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PURPOSE: To investigate the role and mechanism of connexin 43ï¼Cx43ï¼in odontoblast differentiation of human dental pulp cells (hDPCs) induced by lipopolysaccharide (LPS). METHODS: The maxillary first molar injury model of SD rats was established. The expression pattern of Cx43 in dental pulp repair after injury was detected by immunofluorescence(IF) staining. hDPCs was respectively stimulated with 0, 1, 10, 100 and 1 000 ng/mL LPS for 6 h to screen the optimal concentration, and then the expression of Cx43 was inhibited and overexpressed in hDPCs. Quantitative real-time PCR(qRT-PCR) and Western blot(WB) were used to detect the expression of Cx43 and dentin sialophosphoprotein (DSPP), dental matrix protein-1 (DMP-1), osterix (Osx) and extracellular signal-regulated kinase (ERK) activity. Furthermore, hDPCs were treated with specific Cx43 channel inhibitors to investigate the effect of Cx43-mediated channel activity in odontoblast differentiation of hDPCs, and to explore the role and mechanism of Cx43 in regulating odontoblast differentiation of hDPCs induced by LPS. Statistical analysis was performed with SPSS 26.0 software package. RESULTS: IF results showed that Cx43 was mainly expressed in the odontoblast layer in healthy dental pulp tissues. At 3-24 h after tooth injury, the expression of Cx43 decreased and then gradually increased to the normal level; from 3 days to 2 weeks after injury, the expression of Cx43 tended to be down-regulated which was in the odontoblast layer and pulp proper. The expression of DSPP mRNA was significantly up-regulated in the hDPCs stimulated with 10 ng/mL LPS for 6 h(Pï¼0.01). Inhibition of Cx43 significantly up-regulated the expression of DSPP, DMP-1 and Osx mRNA induced by LPS in hDPCs(Pï¼0.05), while overexpression of Cx43 obviously inhibited the expression of factors related to LPS-induced odontoblast differentiation(Pï¼0.01) and the fluorescence intensity of DSPP. 10 ng/mL LPS activated ERK signal in hDPCs, and overexpression of Cx43 significantly attenuated the activity of ERK signal induced by LPS(Pï¼0.01). Inhibition of Cx43-mediated hemichannel (HC) promoted mRNA expression of factors related to odontoblast differentiation in hDPCs and the activity of ERK signal induced by LPS(Pï¼0.05), while blocking Cx43-mediated gap junction channel (GJC) inhibited odontoblast differentiation. CONCLUSIONS: Cx43 participates in the regulation of dental pulp repair after injury, and its expression shows a downward trend as a whole. Inhibition of Cx43 or blocking of HC promotes LPS-induced ERK signal activity and odontoblast differentiation of hDPCs.
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Conexina 43 , Lipopolisacáridos , Animales , Humanos , Ratas , Diferenciación Celular/fisiología , Células Cultivadas , Conexina 43/metabolismo , Pulpa Dental/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Lipopolisacáridos/farmacología , Lipopolisacáridos/metabolismo , Odontoblastos/metabolismo , Ratas Sprague-Dawley , ARN Mensajero/metabolismoRESUMEN
Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H+ mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade.
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Carcinoma Hepatocelular , Carnosina , Neoplasias Hepáticas , Humanos , Homeostasis , Lisosomas , Hipoxia , Concentración de Iones de Hidrógeno , Microambiente TumoralRESUMEN
OBJECTIVE: Although endoscopic drill has the advantages in manipulation and hemostasis, whose low efficiency and blurred vision reduce the efficacy of lumbar endoscopic unilateral laminotomy with bilateral decompression (LE-ULBD). The present study was designed to evaluate the safety and efficacy of full-visualized trephine/osteotome in the LE-ULBD surgery for severe lumbar stenosis. METHODS: Fifty-seven severe lumbar stenosis patients who underwent LE-ULBD between January 2020 to January 2023 were enrolled, who were divided into drill and visualized trephine groups. The medical records including demographics, operative duration, intraoperative electrophysiological findings, postoperative hospital stay or hospital stay, postoperative outcomes and complications were retrospectively reviewed and analyzed. RESULTS: A total of 57 patients included 15 in drill and 42 in trephine group were enrolled in the study. There was significant difference in the pre- and postoperative visual analogue scale and Oswestry Disability Index scores in both groups (p < 0.05). The mean operative duration in the trephine group (101.05 ± 12.18 minutes) was shorter than that in the drill group (134.67 ± 9.68 minutes) (p < 0.05). There was no statistical difference between the 2 groups in electrophysiological monitoring, posthospital stays, postoperative outcomes and complications. Abnormal free-electromyography (EMG) were recorded in 2 (13.3%) and 5 patients (11.9%) in the drill and trephine group. Intraoperative somatosensory evoked potential changes occurred in 3 (20%) and 3 patients (7.1%) in the drill and trephine group and all patients recovered immediately when surgery ended. No serious complications and recurrence occurred in all the patients. CONCLUSION: Full-visualized trephine/osteotome has been approved to be convenient, safe and efficient in our study, which combined with translaminar inside-out technique and EMG monitoring especially free-EMG may offer a new choice in LE-ULBD surgery for lumbar stenosis patients.
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BACKGROUND: Ganglioglioma is a rare, slowly proliferating mixed glioneuronal tumor, with the highest incidence observed in children and young adults, but it can also occur in adults. OBJECTIVE: This study aimed to compare the imaging characteristics of ganglioglioma in children/adolescents and adults to facilitate radiographic diagnosis. METHODS: In this retrospective study, a total of 32 patients were included and divided into two groups: the child/adolescent group (age < 18 years, n=19) and the adult group (age ≥ 18 years, n=13). Various variables were analyzed, including maximum diameter, location, periphery, border, calcification, unenhanced CT attenuation, T1WI, T2WI/FLAIR, and DWI signal intensity, enhancement pattern, degree of enhancement, homogeneity of enhancement, solid/cystic component, peri-tumoral edema, intra-tumoral septa, peri-tumoral capsule, and intra-tumoral hemorrhage. RESULTS: Most gangliogliomas were situated in the peripheral regions, particularly in the temporal lobe. The majority exhibited hypointense/isointense signals on T1WI and hyperintense signals on T2WI/FLAIR and DWI, with predominantly heterogeneous nodular enhancement. Peri-tumoral edema was significantly less frequent in the child/adolescent group, while marked enhancement was significantly more common in the adult group. There was no significant difference in maximum diameter between the child/adolescent group and the adult group. CONCLUSION: Peri-tumoral edema was significantly less prevalent in the child/adolescent group, whereas marked enhancement was significantly more frequent in the adult group. To ensure accurate results, a larger case series should be conducted to validate our findings.
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Tumor metabolic reprogramming and epigenetic modification work together to promote tumorigenesis and development. Protein lysine acetylation, which affects a variety of biological functions of proteins, plays an important role under physiological and pathological conditions. Here, through immunoprecipitation and mass spectrum data, we show that phosphoglycerate mutase 5 (PGAM5) deacetylation enhances malic enzyme 1 (ME1) metabolic enzyme activity to promote lipid synthesis and proliferation of liver cancer cells. Mechanistically, we demonstrate that the deacetylase SIRT2 mediates PGAM5 deacetylation to activate ME1 activity, leading to ME1 dephosphorylation, subsequent lipid accumulation and the proliferation of liver cancer cells. Taken together, our study establishes an important role for the SIRT2-PGAM5-ME1 axis in the proliferation of liver cancer cells, suggesting a potential innovative cancer therapy.
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Neoplasias Hepáticas , Sirtuina 2 , Humanos , Sirtuina 2/genética , Sirtuina 2/metabolismo , Metabolismo de los Lípidos , Fosfoglicerato Mutasa/genética , Fosfoglicerato Mutasa/metabolismo , Proliferación Celular , Lípidos , Acetilación , Fosfoproteínas Fosfatasas/metabolismo , Proteínas Mitocondriales/metabolismoRESUMEN
Branched-chain amino acid (BCAA) catabolism is related to tumorigenesis. However, the underlying mechanism and specific contexts in which BCAAs affect tumor progression remain unclear. Here, we demonstrate that BCAA catabolism is activated in liver cancer cells without glutamine. Enhanced BCAA catabolism leads to BCAA-derived carbon and nitrogen flow toward nucleotide synthesis, stimulating cell-cycle progression and promoting cell survival. Mechanistically, O-GlcNAcylation increases under glutamine-deprivation conditions and stabilizes the PPM1K protein, leading to dephosphorylation of BCKDHA and enhanced decomposition of BCAAs. Dephosphorylation of BCKDHA and high expression of PPM1K promote tumorigenesis in vitro and in vivo and are closely related to the poor prognosis of clinical patients with hepatocellular carcinoma (HCC). Inhibition of BCAA and glutamine metabolism can further retard HCC growth in vivo. These results not only elucidate a mechanism by which BCAA catabolism affects tumorigenesis but also identify pBCKDHA and PPM1K as potential therapeutic targets and predictive biomarkers.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Glutamina/metabolismo , Aminoácidos de Cadena Ramificada/metabolismo , CarcinogénesisRESUMEN
Phosphoglycerate dehydrogenase (PHGDH) is a key serine biosynthesis enzyme whose aberrant expression promotes various types of tumors. Recently, PHGDH has been found to have some non-canonical functions beyond serine biosynthesis, but its specific mechanisms in tumorigenesis remain unclear. Here, we show that PHGDH localizes to the inner mitochondrial membrane and promotes the translation of mitochondrial DNA (mtDNA)-encoded proteins in liver cancer cells. Mechanistically, we demonstrate that mitochondrial PHGDH directly interacts with adenine nucleotide translocase 2 (ANT2) and then recruits mitochondrial elongation factor G2 (mtEFG2) to promote mitochondrial ribosome recycling efficiency, thereby promoting mtDNA-encoded protein expression and subsequent mitochondrial respiration. Moreover, we show that treatment with a mitochondrial translation inhibitor or depletion of mtEFG2 diminishes PHGDH-mediated tumor growth. Collectively, our findings uncover a previously unappreciated function of PHGDH in tumorigenesis acting via promotion of mitochondrial translation and bioenergetics.
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Neoplasias Hepáticas , Fosfoglicerato-Deshidrogenasa , Humanos , Fosfoglicerato-Deshidrogenasa/genética , Fosfoglicerato-Deshidrogenasa/metabolismo , Línea Celular Tumoral , Serina , Neoplasias Hepáticas/genética , Carcinogénesis , ADN MitocondrialRESUMEN
BACKGROUND: A radicular groove is an anatomic malformation that usually initiates at the central fossa, extending along the root at varying lengths and depths and predisposes the involved tooth to a severe periodontal defect. Severe grooves that extend to the root apex often lead to complex combined periodontal-endodontic lesions. They are a serious challenge for doctors to diagnose and treat. CASE SUMMARY: In this report, we described a patient with a maxillary lateral incisor with a deep palatogingival groove with two roots, which led to complex combined periodontal-endodontic lesions. Suggested treatment modalities included curettage of the affected tissues, elimination of the groove by grinding and/or sealing with a variety of filling materials, and surgical procedures. In this case, a combination of endodontic therapy, intentional replantation, and root resection were used, which resulted in periodontal/periradicular healing after 12 mo. CONCLUSION: Intentional replantation and root resection offer a predictable procedure and should be considered a viable treatment modality for the management of palatogingival grooves, especially for two-rooted teeth.
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Somatic symptom disorder (SSD), which occurs in about 5-7 percent of the adult population, involves heightened physical and emotional sensitivity to pain. However, its neural mechanism remains elusive and thus hinders effective clinical intervention. In this study, we employed chronic restraint stress (CRS)-induced hyperalgesia as a mouse model to investigate the neural mechanism underlying SSD and its pharmacological treatment. We found that CRS induced hyperactivity of anterior cingulate cortex (ACC), whereas chemogenetic inhibition of such hyperactivity could prevent CRS-induced hyperalgesia. Systematic application and ACC local infusion of fluoxetine alleviated CRS-induced hyperalgesia. Moreover, we found that fluoxetine exerted its anti-hyperalgesic effects through inhibiting the hyperactivity of ACC and upregulating 5-HT1A receptors. Our study thus uncovers the functional role of 5-HT signaling in modulating pain sensation and provides a neural basis for developing precise clinical intervention for SSD.
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Fluoxetina , Hiperalgesia , Animales , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Giro del Cíngulo , Hiperalgesia/tratamiento farmacológico , Ratones , Dolor/tratamiento farmacológico , SerotoninaRESUMEN
Aims: Subarachnoid hemorrhage (SAH) is a devastating stroke subtype. Following SAH, erythrocyte lysis contributes to cell death and brain injuries. Blockage of the anti-phagocytic receptor Cluster of Differentiation 47 (CD47) enhances phagocyte clearance of erythrocytes, though it has not been well-studied post-SAH. The current study aims to determine whether anti-CD47 treatment can enhance blood clearance after experimental SAH. Methods: The prechiasmatic blood injection model of SAH was used in mice. Mice were either treated with the CD47-blocking antibody or IgG as control. The effect of the anti-CD47 antibody on blood clearance and neurological function following SAH was determined. Neuroinflammation and neuronal injury were compared between the treatment and control samples on day 1 and day 7 after SAH using flow cytometry, immunofluorescence, Fluoro-Jade C, and Nissl staining, RT-PCR, and Western blot analysis. Results: CD47-blocking antibody sped-up blood clearance after SAH, and resulted in less neuronal injury and neurological deficits than control samples. Microglia played a role in the anti-CD47 blockade. Following SAH Following SAH, CD47 antibody-treated mice had less neuroinflammation and lower levels of apoptosis compared to controls and both one and 7 days. Conclusions: CD47 antibody treatment has a neuroprotective effect following SAH, by increasing blood clearance rate and reducing brain injury. These findings suggest CD47 antibody treatment may improve SAH patient outcomes.
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Lesiones Encefálicas , Fármacos Neuroprotectores , Hemorragia Subaracnoidea , Animales , Anticuerpos Bloqueadores/farmacología , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/etiología , Antígeno CD47/metabolismo , Ratones , Microglía/metabolismo , Fármacos Neuroprotectores/farmacología , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/metabolismoRESUMEN
α-Enolase 1 (ENO1) is a critical glycolytic enzyme whose aberrant expression drives the pathogenesis of various cancers. ENO1 has been indicated as having additional roles beyond its conventional metabolic activity, but the underlying mechanisms and biological consequences remain elusive. Here, we show that ENO1 suppresses iron regulatory protein 1 (IRP1) expression to regulate iron homeostasis and survival of hepatocellular carcinoma (HCC) cells. Mechanistically, we demonstrate that ENO1, as an RNA-binding protein, recruits CNOT6 to accelerate the messenger RNA decay of IRP1 in cancer cells, leading to inhibition of mitoferrin-1 (Mfrn1) expression and subsequent repression of mitochondrial iron-induced ferroptosis. Moreover, through in vitro and in vivo experiments and clinical sample analysis, we identified IRP1 and Mfrn1 as tumor suppressors by inducing ferroptosis in HCC cells. Taken together, this study establishes an important role for the ENO1-IRP1-Mfrn1 pathway in the pathogenesis of HCC and reveals a previously unknown connection between this pathway and ferroptosis, suggesting a potential innovative cancer therapy.
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Carcinoma Hepatocelular , Ferroptosis , Proteína 1 Reguladora de Hierro/metabolismo , Neoplasias Hepáticas , Biomarcadores de Tumor , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Ferroptosis/genética , Humanos , Hierro/metabolismo , Proteína 1 Reguladora de Hierro/genética , Neoplasias Hepáticas/genética , Fosfopiruvato Hidratasa/genética , ARN Mensajero/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
OBJECTIVES: Pediatric trigeminal neuralgia has been rarely reported in the literature, which were only 28 cases. Although microvascular decompression (MVD) has been widely accepted as effective therapy for trigeminal neuralgia, the etiology and surgical treatment of pediatric ones are seldom addressed. We report our experience with MVD for pediatric trigeminal neuralgia patients with emphasis on the vascular conflict patterns and surgical skills. METHODS: This retrospective report included 11 pediatric TN patients, who underwent MVD and were followed for 3-86 months. The data were retrospectively analyzed with emphasis on the clinical features. RESULTS: This series included 4 boys and 7 girls with average age of 13 ± 3.4 years old, their onset age were from 7 to 18 years old. The singular vein and combined artery/vein conflictions account for 7/11. 9 (81.8%) patients achieved immediate excellent outcomes. One recurrence was observed after 5 months and refused the second surgery. CONCLUSIONS: The etiology of pediatric onset trigeminal neuralgia is still vascular conflict, whose patterns are different from adults, of which combined artery/vein and singular venous compression patterns have a much more higher proportion. Because of the smaller operative space and fragile-thin venous wall with adhesion to other structures, it is much more difficult to decompress the trigeminal nerve among pediatric patients. Sufficient arachnoid release, full exploration, and decompression along the trigeminal nerve were necessary, which will increase the excellent rate among pediatric patients.
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Cirugía para Descompresión Microvascular , Neuralgia del Trigémino , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Estudios Retrospectivos , Resultado del Tratamiento , Neuralgia del Trigémino/etiología , Neuralgia del Trigémino/cirugía , VenasRESUMEN
The goal of this paper was to report a new variant of oesophageal atresia: an H-type congenital tracheo-oesophageal fistula associated with oesophageal segmental stenosis distal to the fistula. Although symptoms were present from birth, we did not differentiate the new anatomical variant preoperatively. The patient was treated by fistula ligation, segmental resection of the distal oesophagus and end-to-end anastomosis of the oesophagus by thoracoscopic surgery. Here we describe the clinical history and management of the newborn infant, together with diagnostic recommendations to prevent misdiagnosis in the management of this condition.
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Atresia Esofágica , Estenosis Esofágica , Fístula Traqueoesofágica , Anastomosis Quirúrgica , Atresia Esofágica/complicaciones , Atresia Esofágica/diagnóstico por imagen , Atresia Esofágica/cirugía , Estenosis Esofágica/diagnóstico por imagen , Estenosis Esofágica/etiología , Estenosis Esofágica/cirugía , Humanos , Lactante , Recién Nacido , Toracoscopía , Fístula Traqueoesofágica/diagnóstico por imagen , Fístula Traqueoesofágica/etiología , Fístula Traqueoesofágica/cirugíaRESUMEN
OBJECTIVE: The aim of the present study was to evaluate the efficacy and safety of microvascular decompression (MVD) for primary hemifacial spasm (HFS) in patients aged ≥70 years and to compare the outcome with a control cohort of younger patients(<70 years). METHODS: In this retrospective study, subjects were divided into two groups: an elderly group (patients who were ≥70 years) and a younger group. We compared demographic and clinical data, surgical outcome, MVD-related complications, and duration of operation and hospitalization after MVD between the two groups. RESULTS: At a mean follow-up of 32 ± 4.2 months, 188 elderly patients (90.4%) reported an effective outcome without need for any medication versus 379 (91.1%) of the younger cohort. There was no mortality in both cohorts. The prevalence of delayed facial palsy was 4.8% in the elderly group and 4.1% in the younger group. One (0.5%) patient in the elderly group and 3 (0.7%) patients in the younger group suffered cerebrospinal fluid (CSF) leakage. There was no significant difference between the two groups in terms of MVD-related complications, such as delayed facial palsy, hearing impairment, CSF leakage, and hematoma. CONCLUSIONS: MVD is an effective treatment option in elderly patients with HFS as well as in younger patients. Age itself seems to be no relevant contraindication or, alternatively, risk factor regarding MVD.
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Parálisis Facial , Espasmo Hemifacial , Cirugía para Descompresión Microvascular , Anciano , Parálisis Facial/etiología , Espasmo Hemifacial/etiología , Espasmo Hemifacial/cirugía , Humanos , Cirugía para Descompresión Microvascular/métodos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Microvascular decompression (MVD) has become accepted as an effective therapeutic option for hemifacial spasm (HFS); however, the curative rate of MVD for HFS varies widely (50-98%) in different medical centers. This study could contribute to the improvement of the MVD procedure. METHODS: We retrospectively analyzed 32 patients in whom initial MVD failed in other hospitals and who underwent a second MVD at our center. The clinical characteristics, operative findings, outcome of the second MVD, and complications were recorded. RESULTS: There were 18 women and 14 men (56.3 and 43.7%, respectively). The left-to-right ratio was 19:13. The mean age of the patients was 59.8 years. We found an undiscovered conflict site located in zone 4 in 10 patients and in the root entry zone in 8 patients. The initial MVD failed in nine patients because of ignorance of the arterioles that originate from the anterior inferior cerebellar artery. There were no special findings in four patients. No Teflon felts were found in the whole surgical field in one patient. CONCLUSION: Omission of the offending vessel is the most common cause of an unsuccessful MVD. Intraoperative abnormal muscle response associated with the Z-L response is a good measure to correctly identify the involved arterioles.
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Espasmo Hemifacial , Cirugía para Descompresión Microvascular , Arteria Basilar/cirugía , Femenino , Espasmo Hemifacial/etiología , Espasmo Hemifacial/cirugía , Humanos , Masculino , Cirugía para Descompresión Microvascular/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Metastasis is responsible for the majority of breast cancer-related deaths, however, the mechanisms underlying metastasis in this disease remain largely elusive. Here we report that under hypoxic conditions, alternative splicing of MBD2 is suppressed, favoring the production of MBD2a, which facilitates breast cancer metastasis. Specifically, MBD2a promoted, whereas its lesser known short form MBD2c suppressed metastasis. Activation of HIF1 under hypoxia facilitated MBD2a production via repression of SRSF2-mediated alternative splicing. As a result, elevated MBD2a outcompeted MBD2c for binding to promoter CpG islands to activate expression of FZD1, thereby promoting epithelial-to-mesenchymal transition and metastasis. Strikingly, clinical data reveal significantly correlated expression of MBD2a and MBD2c with the invasiveness of malignancy, indicating opposing roles for MBD2 splicing variants in regulating human breast cancer metastasis. Collectively, our findings establish a novel link between MBD2 switching and tumor metastasis and provide a promising therapeutic strategy and predictive biomarkers for hypoxia-driven breast cancer metastasis. SIGNIFICANCE: This study defines the opposing roles and clinical relevance of MBD2a and MBD2c, two MBD2 alternative splicing products, in hypoxia-driven breast cancer metastasis. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/5/1265/F1.large.jpg.
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Empalme Alternativo , Neoplasias de la Mama/patología , Proteínas de Unión al ADN/genética , Receptores Frizzled/genética , Animales , Neoplasias de la Mama/genética , Línea Celular Tumoral , Movimiento Celular/genética , Islas de CpG , Transición Epitelial-Mesenquimal/genética , Femenino , Receptores Frizzled/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones Desnudos , MicroARNs/genética , Regiones Promotoras Genéticas , Factores de Empalme Serina-Arginina/genética , Hipoxia Tumoral/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The MYC oncoprotein activates and represses gene expression in a transcription-dependent or transcription-independent manner. Modification of mRNA emerges as a key gene expression regulatory nexus. We sought to determine whether MYC alters mRNA modifications and report here that MYC promotes cancer progression by down-regulating N6-methyladenosine (m6 A) preferentially in transcripts of a subset of MYC-repressed genes (MRGs). We find that MYC activates the expression of ALKBH5 and reduces m6 A levels in the mRNA of the selected MRGs SPI1 and PHF12. We also show that MYC-regulated m6 A controls the translation of MRG mRNA via the specific m6 A reader YTHDF3. Finally, we find that inhibition of ALKBH5, or overexpression of SPI1 or PHF12, effectively suppresses the growth of MYC-deregulated B-cell lymphomas, both in vitro and in vivo. Our findings uncover a novel mechanism by which MYC suppresses gene expression by altering m6 A modifications in selected MRG transcripts promotes cancer progression.
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Desmetilasa de ARN, Homólogo 5 de AlkB , Neoplasias , Adenosina , Desmetilasa de ARN, Homólogo 5 de AlkB/genética , Desmetilasa de ARN, Homólogo 5 de AlkB/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/genética , ARN Mensajero/genéticaRESUMEN
The transcriptional role of cMyc (or Myc) in tumorigenesis is well appreciated; however, it remains to be fully established how extensively Myc is involved in the epigenetic regulation of gene expression. Here, we show that by deactivating succinate dehydrogenase complex subunit A (SDHA) via acetylation, Myc triggers a regulatory cascade in cancer cells that leads to H3K4me3 activation and gene expression. We find that Myc facilitates the acetylation-dependent deactivation of SDHA by activating the SKP2-mediated degradation of SIRT3 deacetylase. We further demonstrate that Myc inhibition of SDH-complex activity leads to cellular succinate accumulation, which triggers H3K4me3 activation and tumour-specific gene expression. We demonstrate that acetylated SDHA at Lys 335 contributes to tumour growth in vitro and in vivo, and we confirm increased tumorigenesis in clinical samples. This study illustrates a link between acetylation-dependent SDHA deactivation and Myc-driven epigenetic regulation of gene expression, which is critical for cancer progression.
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Transformación Celular Neoplásica , Complejo II de Transporte de Electrones/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas Proto-Oncogénicas c-myc/metabolismo , Acetilación , Ciclo del Ácido Cítrico , Complejo II de Transporte de Electrones/genética , Epigénesis Genética , Células HEK293 , Humanos , Ácido Succínico/metabolismoRESUMEN
Background: To verify the hypothesis that the nature of trigeminal neuralgia (TN) is an ectopic impulse induced by sodium channel modulated by cytokines, we conducted an animal study using the infraorbital nerve chronic constriction injury (CCI) model in rats.Method: The expression of Nav1.3 or IL-6 in the infraorbital nerve (ION) and trigeminal ganglion (TG) were detected by western blot and immunocytochemistry after administration of antisense oligodeoxynucleotide sequence (AS), IL-6 or Anti-IL-6.Results: With intrathecal administration of AS or mismatch oligodeoxynucleotide sequence (MM) in the CCI rats, the Nav1.3-IR in ION and TG accounted for 2.2 ± 0.51% and 8.5 ± 3.1% in AS+CCI group vs. 6.9 ± 1.3% and 38.7 ± 4.8% in MM+CCI group (p < 0.05), respectively. While with local administration of IL-6 in those with sham operation, it accounted for 7.4 ± 2.1% and 45.5 ± 3.4% in IL-6+ sham group vs. 1.9 ± 0.67% and 8.1 ± 1.3% in vehicle+sham group (p < 0.05); with local administration of anti-IL-6 in CCI rats, 4.5 ± 0.78% and 32.1 ± 9.6% in Anti-IL-6+ CCI group vs 8.9 ± 2.1% and 61.4 ± 11.2% in vehicle+CCI group (p < 0.05).Discussion: We believe that the emergence of Nav1.3 from the compressed trigeminal nerve might be an important structural basis for the development of the ectopic excitability on the axon and IL-6 may play a role of necessary precondition.
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Interleucina-6/metabolismo , Canal de Sodio Activado por Voltaje NAV1.3/metabolismo , Síndromes de Compresión Nerviosa/metabolismo , Neuralgia del Trigémino/metabolismo , Animales , Constricción Patológica , Masculino , Ratas , Ratas Sprague-Dawley , Nervio Trigémino/metabolismo , Regulación hacia ArribaRESUMEN
PURPOSE: Microvascular decompression (MVD) surgery has been accepted as a potentially curative method for hemifacial spasm (HFS). The primary cause of failure of MVD is incomplete decompression of the offending vessel due to inadequate visualization. This study is aimed at evaluating the benefit of endoscopic visualization and the value of fully endoscopic MVD. METHODS: From March 2016 to March 2018, 45 HFS patients underwent fully endoscopic MVD in our department. From opening the dura to preparing to close, the assistant held the endoscope and the surgeon operated. Abnormal muscle response (AMR) and brainstem auditory evoked potentials (BAEP) were monitored. For every patient, the offending vessel was transposed or interposed and achieved complete decompression. AMR was used to evaluate the adequacy of decompression at the end of the surgery. The intra-operative findings and postoperative outcomes and complications were analyzed. RESULTS: Immediately after surgeries, 39 patients (86.7%) achieved excellent result; 2 cases (4.4%) had good result. So the postoperative effective rate was 91.1% (41/45). During 12-36 month follow-up, the outcomes were excellent in 42 cases (93.3%) and good in 2 cases (4.4%), and the effective rate reached to 97.8% (44/45). No recurrence was noted. The postoperative complications were found in 2 patients (4.4%). One patient (2.2%) showed delayed facial palsy on the tenth day but was fully recovered 1 month later. Intracranial infection was noticed in 1 patient (2.2%) and was cured by using intravenous antibiotics for 2 weeks. There was no hearing impairment, hoarseness, or other complications. CONCLUSIONS: Fully endoscopic MVD is both safe and effective in the treatment of HFS. Electrophysiological monitoring is helpful to gain a good result and reduce hearing impairment.