RESUMO
BACKGROUND: Lamb-Shaffer syndrome (LAMSHF, OMIM: 616803) is a rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, poor expressive speech, which is attributed to haploinsufficiency by heterozygous variants of SOX5 gene (SRY-Box Transcription Factor 5, HGNC: 11201) on chromosome 12p12. A total of 113 cases have been reported in the world, however, only 3 cases have been reported.in China. Here, we aimed to report novel variants of SOX5 gene and provide examples for clinical diagnosis by reporting the clinical phenotype of a series of Chinese patients with LAMSHF. METHODS: This study retrospectively collected the information of families of LAMSHF patients in China. Whole Exome Sequencing (WES) were performed to confirm the diagnosis of 4 children with unexplained developmental delay or epilepsy. A minigene splicing assay was used to verify whether the splice variant affected splicing. Meanwhile, a literature review was conducted to analyze the clinical and genetic characteristics of patients with LAMSHF. RESULTS: Three of the LAMSHF patients had a de novo heterozygous mutation in the SOX5 gene respectively, c.290delC (p.Pro97fs*30), chr12:23686019_24048958del, c.1772-1C > A, and the remaining one had a mutation inherited from his father, c.1411C > T (p.Arg471*). The main clinical manifestations of these children were presented with global developmental delays, and one of them also had seizures. And the results of the minigene experiment indicated that the splice variant, c.1772-1C > A, transcribed a novel mRNA product which leaded to the formation of a truncated protein. CONCLUSIONS: Through a comprehensive review and analysis of existing literature and this study showed intellectual disability, speech delay and facial dysmorphisms were common clinical manifestation, while the seizures and EEG abnormalities were rare (21/95, 22.16%). Notably, we represent the largest sample size of LAMSHF in Asia that encompasses previously unreported SOX5 gene mutation, and a minigene testing have been conducted to validate the pathogenicity of the c.1772-1C > A splice variant. The research further expands the phenotype and genotype of LAMSHF while offers novel insights for potential pathogenicity of genes locus.
Assuntos
Fatores de Transcrição SOXD , Humanos , Masculino , Feminino , China , Fatores de Transcrição SOXD/genética , Pré-Escolar , Criança , Estudos Retrospectivos , Sequenciamento do Exoma , Mutação/genética , Lactente , Deficiência Intelectual/genética , Deficiências do Desenvolvimento/genéticaRESUMO
OBJECTIVE: MicroRNA-23b-3p has been demonstrated to act as a safeguard against several autoimmune diseases. However, its role in Sjögren's syndrome (SS) remains unclear. METHODS: In order to investigate its role in SS, we administered agomiR-23b-3p or agomiR-NC to non-obese diabetic (NOD) mice via tail vein weekly for 6 weeks. The study examined the saliva flow rate, histological changes in submandibular glands, and levels of autoantibodies. Additionally, the levels of several cytokines, cell apoptosis, and NF-κB signaling were evaluated. The protective effect of miR-23b-3p was confirmed in a cell model. RESULTS: The results demonstrated that miR-23b-3p overexpression improved salivary flow rates, inhibited lymphocyte infiltration, reduced cytokine levels, and suppressed cell apoptosis in NOD mice. Moreover, NF-κB signaling was inactivated following miR-23b-3p overexpression. In a cellular model of SS, overexpression of miR-23b-3p protected submandibular gland epithelial cells exposed to IFN-γ against apoptosis and inflammation by targeting SOX6. CONCLUSIONS: The study concludes that miR-23b-3p alleviates SS by targeting SOX6 and inhibiting the NF-κB signaling pathway. The miR-23b-3p/SOX6 axis represents a promising avenue for the development of novel therapeutic strategies for SS.
Assuntos
Apoptose , Camundongos Endogâmicos NOD , MicroRNAs , NF-kappa B , Fatores de Transcrição SOXD , Transdução de Sinais , Síndrome de Sjogren , Animais , MicroRNAs/genética , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , NF-kappa B/metabolismo , Camundongos , Fatores de Transcrição SOXD/genética , Fatores de Transcrição SOXD/metabolismo , Apoptose/genética , Humanos , Feminino , Glândula Submandibular/patologia , Glândula Submandibular/metabolismoRESUMO
BACKGROUND: Psoriasis is a complex and recurrent chronic inflammatory skin disease, and the abnormal proliferation of keratinocytes plays a crucial role in the pathogenesis of psoriasis. Long non-coding RNAs (lncRNAs) play an indispensable role in regulating cellular functions. This research aims to explore the potential impact of lncRNA MIR181A2HG on the regulation of keratinocyte proliferation. METHODS: The expression level of MIR181A2HG and the mRNA level of KRT6, KRT16, and SOX6 were assessed using qRT-PCR. The viability and proliferation of keratinocytes were evaluated using CCK-8 and EdU assays. Cell cycle analysis was performed using flow cytometry. Dual-luciferase reporter assays were applied to test the interaction among MIR181A2HG/miR-223-3p/SOX6. Protein level was detected by Western blotting analysis. RESULTS: The findings indicated that psoriasis lesions tissue exhibited lower levels of MIR181A2HG expression compared to normal tissue. The overexpression of MIR181A2HG resulted in the inhibition of HaCaT keratinocytes proliferation. The knockdown of MIR181A2HG promoted cell proliferation. The dual-luciferase reporter assay and rescue experiments provided evidence of the interaction among MIR181A2HG, SOX6, and miR-223-3p. CONCLUSIONS: The lncRNA MIR181A2HG functions as a miR-223-3p sponge targeting SOX6 to regulate the proliferation of keratinocytes, which suggested that MIR181A2HG/miR-223-3p/SOX6 might be potential diagnostic and therapeutic targets for psoriasis.
Assuntos
Proliferação de Células , Queratinócitos , MicroRNAs , Psoríase , RNA Longo não Codificante , Fatores de Transcrição SOXD , Humanos , MicroRNAs/metabolismo , MicroRNAs/genética , Queratinócitos/metabolismo , Proliferação de Células/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fatores de Transcrição SOXD/metabolismo , Fatores de Transcrição SOXD/genética , Psoríase/genética , Psoríase/metabolismo , Psoríase/patologia , Células HaCaTRESUMO
The identification of regulatory networks contributing to fetal/adult gene expression switches is a major challenge in developmental biology and key to understand the aberrant proliferation of cancer cells, which often reactivate fetal oncogenes. One key example is represented by the developmental gene LIN28B, whose aberrant reactivation in adult tissues promotes tumor initiation and progression. Despite the prominent role of LIN28B in development and cancer, the mechanisms of its transcriptional regulation are largely unknown. Here, by using quantitative RT-PCR and single cell RNA sequencing data, we show that in erythropoiesis the expression of the transcription factor SOX6 matched a sharp decline of LIN28B mRNA during human embryo/fetal to adult globin switching. SOX6 overexpression repressed LIN28B not only in a panel of fetal-like erythroid cells (K562, HEL and HUDEP1; ≈92% p < 0.0001, 54% p = 0.0009 and ≈60% p < 0.0001 reduction, respectively), but also in hepatoblastoma HepG2 and neuroblastoma SH-SY5H cells (≈99% p < 0.0001 and ≈59% p < 0.0001 reduction, respectively). SOX6-mediated repression caused downregulation of the LIN28B/Let-7 targets, including MYC and IGF2BP1, and rapidly blocks cell proliferation. Mechanistically, Lin28B repression is accompanied by SOX6 physical binding within its locus, suggesting a direct mechanism of LIN28B downregulation that might contribute to the fetal/adult erythropoietic transition and restrict cancer proliferation.
Assuntos
Proteínas de Ligação a RNA , Fatores de Transcrição SOXD , Humanos , Fatores de Transcrição SOXD/genética , Fatores de Transcrição SOXD/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Linhagem Celular Tumoral , Regulação da Expressão Gênica no Desenvolvimento , Eritropoese/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Células Hep G2 , Células K562 , Regulação Neoplásica da Expressão Gênica , Células Eritroides/metabolismoRESUMO
We investigated the influence of 17ß-estradiol (17ß-E2) on cartilage extracellular matrix (ECM) homeostasis in postmenopausal women. We focused on the roles of estrogen receptors (ESR) and SOX6 in 17ß-E2-mediated stimulation of ECM metabolism during chondrocyte (CH) degeneration. We compared the expression of anabolic genes (collagen II and aggrecan) and catabolic genes (MMPs and TIMPs) in IL-1ß-induced CH degeneration in vitro, with and without 17ß-E2 supplementation. We separately silenced the SOX6, ESR1, and ESR2 genes in CHs to determine their impact on 17ß-E2 treatment. Additionally, we used Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) and luciferase assays to investigate protein-DNA interactions within ESR2 and SOX6-promoter complexes. After three days of IL-1ß treatment, ESR1/2, SOX6, collagen II, aggrecan, and TIMP1/3 were decreased, while MMP3/9/13 were increased. The addition of 17ß-E2 partially reversed these effects, but silencing SOX6, ESR1, or ESR2 weakened the protective effects of 17ß-E2. Silencing ESR2, but not ESR1, abolished the upregulation of SOX6 induced by 17ß-E2. ESR2 was found to bind the SOX6 promoter and regulate SOX6 expression. 17ß-E2 upregulates SOX6 through ESR2 mediation, and the synergistic effect of 17ß-E2 and ESR2 on SOX6 balances ECM metabolism in CHs.
Assuntos
Condrócitos , Estradiol , Receptor beta de Estrogênio , Matriz Extracelular , Interleucina-1beta , Fatores de Transcrição SOXD , Condrócitos/metabolismo , Condrócitos/efeitos dos fármacos , Estradiol/farmacologia , Humanos , Receptor beta de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Feminino , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos dos fármacos , Fatores de Transcrição SOXD/metabolismo , Fatores de Transcrição SOXD/genética , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacologia , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Regiões Promotoras Genéticas/genética , Células CultivadasRESUMO
SRY-box transcription factor 6 (SOX6) is a member of the SOX gene family and inhibits the proliferation of cervical cancer cells by inducing cell cycle arrest. However, the final cell fate and significance of these cell-cycle-arrested cervical cancer cells induced by SOX6 remains unclear. Here, we report that SOX6 inhibits the proliferation of cervical cancer cells by inducing cellular senescence, which is mainly mediated by promoting transforming growth factor beta 2 (TGFB2) gene expression and subsequently activating the TGFß2-Smad2/3-p53-p21WAF1/CIP1-Rb pathway. SOX6 promotes TGFB2 gene expression through the MAP4K4-MAPK (JNK/ERK/p38)-ATF2 and WT1-ATF2 pathways, which is dependent on its high-mobility group (HMG) domain. In addition, the SOX6-induced senescent cervical cancer cells are resistant to cisplatin treatment. ABT-263 (navitoclax) and ABT-199 (venetoclax), two classic senolytics, can specifically eliminate the SOX6-induced senescent cervical cancer cells, and thus significantly improve the chemosensitivity of cisplatin-resistant cervical cancer cells. This study uncovers that the MAP4K4/WT1-ATF2-TGFß2 axis mediates SOX6-induced cellular senescence, which is a promising therapeutic target in improving the chemosensitivity of cervical cancer.
Assuntos
Fator 2 Ativador da Transcrição , Senescência Celular , Fatores de Transcrição SOXD , Transdução de Sinais , Proteína Smad2 , Fator de Crescimento Transformador beta2 , Neoplasias do Colo do Útero , Animais , Feminino , Humanos , Camundongos , Fator 2 Ativador da Transcrição/metabolismo , Fator 2 Ativador da Transcrição/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteína Smad2/metabolismo , Proteína Smad3 , Fatores de Transcrição SOXD/metabolismo , Fatores de Transcrição SOXD/genética , Fator de Crescimento Transformador beta2/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/genéticaRESUMO
Healing of large calvarial bone defects remains challenging. An RNA-guided Split dCas12a system is previously harnessed to activate long non-coding RNA H19 (lncRNA H19, referred to as H19 thereafter) in bone marrow-derived mesenchymal stem cells (BMSCs). H19 activation in BMSCs induces chondrogenic differentiation, switches bone healing pathways, and improves calvarial bone repair. Since adipose-derived stem cells (ASCs) can be harvested more easily in large quantity, here it is aimed to use ASCs as an alternative cell source. However, H19 activation alone using the Split dCas12a system in ASCs failed to elicit evident chondrogenesis. Therefore, split dCas12a activators are designed more to co-activate other chondroinductive transcription factors (Sox5, Sox6, and Sox9) to synergistically potentiate differentiation. It is found that co-activation of H19/Sox5/Sox6 in ASCs elicited more potent chondrogenic differentiation than activation of Sox5/Sox6/Sox9 or H19 alone. Co-activating H19/Sox5/Sox6 in ASCs significantly augmented in vitro cartilage formation and in vivo calvarial bone healing. These data altogether implicated the potentials of the Split dCas12a system to trigger multiplexed gene activation in ASCs for differentiation pathway reprogramming and tissue regeneration.
Assuntos
Diferenciação Celular , Condrogênese , RNA Longo não Codificante , Fatores de Transcrição SOXD , Crânio , Fatores de Transcrição SOXD/metabolismo , Fatores de Transcrição SOXD/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Animais , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Tecido Adiposo/citologia , Células-Tronco/metabolismo , Células-Tronco/citologia , Osteogênese/genéticaRESUMO
BACKGROUND: Diabetic nephropathy (DN) is a complication caused by diabetes. Circular RNAs (circRNAs) are a kind of RNA with a closed circular structure, which has high stability and is involved in many disease-related processes. The mechanism of circRNA TAO kinase 1 (circTAOK1) in the pathogenesis and development of DN is unclear. METHODS: CircTAOK1, microRNA (miR)-142-3p, and sex-determining region Y-box transcription factor 6 (SOX6) mRNA levels were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). Cell counting kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used to analyze cell proliferation. Cell cycle distribution was detected by flow cytometry. Western blot assay was performed to test B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X (Bax), cleaved-caspase 3, and fibronectin (FN), collagen I (Col I), and collagen IV (Col IV) protein levels. ELISA assay was used to measure interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor (TNF-α) levels. The reactive oxygen species (ROS) and malondialdehyde (MDA) levels and the superoxide dismutase (SOD) activity were assessed by the corresponding kits. And the correlation between miR-142-3p and circTAOK1 or SOX6 was confirmed by dual luciferase reporter assay, RNA immunoprecipitation assay and RNA pull down assay. RESULTS: CircTAOK1 and SOX6 expression levels were up-regulated, while miR-142-3p expression was down-regulated in DN serum and HG-treated HK-2 cells. Knockdown of circTAOK1 could inhibit cell injury of HG-induced HK-2 cells. The inhibitory effect of circTAOK1 knockdown on HG-induced HK-2 cell injury was restored by miR-142-3p downregulation. CircTAOK1 acted as a sponge for miR-142-3p, and SOX6 was targeted by miR-142-3p. The overexpression of SOX6 could recover the effect of miR-142-3p overexpression on HG-induced HK-2 cell injury. CircTAOK1 regulated the expression of SOX6 by targeting miR-142-3p. CONCLUSION: CircTAOK1 knockdown inhibited HG-induced HK-2 cell damage in DN by the miR-142-3p/SOX6 axis.
Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , MicroRNAs , Humanos , Nefropatias Diabéticas/genética , Apoptose/genética , Estresse Oxidativo/genética , Inflamação/genética , Colágeno Tipo I , Glucose/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2 , MicroRNAs/genética , Fatores de Transcrição SOXD/genéticaRESUMO
Members of the SRY-related box (SOX) subfamily D (SoxD) of transcription factors are well conserved among vertebrate species and play important roles in different stages of male reproductive development. In mammals, the SoxD subfamily contains three members: SOX5, SOX6 and SOX13. Here, we describe their implications in testicular development and spermatogenesis, contributing to fertility. We also cover the mechanisms of action of SoxD transcription factors in gene regulation throughout male development. The specificity of activation of target genes by SoxD members depends, in part, on their post-translational modifications and interactions with other partners. Sperm production in adult males requires the coordination in the regulation of gene expression by different members of the SoxD subfamily of transcription factors in the testis. Specifically, the regulation of genes promoting adequate spermatogenesis by SoxD members is discussed in comparison between species.
Assuntos
Fatores de Transcrição SOXD , Sêmen , Animais , Masculino , Fatores de Transcrição SOXD/genética , Fatores de Transcrição SOXD/metabolismo , Sêmen/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação da Expressão Gênica , Testículo/metabolismo , Mamíferos/metabolismoRESUMO
The commitment of mesenchymal stem cells (MSCs) to preadipocytes and the termination of differentiation to adipocytes are critical for maintaining systemic energy homeostasis. However, our knowledge of the molecular mechanisms governing the commitment of MSCs to preadipocytes and the subsequent termination of their differentiation into adipocytes remain limited. Additionally, the role of Sox6 sex-determining region Y (SRY)-box6 (Sox6), a transcription factor that regulates gene transcription, is reportedly involved in various cellular processes, including adipogenesis; however, its function in regulating preadipocyte development and the factors involved in the termination of adipogenic differentiation remain unexplored. Therefore, we investigated the role of Sox6 in regulating the differentiation of adipocytes by monitoring the effects of its overexpression in C3H10T1/2 cells (in vitro) and C57BL/6J mouse (in vivo) models of adipogenesis. We observed lower Sox6 expression in the adipose tissue of obese mice than that in control mice. Sox6 overexpression inhibited the differentiation of MSC by directly binding to the lysyl oxidase (Lox) and preadipocyte factor 1 (Pref1) promoters, which was potentiated by histone deacetylase-1(HDAC1). Our findings suggest that Sox6 is a key regulator of MSC commitment to adipocytes; therefore, targeting the Sox6-mediated regulation of this process could offer potential therapeutic avenues for addressing obesity and related metabolic disorders.
Assuntos
Adipogenia , Células-Tronco Mesenquimais , Animais , Camundongos , Adipogenia/genética , Diferenciação Celular/genética , Camundongos Endogâmicos C57BL , Proteína-Lisina 6-Oxidase/genética , Proteína-Lisina 6-Oxidase/metabolismo , Fatores de Transcrição SOXD/genética , Fatores de Transcrição SOXD/metabolismoRESUMO
BACKGROUND: Bladder cancer is one of the most common malignant tumors of the urinary system, and its incidence is increasing worldwide. However, the underlying mechanisms that trigger migration, invasion and chemotherapy resistance are unclear. RESULTS: Bioinformatics analysis of bladder cancer cohort indicated that LINC00839 is deregulated in bladder cancer. LINC00839 was validated and highly expressed in bladder cancer patients and cell lines. In addition, LINC00839 induced the migration, invasion and Gemcitabine resistance of bladder cancer cells. We identified that the transcription factor EGR1 directly repressed LINC00839 and thereby suppressed the migration and invasion of bladder cancer cells. Furthermore, LINC00839 interacted with miR-142, which subsequently regulated the expression of SOX5, a well-studied oncogene and targeted by miR-142. In addition, EGR1 served as a suppressive transcription factor of SOX5. Therefore, EGR1 directly or indirectly regulates SOX5 via LINC00839/miR-142 axis. LINC00839 induced Gemcitabine resistance by promoting autophagy. CONCLUSIONS: EGR1, LINC00839/miR-142 and SOX5 form a coherent feed-forward loop that modulates the migration, invasion and Gemcitabine resistance of bladder cancer.
Assuntos
MicroRNAs , Neoplasias da Bexiga Urinária , Humanos , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Gencitabina , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , MicroRNAs/metabolismo , Fatores de Transcrição SOXD/genética , Fatores de Transcrição SOXD/metabolismo , Fatores de Transcrição/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , RNA não Traduzido/genéticaRESUMO
Our understanding of the molecular basis for cellular senescence remains incomplete, limiting the development of strategies to ameliorate age-related pathologies by preventing stem cell senescence. Here, we performed a genome-wide CRISPR activation (CRISPRa) screening using a human mesenchymal precursor cell (hMPC) model of the progeroid syndrome. We evaluated targets whose activation antagonizes cellular senescence, among which SOX5 outperformed as a top hit. Through decoding the epigenomic landscapes remodeled by overexpressing SOX5, we uncovered its role in resetting the transcription network for geroprotective genes, including HMGB2. Mechanistically, SOX5 binding elevated the enhancer activity of HMGB2 with increased levels of H3K27ac and H3K4me1, raising HMGB2 expression so as to promote rejuvenation. Furthermore, gene therapy with lentiviruses carrying SOX5 or HMGB2 rejuvenated cartilage and alleviated osteoarthritis in aged mice. Our study generated a comprehensive list of rejuvenators, pinpointing SOX5 as a potent driver for rejuvenation both in vitro and in vivo.
Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Rejuvenescimento , Humanos , Camundongos , Animais , Proteína HMGB2/genética , Proteína HMGB2/metabolismo , Senescência Celular/genética , Fatores de Transcrição/genética , Fatores de Transcrição SOXD/genética , Fatores de Transcrição SOXD/metabolismoRESUMO
Lamb-Shaffer Syndrome (LSS; OMIM #616803; ORPHA #313892; ORPHA #313884) is an infrequent genetic disorder that affects multiple aspects of human development especially those related to the development of the nervous system. LSS is caused by variants in the SOX5 gene. At the molecular level, SOX5 gene encodes for a transcription factor containing a High Mobility Group (HMG) DNA-Binding domain with relevant functions in brain development in different vertebrate species. Clinical features of Lamb-Shaffer syndrome may include intellectual disability, delayed speech and language development, attention deficits, hyperactivity, autism spectrum disorder, visual problems and seizures. Additionally, patients with the syndrome may present distinct facial dimorphism such as a wide mouth with full lips, small chin, broad nasal bridge, and deep-set eyes. Other physical features that have been reported in some patients include short stature, scoliosis, and joint hypermobility. Here, we report the clinical and molecular characterization of a Spanish LSS cohort of new 20 patients and review all the patients published so far which amount for 111 patients. The most frequent features included developmental delay, intellectual disability, visual problems, poor speech development and facial dysmorphic features. Strikingly, pain insensitivity and hypermetropia seems to be more frequent than previously reported, based on the frequency seen in the Spanish cohort. Eighty-three variants have been reported so far, single nucleotide variants (SNV) and copy number variants represent 47% and 53%, respectively, from the total of variants reported. Similarly to previous reports, the majority of the SNVs variants of the novel patients reported herein fall in the HMG domain of the protein. However, new variants, affecting other functional domains, were also detected. In conclusion, LLS is a rare genetic disorder mostly characterized by a wide range of developmental and neurological symptoms. Early diagnosis would allow to start of care programs, clinical follow up, prospective studies and appropriate genetic counseling, to promote clinical and social improvement to have profound lifelong benefits for patients and their families. Further research is needed to better understand the underlying mechanisms of the syndrome related to SOX5 haploinsufficiency.
Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Humanos , Deficiência Intelectual/genética , Transtorno do Espectro Autista/genética , Estudos Prospectivos , Haploinsuficiência , Síndrome , Fenótipo , Fatores de Transcrição SOXD/genéticaRESUMO
BACKGROUND: This study aimed to investigate the expression and prognostic significance of SOX5 in esophageal squamous cell carcinoma (ESCC). METHODS: Gene Expression Omnibus (GEO) data were analyzed to assess SOX5 expression in ESCC and normal tissues. Survival analysis was performed to evaluate its prognostic significance. Pathway enrichment analysis was conducted to identify pathways associated with low SOX5 expression. Methylation status of CpG sites in ESCC cases was examined, and SOX5 expression was evaluated. Differential expression and ChIP-seq data analyses were used to identify genes significantly correlated with SOX5 and to obtain target genes. A protein-protein interaction (PPI) network was constructed using hub genes, and their association with immune cell infiltration was determined. In vitro ESCC cell experiments validated the findings. RESULTS: SOX5 was significantly downregulated in ESCC samples compared to normal samples. Its downregulation was associated with shorter survival in ESCC patients. Pathway enrichment analysis revealed enrichment in regulated necrosis, NLRP3 inflammasome, formation of the cornified envelope, and PD-1 signaling. Methylation status of two CpG sites negatively correlated with SOX5 expression. Differential expression analysis identified 122 genes significantly correlated with SOX5, and 28 target genes were obtained from ChIP-seq analysis. Target genes were enriched in DNA replication, cell cycle, spindle, and ATPase activity. Five hub genes were identified, and the PPI network showed significant associations with immune cell infiltration. In vitro experiments confirmed SOX5 downregulation, upregulation of hub genes, and their functional effects on ESCC cell apoptosis and proliferation. CONCLUSIONS: These findings enhance understanding of SOX5 in ESCC and potential therapeutic strategies.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/patologia , Prognóstico , Perfilação da Expressão Gênica , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Fatores de Transcrição SOXD/genéticaRESUMO
Dysregulated circWHSC1 has been shown to play potential roles in diverse cancer types, including ovarian cancer, endometrial cancer and hepatocellular carcinoma (HCC). The objective of this study was to investigate its expression, underlying role and regulatory mechanism in non-small-cell lung cancer (NSCLC). The expression of circWHSC1 was determined by real-time PCR. After knockdown of circWHSC1 expression in NSCLC cells, the proliferation, migration, and invasion were detected using CCK-8, colony formation, and Transwell assays, and the effects of circWHSC1 on NSCLC tumorigenesis in vivo was also investigated. With the help of luciferase reporter and pull-down assays, we further explored the downstream mechanism of circWHSC1 in NSCLC cells. CircWHSC1 was highly expressed in NSCLC tissues and cell lines. The inhibition of circWHSC1 suppressed the malignant properties of NSCLC cells, as evidenced by the reduction of proliferation, migration and invasion. CircWHSC1 sponged miR-590-5p and functioned as an oncogene in NSCLC by increasing sex determining region Y-boxprotein 5 (SOX5) expression. CircWHSC1 may contribute to the oncogenicity of NSCLC via the regulation of miR-590-5p/SOX5 axis, which might be a novel therapeutic target in NSCLC.
Assuntos
Carcinoma Hepatocelular , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Hepáticas , Neoplasias Pulmonares , MicroRNAs , Feminino , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Prognóstico , Linhagem Celular Tumoral , Proliferação de Células/genética , Biomarcadores , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição SOXD/genética , Fatores de Transcrição SOXD/metabolismoRESUMO
To delineate further the clinical phenotype of Lamb-Shaffer Syndrome (LSS) 16 unpublished patients with heterozygous variation in SOX5 were identified either through the UK Decipher database or the study team was contacted by clinicians directly. Clinical phenotyping tables were completed for each patient by their responsible clinical geneticist. Photos and clinical features were compared to assess key phenotypes and genotype-phenotype correlation. We report 16 SOX5 variants all of which meet American College of Medical Genetics/Association for Clinical Genomic Science ACMG/ACGS criteria class IV or V. 7/16 have intragenic deletions of SOX5 and 9/16 have single nucleotide variants (including both truncating and missense variants). The cohort includes two sets of monozygotic twins and parental gonadal mosaicism is noted in one family. This cohort of 16 patients is compared with the 71 previously reported cases and corroborates previous phenotypic findings. As expected, the most common findings include global developmental delay with prominent speech delay, mild to moderate intellectual disability, behavioral abnormalities and sometimes subtle characteristic facial features. We expand in more detail on the behavioral phenotype and observe that there is a greater tendency toward lower growth parameters and microcephaly in patients with single nucleotide variants. This cohort provides further evidence of gonadal mosaicism in SOX5 variants; this should be considered when providing genetic counseling for couples with one affected child and an apparently de novo variant.
Assuntos
Deficiência Intelectual , Transtornos do Desenvolvimento da Linguagem , Criança , Humanos , Deficiências do Desenvolvimento/genética , Fenótipo , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Nucleotídeos , Fatores de Transcrição SOXD/genéticaRESUMO
BACKGROUND: Osteoarthritis (OA) is a serious degenerative disease of articular cartilage, which has a great impact on the quality of life of patients. Circular RNA (circRNA) plays an important role in OA progression. Our study aims to explore the role and mechanism of circ_0003800 in OA. METHODS: Circ_0003800, microRNA-197-3p (miR-197-3p) and SRY-box transcription factor 5 (SOX5) contents were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell Counting Kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, western blot and enzyme-linked immunosorbent assay (ELISA) were deployed to evaluate cell proliferation, apoptosis, extracellular matrix (ECM) degradation, inflammatory response and oxidative stress. Interaction of miR-197-3p and circ_0003800 or SOX5 was evidenced by dual-luciferase reporter system, RNA immunoprecipitation (RIP) and RNA pull down assays. RESULTS: OA tissues and model cells had higher abundance of circ_0003800 and SOX5, while miR-197-3p content was lower. Functionally, circ_0003800 knockdown alleviated IL-1ß-mediated injury in C28/I2 cells. Mechanistically, circ_0003800 could sponge miR-197-3p, and miR-197-3p could target SOX5. Besides, in-miR-197-3p reversed the suppressive effect of circ_0003800 downregulation on IL-1ß-induced C28/I2 cell injury, and SOX5 overexpression could also diminish the inhibitory effect of miR-197-3p on IL-1ß-induced C28/I2 cell injury. CONCLUSION: Circ_0003800 exacerbates IL-1ß-induced chondrocyte injury via miR-197-3p/SOX5 axis.
Assuntos
MicroRNAs , RNA Circular , Humanos , Apoptose , Condrócitos , MicroRNAs/genética , Qualidade de Vida , RNA Circular/genética , Fatores de Transcrição SOXD/genética , Interleucina-1beta/farmacologiaRESUMO
Circular RNAs (circRNAs) have important regulation in in sepsis-related acute lung injury (ALI). Circ_0001498 was significantly overexpressed in sepsis-induced acute respiratory distress syndrome. The aims of this study were to explore role and mechanism of circ_0001498 in lipopolysaccharide (LPS)-treated WI-38 cells. Human samples were collected from 56 sepsis patients and 46 healthy volunteers at Liyang People's Hospital. Circ_0001498, microRNA-574-5p (miR-574-5p) or sex-determining region Y-related high-mobility-group box 6 (SOX6) levels were detected via reverse transcription-quantitative polymerase chain reaction assay. Cell viability was determined through Cell Counting Kit-8 assay. Apoptosis rate was examined by flow cytometry. Western blot was used for measurement of proteins. Inflammatory cytokines were detected via enzyme-linked immunosorbent assay. Target relation was analyzed via dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Circ_0001498 was overexpressed in sepsisrelated ALI patients and LPS-treated WI-38 cells. Silencing circ_0001498 reduced LPS-induced cell apoptosis and inflammation. Circ_0001498 interacted with miR-574-5p. The regulation of circ_0001498 knockdown was abolished by miR-574-5p inhibitor. Furthermore, miR-574-5p directly targeted SOX6 and circ_0001498 upregulated SOX6 via targeting miR-574-5p. Overexpression of miR-574-5p alleviated LPS-induced cell injury by downregulating SOX6. This research identified that circ_0001498 facilitated sepsis-related ALI progression by targeting miR-574-5p to upregulate SOX6.
Assuntos
Lesão Pulmonar Aguda , MicroRNAs , RNA Circular , Fatores de Transcrição SOXD , Sepse , Humanos , Apoptose , Proliferação de Células , Inflamação , Lipopolissacarídeos , Pulmão , MicroRNAs/genética , Sepse/complicações , Sepse/genética , Fatores de Transcrição SOXD/genética , RNA Circular/genéticaRESUMO
BACKGROUND: Transcription factor SOX6 belongs to Sry-related high-mobility-group box (SOX) family, has been reported to be downregulated and acts as a tumor-suppressor gene in various solid tumors, but in acute myeloid leukemia (AML) is incompletely understood. METHODS: The SOX6 expression was analyzed between AML patients and normal controls from public data and our research cohort. Correlations between SOX6 expression and clinical, genetic features together with survival were further analyzed. RESULTS: In both public and our present datasets, we demonstrated that SOX6 expression is notably downregulated in AML patients compared with normal controls. Moreover, the expression level of SOX6 was dynamic, along with the disease status. SOX6 was significantly decreased in relapsed/refractory AML compared with complete remission AML. Clinically, SOX6 underexpression was significantly correlated with bone marrow blasts, and WBC counts. Furthermore, decreased expression of SOX6 was more common in core binding factor AML (CBF-AML), rarely found in complex karyotype AML (CK-AML), and correlated with FLT3 mutations. By survival analyses, low-expression of SOX6 was associated with shorter overall survival (OS) and event-free survival (EFS) among cytogenetic normal AML (CN-AML) patients. Moreover, both univariate and multivariate analyses showed that low SOX6 expression was an independent unfavorable prognostic biomarker for CN-AML. CONCLUSIONS: Our findings indicated that SOX6 underexpression, as a frequent event in AML, was associated with genetic abnormalities and prognosis in AML. SOX6 might be a valuable biomarker for risk stratification, predicting prognosis and relapse of AML.
Assuntos
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/patologia , Medula Óssea/metabolismo , Análise de Sobrevida , Prognóstico , Contagem de Leucócitos , Mutação , Fatores de Transcrição SOXD/genéticaRESUMO
Background/Aims: Chemoresistance is a common event after cancer chemotherapy, which is associated with the deregulation of circular RNAs (circRNAs). The objective of this study was to clarify the role of circ-LDLRAD3 in cisplatin (DDP)-resistant gastric cancer (GC). Methods: The expression of circ-LDLRAD3, miR-588, and SRY-box transcription factor 5 (SOX5) mRNA was detected by quantitative real-time polymerase chain reaction. Cell viability and the half maximal inhibitory concentration (IC50) value were measured by CCK8 assay. Cell proliferation was assessed by colony formation and EdU assays. Cell apoptosis and cell invasion were assessed by flow cytometry assay and transwell assay, respectively. The expression of SOX5 protein was detected by Western blotting. A xenograft model was established to verify the role of circ-LDLRAD3 in vivo. Exosomes were isolated by differential centrifugation and identified by transmission electron microscopy and the expression of exosome-related proteins. Results: circ-LDLRAD3 was overexpressed in DDP-resistant GC tissues and cells. circ-LDLRAD3 knockdown decreased the IC50 of DDP-resistant cells and suppressed cell proliferation, survival and invasion. miR-588 was a target of circ-LDLRAD3, and miR-588 inhibition attenuated the inhibition of DDP resistance, proliferation, survival and invasion in DDP-resistant GC cells caused by circ-LDLRAD3 knockdown. SOX5 was a target of miR-588, and the inhibition of the DDP resistance, proliferation, survival and invasion of DDP-resistant GC cells by miR-588 restoration was largely rescued SOX5 overexpression. circ-LDLRAD3 knockdown inhibited DDP resistance and tumor growth in vivo. circ-LDLRAD3 was overexpressed in exosomes isolated from DDP-resistant GC cells. Conclusions: circ-LDLRAD3 knockdown reduced DDP resistance and blocked the malignant development of DDP-resistant GC by modulating the miR-588/SOX5 pathway.