-labeled OTSA101 as in vitro properties. The biodistribution, intratumoral distribution, absorbed doses, and therapeutic effects of the chelate-conjugated OTSA101 antibodies were assessed in the synovial sarcoma mouse model SYO-1. Of the three conjugates, DOTAGA conjugation had the smallest impact on the binding affinity (p < 0.01). The labeling efficiencies of DOTAGA-OTSA101 and DO3A-OTSA101 were 1.8-fold higher than that of DOTA-OTSA101 (p < 0.01). The stabilities were similar between 225 Ac-labeled DOTA-OTSA101, DOTAGA-OTSA101, and DO3A-OTSA101in serum at 37 and 4°C. The dosimetric analysis based on the biodistribution revealed significantly higher tumor-absorbed doses by 225 Ac-labeled DOTA-OTSA101 and DOTAGA-OTSA101 compared with 225 Ac-DO3A-OTSA101 (p < 0.05). 225 Ac-DOTAGA-OTSA101 exhibited the highest tumor-to-bone marrow ratio, with bone marrow being the dose-limiting tissue. The therapeutic and adverse effects were not significantly different between the three conjugates. Our findings indicate that among the three evaluated chelates, DOTAGA appears to be the most promising chelate to produce 225 Ac-labeled OTSA101 with high binding affinity and high radiochemical yields while providing high absorbed doses to tumors and limited absorbed doses to bone marrow.


Asunto(s)
Quelantes , Neoplasias , Animales , Ratones , Distribución Tisular , Quelantes/química , Ésteres
4.
Cell Rep ; 42(5): 112479, 2023 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-37178686

RESUMEN

CREB/ATF transcription factor OASIS/CREB3L1 is upregulated in long-term-cultured astrocytes undergoing cell-cycle arrest due to loss of DNA integrity by repeated replication. However, the roles of OASIS in the cell cycle remain unexplored. We find that OASIS arrests the cell cycle at G2/M phase after DNA damage via direct induction of p21. Cell-cycle arrest by OASIS is dominant in astrocytes and osteoblasts, but not in fibroblasts, which are dependent on p53. In a brain injury model, Oasis-/- reactive astrocytes surrounding the lesion core show sustained growth and inhibition of cell-cycle arrest, resulting in prolonged gliosis. We find that some glioma patients exhibit low expression of OASIS due to high methylation of its promoter. Specific removal of this hypermethylation in glioblastomas transplanted into nude mice by epigenomic engineering suppresses the tumorigenesis. These findings suggest OASIS as a critical cell-cycle inhibitor with potential to act as a tumor suppressor.


Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Proteína p53 Supresora de Tumor , Ratones , Animales , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Ratones Desnudos , Puntos de Control del Ciclo Celular , Factores de Transcripción Activadores/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo
5.
Cancer Med ; 12(8): 9668-9683, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36722116

RESUMEN

BACKGROUND: Synovial sarcoma (SS) has limited treatment options and there is an urgent need to develop a novel therapeutic strategy to treat SS. Blue light (BL) has been shown to inhibit the growth of several cancer cells. However, the efficacy of BL in soft tissue sarcomas such as SS has not been demonstrated, and the detailed mechanism underlying the antitumor activity of BL is not fully understood. In this study, we investigated the antitumor effect of BL on SS. METHODS: Human SS cell lines were continuously irradiated with BL using light-emitting diodes (LEDs) in an incubator for in vitro analysis. The chicken chorioallantoic membrane (CAM) tumors and xenograft tumors in mice were subjected to daily BL irradiation with LEDs. RESULTS: BL caused growth inhibition of SS cells and histological changes in CAM tumors. BL also suppressed the migration and invasion abilities of SS cells. The type of cell death in SS cells was revealed to be apoptosis. Furthermore, BL induced excessive production of reactive oxygen species (ROS) in mitochondria, resulting in oxidative stress and malfunctioned mitochondria. Reducing the production of ROS using N-acetylcysteine (NAC), a ROS scavenger, attenuated the inhibitory effect of BL on SS cells and mitochondrial dysfunction. In addition, BL induced autophagy, which was suppressed by the administration of NAC. The autophagy inhibitor of 3-methyladenine and small interfering RNA against the autophagy marker light chain 3B facilitated apoptotic cell death. Moreover, BL suppressed tumor growth in a mouse xenograft model. CONCLUSION: Taken together, our results revealed that BL induced apoptosis via the ROS-mitochondrial signaling pathway, and autophagy was activated in response to the production of ROS, which protected SS cells from apoptosis. Therefore, BL is a promising candidate for the development of an antitumor therapeutic strategy targeting SS.


Asunto(s)
Sarcoma Sinovial , Humanos , Ratones , Animales , Especies Reactivas de Oxígeno/metabolismo , Sarcoma Sinovial/terapia , Sarcoma Sinovial/patología , Apoptosis , Autofagia , Mitocondrias , Línea Celular Tumoral
6.
Nat Commun ; 14(1): 621, 2023 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-36739439

RESUMEN

DNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine with S-adenosyl-L-methionine. Methylation regulates gene expression, serving a variety of physiological and pathophysiological roles. The chemical mechanisms regulating DNMT enzymatic activity, however, are not fully elucidated. Here, we show that protein S-nitrosylation of a cysteine residue in DNMT3B attenuates DNMT3B enzymatic activity and consequent aberrant upregulation of gene expression. These genes include Cyclin D2 (Ccnd2), which is required for neoplastic cell proliferation in some tumor types. In cell-based and in vivo cancer models, only DNMT3B enzymatic activity, and not DNMT1 or DNMT3A, affects Ccnd2 expression. Using structure-based virtual screening, we discovered chemical compounds that specifically inhibit S-nitrosylation without directly affecting DNMT3B enzymatic activity. The lead compound, designated DBIC, inhibits S-nitrosylation of DNMT3B at low concentrations (IC50 ≤ 100 nM). Treatment with DBIC prevents nitric oxide (NO)-induced conversion of human colonic adenoma to adenocarcinoma in vitro. Additionally, in vivo treatment with DBIC strongly attenuates tumor development in a mouse model of carcinogenesis triggered by inflammation-induced generation of NO. Our results demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by NO, and DBIC protects against tumor formation by preventing aberrant S-nitrosylation of DNMT3B.


Asunto(s)
ADN (Citosina-5-)-Metiltransferasas , Epigénesis Genética , Animales , Humanos , Ratones , Transformación Celular Neoplásica/genética , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN , Metilasas de Modificación del ADN/metabolismo , ADN Metiltransferasa 3B
7.
Cancer Med ; 12(6): 6594-6602, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36345163

RESUMEN

The aldehyde degrading function of the ALDH2 enzyme is impaired by Glu504Lys polymorphisms (rs671, termed A allele), which causes alcohol flushing in east Asians, and elevates the risk of esophageal cancer among habitual drinkers. Recent studies suggested that the ALDH2 variant may lead to higher levels of DNA damage caused by endogenously generated aldehydes. This can be a threat to genome stability and/or cell viability in a synthetic manner in DNA repair-defective settings such as Fanconi anemia (FA). FA is an inherited bone marrow failure syndrome caused by defects in any one of so far identified 22 FANC genes including hereditary breast and ovarian cancer (HBOC) genes BRCA1 and BRCA2. We have previously reported that the progression of FA phenotypes is accelerated with the ALDH2 rs671 genotype. Individuals with HBOC are heterozygously mutated in either BRCA1 or BRCA2, and the cancer-initiating cells in these patients usually undergo loss of the wild-type BRCA1/2 allele, leading to homologous recombination defects. Therefore, we hypothesized that the ALDH2 genotypes may impact breast cancer development in BRCA1/2 mutant carriers. We genotyped ALDH2 in 103 HBOC patients recruited from multiple cancer centers in Japan. However, we were not able to detect any significant differences in clinical stages, histopathological classification, or age at clinical diagnosis across the ALDH2 genotypes. Unlike the effects in hematopoietic cells of FA, our current data suggest that there is no impact of the loss of ALDH2 function in cancer initiation and development in breast epithelium of HBOC patients.


Asunto(s)
Aldehído Deshidrogenasa Mitocondrial , Neoplasias de la Mama , Anemia de Fanconi , Femenino , Humanos , Aldehído Deshidrogenasa Mitocondrial/genética , Proteína BRCA1/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Pueblos del Este de Asia , Anemia de Fanconi/genética , Anemia de Fanconi/patología , Predisposición Genética a la Enfermedad , Mutación , Proteína BRCA2/genética
8.
Elife ; 112022 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-35042581

RESUMEN

In the thymus, the thymic epithelium provides a microenvironment essential for the development of functionally competent and self-tolerant T cells. Previous findings showed that modulation of Wnt/ß-catenin signaling in mouse thymic epithelial cells (TECs) disrupts embryonic thymus organogenesis. However, the role of ß-catenin in TECs for postnatal T-cell development remains to be elucidated. Here, we analyzed gain-of-function (GOF) and loss-of-function (LOF) of ß-catenin highly specific in mouse TECs. We found that GOF of ß-catenin in TECs results in severe thymic dysplasia and T-cell deficiency beginning from the embryonic period. By contrast, LOF of ß-catenin in TECs reduces the number of cortical TECs and thymocytes modestly and only postnatally. These results indicate that fine-tuning of ß-catenin expression within a permissive range is required for TECs to generate an optimal microenvironment to support postnatal T-cell development.


Asunto(s)
Células Epiteliales/metabolismo , Linfocitos T/metabolismo , Timo/metabolismo , beta Catenina/metabolismo , Animales , Femenino , Ratones
9.
Cancer Sci ; 113(2): 721-732, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34935247

RESUMEN

Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12-18 months. Frizzled homolog 10 (FZD10) is overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of ß-radioimmunotherapy (RIT) with the 90 Y-labeled anti-FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α-RIT with OTSA101 labeled with the α-emitter 225 Ac. Competitive inhibition and cell binding assays showed that specific binding of 225 Ac-labeled OTSA101 to SYO-1 synovial sarcoma cells was comparable to that of the imaging agent 111 In-labeled OTSA101. Biodistribution studies showed high uptake in SYO-1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of 225 Ac-labeled OTSA101 for tumors was 7.8 Bd higher than that of 90 Y-labeled OTSA101. 90 Y- and 225 Ac-labeled OTSA101 decreased tumor volume and prolonged survival. 225 Ac-labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. 225 Ac-labeled OTSA101 induced a larger amount of necrosis and apoptosis than 90 Y-labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment-related mortality or obvious toxicity, except for temporary body weight loss, was observed. 225 Ac-labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO-1. RIT with 225 Ac-labeled OTSA101 is a promising therapeutic option for synovial sarcoma.


Asunto(s)
Actinio/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Receptores Frizzled/antagonistas & inhibidores , Sarcoma Sinovial/radioterapia , Actinio/química , Actinio/farmacocinética , Partículas alfa/uso terapéutico , Animales , Anticuerpos Monoclonales Humanizados/química , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacocinética , Línea Celular Tumoral , Receptores Frizzled/inmunología , Receptores Frizzled/metabolismo , Humanos , Ratones , Radioinmunoterapia , Dosificación Radioterapéutica , Inducción de Remisión , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patología , Distribución Tisular/efectos de la radiación , Carga Tumoral/efectos de la radiación , Ensayos Antitumor por Modelo de Xenoinjerto , Radioisótopos de Itrio/química , Radioisótopos de Itrio/farmacocinética , Radioisótopos de Itrio/uso terapéutico
10.
iScience ; 24(7): 102758, 2021 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-34355142

RESUMEN

Derlin family members (Derlins) are primarily known as components of the endoplasmic reticulum-associated degradation pathway that eliminates misfolded proteins. Here we report a function of Derlins in the brain development. Deletion of Derlin-1 or Derlin-2 in the central nervous system of mice impaired postnatal brain development, particularly of the cerebellum and striatum, and induced motor control deficits. Derlin-1 or Derlin-2 deficiency reduced neurite outgrowth in vitro and in vivo and surprisingly also inhibited sterol regulatory element binding protein 2 (SREBP-2)-mediated brain cholesterol biosynthesis. In addition, reduced neurite outgrowth due to Derlin-1 deficiency was rescued by SREBP-2 pathway activation. Overall, our findings demonstrate that Derlins sustain brain cholesterol biosynthesis, which is essential for appropriate postnatal brain development and function.

11.
Cancer Sci ; 112(10): 4208-4219, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34363714

RESUMEN

Previous studies reported the critical role of the brefeldin A-inhibited guanine nucleotide exchange protein 3-prohibitin 2 (BIG3-PHB2) complex in modulating estrogen signaling activation in breast cancer cells, yet its pathophysiological roles in osteosarcoma (OS) cells remain elusive. Here, we report a novel function of BIG3-PHB2 in OS malignancy. BIG3-PHB2 complexes were localized mainly in mitochondria in OS cells, unlike in estrogen-dependent breast cancer cells. Depletion of endogenous BIG3 expression by small interfering RNA (siRNA) treatment led to significant inhibition of OS cell growth. Disruption of BIG3-PHB2 complex formation by treatment with specific peptide inhibitor also resulted in significant dose-dependent suppression of OS cell growth, migration, and invasion resulting from G2/M-phase arrest and in PARP cleavage, ultimately leading to PARP-1/apoptosis-inducing factor (AIF) pathway activation-dependent apoptosis in OS cells. Subsequent proteomic and bioinformatic pathway analyses revealed that disruption of the BIG3-PHB2 complex might lead to downregulation of inner mitochondrial membrane protein complex activity. Our findings indicate that the mitochondrial BIG3-PHB2 complex might regulate PARP-1/AIF pathway-dependent apoptosis during OS cell proliferation and progression and that disruption of this complex may be a promising therapeutic strategy for OS.


Asunto(s)
Neoplasias Óseas/patología , Proliferación Celular/fisiología , Supervivencia Celular/fisiología , Factores de Intercambio de Guanina Nucleótido/fisiología , Mitocondrias/metabolismo , Osteosarcoma/patología , Proteínas Represoras/fisiología , Animales , Apoptosis/fisiología , Factor Inductor de la Apoptosis/metabolismo , Neoplasias Óseas/metabolismo , Neoplasias Óseas/terapia , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Péptidos de Penetración Celular/farmacología , Bases de Datos Factuales , Regulación hacia Abajo , Puntos de Control de la Fase G2 del Ciclo Celular , Silenciador del Gen , Factores de Intercambio de Guanina Nucleótido/efectos de los fármacos , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Puntos de Control de la Fase M del Ciclo Celular , Proteínas de la Membrana/metabolismo , Ratones , Ratones Desnudos , Membranas Mitocondriales/metabolismo , Invasividad Neoplásica , Trasplante de Neoplasias , Osteosarcoma/metabolismo , Osteosarcoma/terapia , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Prohibitinas , ARN Interferente Pequeño/metabolismo , Proteínas Represoras/efectos de los fármacos , Proteínas Represoras/metabolismo
12.
J Hum Genet ; 66(9): 927-935, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34285339

RESUMEN

Breast cancer is a heterogeneous disease that develops through a multistep process via the accumulation of genetic/epigenetic alterations in various cancer-related genes. Current treatment options for breast cancer patients include surgery, radiotherapy, and chemotherapy including conventional cytotoxic and molecular-targeted anticancer drugs for each intrinsic subtype, such as endocrine therapy and antihuman epidermal growth factor receptor 2 (HER2) therapy. However, these therapies often fail to prevent recurrence and metastasis due to resistance. Overall, understanding the molecular mechanisms of breast carcinogenesis and progression will help to establish therapeutic modalities to improve treatment. The recent development of comprehensive omics technologies has led to the discovery of driver genes, including oncogenes and tumor-suppressor genes, contributing to the development of molecular-targeted anticancer drugs. Here, we review the development of anticancer drugs targeting cancer-specific functional therapeutic targets, namely, MELK (maternal embryonic leucine zipper kinase), TOPK (T-lymphokine-activated killer cell-originated protein kinase), and BIG3 (brefeldin A-inhibited guanine nucleotide-exchange protein 3), as identified through comprehensive breast cancer transcriptomics.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Descubrimiento de Drogas , Genómica , Neoplasias de la Mama/genética , Femenino , Humanos
13.
Nat Genet ; 52(7): 669-679, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32514122

RESUMEN

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.


Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad/etnología , Variación Genética , Humanos , Patrón de Herencia , Japón , Masculino , Factores Sexuales , Factores de Transcripción/genética
14.
Int J Oncol ; 56(2): 581-595, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31894262

RESUMEN

Polypeptide N­acetylgalactosaminyltransferase 6 (GALNT6), which is involved in the initiation of O­glycosylation, has been reported to play crucial roles in mammary carcinogenesis through binding to several substrates; however, its biological roles in mediating growth­promoting effects remain unknown. The present study demonstrated a crucial pathophysiological role of GALNT6 through its O­glycosylation of lectin galactoside­binding soluble 3 binding protein (LGALS3BP), a secreted growth­promoting glycoprotein, in breast cancer growth. The Cancer Genome Atlas data analysis revealed that high expression levels of GALNT6 were significantly associated with poor prognosis of breast cancer. GALNT6 O­glycosylated LGALS3BP in breast cancer cells, whereas knockdown of GALNT6 by siRNA led to the inhibition of both the O­glycosylation and secretion of LGALS3BP, resulting in the suppression of breast cancer cell growth. Notably, LGALS3BP is potentially O­glycosylated at three sites (T556, T571 and S582) by GALNT6, thereby promoting autocrine cell growth, whereas the expression of LGALS3BP with three Ala substitutions (T556A, T571A and S582A) in cells drastically reduced GALNT6­dependent LGALS3BP O­glycosylation and secretion, resulting in suppression of autocrine growth­promoting effect. The findings of the present study suggest that the GALNT6­LGALS3BP axis is crucial for breast cancer cell proliferation and may be a therapeutic target and biomarker for mammary tumors.


Asunto(s)
Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , N-Acetilgalactosaminiltransferasas/metabolismo , Sustitución de Aminoácidos , Antígenos de Neoplasias/genética , Comunicación Autocrina , Biomarcadores de Tumor/genética , Mama/patología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Proliferación Celular/genética , Conjuntos de Datos como Asunto , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Glicosilación , Humanos , N-Acetilgalactosaminiltransferasas/genética , ARN Interferente Pequeño/metabolismo , Polipéptido N-Acetilgalactosaminiltransferasa
15.
Cancer Sci ; 111(1): 209-218, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31724785

RESUMEN

Analysis of anticancer immunity aids in assessing the prognosis of patients with breast cancer. From 250 operated breast cancers, we focused on serum levels of C-C motif chemokine ligand 5 (CCL5), which is involved in cancer immune reactions. Serum levels of CCL5 were measured using a cytometric bead-based immunoassay kit and CCL5 expression in cancer cells was determined using immunohistochemical staining. In addition, mRNA in cancer and stromal cells was analyzed by microdissection and comparison with the public dataset. Disease-free survival (DFS) of patients with high CCL5 levels (cut-off, 13.87 ng/mL; n = 192) was significantly better than those with low CCL5 levels (n = 58; hazard ratio, 0.20; 95% confidence interval, 0.10-0.39; P < .0001). An improved overall survival was observed in patients with high CCL5 levels compared to those with low CCL5 levels (P = .024). On the contrary, high immunohistochemical expression of CCL5 in cancer cells was significantly associated with decreased DFS. As serum CCL5 levels did not correlate with CCL5 expression in cancer cells and the relative expression of mRNA CCL5 was elevated in stromal cells in relation to cancer cells, serum CCL5 might be derived not from cancer cells, but from stromal cells. Expression of CCL5 in serum, but not in cancer cells, might contribute to improved patient prognosis mediating through not only immune reaction, but through other mechanisms. Determination of circulating CCL5 levels could be useful for predicting patient prognosis.


Asunto(s)
Neoplasias de la Mama/sangre , Neoplasias de la Mama/mortalidad , Quimiocina CCL5/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , ARN Mensajero/metabolismo
16.
Sci Rep ; 9(1): 17332, 2019 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-31757997

RESUMEN

Genome-wide association studies (GWAS) have successfully identified about 70 genomic loci associated with breast cancer. Owing to the complexity of linkage disequilibrium and environmental exposures in different populations, it is essential to perform regional GWAS for better risk prediction. This study aimed to investigate the genetic architecture and to assess common genetic risk model of breast cancer with 6,669 breast cancer patients and 21,930 female controls in the Japanese population. This GWAS identified 11 genomic loci that surpass genome-wide significance threshold of P < 5.0 × 10-8 with nine previously reported loci and two novel loci that include rs9862599 on 3q13.11 (ALCAM) and rs75286142 on 21q22.12 (CLIC6-RUNX1). Validation study was carried out with 981 breast cancer cases and 1,394 controls from the Aichi Cancer Center. Pathway analyses of GWAS signals identified association of dopamine receptor medicated signaling and protein amino acid deacetylation with breast cancer. Weighted genetic risk score showed that individuals who were categorized in the highest risk group are approximately 3.7 times more likely to develop breast cancer compared to individuals in the lowest risk group. This well-powered GWAS is a representative study to identify SNPs that are associated with breast cancer in the Japanese population.


Asunto(s)
Neoplasias de la Mama/genética , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple , Antígenos CD/genética , Estudios de Casos y Controles , Moléculas de Adhesión Celular Neuronal/genética , Canales de Cloruro/genética , Mapeo Cromosómico , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Proteínas Fetales/genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Humanos , Japón , Desequilibrio de Ligamiento
17.
Cell Rep ; 29(9): 2901-2916.e6, 2019 11 26.
Artículo en Inglés | MEDLINE | ID: mdl-31775054

RESUMEN

The thymic function to produce self-protective and self-tolerant T cells is chiefly mediated by cortical thymic epithelial cells (cTECs) and medullary TECs (mTECs). Recent studies including single-cell transcriptomic analyses have highlighted a rich diversity in functional mTEC subpopulations. Because of their limited cellularity, however, the biochemical characterization of TECs, including the proteomic profiling of cTECs and mTECs, has remained unestablished. Utilizing genetically modified mice that carry enlarged but functional thymuses, here we show a combination of proteomic and transcriptomic profiles for cTECs and mTECs, which identified signature molecules that characterize a developmental and functional contrast between cTECs and mTECs. Our results reveal a highly specific impact of the thymoproteasome on proteasome subunit composition in cTECs and provide an integrated trans-omics platform for further exploration of thymus biology.


Asunto(s)
Células Epiteliales/metabolismo , Proteómica/métodos , Timo/fisiopatología , Diferenciación Celular , Humanos
18.
Anticancer Res ; 39(9): 5009-5018, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31519608

RESUMEN

BACKGROUND/AIM: Interleukin (IL)-18, which belongs to the IL-1 superfamily of cytokines, is a known interferon-gamma (IFN-γ)-inducing factor. Since IFN-γ plays an essential role in anticancer immunity mediated through cytotoxic T cells, IL-18 may also contribute to the function of immunosurveillance. The aim of the study was to examine the association of IL-18 with the outcomes of patients with breast cancer. PATIENTS AND METHODS: Serum IL-18 levels were determined at baseline in 270 patients operated for breast cancer, and the relapse-free survival (RFS) was compared between IL-18-high and -low groups. The relationships between IL-18 and tumor-infiltrating lymphocytes (TILs) or the neutrophil-to-lymphocyte ratio (NLR) were also investigated. RESULTS: The RFS of patients was significantly better in the IL-18-low group than in the IL-18-high group (p=0.032). According to the multivariate analysis, IL-18 was a significant and independent predictive factor for RFS (hazard ratio(HR)=0.336; 95% confidence interval(CI)=0.147-0.727; p=0.0053). No association was observed between the IL-18 levels and TILs or NLRs. CONCLUSION: IL-18 levels may be useful for predicting the prognosis of patients who have received surgical treatment for breast cancer.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama/sangre , Neoplasias de la Mama/mortalidad , Interleucina-18/sangre , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Citocinas/sangre , Citocinas/metabolismo , Femenino , Humanos , Recuento de Leucocitos , Recuento de Linfocitos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neutrófilos/inmunología , Neutrófilos/metabolismo , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROC , Valores de Referencia , Estudios Retrospectivos , Carga Tumoral
19.
Biochem Biophys Res Commun ; 518(1): 183-189, 2019 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-31421830

RESUMEN

Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) interacts with and inhibits the tumor suppressor function of prohibitin-2 (PHB2), and recent in vivo studies have demonstrated that the BIG3-PHB2 interaction is a promising target for breast cancer therapy. However, little biophysical characterization on BIG3 and its interaction with PHB2 has been reported. Here we compared the calculated 8-class secondary structure of the N-terminal domains of BIG family proteins and identified a loop region unique to BIG3. Our biophysical characterization demonstrated that this loop region significantly affects the colloidal and thermodynamic stability of BIG3 and the thermodynamic and kinetic profile of its interaction with PHB2. These results establish a model for the BIG3-PHB2 interaction and an entry for drug discovery for breast cancer.


Asunto(s)
Fenómenos Biofísicos , Neoplasias de la Mama/metabolismo , Secuencia Conservada , Factores de Intercambio de Guanina Nucleótido/química , Factores de Intercambio de Guanina Nucleótido/metabolismo , Proteínas Represoras/metabolismo , Secuencia de Aminoácidos , Coloides/química , Femenino , Humanos , Cinética , Modelos Biológicos , Prohibitinas , Unión Proteica , Dominios Proteicos , Estabilidad Proteica , Estructura Secundaria de Proteína , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Temperatura
20.
Nat Commun ; 9(1): 4083, 2018 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-30287823

RESUMEN

Pathogenic variants in highly penetrant genes are useful for the diagnosis, therapy, and surveillance for hereditary breast cancer. Large-scale studies are needed to inform future testing and variant classification processes in Japanese. We performed a case-control association study for variants in coding regions of 11 hereditary breast cancer genes in 7051 unselected breast cancer patients and 11,241 female controls of Japanese ancestry. Here, we identify 244 germline pathogenic variants. Pathogenic variants are found in 5.7% of patients, ranging from 15% in women diagnosed <40 years to 3.2% in patients ≥80 years, with BRCA1/2, explaining two-thirds of pathogenic variants identified at all ages. BRCA1/2, PALB2, and TP53 are significant causative genes. Patients with pathogenic variants in BRCA1/2 or PTEN have significantly younger age at diagnosis. In conclusion, BRCA1/2, PALB2, and TP53 are the major hereditary breast cancer genes, irrespective of age at diagnosis, in Japanese women.


Asunto(s)
Neoplasias de la Mama/genética , Mutación de Línea Germinal , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad
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