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Canine urothelial carcinoma (cUC) is one of the most malignant tumors affecting dogs; however, its proliferative mechanism is yet to be fully elucidated. The ubiquitin-proteasome system (UPS) is an important metabolic pathway regulating protein degradation, and its dysfunction leads to apoptosis. We investigated the antitumor effect of the proteasome inhibitor bortezomib, which blocks the UPS. Bortezomib inhibited cell growth in cUC cell lines by inducing apoptosis in vitro. These findings suggest the potential of bortezomib as a novel therapeutic drug for dogs with cUC.
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BACKGROUND AND AIMS: EUS-guided fine-needle biopsy (EUS-FNB) performed with a Franseen needle or Fork-tip needle enables greater tissue acquisition. However, it is unknown whether EUS-FNB could contribute to lymphadenopathy genomic profiling. The aim of this study was to determine the efficacy of EUS-FNB using a Franseen or Fork-tip needle for tissue acquisition and genomic profiling in patients with lymphadenopathy. PATIENTS AND METHODS: Patients with abdominal lymphadenopathy who underwent EUS-guided fine needle aspiration (FNA)/EUS-FNB were included in this study. The amount of acquired tissue and its suitability for genomic profiling were compared between FNA and FNB. Specimen quality was evaluated by a widely used pathologic adequacy scoring system (0: insufficient; 1 to 2: cytologic; 3: limited histologic; 4 to 5: sufficient histologic). The criteria of FoundationOne CDx (F1CDx) and NCC Oncopanel (NOP) were used to assess the suitability for genomic profiling. RESULTS: In total, 72 patients underwent EUS-FNA, and the other 20 patients underwent EUS-FNB. The pathologic adequacy score and suitability for genomic profiling based on the criteria were significantly higher for FNB than for FNA [histologic adequacy score: 5 (4 to 5) versus 3 (0 to 5), P<0.01; F1CDx: 16.7% vs. 0%, P=0.01; NOP: 66.7% vs. 7.5%, P<0.01]. In multivariate analysis, EUS-FNB was identified as the only factor that influenced the suitability for genomic profiling based on the above-mentioned criteria (odds ratio 19.5, 95% CI: 3.74-102, P<0.01). CONCLUSIONS: EUS-FNB performed using Franseen or Fork-tip needles may result in greater lymphadenopathy tissue acquisition and thus enhanced suitability for genomic profiling compared with EUS-FNA.
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The classification of clonal plasmacytoid dendritic cell (pDC) proliferation associated with myeloid neoplasms remains a topic of ongoing debate. Although the fifth edition of the World Health Organization classification classifies clonal pDC proliferation into two categories, it is unclear whether this classification adequately captures the complexities of clonal pDC pathogenesis. We present a clinical case featuring myeloid sarcoma with pDC-like cells in cervical lymph nodes and bone marrow (BM). Analysis of biopsy specimens and BM aspirate revealed two distinct cellular populations expressing myeloid and pDC markers. One population exhibited myeloid leukemia and monocyte markers, including MPO, CD13, CD33, CD11b, and CD14, while the other manifested an immunophenotype reminiscent of pDCs, characterized by expression of CD56 and CD123. Additionally, whole exome sequencing and RNA sequencing of BM mononuclear cells were conducted to explore the pathophysiology of this rare malignancy, and unveiled pDC-like cell proliferation driven by IKZF1 and ETV6 mutations originating from clonal hematopoiesis initiated by a DNMT3A mutation. Notably, venetoclax-based therapy exhibited efficacy for achieving and sustaining complete remission. This case provides pivotal insights into the mechanistic aspects of pDC/pDC-like cell proliferation in myeloid sarcoma, offering valuable perspectives on therapeutic strategies.
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Proliferación Celular , ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3A , Células Dendríticas , Factor de Transcripción Ikaros , Mutación , Proteínas Represoras , Sarcoma Mieloide , Humanos , Sarcoma Mieloide/genética , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/patología , Factor de Transcripción Ikaros/genética , ADN Metiltransferasa 3A/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Células Dendríticas/patología , Proteínas Represoras/genética , Masculino , Persona de Mediana Edad , FemeninoRESUMEN
Methotrexate (MTX) is a well-known agent that can potentially cause lymphoproliferative disorder (LPD), known as MTX-related LPD (MTX-LPD). Only two cases of thyroid MTX-LPD have been reported to date. This study aimed to report 11 cases of MTX-LPDs arising in the thyroid gland and discuss their clinicopathological characteristics. Of the 747 patients with cytologically suspected lymphoma, 11 had received MTX. The mean age of the patients with MTX-LPD was 70.2 years (range: 51-82 years), and all were female. The duration of MTX administration ranged from 5 to 31 years (mean: 19.5 years). Nine patients (81.8 %) tested positive for anti-thyroglobulin antibody and/or anti-thyroid peroxidase antibody. In three patients, the tumor decreased in size or disappeared without surgery or chemotherapy after withdrawal of MTX therapy. Histologically, all eight nodules examined were B-cell lymphomas, and seven were mucosa-associated lymphoid tissue (MALT) lymphomas. Epstein-Barr virus-encoded small RNA in situ hybridization showed negative results for all six nodules examined. All five patients who were followed-up at our hospital exhibited progression-free survival for >3 years without chemotherapy. Six patients were transferred to other hospitals, and their follow-up details are unknown. MTX-LPDs occurring in the thyroid are characterized by a high female predominance, positivity for anti-thyroid autoantibodies, high prevalence of MALT lymphomas, negativity for Epstein-Barr virus, and good outcomes without chemotherapy. We recommend that patients with thyroid lymphoma should be checked for a history of MTX.
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An 81-year-old woman who underwent laparoscopic-assisted low anterior resection with instrumented anastomosis using the double stapling technique for rectal cancer 5 years ago was found to have an enlarged anastomotic mass on computed tomography. On colonoscopy, the anastomotic mass was observed as a 30-mm-sized subepithelial lesion, which was presumed to be the submucosa on endoscopic ultrasonography (EUS). EUS-guided fine-needle aspiration was performed; however, no cellular components were collected. Therefore, endoscopic submucosal dissection (ESD) was performed to remove the entire anastomotic mass. However, any lesion in the submucosa was not detected during ESD, and the lesion was suspected to be located deeper than the submucosa. Therefore, EUS was performed from the muscule layer just below the dissected submucosa, and the mass was detected outside the muscle layer in contact with the rectal wall. Upon endoscopic incision of the muscle layer, milky white mucus was excreted into the rectal lumen. Subsequently, the scope was advanced to an area outside the muscle layer where the mass was located, which was a closed lumen with mucus retention. Surface biopsy of the closed lumen revealed normal colonic mucosa. Therefore, the subepithelial lesion was diagnosed as an implantation cyst arising outside the rectal wall.
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Endosonografía , Humanos , Femenino , Anciano de 80 o más Años , Endosonografía/métodos , Quistes/cirugía , Quistes/diagnóstico por imagen , Neoplasias del Recto/cirugía , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/patología , Resección Endoscópica de la Mucosa/métodos , Enfermedades del Recto/cirugía , Enfermedades del Recto/diagnóstico por imagen , Enfermedades del Recto/patología , Miotomía/métodosRESUMEN
AIM: Ovarian serous carcinoma (OSC) and ovarian clear cell carcinoma (OCCC) are two major histological types of epithelial ovarian carcinoma (EOC), each with different biological features and clinical behaviors. Although immunostaining is commonly used for differential diagnosis between OSC and OCCC, correct identification of EOC with mixed-type histology is sometimes a diagnostic challenge. The aim of the present study was to explore candidate genes as potential diagnostic biomarkers that distinguish OSC from OCCC. METHODS: A total of 57 surgical specimens were obtained from EOC patients who had previously undergone primary debulking surgery. Total RNAs were extracted from fresh-frozen tissues of EOC patients, and were used for comprehensive gene expression analysis using DNA microarray technology. RESULTS: Ten candidate genes, FXYD2, TMEM101, GABARAPL1, ARG2, GLRX, RBPMS, GDF15, PPP1R3B, TOB1, and GSTM3 were up-regulated in OCCC compared to OSC. All EOC patients were divided into two groups according to hierarchical clustering using a 10-gene signature. CONCLUSION: Our data suggest that the 10 candidate genes would be an excellent marker for distinguishing OSC from OCCC. Furthermore, the molecular signatures of the 10 genes may enlighten us on the differences in carcinogenesis, and provide a theoretical basis for OCCC's resistance to chemotherapy in the future.
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Adenocarcinoma de Células Claras , Cistadenocarcinoma Seroso , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patología , Persona de Mediana Edad , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Anciano , Diagnóstico Diferencial , Perfilación de la Expresión Génica , Adulto , Biomarcadores de Tumor/genéticaRESUMEN
Little is known about the perioperative complications and treatment outcomes of repairing perineal hernias using semitendinosus muscle transposition (SMT) in small-breed dogs. The objective of this study was to retrospectively evaluate the complications and prognosis of perineal hernia repair using SMT in 33 small, male dogs (weighing < 15 kg). Before the study began, the medical records of all small-breed dogs that underwent SMT from March 2013 to June 2022 at the Veterinary Medical Center, University of Tokyo were analyzed, and telephone interviews were conducted with their owners or referring physicians. Short-term complications were observed in 42.4% of the patients. Lameness was the most common complication, although all cases were resolved within a few days. The recurrence rate during the study period (median: 265 d) was 9.1%. The results of this study showed that transposition of the semitendinosus muscle is more invasive than other surgical procedures for perineal hernias. It is, however, an effective alternative when repair with internal obturator muscle transposition alone is expected to be difficult, such as severe atrophy of the internal obturator muscle or herniation in the ventral direction, and in cases with a history of surgery by transposition of the internal obturator muscle.
On sait peu de choses sur les complications peropératoires et les résultats du traitement de la réparation des hernies périnéales à l'aide de la transposition du muscle semi-tendineux (SMT) chez les chiens de petite race. L'objectif de cette étude était d'évaluer rétrospectivement les complications et le pronostic de la réparation d'une hernie périnéale par SMT chez 33 petits chiens mâles (pesant < 15 kg). Avant le début de l'étude, les dossiers médicaux de tous les chiens de petite race ayant subi une SMT de mars 2013 à juin 2022 au Veterinary Medical Center de l'Université de Tokyo ont été analysés et des entrevues téléphoniques ont été menées avec leurs propriétaires ou médecins vétérinaires référents. Des complications à court terme ont été observées chez 42,4 % des patients. La boiterie était la complication la plus courante, bien que tous les cas aient été résolus en quelques jours. Le taux de récidive au cours de la période d'étude (médiane: 265 jours) était de 9,1 %. Les résultats de cette étude ont démontré que la transposition du muscle semi-tendineux est plus invasive que les autres interventions chirurgicales pour les hernies périnéales. Il s'agit cependant d'une alternative efficace lorsque la réparation par transposition du muscle obturateur interne seul s'annonce difficile, comme une atrophie sévère du muscle obturateur interne ou une hernie dans le sens ventral, et dans les cas d'antécédents chirurgicaux par transposition du muscle obturateur interne.(Traduit par Docteur Serge Messier).
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Enfermedades de los Perros , Músculos Isquiosurales , Animales , Perros , Masculino , Enfermedades de los Perros/cirugía , Hernia/veterinaria , Perineo/cirugía , Estudios RetrospectivosRESUMEN
Idiopathic pulmonary arterial hypertension is a progressive and life-threatening disease with pulmonary vasculature remodeling, leading to right-sided heart failure. Epoprostenol (prostaglandin I2) is highly recommended for patients with severe pulmonary arterial hypertension (PAH) categorized by the World Health Organization as functional class III or IV. It has been reported that prostaglandin I2 analogs can cause thyroid gland swelling and abnormal thyroid function. A 34-year-old woman was diagnosed with idiopathic pulmonary arterial hypertension and started receiving continuous intravenous epoprostenol. Three years after starting epoprostenol, she began complaining of neck swelling and was diagnosed with Graves' disease. The patient's thyroid function was controlled by thiamazole and levothyroxine; nevertheless, her thyroid gland enlargement worsened as the epoprostenol dose was titrated. After 20 years, she developed respiratory failure with a giant goiter leading to airway stenosis, and she passed away. The pathological autopsy confirmed a massive goiter associated with hyperthyroidism and airway stenosis. We experienced a case of idiopathic pulmonary hypertension with a giant goiter and airway stenosis after long-term intravenous epoprostenol therapy.
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UHRF proteins catalyze the ubiquitination of target proteins and are involved in regulating gene expression. Some studies reported a reduced expression of UHRF2 in acute leukemia cells, but the role of UHRF2 in hematopoiesis remains unknown. Here, we generated Uhrf2-/- mice to clarify the role of UHRF2 deletion in hematopoiesis. Compared to Uhrf2+/+ mice, Uhrf2-/- mice showed no differences in complete blood counts, as well as bone marrow (BM) findings and spleen weights. Proportions of cells in progenitor fractions in BM were comparable between Uhrf2+/+ mice and Uhrf2-/- mice. However, in competitive repopulation assays with BM transplants (BMT), the proportions of Uhrf2-/- cells were decreased relative to Uhrf2+/+ cells in all lineages. After the second BMT, Uhrf2-/- neutrophils were few, while 20-30% of Uhrf2-/- T cells and B cells were still detected. RNA sequencing showed downregulation of some genes associated with stem-cell function in Uhrf2-/- hematopoietic stem/progenitor cells (HSPCs). Interestingly, trimethylated histone H3 lysine 9 was increased in Uhrf2-/- HSPCs in a cleavage under targets and tagmentation assay. While UHRF2 deletion did not cause hematologic malignancy or confer a growth advantage of HSPCs, our results suggest that UHRF2 may play a role in the regulation of hematopoiesis.
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Linfocitos B , Células Madre Hematopoyéticas , Animales , Ratones , Bioensayo , Catálisis , Regulación hacia AbajoRESUMEN
Gliomas are the most prevalent primary tumor of the central nervous system. Despite advances in imaging technologies, neurosurgical techniques, and radiotherapy, a cure for high-grade glioma remains elusive. Several groups have reported that protein tyrosine phosphatase receptor type Z (PTPRZ) is highly expressed in glioblastoma, and that targeting PTPRZ attenuates tumor growth in mice. PTPRZ is modified with diverse glycan, including the PTPRZ-unique human natural killer-1 capped O-mannosyl core M2 glycans. However, the regulation and function of these unique glycans are unclear. Using CRISPR genome-editing technology, we first demonstrated that disruption of the PTPRZ gene in human glioma LN-229 cells resulted in profoundly reduced tumor growth in xenografted mice, confirming the potential of PTPRZ as a therapeutic target for glioma. Furthermore, multiple glycan analyses revealed that PTPRZ derived from glioma patients and from xenografted glioma expressed abundant levels of human natural killer-1-capped O-Man glycans via extrinsic signals. Finally, since deficiency of O-Man core M2 branching enzyme N-acetylglucosaminyltransferase IX (GnT-IX) was reported to reduce PTPRZ protein levels, we disrupted the GnT-IX gene in LN-229 cells and found a significant reduction of glioma growth both in vitro and in the xenograft model. These results suggest that the PTPR glycosylation enzyme GnT-IX may represent a promising therapeutic target for glioma.
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Glioma , N-Acetilglucosaminiltransferasas , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores , Animales , Humanos , Ratones , Encéfalo/enzimología , Encéfalo/fisiopatología , Glioma/fisiopatología , N-Acetilglucosaminiltransferasas/genética , N-Acetilglucosaminiltransferasas/metabolismo , Polisacáridos/metabolismo , Línea Celular Tumoral , Femenino , Ratones SCID , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/deficiencia , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/metabolismo , Técnicas de Silenciamiento del GenRESUMEN
Podoplanin (PDPN) is a prognostic factor and is involved in several mechanisms of tumor progression in human squamous cell carcinoma (SCC). Canine non-tonsillar SCC (NTSCC) is a common oral tumor in dogs and has a highly invasive characteristic. In this study, we investigated the function of PDPN in canine NTSCC. In canine NTSCC clinical samples, PDPN overexpression was observed in 80% of dogs with NTSCC, and PDPN expression was related to ki67 expression. In PDPN knocked-out canine NTSCC cells, cell proliferation, cancer stemness, and migration were suppressed. As the mechanism of PDPN-mediated cell proliferation, PDPN knocked-out induced apoptosis and G2/M cell cycle arrest in canine NTSCC cells. These findings suggest that PDPN promotes tumor malignancies and may be a novel biomarker and therapeutic target for canine NTSCC.
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Carcinoma de Células Escamosas , Enfermedades de los Perros , Animales , Perros , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/veterinaria , Proliferación Celular , BiomarcadoresRESUMEN
Mucosal melanoma metastasizes at an early stage of the disease in human and dog. We revealed that overexpression of podoplanin in tumor invasion fronts (IF) was related to poor prognosis of dogs with mucosal melanoma. Moreover, podoplanin expressed in canine mucosal melanoma cells promotes proliferation and aggressive amoeboid invasion by activating Rho-associated kinase (ROCK)-myosin light chain 2 (MLC2) signaling. PDPN-ROCK-MLC2 signaling plays a role in cell-cycle arrest and cellular senescence escape as a mechanism for regulating proliferation. Podoplanin induces amoeboid invasion in the IFs of mouse xenografted tumor tissues, similar to canine mucosal melanoma clinical samples. We further identified that podoplanin expression was related to poor prognosis of human patients with mucosal melanoma, and human mucosal melanoma with podoplanin-high expression enriched gene signatures related to amoeboid invasion, similar to canine mucosal melanoma. Overall, we propose that podoplanin promotes canine and human mucosal melanoma metastasis by inducing aggressive amoeboid invasion and naturally occurring canine mucosal melanoma can be a novel research model for podoplanin expressing human mucosal melanoma. IMPLICATIONS: Podoplanin could be a new therapeutic target to restrict the metastatic dissemination of canine and human mucosal melanoma.
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Amoeba , Melanoma , Humanos , Perros , Animales , Ratones , Melanoma/patología , Factores de Transcripción , Transducción de Señal , Línea Celular TumoralRESUMEN
High-grade B-cell lymphoma with 11q aberrations (HGBL-11q) has been classified for the first time as a high-grade mature B-cell neoplasm according to the 5th edition of the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. HGBL-11q is morphologically and immunohistochemically similar to Burkitt lymphoma (BL) or HGBL; it is characterized by gain in the 11q23.2-11q23.3 region and loss in the 11q24.1-qter region but it lacks MYC translocation. HGBL-11q is a rare tumor, and its exact frequency in Japan remains unclear. In this study, we classified 113 Germinal center B-cell (GCB) type aggressive B-cell lymphomas (BCLs), which were divided into BL, high-grade (HG), and large cell (LC) morphologies. We performed fluorescence in situ hybridization (FISH) to identify 11q aberrations. Nine patients had 11q aberrations (7.96%, 9/113), including six HGBL-11q. The age range was from 8 to 87 years, and all were male. Six out of 14 patients with HG morphology were diagnosed with HGBL-11q (6/14, 42.9%). HGBL-11q has been found to occur primarily in children and young adults but also in middle-aged and older adults. Patients with HG morphology without MYC translocation should undergo FISH for 11q aberrations regardless of age. However, the pathogenesis, clinical findings, and prognosis of HGBL-11q remain unclear. The accumulation of cases with an accurate HGBL-11q diagnosis in daily practice and accurate and detailed data on HGBL-11q will contribute to further understanding of 11q aberrations.
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Linfoma de Burkitt , Aberraciones Cromosómicas , Masculino , Humanos , Femenino , Hibridación Fluorescente in Situ , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/genética , Translocación Genética , JapónRESUMEN
We previously identified the AKT-phosphorylation sites in nuclear receptors and showed that phosphorylation of S379 in mouse retinoic acid γ and S518 in human estrogen receptor α regulate their activity independently of the ligands. Since this site is conserved at S510 in human liver receptor homolog 1 (hLRH1), we developed a monoclonal antibody (mAb) that recognized the phosphorylation form of hLRH1S510 (hLRH1pS510) and verified its clinicopathological significance in hepatocellular carcinoma (HCC). We generated the anti-hLRH1pS510 mAb and assessed its selectivity. We then evaluated the hLRH1pS510 signals in 157 cases of HCC tissues by immunohistochemistry because LRH1 contributes to the pathogenesis of diverse cancers. The developed mAb specifically recognized hLRH1pS510 and worked for immunohistochemistry of formalin-fixed paraffin-embedded tissues. hLRH1pS510 was exclusively localized in the nucleus of HCC cells, but the signal intensity and positive rates varied among the subjects. According to the semi-quantification, 45 cases (34.9%) showed hLRH1pS510-high, and the remaining 112 cases (65.1%) exhibited hLRH1pS510-low. There were significant differences in the recurrence-free survival (RFS) between the two groups, and the 5-year RFS rates in the hLRH1pS510-high and hLRH1pS510-low groups were 26.5% and 46.1%, respectively. In addition, high hLRH1pS510 was significantly correlated with portal vein invasion, hepatic vein invasion, and high levels of serum alpha-fetoprotein (AFP). Furthermore, multivariable analysis revealed that hLRH1pS510-high was an independent biomarker for HCC recurrence. We conclude that aberrant phosphorylation of hLRH1S510 is a predictor of poor prognosis for HCC. The anti-hLRH1pS510 mAb could provide a powerful tool to validate the relevance of hLRH1pS510 in pathological processes such as tumor development and progression.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , alfa-Fetoproteínas/metabolismo , Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Fosforilación , Pronóstico , Serina , HumanosRESUMEN
BACKGROUND: Ovarian cancer has the worst outcome among gynecological malignancies; therefore, biomarkers that could contribute to the early diagnosis and/or prognosis prediction are urgently required. In the present study, we focused on the secreted protein spondin-1 (SPON1) and clarified the prognostic relevance in ovarian cancer. METHODS: We developed a monoclonal antibody (mAb) that selectively recognizes SPON1. Using this specific mAb, we determined the expression of SPON1 protein in the normal ovary, serous tubal intraepithelial carcinoma (STIC), and ovarian cancer tissues, as well as in various normal adult tissues by immunohistochemistry, and verified its clinicopathological significance in ovarian cancer. RESULTS: The normal ovarian tissue was barely positive for SPON1, and no immunoreactive signals were detected in other healthy tissues examined, which was in good agreement with data obtained from gene expression databases. By contrast, upon semi-quantification, 22 of 242 ovarian cancer cases (9.1%) exhibited high SPON1 expression, whereas 64 (26.4%), 87 (36.0%), and 69 (28.5%) cases, which were designated as SPON1-low, possessed the moderate, weak, and negative SPON1 expression, respectively. The STIC tissues also possessed SPON1-positive signals. The 5-year recurrence-free survival (RFS) rate in the SPON1-high group (13.6%) was significantly lower than that in the SPON1-low group (51.2%). In addition, high SPON1 expression was significantly associated with several clinicopathological variables. Multivariable analysis revealed that high SPON1 was an independent prognostic factor for RFS of ovarian cancer. CONCLUSIONS: SPON1 represents a prognostic biomarker for ovarian cancer, and the anti-SPON1 mAb could be valuable as an outcome predictor.
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Cistadenocarcinoma Seroso , Neoplasias de las Trompas Uterinas , Neoplasias Ováricas , Adulto , Femenino , Humanos , Neoplasias Ováricas/genética , Pronóstico , Cistadenocarcinoma Seroso/patología , Neoplasias de las Trompas Uterinas/patología , Biomarcadores , Biomarcadores de Tumor/metabolismoRESUMEN
Astrocytes are the most abundant glial cell type in the brain, where they participate in various homeostatic functions. Transcriptomically, diverse astrocyte subpopulations play distinct roles during development and disease progression. However, the biochemical identification of astrocyte subtypes, especially by membrane surface protein glycosylation, remains poorly investigated. Protein tyrosine phosphatase receptor type zeta (PTPRZ) is a highly expressed membrane protein in CNS glia cells that can be modified with diverse glycosylation, including the unique HNK-1 capped O-mannosyl (O-Man) core M2 glycan mediated by brain-specific branching enzyme GnT-IX. Although PTPRZ modified with HNK-1 capped O-Man glycans (HNK-1-O-Man+ PTPRZ) is increased in reactive astrocytes of demyelination model mice, whether such astrocytes emerge in a broad range of disease-associated conditions or are limited to conditions associated with demyelination remains unclear. Here, we show that HNK-1-O-Man+ PTPRZ localizes in hypertrophic astrocytes of damaged brain areas in patients with multiple sclerosis. Furthermore, we show that astrocytes expressing HNK-1-O-Man+ PTPRZ are present in two demyelination mouse models (cuprizone-fed mice and a vanishing white matter disease model), while traumatic brain injury does not induce glycosylation. Administration of cuprizone to Aldh1l1-eGFP and Olig2KICreER/+ ;Rosa26eGFP mice revealed that cells expressing HNK-1-O-Man+ PTPRZ are derived from cells in the astrocyte lineage. Notably, GnT-IX but not PTPRZ mRNA was up-regulated in astrocytes isolated from the corpus callosum of cuprizone model mice. These results suggest that the unique PTPRZ glycosylation plays a key role in the patterning of demyelination-associated astrocytes.
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Astrocitos , Enfermedades Desmielinizantes , Animales , Ratones , Astrocitos/metabolismo , Encéfalo/metabolismo , Cuprizona/toxicidad , Cuprizona/metabolismo , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/genética , Modelos Animales de Enfermedad , Glicosilación , Ratones Endogámicos C57BL , Polisacáridos/metabolismo , Proteínas Tirosina Fosfatasas/metabolismoRESUMEN
BACKGROUND: Cell adhesion is indispensable for appropriate tissue architecture and function in multicellular organisms. Besides maintaining tissue integrity, cell adhesion molecules, including tight-junction proteins claudins (CLDNs), exhibit the signaling abilities to control a variety of physiological and pathological processes. However, it is still fragmentary how cell adhesion signaling accesses the nucleus and regulates gene expression. METHODS: By generating a number of knockout and rescued human breast cell lines and comparing their phenotypes, we determined whether and how CLDN4 affected breast cancer progression in vitro and in vivo. We also identified by RNA sequencing downstream genes whose expression was altered by CLDN4-adhesion signaling. Additionally, we analyzed by RT-qPCR the CLDN4-regulating genes by using a series of knockout and add-back cell lines. Moreover, by immunohistochemistry and semi-quantification, we verified the clinicopathological significance of CLDN4 and the nuclear receptor LXRß (liver X receptor ß) expression in breast cancer tissues from 187 patients. RESULTS: We uncovered that the CLDN4-adhesion signaling accelerated breast cancer metabolism and progression via LXRß. The second extracellular domain and the carboxy-terminal Y197 of CLDN4 were required to activate Src-family kinases (SFKs) and the downstream AKT in breast cancer cells to promote their proliferation. Knockout and rescue experiments revealed that the CLDN4 signaling targets the AKT phosphorylation site S432 in LXRß, leading to enhanced cell proliferation, migration, and tumor growth, as well as cholesterol homeostasis and fatty acid metabolism, in breast cancer cells. In addition, RT-qPCR analysis showed the CLDN4-regulated genes are classified into at least six groups according to distinct LXRß- and LXRßS432-dependence. Furthermore, among triple-negative breast cancer subjects, the "CLDN4-high/LXRß-high" and "CLDN4-low and/or LXRß-low" groups appeared to exhibit poor outcomes and relatively favorable prognoses, respectively. CONCLUSIONS: The identification of this machinery highlights a link between cell adhesion and transcription factor signalings to promote metabolic and progressive processes of malignant tumors and possibly to coordinate diverse physiological and pathological events.