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1.
Med Oncol ; 36(11): 92, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31560094

RESUMO

Although MYC proto-oncogene (C-MYC) amplification has been consistently reported to be a potential marker for prostate cancer (PCa) progression and prognosis, the clinicopathological and prognostic significance of C-MYC protein expression remains controversial. Overexpression of SOX4 has been shown to play important roles in multiple cancers including PCa. However, the link between these two critical genetic aberrations is unclear. In the current study, we showed that C-MYC was overexpressed in 16.2% (17/105) of Chinese patients with localized PCa. Overexpression of C-MYC was significantly associated with high Gleason scores (P = 0.012) and high Ki67 labeling index (P = 0.005). C-MYC overexpression was correlated with cancer-related mortality and suggested to be an unfavorable prognostic factor in Chinese PCa patients (P = 0.018). Overexpression of C-MYC is associated with SOX4 overexpression in PCa tissues. Notably, SOX4 is a direct target gene of C-MYC; C-MYC activates SOX4 expression via binding to its promoter. In addition, Co-IP analysis demonstrated a physical interaction between C-MYC and SOX4 protein in PCa cells. Clinically, C-MYC+/SOX4+ characterized poor prognosis in a subset of PCa patients. In total, C-MYC overexpression may contribute to PCa progression by activating SOX4. Our findings highlight an important role of C-MYC/SOX4 in PCa progression in a subset of PCa patients.


Assuntos
Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-myc/biossíntese , Fatores de Transcrição SOXC/biossíntese , Idoso , Linhagem Celular Tumoral , Células HEK293 , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Análise Serial de Tecidos
2.
Braz J Med Biol Res ; 52(10): e8631, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31531526

RESUMO

The long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3), a tumor suppressor, is critical for the carcinogenesis and progression of different cancers, including hepatocellular carcinoma (HCC). To date, the roles of lncRNA MEG3 in HCC are not well illustrated. Therefore, this study used western blot and qRT-PCR to evaluate the expression of MEG3, miR-9-5p, and Sex determining Region Y-related HMG-box 11 (SOX11) in HCC tissues and cell lines. RNA pull-down and luciferase reporter assay were used to evaluate these molecular interactions. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and flow cytometry detected the viability and apoptosis of HCC cells, respectively. The results showed that MEG3 and SOX11 were poorly expressed but miR-9-5p was highly expressed in HCC. The expression levels of these molecules suggested a negative correlation between MEG3 and miR-9-5p and a positive correlation with SOX11, confirmed by Pearson's correlation analysis and biology experiments. Furthermore, MEG3 could combine with miR-9-5p, and SOX11 was a direct target of miR-9-5p. Moreover, MEG3 over-expression promoted cell apoptosis and growth inhibition in HCC cells through sponging miR-9-5p to up-regulate SOX11. Therefore, the interactions among MEG3, miR-9-5p, and SOX11 might offer a novel insight for understanding HCC pathogeny and provide potential diagnostic markers and therapeutic targets for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Fatores de Transcrição SOXC/genética , Apoptose/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Longo não Codificante/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição SOXC/metabolismo , Ativação Transcricional , Transfecção , Regulação para Cima
3.
Nat Commun ; 10(1): 4042, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492871

RESUMO

Tissue injury induces changes in cellular identity, but the underlying molecular mechanisms remain obscure. Here, we show that upon damage in a mouse model, epidermal cells at the wound edge convert to an embryonic-like state, altering particularly the cytoskeletal/extracellular matrix (ECM) components and differentiation program. We show that SOX11 and its closest relative SOX4 dictate embryonic epidermal state, regulating genes involved in epidermal development as well as cytoskeletal/ECM organization. Correspondingly, postnatal induction of SOX11 represses epidermal terminal differentiation while deficiency of Sox11 and Sox4 accelerates differentiation and dramatically impairs cell motility and re-epithelialization. Amongst the embryonic genes reactivated at the wound edge, we identify fascin actin-bundling protein 1 (FSCN1) as a critical direct target of SOX11 and SOX4 regulating cell migration. Our study identifies the reactivated embryonic gene program during wound repair and demonstrates that SOX11 and SOX4 play a central role in this process.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Fatores de Transcrição SOXC/genética , Cicatrização/genética , Ferimentos e Lesões/genética , Animais , Diferenciação Celular/genética , Movimento Celular/genética , Citoesqueleto/metabolismo , Células Epidérmicas/citologia , Células Epidérmicas/metabolismo , Epiderme/embriologia , Epiderme/metabolismo , Matriz Extracelular , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Receptores Odorantes/genética , Receptores Odorantes/metabolismo , Fatores de Transcrição SOXC/metabolismo , Ferimentos e Lesões/embriologia
4.
DNA Cell Biol ; 38(9): 1013-1021, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31386568

RESUMO

Increasing evidence has indicated that long noncoding RNAs (lncRNAs) could participate in diverse cancers. Among these, lymphoid enhancer-binding factor 1 antisense RNA 1 (LEF1-AS1) was recently identified as an oncogenic lncRNA, but little is known about its function in non-small-cell lung cancer (NSCLC). In the present study, we found that LEF1-AS1 was markedly upregulated in lung cancer tissues and could promote NSCLC cell proliferation and migration in vivo and in vitro. LEF1-AS1 could bind with miR-489 and further negatively regulate miR-489 to promote SRY-related HMG box transcription factor 4 (SOX4) expression. In conclusion, these data suggested that LEF1-AS1 promoted NSCLC tumorigenesis dependent on the miR-489-SOX4 axis and implicated the potential application of LEF1-AS1 for the prognosis and treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Fator 1 de Ligação ao Facilitador Linfoide/genética , RNA Antissenso/genética , RNA Longo não Codificante/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Regulação para Cima
5.
DNA Cell Biol ; 38(10): 1125-1133, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31408364

RESUMO

Mammary gland involution is a regressive process for the gland to return to its prepregnancy state after lactation and comprises an initial reversible and second remodeling stage. Although many genes and the multiple expression profiles of their mRNAs have been found in this process, the mechanisms controlling the profiles are largely unknown. In this study, we identified and analyzed transcription factor Sox4 in mammary gland involution. Elevated expression of Sox4 gene in the first stage (48 h after weaning) was observed at the mRNA and protein levels in the mouse mammary gland. Immunohistochemistry of the involuting gland indicated that Sox4 was located in the nuclei of epithelial cells. Nuclear Sox4 was also detected in the second stage, but unlikely to be involved in cell death, one of the characteristic events of involution. To clarify the functional roles of Sox4 in involution, we introduced a model, including a normal mammary epithelial cell line, for finding candidate target genes of this transcription factor and examined its effect on tenascin C mRNA expression.


Assuntos
Núcleo Celular/genética , Glândulas Mamárias Animais/metabolismo , RNA Mensageiro/genética , Fatores de Transcrição SOXC/genética , Tenascina/genética , Animais , Animais Recém-Nascidos , Morte Celular , Linhagem Celular , Núcleo Celular/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Lactação/fisiologia , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Camundongos , Gravidez , Ligação Proteica , RNA Mensageiro/metabolismo , Fatores de Transcrição SOXC/metabolismo , Tenascina/metabolismo , Transcrição Genética , Desmame
6.
Int J Oncol ; 55(2): 359-370, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268162

RESUMO

Sry­Related HMG­BOX­4 (SOX4) is a developmental transcription factor that is overexpressed in as many as 23% of bladder cancer patients; however, the role of SOX4 in bladder cancer tumorigenesis is not yet well understood. Given the many roles of SOX4 in embryonic development and the context­dependent regulation of gene expression, in this study, we sought to determine the role of SOX4 in bladder cancer and to identify SOX4­regulated genes that may contribute to tumorigenesis. For this purpose, we employed a CRISPR interference (CRISPRi) method to transcriptionally repress SOX4 expression in T24 bladder cancer cell lines, 'rescued' these cell lines with the lentiviral­mediated expression of SOX4, and performed whole genome expression profiling. The cells in which SOX4 was knocked down (T24­SOX4­KD) exhibited decreased invasive capabilities, but no changes in migration or proliferation, whereas rescue experiments with SOX4 lentiviral vector restored the invasive phenotype. Gene expression profiling revealed 173 high confidence SOX4­regulated genes, including WNT5a as a potential target of repression by SOX4. Treatment of the T24­SOX4­KD cells with a WNT5a antagonist restored the invasive phenotype observed in the T24­scramble control cells and the SOX4 lentiviral­rescued cells. High WNT5a expression was associated with a decreased invasion and WNT5a expression inversely correlated with SOX4 expression, suggesting that SOX4 can negatively regulate WNT5a levels either directly or indirectly and that WNT5a likely plays a protective role against invasion in bladder cancer cells.


Assuntos
Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição SOXC/metabolismo , Neoplasias da Bexiga Urinária/patologia , Proteína Wnt-5a/metabolismo , Apoptose , Humanos , Invasividade Neoplásica , Prognóstico , RNA Interferente Pequeno/genética , Fatores de Transcrição SOXC/antagonistas & inibidores , Fatores de Transcrição SOXC/genética , Células Tumorais Cultivadas , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Proteína Wnt-5a/genética
7.
Int J Mol Med ; 44(1): 185-195, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059001

RESUMO

MicroRNAs (miRs) are small, non­coding RNAs that can act as oncogenes or tumor suppressor genes in human cancer. Recent studies have revealed that miR­199a­5p is abnormally expressed in various types of human cancer; however, the potential role of miR­199a­5p in oral squamous cell carcinoma (OSCC) remains elusive. The present study investigated the role of miR­199a­5p in OSCC cells and explored the potential molecular mechanism. Reverse transcription­quantitative polymerase chain reaction was used to measure miR­199a­5p expression in OSCC tissues and adjacent normal oral epithelial tissues. Cell invasion and migration were evaluated using Transwell invasion and wound­healing assays in OSCC cells post­transfection with miR­199a­5p mimics or negative control mimics. In addition, a luciferase reporter assay was conducted to identify the target gene of miR­199a­5p in OSCC cells. The results demonstrated that miR­199a­5p expression was significantly downregulated in OSCC tissues and cell lines, and was associated with tumor progression in OSCC. Furthermore, overexpression of miR­199a­5p inhibited cell invasion and migration, and blocked the epithelial­mesenchymal transition (EMT) cascade. Notably, the results revealed that the EMT­related transcription factor SRY­box 4 (SOX4) was a direct target gene of miR­199a­5p, as determined by the direct binding of miR­199a­5p with the 3'­untranslated region of SOX4. In addition, knockdown of SOX4 by small interfering RNA­SOX4 suppressed proliferation, migration and invasion of OSCC cells. Conversely, overexpression of SOX4 rescued the suppressive effects of miR­199a­5p on cell migration and invasion. Collectively, these data indicated that miR­199a­5p may inhibit the migration and invasion of OSCC cells via targeting the EMT­related transcription factor SOX4, thus suggesting that miR­199a­5p may serve as a prognostic biomarker and therapeutic target in the treatment of OSCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Movimento Celular , Transição Epitelial-Mesenquimal , MicroRNAs/metabolismo , Neoplasias Bucais/metabolismo , Proteínas de Neoplasias/metabolismo , RNA Neoplásico/metabolismo , Fatores de Transcrição SOXC/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Invasividade Neoplásica , Proteínas de Neoplasias/genética , RNA Neoplásico/genética , Fatores de Transcrição SOXC/genética
8.
Pathol Res Pract ; 215(7): 152442, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31078342

RESUMO

OBJECTIVE: Osteoarthritis (OA) is a degenerative disease and the molecular mechanism of OA remains unclear. Transcription factor SOX11 has been proved to be involved in the development progress of OA. The present study aimed to evaluate the potential function of SOX11 during the development of OA. METHODS: SOX11 expression in patients with OA and health donator was determined with qRT-PCR. Subsequently, in vitro OA model was established by treating the chondrocyte cells CHON-001 with IL-1ß. Next, we validated the function of SOX11 in in vitro OA model by using siRNAs. Finally, the relationship between SOX11 and TNF-α was explored. RESULTS: SOX11 was upregulated in patients with OA and in IL-1ß treated cells. IL-1ß significantly increased both the mRNA and protein levels of MMP13 and cleaved caspase 3, while decreased collagen II and aggrecan in CHON-001 cells. In addition, knockdown of SOX11 could significantly decrease IL-1ß-induced apoptosis in CHON-001 cells. Meanwhile, IL-1ß induced OA like phenomenon was significantly reversed by siRNA interference. Moreover, inhibition of SOX11 decreased the level of TNF-α in patients with OA and in IL-1ß treated cell supernatant. CONCLUSION: Inhibition of SOX11 could improve IL-1ß-induced OA like phenomenon in CHON-001 cells, which suggesting SOX11 played an important role during the pathogenesis of OA. Thus, we hypothesized that SOX11 could be a potential target for the treatment of patients with OA.


Assuntos
Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Osteoartrite do Joelho/metabolismo , Fatores de Transcrição SOXC/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Agrecanas/metabolismo , Apoptose/efeitos dos fármacos , Cartilagem Articular/patologia , Caspase 3/metabolismo , Linhagem Celular , Condrócitos/efeitos dos fármacos , Colágeno Tipo II/metabolismo , Humanos , Interleucina-1beta/farmacologia , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Osteoartrite do Joelho/patologia , RNA Interferente Pequeno , Fatores de Transcrição SOXC/genética
9.
Biochimie ; 162: 8-14, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30935961

RESUMO

We previously reported that SOX4 is overexpressed in endometrial cancer and that it partially contributes to hypermethylation of miR-129-2 and miR-203. The current study seeks to identify methylation and expression levels of the SOX gene family in endometrial carcinomas. Methylation levels of the 16 SOX gene family members were measured by combining bisulfite restriction analysis (COBRA), MassARRAY, and pyrosequencing assays of cell lines and endometrial cancer samples. Gene expression was determined by RT-qPCR. The methylation level of the SOX11 locus was correlated with clinicopathologic factors in primary endometrial tumors and in TCGA endometrial cohort. It was also examined in DNA of serum and endometrial specimens from a longitudinal cohort of early stage endometrial cancer patients. COBRA assays indicated that hypermethylation of SOX1, SOX2, SOX11, SOX14, SOX15, SOX17, and SOX18 was present in endometrial cancer cell lines and not in the normal control. SOX11 expression was reactivated only by a DNA methylation inhibitor. Moreover, aberrant DNA methylation of SOX11 was detected in the majority of endometrioid endometrial carcinomas (n=114) and none of the 22 adjacent normal endometrial samples (P<0.0001). The methylation status of SOX11 associated significantly with microsatellite instability and MLH1 methylation in endometrial tumors (P<0.0001), and this finding was validated in TCGA endometrial cohort. Furthermore, SOX11 was not hypermethylated in serum DNA from early stage endometrial cancer patients. This study found that hypermethylation of SOX11 is common in endometrial carcinomas and strongly associates with microsatellite instability and MLH1 methylation.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Neoplasias do Endométrio/genética , Instabilidade de Microssatélites , Fatores de Transcrição SOXC/genética , Linhagem Celular Tumoral , Estudos de Coortes , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estudos Longitudinais , Proteína 1 Homóloga a MutL/genética
10.
J BUON ; 24(1): 249-255, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941977

RESUMO

PURPOSE: To explore the regulatory roles of microRNA-140 and SOX4 in prostate cancer (PCa) tissues and paracancerous tissues, and their underlying mechanism. METHODS: MicroRNA-140 expressions in PCa tissues, paracancerous tissues and PCa cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Proliferation, apoptosis and cell cycle of PCa cells after altering expressions of microRNA-140 and SOX4 were detected by MTT assay and flow cytometry, respectively. The regulatory effect of microRNA-140 on SOX4 was detected by Western blot and qRT-PCR. The binding condition of microRNA-140 on SOX4 was verified by luciferase reporter gene assay. RESULTS: MicroRNA-140 was downregulated in PCa tissues compared to paracancerous tissues. In particular, lower expression of microRNA-140 was found in PCa with Grade I+II compared to Grade III+IV. In vitro, microRNA-140 expression was negatively correlated with proliferative and invasive abilities, while positively correlated with apoptosis of PCa cells. MicroRNA-140 promoted cell cycle arrest in G0/G1 phase. SOX4 expression was inhibited by microRNA-140 overexpression in PCa cells. CONCLUSIONS: Downregulated microRNA-140 promotes proliferation and cell cycle arrest, but inhibits apoptosis of PCa cells. MicroRNA-140 inhibits PCa development via degrading SOX4.


Assuntos
Apoptose , Pontos de Checagem do Ciclo Celular , Proliferação de Células , MicroRNAs/genética , Neoplasias da Próstata/patologia , Fatores de Transcrição SOXC/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteólise , Fatores de Transcrição SOXC/genética , Células Tumorais Cultivadas
11.
J Exp Clin Cancer Res ; 38(1): 138, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30922366

RESUMO

BACKGROUND: SOX11 is a transcription factor that plays an important role in mantle cell lymphoma development. However, its functional role in head and neck squamous cell carcinoma (HNSCC) remains unknown. METHODS: Protein expression was measured with Western blotting, immunohistochemistry or quantitative proteomics, and gene expression was measured with quantitative RT-PCR. Functional role of SOX11 in HNSCC was evaluated with MTS/apoptosis, migration, invasion assays and a xenograft model. A SOX11-targeting gene, SDCCAG8, was confirmed with chromatin immunoprecipitation (ChIP), luciferase reporter and rescue assays. RESULTS: SOX11 was up-regulated in recurrent versus primary HNSCC and in highly invasive versus low invasive HNSCC cell lines. Silencing SOX11 in HNSCC cell lines significantly inhibited the cell proliferation, migration, invasion and resistance to Cisplatin, and vice versa. Quantitative proteomic analysis of SOX11-silencing HNSCC cells revealed a number of differentially expressed proteins, including a down-regulated tumor antigen SDCCAG8. Silencing of SDCCAG8 in HNSCC cells also significantly inhibited the cell proliferation, migration and invasion, and vice versa. ChIP assays demonstrated that endogenous SOX11 strongly bound to Sdccag8 gene promoter in highly invasive HNSCC cells. When over-expressed in low invasive HNSCC cells, wild type SOX11 but not mutant SOX11 induced the promoter activity of Sdccag8 and significantly induced the expression of SDCCAG8. However, exogenous mutant SOX11 abolished the expression of SDCCAG8 in highly invasive HNSCC cells. In addition, the inhibitory effects of SOX11 knockdown were partially rescued by over-expression of SDCCAG8 in HNSCC cells. CONCLUSION: Collectively, our findings indicate SOX11 promotes HNSCC progression via the regulation of SDCCAG8.


Assuntos
Autoantígenos/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Proteínas de Neoplasias/metabolismo , Fatores de Transcrição SOXC/metabolismo , Regulação para Cima , Animais , Autoantígenos/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Camundongos , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Fatores de Transcrição SOXC/genética
12.
Mol Cancer ; 18(1): 45, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30922402

RESUMO

BACKGROUND: Circular RNAs (circRNAs) are a novel type of noncoding RNAs and play important roles in tumorigenesis, including gastric cancer (GC). However, the functions of most circRNAs remain poorly understood. In our study, we aimed to investigate the functions of a new circRNA circ-DONSON in GC progression. METHODS: The expression of circ-DONSON in gastric cancer tissues and adjacent normal tissues was analyzed by bioinformatics method, qRT-PCR, Northern blotting and in situ hybridization (ISH). The effects of circ-DONSON on GC cell proliferation, apoptosis, migration and invasion were measured by using CCK8, colony formation, EdU, immunofluorescence (IF), FACS and Transwell assays. qRT-PCR and Western blotting were utilized to validate how circ-DONSON regulates SOX4 expression. ChIP, DNA fluorescence in situ hybridization (DNA-FISH) and DNA accessibility assays were used to investigate how circ-DONSON regulates SOX4 transcription. The interaction between circ-DONSON and NURF complex was evaluated by mass spectrum, RNA immunoprecipitation (RIP), pulldown and EMSA assays. Xenograft mouse model was used to analyze the effect of circ-DONSON on GC growth in vivo. RESULTS: Elevated expression of circ-DONSON was observed in GC tissues and positively associated with advanced TNM stage and unfavorable prognosis. Silencing of circ-DONSON significantly suppressed the proliferation, migration and invasion of GC cells while promoting apoptosis. circ-DONSON was localized in the nucleus, recruited the NURF complex to SOX4 promoter and initiated its transcription. Silencing of the NURF complex subunit SNF2L, BPTF or RBBP4 similarly attenuated GC cell growth and increased apoptosis. circ-DONSON knockdown inhibited GC growth in vivo. CONCLUSION: circ-DONSON promotes GC progression through recruiting the NURF complex to initiate SOX4 expression.


Assuntos
Antígenos Nucleares/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/genética , RNA/genética , Proteína 4 de Ligação ao Retinoblastoma/metabolismo , Fatores de Transcrição SOXC/metabolismo , Neoplasias Gástricas/patologia , Fatores de Transcrição/metabolismo , Animais , Antígenos Nucleares/genética , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA/genética , Progressão da Doença , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Proteínas do Tecido Nervoso/genética , Prognóstico , Proteína 4 de Ligação ao Retinoblastoma/genética , Fatores de Transcrição SOXC/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Taxa de Sobrevida , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(1): 20-24, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-30738442

RESUMO

OBJECTIVE: To study the expression of SOX4 gene in patients with acute myeloid leukemia (AML) and its correlation with clinical features and prognosis, and to explore the role of this gene in acute myeloid leukemia. METHODS: The real-time guantitative PCR was used to detect the expression level of SOX4 gene in bone marrow of 96 patients with newby diagmsed AML, and the features and prognosis was analyzed. RESULTS: The level of SOX4 expression in the 96 AML patients was significantly higher than that in healthy controls (P<0.01), and the expression of SOX4 gene was not significanly different between M1-M5 (P<0.05). The expression of SOX4 gene was no significanly different between different sex, nationality, and remission after chemotherapy (P>0.05). In AML patients the SOX4 gene expression level did not significantly correlated with the white blood cell count, hemoglobin level, platelet count primitive cell count, reticulocyte count and other laboratory indexes ( P>0.05), while which correlated with the overall survival (OS) (P<0.01) and erent-free survival (EFS) (P<0.05). CONCLUSION: The high expression of SOX4 gene affects the survival time of patients (OS, EFS), suggesting that may be one of the unfavorable prognostic factors for the AML patients.


Assuntos
Leucemia Mieloide Aguda , Fatores de Transcrição SOXC/genética , Medula Óssea , Humanos , Contagem de Leucócitos , Prognóstico , Fatores de Transcrição SOXC/metabolismo
14.
Med Sci Monit ; 25: 1410-1422, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30793707

RESUMO

BACKGROUND Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a functional long non-coding RNA involved in many biologic processes. The study was aimed to explore the functional roles of MALAT1 in osteosarcoma progression. MATERIAL AND METHODS A total of 76 osteosarcoma tissues and paired adjacent non-tumor tissues were collected from surgical resection. MALAT1, miRNAs, and genes mRNA expression levels were detected using quantitative real-time PCR (qRT-PCR). Protein expression level, cell proliferation, migration, and invasion were assessed using western blot, Cell Counting Kit-8 (CCK-8), wound-healing assay, and Matrigel invasion assay respectively. The target relationships among miRNAs, MALAT1, and mRNA were detected via dual-luciferase reporter assay. RESULTS We found that MALAT1 was frequently upregulated in osteosarcoma samples and cell lines and a high level of MALAT1 predicted poor overall survival in osteosarcoma patients. Knockdown of MALAT1 inhibited proliferation, migration, and invasion of osteosarcoma cells. Further study showed a positive correlation between MALAT1 and c-Met or SOX4 expression. Mechanistic investigations demonstrated that MALAT1, as a competing endogenous RNA (ceRNA), regulated osteosarcoma proliferation and metastasis through competitively binding to miR-34a/c-5p and miR-449a/b. CONCLUSIONS Taken together, our study illustrates a new regulatory mechanism for MALAT1 and may provide a novel therapeutic strategy for the treatment of osteosarcoma.


Assuntos
Neoplasias Ósseas/metabolismo , MicroRNAs/metabolismo , Osteossarcoma/metabolismo , RNA Longo não Codificante/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Fatores de Transcrição SOXC/metabolismo , Adolescente , Adulto , Apoptose/fisiologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Criança , Feminino , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Osteossarcoma/genética , Osteossarcoma/patologia , RNA Longo não Codificante/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores Proteína Tirosina Quinases/genética , Fatores de Transcrição SOXC/genética , Transdução de Sinais , Regulação para Cima
15.
Oncol Rep ; 41(4): 2351-2360, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30720133

RESUMO

The development of cervical cancer (CC) is a multi­gene, multi­step carcinogenic process that involves complex genetic and epigenetic mechanisms. SRY­related HMG­box gene 11 (SOX11) is a member of the SOX family of transcription factors with an emerging crucial role in the development of various tumor types. To elucidate the function of SOX11 in cervical carcinogenesis, the expression level of SOX11 during the development of human CC was analyzed by immunohistochemistry and western blot analysis. Additionally, the methylation status of the SOX11 was examined using bisulfite sequencing and methylation­specific polymerase chain reaction. The SOX11 expression and promoter methylation in human CC cell lines were also determined. The effect of SOX11 expression restoration after 5­aza­2'­deoxycytidine (5­Aza­dC) treatment on the CC cell proliferation ability was evaluated in CC cell lines. SOX11 was highly expressed in normal cervix (NC) and precancerous low­grade squamous intraepithelial lesions, but weakly expressed or virtually absent in precancerous high­grade squamous intraepithelial lesions and CC, which is consistent with the result of the western blot analysis. Hypermethylation of the SOX11 promoter was detected in CC, which was significantly higher than that in NC samples at each CpG site. The expression level of SOX11 in the CC cell lines was downregulated compared with the positive control, Tera­1human teratoma cell line. Upon 5­Aza­dC treatment, SOX11 expression was significantly upregulated in the CC cell lines at the mRNA and protein levels, and cell proliferation was inhibited. The results indicated that the downregulation of SOX11 in CC is due to the hypermethylation of the SOX11 promoter region. Thus, SOX11 methylation may have a role in the growth of CC cells and cervical carcinogenesis.


Assuntos
Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição SOXC/genética , Proteínas Supressoras de Tumor/genética , Neoplasias do Colo do Útero/genética , Adulto , Azacitidina/farmacologia , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Colo do Útero/patologia , Ilhas de CpG/genética , Metilação de DNA/efeitos dos fármacos , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Epigênese Genética , Feminino , Humanos , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Fatores de Transcrição SOXC/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima/efeitos dos fármacos , Neoplasias do Colo do Útero/patologia
16.
Cell Tissue Res ; 376(2): 247-255, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30617615

RESUMO

Cartilage has a limited capacity to heal. Previously, we have shown that overexpression of Sox11 in rMSCs (Rat Mesenchymal Stem Cells) by lentivirus-mediated gene transfer leads to enhanced tri-lineage differentiation and accelerated bone formation in fracture model of rats. We observed that the fracture repair in the rats that received Sox11-modified rMSCs injection proceeded through an endochondral ossification process much faster than those in the control groups. However, the detailed role of Sox11 in rMSCs chondrogenic differentiation, as well as cartilage defect, is still not clearly clarified. Therefore, this study tests the hypothesis that Sox11 promotes chondrogenesis and cartilage defect repair by regulating ß-catenin. Sox11 was transduced into rMSCs using lentiviruses. The expression levels of ß-catenin and its downstream genes were evaluated by quantitative RT-PCR. The transcriptional activation of ß-catenin was proved by dual-luciferase reporter assay and co-immunoprecipitation was performed to evaluate Sox11-ß-catenin interaction. In addition, a cartilage defect model in SD rats was used to evaluate the cartilage regeneration ability of Sox11-modified rMSCs in vivo. We found that Sox11 transcriptionally activated ß-catenin expression and discovered the core promoter region (from - 242 to - 1414) of ß-catenin gene for Sox11 binding. In addition, Sox11 might regulate ß-catenin at the post-transcriptional level by protein-protein interaction. Finally, using a cartilage defect model in rats, we found Sox11-modified rMSCs could improve cartilage regeneration. Taken together, our study shows that Sox11 is an important regulator of chondrogenesis and Sox11-modified rMSCs may have clinical implication for accelerating cartilage defect healing.


Assuntos
Cartilagem/fisiologia , Condrogênese , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Osteoartrite/terapia , Fatores de Transcrição SOXC/metabolismo , Animais , Diferenciação Celular , Terapia Genética , Modelos Animais , Osteogênese , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição SOXC/genética , Transcrição Genética , beta Catenina/genética
17.
Am J Hum Genet ; 104(2): 246-259, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30661772

RESUMO

SOX4, together with SOX11 and SOX12, forms group C of SRY-related (SOX) transcription factors. They play key roles, often in redundancy, in multiple developmental pathways, including neurogenesis and skeletogenesis. De novo SOX11 heterozygous mutations have been shown to cause intellectual disability, growth deficiency, and dysmorphic features compatible with mild Coffin-Siris syndrome. Using trio-based exome sequencing, we here identify de novo SOX4 heterozygous missense variants in four children who share developmental delay, intellectual disability, and mild facial and digital morphological abnormalities. SOX4 is highly expressed in areas of active neurogenesis in human fetuses, and sox4 knockdown in Xenopus embryos diminishes brain and whole-body size. The SOX4 variants cluster in the highly conserved, SOX family-specific HMG domain, but each alters a different residue. In silico tools predict that each variant affects a distinct structural feature of this DNA-binding domain, and functional assays demonstrate that these SOX4 proteins carrying these variants are unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. These variants are not found in the gnomAD database of individuals with presumably normal development, but 12 other SOX4 HMG-domain missense variants are recorded and all demonstrate partial to full activity in the reporter assay. Taken together, these findings point to specific SOX4 HMG-domain missense variants as the cause of a characteristic human neurodevelopmental disorder associated with mild facial and digital dysmorphism.


Assuntos
Anormalidades Múltiplas/genética , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição SOXC/genética , Sequência de Aminoácidos , Animais , Criança , Pré-Escolar , Síndrome de Coffin-Lowry/genética , Estudos de Coortes , Sequência Conservada , DNA/genética , DNA/metabolismo , Feminino , Domínios HMG-Box/genética , Heterozigoto , Humanos , Masculino , Fatores de Transcrição SOX/química , Fatores de Transcrição SOX/genética , Fatores de Transcrição SOXC/química , Fatores de Transcrição SOXC/metabolismo , Ativação Transcricional , Xenopus/anatomia & histologia , Xenopus/embriologia , Xenopus/genética , Proteínas de Xenopus/química , Proteínas de Xenopus/genética
18.
Biotechnol Appl Biochem ; 66(2): 240-246, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30517979

RESUMO

Hepatocellular carcinoma (HCC) is the most common type of liver cancer with high mortality. Identifying key molecules involved in the regulation of HCC development is of great clinical significance. SOX11 is a transcription factor belonging to group C of Sry-related high mobility group box family whose abnormal expression is frequently seen in many kinds of human cancers. Here, we noted that the expression of SOX11 was decreased in human HCC tumors compared with that in matched normal tissues. Overexpression of SOX11 promoted growth inhibition and apoptosis in HCC cell line HuH-7. Mechanistically, SOX11 enhanced the expression of nemo-like kinase and the phosphorylation of TCF4, thereby blunting the activation of oncogenic Wnt/ß-catenin signaling pathway in HuH-7 cells. Finally, SOX11 was also found to sensitize HuH-7 cells to chemotherapy drugs cisplatin and 5-fluorouraci. Therefore, our study identifies SOX11 as a potential tumor suppressor in HCC and may hopefully be beneficial for the clinical diagnosis or treatment of HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição SOXC/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Via de Sinalização Wnt , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Fatores de Transcrição SOXC/genética , Proteínas Supressoras de Tumor/genética , beta Catenina/genética , beta Catenina/metabolismo
19.
Blood ; 133(4): 306-318, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30530749

RESUMO

The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the SOX11 locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)-induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11+ MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL.


Assuntos
Ciclina D1/metabolismo , Linfoma de Célula do Manto/genética , Fatores de Transcrição SOXC/genética , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatina/metabolismo , Regulação Neoplásica da Expressão Gênica , Loci Gênicos , Células HEK293 , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Histonas/metabolismo , Humanos , Interleucinas/farmacologia , Fosfotirosina/metabolismo , Ligação Proteica , Processamento de Proteína Pós-Traducional , Fatores de Transcrição SOXC/metabolismo , Regulação para Cima/genética
20.
Dev Biol ; 446(1): 68-79, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30529252

RESUMO

The specialized sensory organs of the vertebrate head are derived from thickened patches of cells in the ectoderm called cranial sensory placodes. The developmental program that generates these placodes and the genes that are expressed during the process have been studied extensively in a number of animals, yet very little is known about how these genes regulate one another. We previously found via a microarray screen that Six1, a known transcriptional regulator of cranial placode fate, up-regulates Irx1 in ectodermal explants. In this study, we investigated the transcriptional relationship between Six1 and Irx1 and found that they reciprocally regulate each other throughout cranial placode and otic vesicle formation. Although Irx1 expression precedes that of Six1 in the neural border zone, its continued and appropriately patterned expression in the pre-placodal region (PPR) and otic vesicle requires Six1. At early PPR stages, Six1 expands the Irx1 domain, but this activity subsides over time and changes to a predominantly repressive effect. Likewise, Irx1 initially expands Six1 expression in the PPR, but later represses it. We also found that Irx1 and Sox11, a known direct target of Six1, reciprocally affect each other. This work demonstrates that the interactions between Six1 and Irx1 are continuous during PPR and placode development and their transcriptional effects on one another change over developmental time.


Assuntos
Orelha Interna/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas do Tecido Nervoso/genética , Placa Neural/metabolismo , Fatores de Transcrição/genética , Proteínas de Xenopus/genética , Animais , Orelha Interna/citologia , Orelha Interna/embriologia , Ectoderma/citologia , Ectoderma/embriologia , Ectoderma/metabolismo , Embrião não Mamífero/citologia , Embrião não Mamífero/embriologia , Embrião não Mamífero/metabolismo , Cabeça/embriologia , Proteínas de Homeodomínio/metabolismo , Hibridização In Situ , Proteínas do Tecido Nervoso/metabolismo , Placa Neural/citologia , Placa Neural/embriologia , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus laevis
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