RESUMO
Abnormal mossy fiber connections in the hippocampus have been implicated in schizophrenia. However, it remains unclear whether this abnormality in the patients is genetically determined and whether it contributes to the onset of schizophrenia. Here, we showed that iPSC-derived hippocampal NPCs from schizophrenia patients with the A/A allele at SNP rs16864067 exhibited abnormal NPC polarity, resulting from the downregulation of SOX11 by this high-risk allele. In the SOX11-deficient mouse brain, abnormal NPC polarity was also observed in the hippocampal dentate gyrus, and this abnormal NPC polarity led to defective hippocampal neurogenesis-specifically, irregular neuroblast distribution and disrupted granule cell morphology. As granule cell synapses, the mossy fiber pathway was disrupted, and this disruption was resistant to activity-induced mossy fiber remodeling in SOX11 mutant mice. Moreover, these mutant mice exhibited diminished PPI and schizophrenia-like behaviors. Activation of hippocampal neurogenesis in the embryonic brain, but not in the adult brain, partially alleviated disrupted mossy fiber connections and improved schizophrenia-related behaviors in mutant mice. We conclude that disrupted mossy fiber connections are genetically determined and strongly correlated with schizophrenia-like behaviors in SOX11-deficient mice. This disruption may reflect the pathological substrate of SOX11-associated schizophrenia.
Assuntos
Fibras Musgosas Hipocampais/metabolismo , Neurogênese , Fatores de Transcrição SOXC/fisiologia , Esquizofrenia/metabolismo , Animais , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Camundongos , Camundongos Transgênicos , Fibras Musgosas Hipocampais/fisiopatologia , Fatores de Transcrição SOXC/genética , Esquizofrenia/fisiopatologia , SinapsesRESUMO
Circular RNAs (circRNAs), emerging as a new type of non-coding RNAs, play important roles in cancers. Instead, the functions and mechanisms of circ_0011385 in cervical cancer (CC) are still inconclusive. Microarray data GSE102686 was downloaded from Gene Expression Omnibus (GEO) database, and were utilized to screen out circRNAs differently expressed in CC tissues. Circ_0011385, miR-149-5p, SRY-box transcription factor 4 (SOX4) mRNA expressions in CC tissues and cells were probed by quantitative real-time PCR (qRT-PCR). CC cell lines with circ_0011385 knockdown were constructed, and he multiplication, migration, invasion, and apoptosis of CC cells were evaluated by cell counting kit-8 (CCK-8) method, transwell assay, and flow cytometry. In addition, the targeting relationships between miR-149-5p and circ_0011385 or SOX4 mRNA 3'UTR were probed by dual-luciferase reporter gene assay and RNA pull-down assay. The regulatory function of circ_0011385 and miR-149-5p on SOX4 expression was studied with western blot. Expressions of circ_0011385 and SOX4 mRNA were raised in CC tissues and cells, while miR-149-5p expression was decreased. Knocking down circ_0011385 restrained the multiplication, migration, and invasion of CC cells and induced the apoptosis. Circ_0011385 directly targeted miR-149-5p, and SOX4 was the target of miR-149-5p, which could be positively regulated by circ_0011385. Circ_0011385 elevates SOX4 expression by targeting miR-149-5p, thus participating in promoting the malignant biological behaviors of CC cells.
Assuntos
MicroRNAs/fisiologia , RNA Circular/fisiologia , Fatores de Transcrição SOXC/fisiologia , Neoplasias do Colo do Útero/etiologia , Adulto , Idoso , Apoptose , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Transcrição SOXC/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologiaRESUMO
Acute myeloid leukemia (AML) is the most common acute leukemia. Rho GTPase activating protein 9 (ARHGAP9) has been reported to be positively correlated with overall survival of AML patients, but the specific molecular function remains unclear. This study aims to further explore the functional role and the molecular mechanism of ARHGAP9 in AML cells. The expression level of ARHGAP9 in AML cells was measured using quantitative real-time PCR (qRT-PCR) and western blot. Cell transfection was performed to interfere ARHGAP9. CCK-8, flow cytometry and TUNEL assays were conducted to detect cell viability, cell cycle distribution and apoptosis, respectively. The binding relationship between SOX4 and ARHGAP9 promoter was verified using luciferase reporter assay and chromatin immunoprecipitation. The results showed that ARHGAP9 was upregulated in AML cells. Interference of ARHGAP9 greatly reduced cell viability and induced cell cycle arrest in G1 phase, accompanied with the reduction of Ki67, PCNA, cyclin D1, cyclin E1, CDK4 and CDK6. In addition, Interference of ARHGAP9 greatly promoted cell apoptosis, accompanied with the decreased protein expression of Bcl-2 and the increased protein expression of Bax, cleaved caspase 3 and cleaved caspase 9. Furthermore, SOX4 directly bound to ARHGAP9 promoter and regulated ARHGAP9 expression. In conclusion, this study suggested that ARHGAP9 interference exerted an anti-tumor effect through inhibiting cell proliferation, blocking cell cycle progression, and promoting cell apoptosis in AML cells. ARHGAP9 may serve as a novel therapeutic target for AML.
Assuntos
Proteínas Ativadoras de GTPase/genética , Leucemia Mieloide Aguda/etiologia , Fatores de Transcrição SOXC/fisiologia , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Humanos , Leucemia Mieloide Aguda/patologia , Regiões Promotoras Genéticas , Regulação para CimaRESUMO
BACKGROUND: Retinoblastoma (RB) is the most common intraocular malignancy in children. Long non-coding RNA X-inactive specific transcript (lncRNA XIST) has been reported to be associated with RB, but research on the mechanism of XIST is not well studied. METHODS: Expressions of XIST, microRNA-140-5p (miR-140-5p), and sex-determining region Y-related high-mobility group box 4 (SOX4) were analyzed by qRT-PCR or Western blot. Relationships of XIST, SOX4, and miR-140-5p were evaluated by dual-luciferase reporter assay and Spearman's analysis. Cell Counting Kit-8 (CCK-8) and Transwell assay were performed to assess the function of XIST on RB cell proliferation and invasion. RESULTS: In RB tissues, XIST and SOX4 expressions were obviously increased, but the miR-140-5p expression was markedly reduced. XIST expression was positively related to SOX4 expression while negatively correlated with miR-140-5p expression, and negative correlation was exhibited between miR-140-5p and SOX4 expression in RB tissues. XIST was confirmed to directly bind to miR-140-5p, and SOX4 was one target of miR-140-5p. XIST knockdown could impede RB cell proliferation and invasion, while miR-140-5p inhibition reversed the effects. In addition, XIST overexpression or miR-140-5p inhibition could abrogate the inhibition of SOX4 silencing on cell proliferation and invasion of RB cells. CONCLUSIONS: XIST was obviously increased in RB tissues and cells, and XIST inhibition repressed the proliferation and invasion of RB cells by miR-140-5p/SOX4 axis, which may provide new understandings of the XIST molecular mechanism in RB.
Assuntos
MicroRNAs/fisiologia , RNA Longo não Codificante/fisiologia , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Fatores de Transcrição SOXC/fisiologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Fatores de Transcrição SOXC/genéticaRESUMO
BACKGROUND: Breast cancer is among the most common malignant cancers worldwide, and breast adenocarcinoma in glandular tissue cells has excessive metastasis and invasion capability. However, little is known on the molecular process by which this disease develops and progresses. OBJECTIVE: In this study, we explored the effects of sex-determining region Y-box 4 (SOX4) protein on proliferation, migration, apoptosis and tumourigenesis of breast adenocarcinoma and its possible mechanisms. METHODS: The SOX4 overexpression or knockdown Michigan Cancer Foundation-7 (MCF-7) cell lines were established. Among the SOX4 overexpression or MCF-7 knockdown cell lines, proliferation, migration ability and apoptosis rate were detected. The expression levels of apoptosis-related proteins (Bax and Cleaved caspase-3) were analysed using Western blot. The effect of SOX4 on tumourigenesis was analysed using the clone formation assay in vitro and tumour xenograft experiment in nude mice. RESULTS: Compared with the overexpression of control cells, proliferation and migration ability of SOX4 overexpression cells significantly increased, the apoptosis rate significantly decreased in addition to the expression levels of Bax and Cleaved caspase-3 (P < 0.05). Compared with the knockdown of control cells, proliferation and migration ability of SOX4 knockdown cells significantly decreased, and the apoptosis rate and expression levels of Bax and Cleaved caspase-3 significantly increased (P < 0.05). Clone formation and tumour growth abilities of SOX4 overexpression cells were significantly higher than those of the control cells (P < 0.05), whereas SOX4 knockdown cells had the opposite effect. CONCLUSION: SOX4 plays an oncogenic role in breast adenocarcinoma tumourigenesis by promoting cell proliferation, migration and inhibiting apoptosis. It can be used as a potential molecular target for breast cancer gene therapy.
Assuntos
Adenocarcinoma/etiologia , Apoptose , Neoplasias da Mama/etiologia , Fatores de Transcrição SOXC/fisiologia , Adenocarcinoma/patologia , Animais , Neoplasias da Mama/patologia , Carcinogênese , Movimento Celular , Proliferação de Células , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Interleukin (IL)-13 is a signature cytokine of type 2 inflammation important for the pathogenesis of various diseases, including allergic diseases. Signal transducer and activator of transcription (STAT) 6 is a critical transcriptional factor for the IL-13 signals; however, it remains unknown how expression of the IL-13-induced genes is differentiated by the transcriptional machineries. In this study, we identified IL-13-induced transcriptional factors in lung fibroblasts using DNA microarrays in which SOX11 was included. Knockdown of SOX11 down-regulated expression of periostin and CCL26, both of which are known to be downstream molecules of IL-13, whereas enforced expression of SOX11 together with IL-13 stimulation enhanced expression of periostin. Moreover, we found that in DNA microarrays combining IL-13 induction and SOX11 knockdown there exist both SOX11-dependent and -independent molecules in IL-13-inducible molecules. In the former, many inflammation-related and fibrosis-related molecules, including periostin and CCL26, are involved. These results suggest that SOX11 acts as a trans-acting transcriptional factor downstream of STAT6 and that in lung fibroblasts the IL-13 signals are hierarchically controlled by STAT6 and SOX11.
Assuntos
Interleucina-13/metabolismo , Pulmão/metabolismo , Fatores de Transcrição SOXC/fisiologia , Fator de Transcrição STAT6/fisiologia , Transdução de Sinais/fisiologia , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Quimiocina CCL26/metabolismo , Regulação para Baixo , Fibroblastos/metabolismo , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Pulmão/citologia , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Transcrição SOXC/genética , Transativadores/metabolismo , Transcrição Gênica , Regulação para CimaRESUMO
BACKGROUND & AIMS: The intestinal epithelium is maintained by intestinal stem cells (ISCs), which produce postmitotic absorptive and secretory epithelial cells. Initial fate specification toward enteroendocrine, goblet, and Paneth cell lineages requires the transcription factor Atoh1, which regulates differentiation of the secretory cell lineage. However, less is known about the origin of tuft cells, which participate in type II immune responses to parasite infections and appear to differentiate independently of Atoh1. We investigated the role of Sox4 in ISC differentiation. METHODS: We performed experiments in mice with intestinal epithelial-specific disruption of Sox4 (Sox4fl/fl:vilCre; SOX4 conditional knockout [cKO]) and mice without disruption of Sox4 (control mice). Crypt- and single-cell-derived organoids were used in assays to measure proliferation and ISC potency. Lineage allocation and gene expression changes were studied by immunofluorescence, real-time quantitative polymerase chain reaction, and RNA-seq analyses. Intestinal organoids were incubated with the type 2 cytokine interleukin 13 and gene expression was analyzed. Mice were infected with the helminth Nippostrongylus brasiliensis and intestinal tissues were collected 7 days later for analysis. Intestinal tissues collected from mice that express green fluorescent protein regulated by the Atoh1 promoter (Atoh1GFP mice) and single-cell RNA-seq analysis were used to identify cells that coexpress Sox4 and Atoh1. We generated SOX4-inducible intestinal organoids derived from Atoh1fl/fl:vilCreER (ATOH1 inducible knockout) mice and assessed differentiation. RESULTS: Sox4cKO mice had impaired ISC function and secretory differentiation, resulting in decreased numbers of tuft and enteroendocrine cells. In control mice, numbers of SOX4+ cells increased significantly after helminth infection, coincident with tuft cell hyperplasia. Sox4 was activated by interleukin 13 in control organoids; SOX4cKO mice had impaired tuft cell hyperplasia and parasite clearance after infection with helminths. In single-cell RNA-seq analysis, Sox4+/Atoh1- cells were enriched for ISC, progenitor, and tuft cell genes; 12.5% of Sox4-expressing cells coexpressed Atoh1 and were enriched for enteroendocrine genes. In organoids, overexpression of Sox4 was sufficient to induce differentiation of tuft and enteroendocrine cells-even in the absence of Atoh1. CONCLUSIONS: We found Sox4 promoted tuft and enteroendocrine cell lineage allocation independently of Atoh1. These results challenge the longstanding model in which Atoh1 is the sole regulator of secretory differentiation in the intestine and are relevant for understanding epithelial responses to parasitic infection.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Células Enteroendócrinas/citologia , Células Caliciformes/citologia , Mucosa Intestinal/citologia , Fatores de Transcrição SOXC/fisiologia , Animais , Diferenciação Celular , Linhagem da Célula , Receptores de Hialuronatos/análise , Camundongos , Fatores de Transcrição SOXC/análiseRESUMO
Here, we show that SOX11, an embryonic mammary marker that is normally silent in postnatal breast cells, is expressed in many oestrogen receptor-negative preinvasive ductal carcinoma in situ (DCIS) lesions. Mature mammary epithelial cells engineered to express SOX11 showed alterations in progenitor cell populations, including an expanded basal-like population with increased aldehyde dehydrogenase (ALDH) activity, and increased mammosphere-forming capacity. DCIS.com cells engineered to express SOX11 showed increased ALDH activity, which is a feature of cancer stem cells. The CD44+/CD24-/ALDH+ cell population was increased in DCIS.com cells that expressed SOX11. Upregulating SOX11 expression in DCIS.com cells led to increased invasive growth both in vitro and when they were injected intraductally in a mouse model of DCIS that recapitulates human disease. Invasive lesions formed sooner and tumour growth was augmented in vivo, suggesting that SOX11 contributes to the progression of DCIS to invasive breast cancer. We identified potential downstream effectors of SOX11 during both microinvasive and invasive tumour growth stages, including several with established links to regulation of progenitor cell function and prenatal developmental growth. Our findings suggest that SOX11 is a potential biomarker for DCIS lesions containing cells harbouring distinct biological features that are likely to progress to invasive breast cancer. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Assuntos
Neoplasias da Mama/etiologia , Carcinoma Ductal de Mama/etiologia , Fatores de Transcrição SOXC/metabolismo , Aldeído Desidrogenase/metabolismo , Animais , Neoplasias da Mama/fisiopatologia , Carcinoma Ductal de Mama/fisiopatologia , Progressão da Doença , Células Epiteliais , Feminino , Humanos , Glândulas Mamárias Animais , Camundongos SCID , Fatores de Transcrição SOXC/fisiologia , Células-Tronco/fisiologia , Regulação para Cima/fisiologiaRESUMO
Sex-determining region Y-box 11 (SOX11) is an important diagnostic marker in mantle cell lymphoma (MCL). However, the direct oncogenic mechanisms and downstream effector pathways implicated in SOX11-driven transformation remain poorly understood. In the present study, we analyzed SOX11 expression in B-NHL, and used lentivirus-mediated RNA interference targeting SOX11 to investigate the resulting changes in cellular processes and the underlying mechanisms in MCL cell lines. We found that patients with higher SOX11 expression have superior overall survival (OS) and progression-free survival (PFS) compared to those with lower SOX11 expression. SOX11 silencing promotes proliferation and inhibiting apoptosis of MCL cell through caspase-9-3-7-PARP signaling, and desensitizes MCL cell to bortezomib. Conclusively, our data suggest that SOX11 represents a useful prognostic marker in mantle cell lymphoma.
Assuntos
Apoptose/genética , Apoptose/fisiologia , Biomarcadores Tumorais/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Linfoma de Célula do Manto/diagnóstico , Fatores de Transcrição SOXC/fisiologia , Transdução de Sinais , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Transplante de Neoplasias , Prognóstico , Fatores de Transcrição SOXC/genéticaRESUMO
The COP9 signalosome has been implicated in pluripotency maintenance of human embryonic stem cells. Yet, the mechanism for the COP9 signalosome to regulate pluripotency remains elusive. Through knocking down individual COP9 subunits, we demonstrate that Cops2, but not the whole COP9 signalosome, is essential for pluripotency maintenance in mouse embryonic stem cells. Down-regulation of Cops2 leads to reduced expression of pluripotency genes, slower proliferation rate, G2/M cell cycle arrest, and compromised embryoid differentiation of embryonic stem cells. Cops2 also facilitates somatic cell reprogramming. We further show that Cops2 binds to Nanog protein and prevent the degradation of Nanog by proteasome. Moreover, Cops2 functions as transcriptional corepressor to facilitate pluripotency maintenance. Altogether, our data reveal the essential role and novel mechanisms of Cops2 in pluripotency maintenance.
Assuntos
Complexo do Signalossomo COP9/metabolismo , Células-Tronco Embrionárias/citologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteína Homeobox Nanog/metabolismo , Proteínas Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Transcrição Gênica/genética , Sequência de Aminoácidos , Animais , Complexo do Signalossomo COP9/antagonistas & inibidores , Complexo do Signalossomo COP9/genética , Complexo do Signalossomo COP9/fisiologia , Autorrenovação Celular , Técnicas de Reprogramação Celular , Corpos Embrioides , Células-Tronco Embrionárias/metabolismo , Técnicas de Silenciamento de Genes , Camundongos , Proteína Homeobox Nanog/genética , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Fator 3 de Transcrição de Octâmero/antagonistas & inibidores , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/fisiologia , Estabilidade Proteica , Proteólise , Interferência de RNA , RNA Interferente Pequeno/genética , Fatores de Transcrição SOXC/antagonistas & inibidores , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/fisiologia , Ovinos/genética , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genéticaRESUMO
Constitutive overactivation of TGFß signaling is a common event in human cancer progression and acts as a major inducer of epithelial-mesenchymal transition (EMT). In pre-metastatic colorectal cancer (CRC) cells, however, this cascade is tightly controlled and the underlying mechanism in TGFß stimulated hyperactivation of downstream Smad pathway remains elusive. In this study, expression of miR-187 was downregulated in colorectal cancer (CRC) compared with adjacent normal tissues. miR-187 could suppress the formation of aggressive phenotype in CRC and inactivate Smad pathway, thus preventing EMT. TGFß stimulation significantly suppressed the expression of miR-187, and overexpressed miR-187 counteracted the influence of TGFß on cell phenotype and downstream pathway. Furthermore, we found that miR-187 directly suppressed the expression of SOX4, NT5E and PTK6, which were identified as essential upstream effectors of Smad pathway. Together with the fact that high SOX4 or NT5E levels were associated with poor prognosis, we also demonstrated that downregulation of miR-187 was closely related to tumor metastasis and poor prognosis in CRC. These findings revealed a plausible mechanism for sustained TGFß activation in cancer progression and might have suggested a novel miR-187-based clinical intervention target for patients with advanced CRC.
Assuntos
Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal , MicroRNAs/fisiologia , Transdução de Sinais/fisiologia , Proteínas Smad/antagonistas & inibidores , Fator de Crescimento Transformador beta/fisiologia , 5'-Nucleotidase/fisiologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Proteínas Ligadas por GPI/fisiologia , Perfilação da Expressão Gênica , Humanos , Proteínas de Neoplasias/fisiologia , Proteínas Tirosina Quinases/fisiologia , Fatores de Transcrição SOXC/fisiologiaRESUMO
Understanding remains incomplete of the mechanisms underlying initiation and progression of prostate cancer, the most commonly diagnosed cancer in American men. The transcription factor SOX4 is overexpressed in many human cancers, including prostate cancer, suggesting it may participate in prostate tumorigenesis. In this study, we investigated this possibility by genetically deleting Sox4 in a mouse model of prostate cancer initiated by loss of the tumor suppressor Pten. We found that specific homozygous deletion of Sox4 in the adult prostate epithelium strongly inhibited tumor progression initiated by homozygous loss of Pten. Mechanistically, Sox4 ablation reduced activation of AKT and ß-catenin, leading to an attenuated invasive phenotype. Furthermore, SOX4 expression was induced by Pten loss as a result of the activation of PI3K-AKT-mTOR signaling, suggesting a positive feedback loop between SOX4 and PI3K-AKT-mTOR activity. Collectively, our findings establish that SOX4 is a critical component of the PTEN/PI3K/AKT pathway in prostate cancer, with potential implications for combination-targeted therapies against both primary and advanced prostate cancers.
Assuntos
PTEN Fosfo-Hidrolase/fisiologia , Neoplasias da Próstata/etiologia , Fatores de Transcrição SOXC/fisiologia , Animais , Carcinogênese , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/fisiologia , beta Catenina/metabolismoRESUMO
OBJECTIVE: The aim of the this study was to analyze the status of sex-determining region Y-related high-mobility group box 4 (SOX4) expression in varied human cancers and its correlation with overall survival in patients with human cancers. METHODS: To observe initially the expression status of SOX4 in twenty kinds of human cancers at protein database (The Human Protein Atlas). We systematically and carefully searched the studies from electronic databases and seriously identified according to eligibility criteria. The correlation between SOX4 expression and overall survival in human cancers was evaluated through Review Manager. RESULTS: We found that SOX4 expression was significantly positive in most types of human cancer tissues, and the positive rate of SOX4 expression was about 78 % in overall cancer tissues. Furthermore, a total of 10 studies which included 1348 cancer patients were included in the final analysis. Meta-analysis showed that SOX4 overexpression was correlated with a poor overall survival and the pooled hazard ratio (HR), and corresponding 95 % confidence interval (CI) was 1.67 (95 % CI 1.01-2.78). From subgroup analyses, we present evidence that SOX4 overexpression was an unfavorable prognostic factor for colorectal cancer patients' recurrence-free survival and gastric cancer patients' overall survival, and the pooled HRs (95 % CI) were 1.73 (95 % CI 1.04-2.88) and 3.74 (95 % CI 1.04-13.45), respectively. CONCLUSIONS: In summary, SOX4 is a potential prognostic biomarker in human cancers.
Assuntos
Biomarcadores Tumorais , Neoplasias/diagnóstico , Fatores de Transcrição SOXC/fisiologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , Imuno-Histoquímica , Análise em Microsséries , Neoplasias/genética , Neoplasias/metabolismo , Prognóstico , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Análise Serial de TecidosRESUMO
Hair cells, the mechanosensory receptors of the inner ear, underlie the senses of hearing and balance. Adult mammals cannot adequately replenish lost hair cells, whose loss often results in deafness or balance disorders. To determine the molecular basis of this deficiency, we investigated the development of a murine vestibular organ, the utricle. Here we show that two members of the SoxC family of transcription factors, Sox4 and Sox11, are down-regulated after the epoch of hair cell development. Conditional ablation of SoxC genes in vivo results in stunted sensory organs of the inner ear and loss of hair cells. Enhanced expression of SoxC genes in vitro conversely restores supporting cell proliferation and the production of new hair cells in adult sensory epithelia. These results imply that SoxC genes govern hair cell production and thus advance these genes as targets for the restoration of hearing and balance.
Assuntos
Orelha Interna/embriologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Células Ciliadas Auditivas/fisiologia , Morfogênese/fisiologia , Fatores de Transcrição SOXC/fisiologia , Animais , Sequência de Bases , Primers do DNA/genética , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Microscopia Confocal , Dados de Sequência Molecular , Sáculo e Utrículo/anatomia & histologia , Análise de Sequência de RNARESUMO
Neurogenesis involves deeply conserved patterning molecules, such as the proneural basic helix-loop-helix transcription factors. Sox proteins and specifically members of the SoxB and SoxC groups are another class of conserved transcription factors with an important role in neuronal fate commitment and differentiation in various species. In this study, we examine the expression of all five Sox genes of the nematode C. elegans and analyze the effect of null mutant alleles of all members of the SoxB and SoxC groups on nervous system development. Surprisingly, we find that, unlike in other systems, neither of the two C. elegans SoxB genes sox-2 (SoxB1) and sox-3 (SoxB2), nor the sole C. elegans SoxC gene sem-2, is broadly expressed throughout the embryonic or adult nervous system and that all three genes are mostly dispensable for embryonic neurogenesis. Instead, sox-2 is required to maintain the developmental potential of blast cells that are generated in the embryo but divide only postembryonically to give rise to differentiated neuronal cell types. Moreover, sox-2 and sox-3 have selective roles in the terminal differentiation of specific neuronal cell types. Our findings suggest that the common themes of SoxB gene function across phylogeny lie in specifying developmental potential and, later on, in selectively controlling terminal differentiation programs of specific neuron types, but not in broadly controlling neurogenesis.
Assuntos
Proteínas de Caenorhabditis elegans/fisiologia , Caenorhabditis elegans/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Sistema Nervoso/embriologia , Neurogênese/fisiologia , Neurônios/citologia , Fatores de Transcrição SOXB1/fisiologia , Alelos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Diferenciação Celular , Linhagem da Célula , Masculino , Neurônios Motores/metabolismo , Mutação , Fatores de Transcrição SOXC/fisiologia , Transdução de Sinais , TransgenesRESUMO
Mesenchymal stem cells (MSCs) are a promising cell resource for tissue engineering. Sry-related high-mobility group box 11 (Sox11) plays critical roles in neural development and organogenesis. In the present study, we investigated the role of Sox11 in regulating trilineage differentiation (osteogenesis, adipogenesis, and chondrogenesis) and migration of MSCs, and explored the effect of systemically administrated Sox11-modified MSCs on bone fracture healing using the rat model of open femur fracture. Our results demonstrated that Sox11 overexpression increased the trilineage differentiation and migration of MSCs, as well as cell viability under oxidative stress. The effect of Sox11 on osteogenesis was confirmed by ectopic bone formation assay conducted in nude mice. In addition, we found that Sox11 could activate the bone morphogenetic protein (BMP)/Smad signaling pathway in MSCs. By dual-luciferase reporter assay, we also demonstrated that Sox11 could transcriptionally activate runt-related transcription factor 2 (Runx2) and CXC chemokine receptor-4 (CXCR4) expression. The activation of the BMP/Smad signaling pathway and Runx2, CXCR4 expression may have a synergic effect, which largely contributed to the effect of Sox11 on MSC fate determination and migration. Finally, using an open femur fracture model in rats, we found that a larger number of MSCs stably expressing Sox11 migrated to the fracture site and improved bone fracture healing. Taken together, our study shows that Sox11 is an important regulator of MSC differentiation and migration, and Sox11-modified MSCs may have clinical implication for accelerating bone fracture healing, which can reduce the delayed unions or nonunions.
Assuntos
Consolidação da Fratura/fisiologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Fatores de Transcrição SOXC/fisiologia , Adipogenia/fisiologia , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular , Movimento Celular , Sobrevivência Celular , Condrogênese/fisiologia , Fraturas do Fêmur/patologia , Fraturas do Fêmur/terapia , Consolidação da Fratura/genética , Transplante de Células-Tronco Mesenquimais , Camundongos , Camundongos Nus , Osteogênese/fisiologia , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Fatores de Transcrição SOXC/genética , Transdução de Sinais , Proteínas Smad/genética , Proteínas Smad/metabolismoRESUMO
Canonical WNT signaling stabilizes ß-catenin to determine cell fate in many processes from development onwards. One of its main roles in skeletogenesis is to antagonize the chondrogenic transcription factor SOX9. We here identify the SOXC proteins as potent amplifiers of this pathway. The SOXC genes, i.e., Sox4, Sox11, and Sox12, are coexpressed in skeletogenic mesenchyme, including presumptive joints and perichondrium, but not in cartilage. Their inactivation in mouse embryo limb bud caused massive cartilage fusions, as joint and perichondrium cells underwent chondrogenesis. SOXC proteins govern these cells cell autonomously. They replace SOX9 in the adenomatous polyposis coli-Axin destruction complex and therein inhibit phosphorylation of ß-catenin by GSK3. This inhibition, a crucial, limiting step in canonical WNT signaling, thus becomes a constitutive event. The resulting SOXC/canonical WNT-mediated synergistic stabilization of ß-catenin contributes to efficient repression of Sox9 in presumptive joint and perichondrium cells and thereby ensures proper delineation and articulation of skeletal primordia. This synergy may determine cell fate in many processes besides skeletogenesis.
Assuntos
Osteogênese , Fatores de Transcrição SOXC/fisiologia , Via de Sinalização Wnt , Animais , Cartilagem/citologia , Cartilagem/embriologia , Condrócitos/fisiologia , Células-Tronco Embrionárias/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Quinase 3 da Glicogênio Sintase/metabolismo , Células HEK293 , Humanos , Camundongos Transgênicos , Fosforilação , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , beta Catenina/genética , beta Catenina/metabolismoRESUMO
BACKGROUND/AIMS: Genetic changes leading to aberrant activation of oncogenes are viewed as a crucial step in colon cancer. Sox4, a member of Sox (Sry-box) family of transcription factors, plays a critical role in tumorigenesis. METHODS: PCR-based microarrays were used to identify potential transcriptional target of Sox4. siRNA was used to knockdown the expression of Sox4. Luciferase and chromatin immunoprecipitation (ChIP) assays were used to test the transcriptional regulations. RESULTS: PCR-based microarrays found that Cyr61, a secreted extracellular matrix-associated signaling protein, was a transcriptional target of Sox4. Overexpression of Sox4 increased, while its knockdown using small interfering RNA (siRNA) reduced Cyr61 expression. A potential Sox4 binding motif located at the proximal Cyr61 promoter was identified. CONCLUSION: Thus, our results suggest a previously unknown Sox4-Cyr61 molecular network, which may control colon cancer cell proliferation and survival.
Assuntos
Neoplasias do Colo/metabolismo , Proteína Rica em Cisteína 61/metabolismo , Fatores de Transcrição SOXC/fisiologia , Regulação para Cima/fisiologia , Sequência de Bases , Neoplasias do Colo/patologia , Primers do DNA , Humanos , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase em Tempo Real , Transdução de SinaisRESUMO
Recent studies have identified SOX11 as a novel diagnostic marker for mantle cell lymphoma (MCL). We quantified SOX11 by a truly mRNA specific qPCR assay in longitudinal peripheral blood samples from 20 patients and evidenced a close relationship of SOX11 expression and clinical status of the patients. In eight patient courses we validated the expression of SOX11 using t(11;14) and demonstrated positive correlation of SOX11 and t(11;14) levels. To the best of our knowledge this is the first report stating that quantification of SOX11 can be used as an minimal residual disease marker equal to the key translocation t(11;14) in MCL.
Assuntos
Biomarcadores Tumorais , Linfoma de Célula do Manto/diagnóstico , Fatores de Transcrição SOXC/fisiologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Estadiamento de Neoplasias , Neoplasia Residual , Translocação GenéticaRESUMO
SOX11, belonging to the family of genes SOXC, is a transcript factor involved in the embryonic neurogenesis and tissue remodeling, also participating in the control of cell proliferation. Its role in lymphomagenesis still remains unknown. Recent studies have shown aberrant SOX11 nuclear protein expression as well as mRNA levels in patients with mantle cell lymphoma (MCL). Although the majority of these lymphomas have an aggressive clinical course, there is a subgroup of patients with an indolent clinical evolution, suggesting a greater heterogeneity of this disease. Currently, there are contradictions regarding the association of SOX11 gene expression and outcome in MCL, while some authors have related the lack of SOX11 expression with good prognosis, others find it associated with an adverse clinical course. This difference in the gene expression could be associated to epigenetic mechanisms such as modifications at the histone level and DNA methylation that would allow the aberrant expression of this gene in some lymphoid neoplasias, including LCM. More knowledge of gene SOX11 in LCM will lead to a greater understanding of those mechanisms involved in the pathogenesis and progression of this lymphoma, also the involvement of SOX11 in these processes.