RESUMO
AIMS: Colon cancer poses a major threat to human health and a heavy burden on the national economy. As a member of the SOX transcription factor family, SRY-box transcription factor 21 (SOX21) is associated with various cancers, but its mechanism of action in colon cancer remains unclear. This study focused on the molecular mechanisms of transcription factor SOX21 in proliferation and metastasis of colon cancer cells. MAIN METHODS: We analyzed SOX21 expression level and its impact on survival in colon cancer patients by bioinformatics analysis. We used public databases for gene correlation, GSEA enrichment analysis. Cell function experiments (colony formation assay, wound healing assay, Transwell migration and invasion assay) were utilized to determine the impact of SOX21 silencing and over-expression on cell proliferation and metastasis. The luciferase reporter assay, CUT&RUN-qPCR assay and Methylation Specific PCR were used to explore SOX21-POU class 4 homeobox 2 (POU4F2) molecular interactions. The molecular mechanisms were verified by Quantitative real-time PCR and Western blot analysis. KEY FINDINGS: SOX21 is highly expressed and affects the overall survival of colon cancer patients. SOX21 can attenuates POU4F2 methylation state by binding with it. In addition, this interaction facilitate its transcriptional activation of Hedgehog pathway, mediates epithelial-mesenchymal transition (EMT), consequently promoting the proliferation and metastasis of colon cancer cells. SIGNIFICANCE: Our study reveals that SOX21 is an oncogenic molecule and suggests its regulatory role in colon carcinogenesis and progression, providing new insights into the treatment of this disease.
Assuntos
Proliferação de Células , Neoplasias do Colo , Transição Epitelial-Mesenquimal , Proteínas Hedgehog , Transdução de Sinais , Humanos , Transição Epitelial-Mesenquimal/genética , Neoplasias do Colo/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Metástase Neoplásica , Movimento Celular , Fatores de Transcrição SOXB2/metabolismo , Fatores de Transcrição SOXB2/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Fator 3 de Transcrição de Octâmero/genéticaRESUMO
Prostate cancer (PCa) has a certain degree of heritability, and metastasis occurs as cancer progresses. However, its underlying mechanism remains largely unknown. We sequenced four cases of cancer without metastasis, four metastatic cancer, and four benign hyperplasia tissues as controls. A total of 1839 damaging mutations were identified. Pathway analysis, gene clustering, and weighted gene co-expression network analysis were employed to find characteristics associated with metastasis. Chr19 had the most mutation density and 1p36 had the highest mutation frequency across the genome. These mutations occurred in 1630 genes, including the most frequently mutated genes TTN and PLEC, and dozens of metastasis-related genes, such as FOXA1, NCOA1, CD34, and BRCA2. Ras signalling and arachidonic acid metabolism were uniquely enriched in metastatic cancer. Gene programmes 10 and 11 showed the signatures indicating the occurrence of metastasis better. A module (135 genes) was specifically associated with metastasis. Of them, 67.41% reoccurred in program 10, with 26 genes further retained as the signature genes related to PCa metastasis, including AGR3, RAPH1, SOX14, DPEP1, and UBL4A. Our study provides new molecular perspectives on PCa metastasis. The signature genes and pathways could be served as potential therapeutic targets for metastasis or cancer progression.
Assuntos
Neoplasias da Próstata , Masculino , Humanos , RNA-Seq , Neoplasias da Próstata/patologia , Perfilação da Expressão Gênica , Mutação , Sequência de Bases , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição SOXB2/genética , Fatores de Transcrição SOXB2/metabolismoRESUMO
The pituitary gland regulates growth, metabolism, reproduction, the stress response, uterine contractions, lactation, and water retention. It secretes hormones in response to hypothalamic input, end organ feedback, and diurnal cues. The mechanisms by which pituitary stem cells are recruited to proliferate, maintain quiescence, or differentiate into specific cell types, especially thyrotropes, are not well understood. We used single-cell RNA sequencing in juvenile P7 mouse pituitary cells to identify novel factors in pituitary cell populations, with a focus on thyrotropes and rare subtypes. We first observed cells coexpressing markers of both thyrotropes and gonadotropes, such as Pou1f1 and Nr5a1. This was validated in vivo by both immunohistochemistry and lineage tracing of thyrotropes derived from Nr5a1-Cre; mTmG mice and demonstrates that Nr5a1-progenitors give rise to a proportion of thyrotropes during development. Our data set also identifies novel factors expressed in pars distalis and pars tuberalis thyrotropes, including the Shox2b isoform in all thyrotropes and Sox14 specifically in Pou1f1-negative pars tuberalis thyrotropes. We have therefore used single-cell transcriptomics to determine a novel developmental trajectory for thyrotropes and potential novel regulators of thyrotrope populations.
Assuntos
Doenças da Hipófise , Adeno-Hipófise , Gravidez , Feminino , Camundongos , Animais , Tireotropina/metabolismo , Hipófise/metabolismo , Fatores de Transcrição/metabolismo , Doenças da Hipófise/metabolismo , Imuno-Histoquímica , Adeno-Hipófise/metabolismo , Fatores de Transcrição SOXB2/metabolismoRESUMO
The SOX transcription factor family is pivotal in controlling aspects of development. To identify genotype-phenotype relationships of SOX proteins, we performed a non-biased study of SOX using 1890 open-reading frame and 6667 amino acid sequences in combination with structural dynamics to interpret 3999 gnomAD, 485 ClinVar, 1174 Geno2MP, and 4313 COSMIC human variants. We identified, within the HMG (High Mobility Group)- box, twenty-seven amino acids with changes in multiple SOX proteins annotated to clinical pathologies. These sites were screened through Geno2MP medical phenotypes, revealing novel SOX15 R104G associated with musculature abnormality and SOX8 R159G with intellectual disability. Within gnomAD, SOX18 E137K (rs201931544), found within the HMG box of ~0.8% of Latinx individuals, is associated with seizures and neurological complications, potentially through blood-brain barrier alterations. A total of 56 highly conserved variants were found at sites outside the HMG-box, including several within the SOX2 HMG-box-flanking region with neurological associations, several in the SOX9 dimerization region associated with Campomelic Dysplasia, SOX14 K88R (rs199932938) flanking the HMG box associated with cardiovascular complications within European populations, and SOX7 A379V (rs143587868) within an SOXF conserved far C-terminal domain heterozygous in 0.716% of African individuals with associated eye phenotypes. This SOX data compilation builds a robust genotype-to-phenotype association for a gene family through more robust ortholog data integration.
Assuntos
Proteínas de Grupo de Alta Mobilidade , Fatores de Transcrição SOX , Humanos , Proteínas de Grupo de Alta Mobilidade/química , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/metabolismo , Fatores de Transcrição SOX/genética , Sequência de Aminoácidos , Dimerização , Genótipo , Fatores de Transcrição SOXF/genética , Fatores de Transcrição SOXF/metabolismo , Fatores de Transcrição SOXB2/genética , Fatores de Transcrição SOXB2/metabolismo , Fatores de Transcrição SOXE/genéticaRESUMO
SOX2 expression levels are crucial for the balance between maintenance and differentiation of airway progenitor cells during development and regeneration. Here, we describe patterning of the mouse proximal airway epithelium by SOX21, which coincides with high levels of SOX2 during development. Airway progenitor cells in this SOX2+/SOX21+ zone show differentiation to basal cells, specifying cells for the extrapulmonary airways. Loss of SOX21 showed an increased differentiation of SOX2+ progenitor cells to basal and ciliated cells during mouse lung development. We propose a mechanism where SOX21 inhibits differentiation of airway progenitors by antagonizing SOX2-induced expression of specific genes involved in airway differentiation. Additionally, in the adult tracheal epithelium, SOX21 inhibits basal to ciliated cell differentiation. This suppressing function of SOX21 on differentiation contrasts SOX2, which mainly drives differentiation of epithelial cells during development and regeneration after injury. Furthermore, using human fetal lung organoids and adult bronchial epithelial cells, we show that SOX2+/SOX21+ regionalization is conserved. Lastly, we show that the interplay between SOX2 and SOX21 is context and concentration dependent leading to regulation of differentiation of the airway epithelium.
Assuntos
Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Epiteliais/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição SOXB2/genética , Fatores de Transcrição SOXB2/metabolismo , Animais , Humanos , Pulmão/crescimento & desenvolvimento , Pulmão/metabolismo , Camundongos , Células-Tronco/metabolismo , Traqueia/metabolismo , TranscriptomaRESUMO
Tegmental nuclei in the ventral midbrain and anterior hindbrain control motivated behavior, mood, memory, and movement. These nuclei contain inhibitory GABAergic and excitatory glutamatergic neurons, whose molecular diversity and development remain largely unraveled. Many tegmental neurons originate in the embryonic ventral rhombomere 1 (r1), where GABAergic fate is regulated by the transcription factor (TF) Tal1. We used single-cell mRNA sequencing of the mouse ventral r1 to characterize the Tal1-dependent and independent neuronal precursors. We describe gene expression dynamics during bifurcation of the GABAergic and glutamatergic lineages and show how active Notch signaling promotes GABAergic fate selection in post-mitotic precursors. We identify GABAergic precursor subtypes that give rise to distinct tegmental nuclei and demonstrate that Sox14 and Zfpm2, two TFs downstream of Tal1, are necessary for the differentiation of specific tegmental GABAergic neurons. Our results provide a framework for understanding the development of cellular diversity in the tegmental nuclei.
Assuntos
Neurônios GABAérgicos/metabolismo , Ácido Glutâmico/metabolismo , Rombencéfalo/metabolismo , Tegmento Mesencefálico/metabolismo , Animais , Diferenciação Celular , Linhagem da Célula , Proteínas de Ligação a DNA/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Embrião de Mamíferos/citologia , Feminino , Proteína Forkhead Box O1/metabolismo , Proteínas de Homeodomínio/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Notch/metabolismo , Fatores de Transcrição SOXB2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína 1 de Leucemia Linfocítica Aguda de Células T/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Here, we revealed the novel role of long non-coding RNAs (lncRNAs) SOX21 antisense RNA 1 (SOX21-AS1)/TSPAN8/GATA6 in progression of lung adenocarcinoma. SOX21-AS1 expression was quantified in lung adenocarcinoma tissues and cells by RT-qPCR. Then, gain- and loss-of-function experiments were conducted in lung adenocarcinoma cells. Expression of GATA6, TSPAN8 and extracellular signal-regulated kinase (ERK) signaling pathway-related genes was determined in lung adenocarcinoma cells by western blot analysis. The interaction and relationship among SOX21-AS1, GATA6 and TSPAN8 were predicted and verified respectively by RNA pull down, RIP, ChIP, and dual-luciferase reporter assays. Next, lung adenocarcinoma cell proliferation, colony formation, invasion and migration were assessed by 5-ethynyl-2'-deoxyuridine staining, colony formation assay and Transwell assay. Xenograft tumors were established in nude mice and the tumor growth was observed and recorded. SOX21-AS1 was observed to be highly expressed in lung adenocarcinoma tissues. The overexpression of SOX21-AS1, GATA6 or TSPAN8 obviously enhanced cell biological functions in lung adenocarcinoma. Meanwhile, SOX21-AS1 interacted with GATA6 which bound to TSPAN8 promoter and promoted TSPAN8 expression, which further enhanced cell colony formation, proliferation and invasion, and also activated ERK signaling pathway. Silencing of SOX21-AS1 and inhibiting its binding to GATA6 downregulate TSPAN8 and thereby exert anti-oncogenic effects in lung adenocarcinoma.
Assuntos
Adenocarcinoma de Pulmão/genética , Fator de Transcrição GATA6/genética , Inativação Gênica , Neoplasias Pulmonares/genética , RNA Longo não Codificante/genética , Tetraspaninas/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fator de Transcrição GATA6/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , MAP Quinase Quinase 1/metabolismo , Camundongos , Camundongos Nus , Invasividade Neoplásica , Transplante de Neoplasias , Fatores de Transcrição SOXB2/metabolismo , Transdução de SinaisRESUMO
Epithelial-repair-dependent mucosal healing (MH) is associated with a more favorable prognosis for patients with inflammatory bowel disease (IBD). MH is accomplished via repair and regeneration of the intestinal epithelium. However, the mechanism underlying MH is ill defined. We found a striking upregulation of peroxisomes in the injured crypts of IBD patients. By increasing peroxisome levels in Drosophila midguts, we found that peroxisome elevation enhanced RAB7-dependent late endosome maturation, which then promoted stem and/or progenitor-cell differentiation via modulation of Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT)-SOX21A signaling. This in turn enhanced ISC-mediated regeneration. Importantly, RAB7 and SOX21 were upregulated in the crypts of IBD patients. Moreover, administration of drugs that increased peroxisome levels reversed the symptoms of dextran sulfate sodium (DSS)-induced colitis in mice. This study demonstrates a peroxisome-mediated epithelial repair mechanism, which opens a therapeutic avenue for the enhancement of MH in IBD patients.
Assuntos
Diferenciação Celular , Neoplasias Colorretais/patologia , Regulação da Expressão Gênica , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/citologia , Peroxissomos/fisiologia , Células-Tronco/citologia , Adolescente , Adulto , Animais , Neoplasias Colorretais/metabolismo , Drosophila melanogaster , Feminino , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/lesões , Mucosa Intestinal/metabolismo , Janus Quinases/genética , Janus Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fatores de Transcrição SOXB2/genética , Fatores de Transcrição SOXB2/metabolismo , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Adulto Jovem , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo , proteínas de unión al GTP Rab7RESUMO
SOX14 is a member of the SOX family of transcription factors mainly involved in the regulation of neural development. Recently, it became evident that SOX14 is one of four hypermethylated genes in cervical carcinoma, considered as a tumor suppressor candidate in this type of malignancy. In this paper we elucidated the role of SOX14 in the regulation of malignant properties of cervical carcinoma cells in vitro. Functional analysis performed in HeLa cells revealed that SOX14 overexpression decreased viability and promoted apoptosis through altering the expression of apoptosis related genes. Our results demonstrated that overexpression of SOX14 initiated accumulation of p53, demonstrating potential cross-talk between SOX14 and the p53 signaling pathway. Further analysis unambiguously showed that SOX14 triggered posttranslational modification of p53 protein, as detected by the significantly increased level of phospho-p53 (Ser-15) in SOX14-overexpressing HeLa cells. Moreover, the obtained results revealed that SOX14 activated p53 protein, which was confirmed by elevated p21Waf1/Cip1, a well known target gene of p53. This study advances our understanding about the role of SOX14 and might explain the molecular mechanism by which this transcription factor could exert tumor suppressor properties in cervical carcinoma.
Assuntos
Fatores de Transcrição SOXB2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Apoptose , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Células HeLa , Humanos , Metilação , Plasmídeos/genética , Plasmídeos/metabolismo , Regiões Promotoras Genéticas , Fatores de Transcrição SOXB2/genética , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologiaRESUMO
Molecular mechanisms preventing self-renewing brain stem cells from oncogenic transformation are poorly defined. We show that the expression levels of SOX5, SOX6, and SOX21 (SOX5/6/21) transcription factors increase in stem cells of the subventricular zone (SVZ) upon oncogenic stress, whereas their expression in human glioma decreases during malignant progression. Elevated levels of SOX5/6/21 promoted SVZ cells to exit the cell cycle, whereas genetic ablation of SOX5/6/21 dramatically increased the capacity of these cells to form glioma-like tumors in an oncogene-driven mouse brain tumor model. Loss-of-function experiments revealed that SOX5/6/21 prevent detrimental hyperproliferation of oncogene expressing SVZ cells by facilitating an antiproliferative expression profile. Consistently, restoring high levels of SOX5/6/21 in human primary glioblastoma cells enabled expression of CDK inhibitors and decreased p53 protein turnover, which blocked their tumorigenic capacity through cellular senescence and apoptosis. Altogether, these results provide evidence that SOX5/6/21 play a central role in driving a tumor suppressor response in brain stem cells upon oncogenic insult. Cancer Res; 77(18); 4985-97. ©2017 AACR.
Assuntos
Neoplasias Encefálicas/patologia , Transformação Celular Neoplásica/patologia , Glioma/patologia , Células-Tronco Neoplásicas/patologia , Fatores de Transcrição SOXB2/metabolismo , Fatores de Transcrição SOXD/fisiologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Senescência Celular , Feminino , Glioma/genética , Glioma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Células-Tronco Neoplásicas/metabolismo , Oncogenes , Fatores de Transcrição SOXB2/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Homeostatic renewal of many adult tissues requires balanced self-renewal and differentiation of local stem cells, but the underlying mechanisms are poorly understood. Here we identified a novel feedback mechanism in controlling intestinal regeneration and tumorigenesis in Drosophila. Sox21a, a group B Sox protein, is preferentially expressed in the committed progenitor named enteroblast (EB) to promote enterocyte differentiation. In Sox21a mutants, EBs do not divide, but cannot differentiate properly and have increased expression of mitogens, which then act as paracrine signals to promote intestinal stem cell (ISC) proliferation. This leads to a feedback amplification loop for rapid production of differentiation-defective EBs and tumorigenesis. Notably, in normal intestine following damage, Sox21a is temporally downregulated in EBs to allow the activation of the ISC-EB amplification loop for epithelial repair. We propose that executing a feedback amplification loop between stem cells and their progeny could be a common mechanism underlying tissue regeneration and tumorigenesis.
Assuntos
Carcinogênese , Diferenciação Celular , Proteínas de Drosophila/metabolismo , Enterócitos/fisiologia , Retroalimentação , Regeneração , Fatores de Transcrição SOXB2/metabolismo , Células-Tronco/fisiologia , Animais , DrosophilaRESUMO
Stem cell self-renewal and differentiation are coordinated to maintain tissue homeostasis and prevent cancer. Mutations causing stem cell proliferation are traditionally the focus of cancer studies. However, the contribution of the differentiating stem cell progenies in tumorigenesis is poorly characterized. Here we report that loss of the SOX transcription factor, Sox21a, blocks the differentiation programme of enteroblast (EB), the intestinal stem cell progeny in the adult Drosophila midgut. This results in EB accumulation and formation of tumours. Sox21a tumour initiation and growth involve stem cell proliferation induced by the unpaired 2 mitogen released from accumulating EBs generating a feed-forward loop. EBs found in the tumours are heterogeneous and grow towards the intestinal lumen. Sox21a tumours modulate their environment by secreting matrix metalloproteinase and reactive oxygen species. Enterocytes surrounding the tumours are eliminated through delamination allowing tumour progression, a process requiring JNK activation. Our data highlight the tumorigenic properties of transit differentiating cells.
Assuntos
Carcinogênese/metabolismo , Proteínas de Drosophila/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Intestinos/citologia , Fatores de Transcrição SOXB2/metabolismo , Células-Tronco/fisiologia , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster , Janus Quinases/genética , Janus Quinases/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Mutação , Fatores de Transcrição SOXB2/genética , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
SOX14 is a member of the SOXB2 subgroup of transcription factors implicated in neural development. Although SOX14 expression profile and function during development was revealed in various animal model systems, the role of this gene during tumor progression is totally unknown. In this study, the expression of SOX14 increases in four cervical cancer cell lines (HeLa, Caski, HT-3 and SiHa) as revealed by real-time PCR and Western blot analyses. Through knocking down or overexpressing SOX14 in SiHa and HeLa cells, the expression level of SOX14 was found to be positively related to cell proliferation and invasion in vitro. Moreover, the TOP-Flash reporter assay and Western blot for ß-catenin genes of the Wnt/ß-catenin pathway, indicated that SOX14 significantly activated Wnt/ß-catenin signaling. Further study showed that the blockage of Wnt/ß-catenin pathway by knocking down ß-catenin resulted in a significant inhibition of cell proliferation and invasion capacity induced by SOX14. To summarize, these results demonstrate that SOX14 can promote proliferation and invasion capacity of cervical cancer cells by activating the Wnt/ß-catenin pathway.
Assuntos
Invasividade Neoplásica/patologia , Fatores de Transcrição SOXB2/metabolismo , Neoplasias do Colo do Útero/patologia , Via de Sinalização Wnt/fisiologia , Western Blotting , Proliferação de Células/fisiologia , Feminino , Células HeLa , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Transfecção , Neoplasias do Colo do Útero/metabolismoRESUMO
SOX14 is a member of the SOXB2 subgroup of transcription factors implicated in neural development. Although the first SOX14 gene in vertebrates was cloned and characterized more than a decade ago and its expression profile during development was revealed in various animal model systems, the role of this gene during neural development is largely unknown. In the present study we analyzed the expression of SOX14 in human NT2/D1 and mouse P19 pluripotent embryonal carcinoma cells. We demonstrated that it is expressed in both cell lines and upregulated during retinoic acid induced neural differentiation. We showed that SOX14 was expressed in both neuronal and non-neuronal differentiated derivatives, as revealed by immunocytochemistry. Since it was previously proposed that increased SOXB2 proteins level interfere with the activity of SOXB1 counteracting partners, we compared expression patterns of SOXB members during retinoic acid induction of embryonal carcinoma cells. We revealed that upregulation of SOX14 expression is accompanied by alterations in the expression patterns of SOXB1 members. In order to analyze the potential cross-talk between them, we generated SOX14 expression construct. The ectopic expression of SOX14 was demonstrated at the mRNA level in NT2/D1, P19 and HeLa cells, while an increased level of SOX14 protein was detected in HeLa cells only. By transient transfection experiments in HeLa cells we showed for the first time that ectopic expression of SOX14 repressed SOX1 expression, whereas no significant effect on SOX2, SOX3 and SOX21 was observed. Data presented here provide an insight into SOX14 expression during in vitro neural differentiation of embryonal carcinoma cells and demonstrate the effect of its ectopic expression on protein levels of SOXB members in HeLa cells. Obtained results contribute to better understanding the role of one of the most conserved SOX proteins.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células-Tronco de Carcinoma Embrionário/metabolismo , Células-Tronco de Carcinoma Embrionário/patologia , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição SOXB2/genética , Tretinoína/farmacologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Biomarcadores/metabolismo , Linhagem Celular , Células-Tronco de Carcinoma Embrionário/efeitos dos fármacos , Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Células HeLa , Humanos , Imuno-Histoquímica , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Fatores de Transcrição SOXB2/metabolismoRESUMO
Sox2 is an important transcriptional regulator in embryonic and adult stem cells. Recently, Sox2 was identified as an oncogene in many endodermal cancers, including colon cancer. There is great interest in how Sox2 cooperates with other transcription factors to regulate stem cell renewal, differentiation, and reprogramming. However, we still lack a general understanding of Sox2 transcriptional action. To determine transcriptional partners of Sox2 in adult cells, we generated mice where gene expression could be induced by an externally applied stimulus. We analyzed the consequences in the intestine where cell turnover is rapid. Sox2 expression, but not Oct4, specifically increased the numbers of stem cells and repressed Cdx2, a master regulator of endodermal identity. In vivo studies demonstrated that Sox21, another member of the SoxB gene family, was a specific, immediate, and cell-autonomous target of Sox2 in intestinal stem cells. In vitro experiments showed that Sox21 was sufficient to repress Cdx2 in colon cancer cells and in pluripotent stem cells. Sox21 was also specifically induced by Sox2 in fibroblasts and inhibition of Sox21 blocked reprogramming to the pluripotent state. These results show that transcriptional induction of Sox21 is a rapid and general mediator of the effects of Sox2 on cell identity in a wide range of cell types.