Suppression of Sox6 in P19 cells leads to failure of neuronal differentiation by retinoic acid and induces retinoic acid‐dependent apoptosis

Hamada-Kanazawa, Michiko; Ishikawa, Kyoko; Ogawa, Daisuke; Kanai, Miyuki; Kawai, Yuichi; Narahara, Masanori; Miyake, Masanobu

doi:10.1016/j.febslet.2004.09.063

Cited by 36 publications

(27 citation statements)

References 16 publications

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“…As mentioned, Sox6 was important for differentiation and neurite outgrowth in the RA-stimulated EC cell line P19 (Hamada-Kanazawa et al, 2004). Similarly, human EC cells induced to differentiate with RA showed regulation of Sox2 and Sox3 expression (Stevanovic, 2003).…”

Section: Sox11 Expression Is Required For Neuro2a Cell Differentiatiomentioning

confidence: 99%

“…Sox 1, 2 and 3 are expressed in spinal neurons of developing chick embryos and downregulation of these factors is requisite for expression of the neuronal markers NeuroM, NeuN and Tuj1, suggesting an important role in regulating commitment to the neuronal phenotype (Bylund et al, 2003). In in vitro models, Sox6, which is also expressed in developing brain, was found to be essential for differentiation and neurite outgrowth of the embryonic carcinoma (EC) cell line P19 following retinoic acid (RA) stimulation (Hamada-Kanazawa et al, 2004). Sox6 was also critical for survival of RA-stimulated P19 cells as evidenced by the increased apoptotic death that ensued upon inhibition of Sox6 expression.…”

Section: Introductionmentioning

confidence: 99%

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SRY-box containing gene 11 (Sox11) transcription factor is required for neuron survival and neurite growth

et al. 2006

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The transcription factor Sox11 is expressed at high levels in developing sensory neurons and injured adult neurons but little is known about its transcriptional targets and function. In this study we examined the role of Sox11 using Neuro2a neuroblastoma cells and cultured mouse dorsal root ganglia (DRG) neurons. Results show Sox11 has an essential role in regulation of neuron survival and neurite outgrowth in Neuro2a cells and primary sensory neurons. Neuro2a cells increase expression of Sox11 as they differentiate in culture. Following addition of 20μM retinoic acid (RA), a stimulus for differentiation that enhances neurite growth and differentiation, Sox11 level rises. RNAi-mediated knockdown of Sox11 in RA-differentiated Neuro2a cells caused a decrease in neurite growth and an increase in the percent of apoptotic cells. RNA expression analysis showed that Sox11 knockdown modulated the level of mRNAs encoding several genes related to cell survival and death. Further validation in the Neuro2a model showed Sox11 knockdown increased expression of the proapoptotic gene BNIP3 (Bcl2 interacting protein 1 NIP3) decreased expression of the anti-apoptotic gene TANK (TRAF family member-associated NFκB activator). Cultured primary DRG neurons also express Sox11 and treatment with Sox11 siRNA caused a significant decrease in neurite growth and branching and a decrease in mRNA encoding actin-related protein complex 3 (Arpc3), an actin organizing protein that may be involved in axon growth. The percent of apoptotic neurons also increased in cultures of DRG neurons treated with Sox11 siRNA. Similar to Neuro2a cells, a decrease in TANK gene expression occurred, suggesting at least some overlap in Sox11 transcriptional targets in Neuro2a and DRG neurons. These data are consistent with a central role for Sox11 in regulating events that promote neurite growth and neuron survival.

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Section: Sox11 Expression Is Required For Neuro2a Cell Differentiatiomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SRY-box containing gene 11 (Sox11) transcription factor is required for neuron survival and neurite growth

et al. 2006

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“…One frequently downregulated gene in ESCC specimen, SOX6, was further characterized. SOX6, a member of the D subfamily of sex determining region y-related transcription factors, encodes a protein that binds to DNA through a high-mobility-group (HMG) domain and plays critical roles in cell fate determination, differentiation, and proliferati on (6)(7)(8)(9). Some Sox factors, such as, SOX2, SOX4, and SOX9, have been identified as tumor suppressors that were frequently downregulated in various cancers (10)(11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Tumor-Suppressive Function of SOX6 in Human Esophageal Squamous Cell Carcinoma

Qin

Tang

Xie

et al. 2011

Clinical Cancer Research

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Purpose: By using cDNA microarray analysis, we identified a transcriptional factor, SOX6, was frequently downregulated in esophageal squamous cell carcinoma (ESCC). The aim of this study is to investigate the role of SOX6 in human esophageal cancer development, and to examine the prevalence and clinical significance of SOX6 downregulation in ESCC.Experimental Design: Expressions of SOX6 mRNA in 50 ESCCs and SOX6 protein in 300 ESCCs were investigated by semiquantitative RT-PCR and immunohistochemistry, respectively. The tumor-suppressive function of SOX6 was characterized by cell growth, foci formation, wound-healing and cell invasive assays, and tumor xenograft experiment. Western blot analysis was applied to detect protein expression levels.Results: SOX6 was frequently downregulated in primary ESCCs in both mRNA level (29/50, 58%) and protein level (149/219, 68.0%), which was significantly associated with the poor differentiation (P ¼ 0.029), lymph node metastases (P ¼ 0.014), advanced TNM stage (P ¼ 0.000), and disease-specific survival (P < 0.001). Multivariate analysis indicated that the downregulation of SOX6 (P ¼ 0.000) was a significant independent prognostic factors for ESCC. Functional studies showed that SOX6 was able to suppress both in vitro and in vivo tumorigenic ability of ESCC cells. The tumor-suppressive mechanism of SOX6 was associated with its role in G1/S cell-cycle arrest by upregulating expressions of p53 and p21 WAF1/CIP1 and downregulating expressions of cyclin D1/CDK4, cyclin A, and b-catenin. Conclusions:We provided the first evidence that SOX6 is a novel tumor-suppressor gene in ESCC development and is a potential prognostic marker in ESCC.

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“…[7][8][9] SOX6 has been proven to play important roles in cell proliferation, differentiation, and cell fate determination. Studies have confirmed that SOX6 is a tumor suppressor and downregulated in various cancers, including esophageal squamous cell carcinoma, hepatocellular carcinoma, and chronic myeloid leukemia.…”

Section: Introductionmentioning

confidence: 99%

The role of Sox6 and Netrin-1 in ovarian cancer cell growth, invasiveness, and angiogenesis

Xiao

Guo

2017

Tumour Biol.

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SOX6 plays important roles in cell proliferation, differentiation, and cell fate determination. It has been confirmed that SOX6 is a tumor suppressor and downregulated in various cancers, including esophageal squamous cell carcinoma, hepatocellular carcinoma, and chronic myeloid leukemia. Netrin-1 is highly expressed in various human cancers and acts as an anti-apoptotic and proangiogenic factor to drive tumorigenesis. The role of SOX6 and netrin-1 in regulating the growth of ovarian tumor cells still remains unclear. Real-time polymerase chain reaction and western blot were used to determine the SOX6 messenger RNA and protein levels, respectively, in ovarian cancer cells and tumor tissues. Stable transfection of SOX6 was conducted to overexpress SOX6 in PA-1 and SW626 cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Invasion of ovarian cancer cells and migration of human umbilical vein endothelial cells were confirmed by Transwell assays. To overexpress netrin-1, ovarian cancer cells with SOX6 restoration was transduced with netrin-1 lentiviral particles. PA-1 xenografts in a nude mice model were used to conduct in vivo evaluation of the role of SOX6 and its relationship with netrin-1 in tumor growth and angiogenesis. In this study, we found significantly reduced SOX6 levels in PA-1, SW626, SK-OV-3, and CaoV-3 ovarian cancer cell lines and human tumor tissues in comparison with normal human ovarian epithelial cells or matched non-tumor tissues. SOX6 overexpression by stable transfection dramatically inhibited proliferation and invasion of PA-1 and SW626 cells. Also, conditioned medium from PA-1 and SW626 cells with SOX6 restoration exhibited reduced ability to induce human umbilical vein endothelial cells migration and tube formation compared with conditioned medium from the cells with transfection control. Furthermore, an inverse relationship between SOX6 and netrin-1 expression was observed in PA-1 and SW626 cells. Overexpression of netrin-1 in ovarian cancer cells with forced SOX6 expression remarkably abrogated the inhibitory effect of SOX6 on proliferation, invasion of the cells, and tumor xenograft growth and vascularity in vivo. Human umbilical vein endothelial cell migration and tube formation were enhanced in the conditioned medium from the ovarian cancer cells transduced with netrin-1 lentivirus particles. Our observations revealed that SOX6 is a tumor suppressor in ovarian cancer cells, and SOX6 exerts an inhibitory effect on the proliferation, invasion, and tumor cell-induced angiogenesis of ovarian cancer cells, whereas nerin-1 plays an opposite role and its expression is inversely correlated with SOX6. Moreover, our findings suggest a new role of SOX6 and netrin-1 for understanding the progression of ovarian cancer and have the potential for the development of new diagnosis and treatment strategies for ovarian cancer.

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Suppression of Sox6 in P19 cells leads to failure of neuronal differentiation by retinoic acid and induces retinoic acid‐dependent apoptosis

Cited by 36 publications

References 16 publications

SRY-box containing gene 11 (Sox11) transcription factor is required for neuron survival and neurite growth

SRY-box containing gene 11 (Sox11) transcription factor is required for neuron survival and neurite growth

Characterization of Tumor-Suppressive Function of SOX6 in Human Esophageal Squamous Cell Carcinoma

The role of Sox6 and Netrin-1 in ovarian cancer cell growth, invasiveness, and angiogenesis

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