SOX2基因在肿瘤中的作用及其分子机理的研究
摘要
SOX (SRY-like HMG box)基因家族是一类具有HMG (high mobility group)特征性结构域的转录因子家族。HMG是DNA结合区域,其基因序列在真核细胞内高度保守。目前,共发现20种SOX基因,分为10个亚类。SOX2是SOX家族组中一个主要成员,表达与胚胎干细胞,在胚胎的各个发育过程中起重要作用。近年来,发现SOX2是诱导人和鼠成体细胞细胞为pluripotency细胞的一个关键和必需的分子。干细胞和肿瘤都具有自我更新等共同特性,在干细胞起关键作用的基因在肿瘤的发生和发展中也起一定作用。
SOX2已被发现在多种肿瘤中高表达,如肺癌、胰腺癌、乳腺癌和神经内分泌癌等；在中枢神经系统发育的早期,SOX2表达于全部的神经上皮,但神经系统发育成熟之后,其表达仅局限于胚基的神经胶质干细胞,而当神经胶质细胞恶变后,在脑胶质瘤中被激活而重新表达,表达显著高于正常组织,并且在RNA和蛋白水平上得到了证实。文献报道在结肠癌中SOX2高表达并且是判断预后的候选生物标记,并且SOX2的表达与干细胞标记CD133以及对化疗药物抵抗有相关性。然而SOX2结肠癌中的作用及其分子机理目前尚无研究。
本研究中,我们在结肠癌细胞中应用基因干涉技术,观察SOX2基因对细胞生物学行为的影响,发现SOX2基因干涉后其增殖、克隆形成以及动物体内致瘤能力明显降低。我们利用了基因组,转录组以及蛋白质组学技术：基因表达芯片,Chip-Seq (chromatin immunoprecipitation-sequencin)和Co-IP-MS-MS (Immunoprecipitation coupled with mass spectrometry),应用系统生物学理念,探讨该基因对肿瘤发生的分子机理。
1.免疫组织化学检测SOX2在结肠癌中的表达
用免疫组织化学检测30例结肠癌组织和配对正常结肠组织SOX2蛋白的表达,结果表明SOX2在癌组织细胞核中的表达显著高于正常组织,差异有显著性。
2.基因干涉技术对SOX2在肿瘤细胞中生物学功能的研究
利用慢病毒介导的基因干涉技术,病毒感染结肠癌细胞后SOX2的表达显著下调,体外功能实验显示,SOX2基因基因干涉后细胞增殖能力和克隆形成能力显著减低,细胞周期呈现S和G2／M期阻滞；动物体内致瘤能力也显著降低。
3.SOX2基因干涉后细胞基因表达谱的改变及生物信息分析
SOX2基因干涉后,通过基因芯片表达谱分析,发现1205个基因的表达因SOX2基因干涉而下调；Go Ontology分析,这些下调的基因参与了数条重要生物过程,如：cell surface receptor linked signal transduction (GO:0007166), BMP signaling pathway (GO:0030509), response to retinoic acid (GO:0032526)等,说明SOX2可能通过这些基因表达水平的调节而调控这些生物过程。
4. Chip-seq SOX2蛋白分子基因组结合位点分析
我们利用Chip-seq技术确定了SOX2在基因组上的结合位点,并与表达谱芯片整合分析,进一步确定了SOX2在转录水平上可能直接调节的基因；并将SOX2在肿瘤中的结合位点与在胚胎干细胞中的结合位点进行比较,两者共有372个结合位点,说明Sox2在肿瘤中和在干细胞中对基因的调节具有一定的保守性。在结肠癌细胞中SOX2在基因组DNA上的结合位点富含AT序列,并且共有一共同motif:wwTGywTT;将SOX2的结合区域向两侧延伸,以发现SOX2结合区域内是否含有其他已知转录因子的结合motif,结果发现了已知的与SOX2有协同作用的OCT家族蛋白的结合motif,并且发现新的转录因子的结合motif如：Fox和HNF等家族蛋白的结合motif,这说明这些蛋白可能与SOX2共同参与对基因表达的调节。
5. Co-IP-MS-MS SOX2相互作用蛋白的鉴定和分析
Co-IP-MS/MS分析共鉴定到与SOX2蛋白相互作用形成复合物的蛋白144个,每个蛋白的可信度都大于0.9,并且每个蛋白在质谱中出现的肽段都至少有两个不同唯一肽段出现。随机选取了4个蛋白进行western-blot验证；我们发现在鉴定到的蛋白中,有很多蛋白为HnRNP家族蛋白,并与以往鉴定到的HnRNP复合物组分相比较,说明SOX2可能是HnRNP复合物的一个组分,SOX2与这蛋白相互作用参与了基因的表达各个过程的调节。
6.整合分析
整合基因表达谱改变、Sox2 DNA结合位点和Sox2相互作用蛋白,我们发现在Sox2基因组的结合区域存在CEBPB转录因子结合motif,在相互作用的蛋白中存在CEBPB蛋白,这说明Sox2可能与和CEBPB共同结合一个的DNA区域内调节基因的表达,这有待于经典的生物学进一步验证。
结论：
SOX2在结肠癌组织的细胞核中的表达显著高于正常组织。SOX2基因干涉降低了结肠癌细胞的体外增殖能力和体内致瘤能力,细胞周期呈现S和G2／M期阻滞。SOX2基因干涉后数条与结肠癌发生相关的生物过程中的基因表达下调。确定了SOX2在基因组上的结合位点和结合特征；SOX2在肿瘤细胞中和人胚胎干细胞中共有372个共同的基因组结合位点,说明Sox2在肿瘤中和在胚胎中对基因的调节具有一定的保守性；基因芯片数据和Chip-seq数据整合分析确定了SOX2可能直接调节94个基因的转录,其中53个基因受SOX2的正调节,41个受SOX2的负调节。蛋白相互作用分析显示SOX2与HNRNP家族蛋白相互结合,这种相互结合可能共同参与了基因表达的调节。
因此,本研究为我们深入了解SOX2基因在肿瘤中作用的分子机理提供研究基础和线索。
SOX (SRY-like HMG box) gene family represents a family of transcriptional factors characterized by the presence of a homologous sequence called the HMG (high mobility group) box in their genes. HMG box is a DNA binding domain that is highly conserved throughout eukaryotic species. So far, twenty SOX genes have been identified in humans and mice, and they can be divided into 10 subgroups on the basis of sequence similarity and genomic organization. SOX genes bind to the minor groove in DNA to control diverse developmental processes. SOX2, one of the key members of the SOX family gene, is highly expressed in embryonic stem cells. Recent research showed that SOX2 is a key transcription factor whose over expression can induce pluripotency in both mouse and human somatic cells. These suggest that SOX2 is the key gene in conferring sternness of cells. The sternness program can also play an important role in cancer because self-renewal is a hallmark of for both stem cells and cancer cells.
Recent research showed that SOX2 are over expressed in malignant glioma, but display minimal expression in normal tissues. They further confirmed by RT-PCR and immunohistochemistry staining that SOX2 mRNA and protein expression were increased in GBM compared to normal brain tissues. We previously completed massively parallel signature sequencing (MPSS) and identified SOX2 as significantly over expressed in GBM tissues compared to normal brain tissues. SOX2 has also been implicated in several cancers including gastric cancer, breast cancer, pancreatic cancer, pulmonary non-small cell and neuroendocrine carcinomas. In addition, SOX2 was identified to be a prognostic marker for human esophageal squamous cell carcinoma and colorectal cancer.
Therefore, SOX2 may be a gene that is predominantly expressed in embryonic and adult stems cells including neural progenitor cells and re-activates in cancers including brain tumors. However, up to the present, systems-wide investigation of the functions of SOX2 has concentrated on embryonic development in mouse embryonic stem cells. To understand how SOX2 exerts its function in a system-wide (genome wide and proteome wide) manner in brain tumors and colorectal cancers, we took advantages of recent advances in genomic and proteomic technologies and conducted a study combining two novel technologies--ChIP-seq analysis and Immunoprecipitation (IP) coupled with mass spectrometry analysis. We report here our results of the genome wide targets of SOX2 in cancer cells identified by ChIP-seq analysis. In addition, we report the components of the SOX2 interactome identified by IP coupled with mass spectrometry analysis. Our integrated analysis provides us with a comprehensive picture for better understanding of the SOX2's role in brain tumors and colorectal cancers.
1. immunohistochemical staining analysis of SOX2 protein in 30 colon cancer tissue.
To analyze its protein expression, we performed Immunohistochemical staining in 30 colorectal cancer tissues and 30 normal adjacent tissues. We observed positive immunoreactivities in colorectal cancer with nucleus staining pattern in 46%(14/30) of cancer tissues, compared to only 7% in the adjacent mucosa tissue cells. Statistical analysis using Pearson Chi-Square (df=1, two-sided) indicates that the difference in SOX2 expression between cancer and adjacent tissues is significant (P<0.01).
2. SOX2 knockdown decreased cell colony formation on soft agar and in vivo tumorigenesis potential.
We knocked down the expression of SOX2 in colorectal cancer cell and gliomas cell, and found that reduced expression of SOX2 correlates with decreased growth rates, colony formation and migration abilities of cancer cells. In addition, knocking down of SOX2 resulted in an accumulation of cells in the G0/G1 phases and a decrease of cells in S and G2/M phases. Using in vivo mouse models, we showed that SOX2 knockdown cells had reduced tumor sizes compared with the MOCK known down cells. Taking together, these data suggested functional important roles of SOX2 in colorectal carcinogenesis.
3. Identification of SOX2 regulated genes by microarrays.
We used Affymetrix array U133 plus 2 to identify genes regulated by SOX2 by comparing expression profiles of parental SW620 cells and SOX2-knockdown SW620 cells. We found that the expression of 1,205 genes was decreased by 2 fold or more in the SOX2 knockdown SW620 cells comparing with the mock control cells.Gene Ontology analysis of down regulated genes by SOX2 knockdown revealed that the GO terms cell surface receptor linked signal transduction (GO:0007166), BMP signaling pathway (GO:0030509). However, there were no significantly (FDR＜0.05) enriched GO terms for the genes that were up regulated by SOX2 knowndown.
4. Identification of DNA binding consensus and SOX2 collaborating TFs in the SOX2 binding regions.
To see whether the human SOX2 binding regions in GBM cells and colon cancer cells have their own unique and enriched binding motif, we used the MotifSampler program to identify binding consensus sequences enriched in the SOX2 binding regions. We found a consensus sequence wwTGywTT and wwTGnwTw in colon cancer cells and glioma cells. We then wondered whether known TFs could bind to the SOX2 binding regions and act as SOX2 cooperators for the regulation of gene expression. In order to systematically search for potential bindings of other transcription factors, we used the MotifScanner program and scanned all TF motif matrices using the human transcription factor subset of the Transfac professional 7.0. Matched matrices with likelihood (LR) ratios of 500 or higher were tabulated and frequencies calculated. Among the top known TF matrices identified with SOX2 in the SOX2-binding region include the known OCT family and some new unknown families such as the FOX family, the HNF family, the GATA family and several others.
5. IP-MS/MS analysis of SOX2 interacting proteins revealed that SOX2 interacts with heterogeneous nuclear ribonucleoproteins.
We carried out IP-MS/MS analysis to determine the interacting protein partners of SOX2 in cancer cells. We identified SOX2 as a protein in the HnRNP complex because it interacts with many heterogeneous nuclear ribonucleoproteins. Comparing the SOX2 interactome and the HNRPNK interactome, we identified 16 proteins that are common interacting proteins for SOX2 and HNRNPK. suggesting that SOX2 is part of the HNRNP complex, interacting with other HNRNP proteins. Protein-protein interaction analysis revealed that HNRNPK interacts with multiple proteins involved in multiple steps in the gene expression including chromatin remodeling, transcription, RNA processing and translation. Gene Ontology analysis of the SOX2 interacting proteins suggested that SOX2 also interacts with proteins involved in multiple steps in regulating gene expression including chromatin remodeling, transcription, RNA processing and translation. This is not surprising in light of SOX2's essential role in development and in conferring sternness property of cells.
SOX2已被发现在多种肿瘤中高表达,如肺癌、胰腺癌、乳腺癌和神经内分泌癌等；在中枢神经系统发育的早期,SOX2表达于全部的神经上皮,但神经系统发育成熟之后,其表达仅局限于胚基的神经胶质干细胞,而当神经胶质细胞恶变后,在脑胶质瘤中被激活而重新表达,表达显著高于正常组织,并且在RNA和蛋白水平上得到了证实。文献报道在结肠癌中SOX2高表达并且是判断预后的候选生物标记,并且SOX2的表达与干细胞标记CD133以及对化疗药物抵抗有相关性。然而SOX2结肠癌中的作用及其分子机理目前尚无研究。
本研究中,我们在结肠癌细胞中应用基因干涉技术,观察SOX2基因对细胞生物学行为的影响,发现SOX2基因干涉后其增殖、克隆形成以及动物体内致瘤能力明显降低。我们利用了基因组,转录组以及蛋白质组学技术：基因表达芯片,Chip-Seq (chromatin immunoprecipitation-sequencin)和Co-IP-MS-MS (Immunoprecipitation coupled with mass spectrometry),应用系统生物学理念,探讨该基因对肿瘤发生的分子机理。
1.免疫组织化学检测SOX2在结肠癌中的表达
用免疫组织化学检测30例结肠癌组织和配对正常结肠组织SOX2蛋白的表达,结果表明SOX2在癌组织细胞核中的表达显著高于正常组织,差异有显著性。
2.基因干涉技术对SOX2在肿瘤细胞中生物学功能的研究
利用慢病毒介导的基因干涉技术,病毒感染结肠癌细胞后SOX2的表达显著下调,体外功能实验显示,SOX2基因基因干涉后细胞增殖能力和克隆形成能力显著减低,细胞周期呈现S和G2／M期阻滞；动物体内致瘤能力也显著降低。
3.SOX2基因干涉后细胞基因表达谱的改变及生物信息分析
SOX2基因干涉后,通过基因芯片表达谱分析,发现1205个基因的表达因SOX2基因干涉而下调；Go Ontology分析,这些下调的基因参与了数条重要生物过程,如：cell surface receptor linked signal transduction (GO:0007166), BMP signaling pathway (GO:0030509), response to retinoic acid (GO:0032526)等,说明SOX2可能通过这些基因表达水平的调节而调控这些生物过程。
4. Chip-seq SOX2蛋白分子基因组结合位点分析
我们利用Chip-seq技术确定了SOX2在基因组上的结合位点,并与表达谱芯片整合分析,进一步确定了SOX2在转录水平上可能直接调节的基因；并将SOX2在肿瘤中的结合位点与在胚胎干细胞中的结合位点进行比较,两者共有372个结合位点,说明Sox2在肿瘤中和在干细胞中对基因的调节具有一定的保守性。在结肠癌细胞中SOX2在基因组DNA上的结合位点富含AT序列,并且共有一共同motif:wwTGywTT;将SOX2的结合区域向两侧延伸,以发现SOX2结合区域内是否含有其他已知转录因子的结合motif,结果发现了已知的与SOX2有协同作用的OCT家族蛋白的结合motif,并且发现新的转录因子的结合motif如：Fox和HNF等家族蛋白的结合motif,这说明这些蛋白可能与SOX2共同参与对基因表达的调节。
5. Co-IP-MS-MS SOX2相互作用蛋白的鉴定和分析
Co-IP-MS/MS分析共鉴定到与SOX2蛋白相互作用形成复合物的蛋白144个,每个蛋白的可信度都大于0.9,并且每个蛋白在质谱中出现的肽段都至少有两个不同唯一肽段出现。随机选取了4个蛋白进行western-blot验证；我们发现在鉴定到的蛋白中,有很多蛋白为HnRNP家族蛋白,并与以往鉴定到的HnRNP复合物组分相比较,说明SOX2可能是HnRNP复合物的一个组分,SOX2与这蛋白相互作用参与了基因的表达各个过程的调节。
6.整合分析
整合基因表达谱改变、Sox2 DNA结合位点和Sox2相互作用蛋白,我们发现在Sox2基因组的结合区域存在CEBPB转录因子结合motif,在相互作用的蛋白中存在CEBPB蛋白,这说明Sox2可能与和CEBPB共同结合一个的DNA区域内调节基因的表达,这有待于经典的生物学进一步验证。
结论：
SOX2在结肠癌组织的细胞核中的表达显著高于正常组织。SOX2基因干涉降低了结肠癌细胞的体外增殖能力和体内致瘤能力,细胞周期呈现S和G2／M期阻滞。SOX2基因干涉后数条与结肠癌发生相关的生物过程中的基因表达下调。确定了SOX2在基因组上的结合位点和结合特征；SOX2在肿瘤细胞中和人胚胎干细胞中共有372个共同的基因组结合位点,说明Sox2在肿瘤中和在胚胎中对基因的调节具有一定的保守性；基因芯片数据和Chip-seq数据整合分析确定了SOX2可能直接调节94个基因的转录,其中53个基因受SOX2的正调节,41个受SOX2的负调节。蛋白相互作用分析显示SOX2与HNRNP家族蛋白相互结合,这种相互结合可能共同参与了基因表达的调节。
因此,本研究为我们深入了解SOX2基因在肿瘤中作用的分子机理提供研究基础和线索。
SOX (SRY-like HMG box) gene family represents a family of transcriptional factors characterized by the presence of a homologous sequence called the HMG (high mobility group) box in their genes. HMG box is a DNA binding domain that is highly conserved throughout eukaryotic species. So far, twenty SOX genes have been identified in humans and mice, and they can be divided into 10 subgroups on the basis of sequence similarity and genomic organization. SOX genes bind to the minor groove in DNA to control diverse developmental processes. SOX2, one of the key members of the SOX family gene, is highly expressed in embryonic stem cells. Recent research showed that SOX2 is a key transcription factor whose over expression can induce pluripotency in both mouse and human somatic cells. These suggest that SOX2 is the key gene in conferring sternness of cells. The sternness program can also play an important role in cancer because self-renewal is a hallmark of for both stem cells and cancer cells.
Recent research showed that SOX2 are over expressed in malignant glioma, but display minimal expression in normal tissues. They further confirmed by RT-PCR and immunohistochemistry staining that SOX2 mRNA and protein expression were increased in GBM compared to normal brain tissues. We previously completed massively parallel signature sequencing (MPSS) and identified SOX2 as significantly over expressed in GBM tissues compared to normal brain tissues. SOX2 has also been implicated in several cancers including gastric cancer, breast cancer, pancreatic cancer, pulmonary non-small cell and neuroendocrine carcinomas. In addition, SOX2 was identified to be a prognostic marker for human esophageal squamous cell carcinoma and colorectal cancer.
Therefore, SOX2 may be a gene that is predominantly expressed in embryonic and adult stems cells including neural progenitor cells and re-activates in cancers including brain tumors. However, up to the present, systems-wide investigation of the functions of SOX2 has concentrated on embryonic development in mouse embryonic stem cells. To understand how SOX2 exerts its function in a system-wide (genome wide and proteome wide) manner in brain tumors and colorectal cancers, we took advantages of recent advances in genomic and proteomic technologies and conducted a study combining two novel technologies--ChIP-seq analysis and Immunoprecipitation (IP) coupled with mass spectrometry analysis. We report here our results of the genome wide targets of SOX2 in cancer cells identified by ChIP-seq analysis. In addition, we report the components of the SOX2 interactome identified by IP coupled with mass spectrometry analysis. Our integrated analysis provides us with a comprehensive picture for better understanding of the SOX2's role in brain tumors and colorectal cancers.
1. immunohistochemical staining analysis of SOX2 protein in 30 colon cancer tissue.
To analyze its protein expression, we performed Immunohistochemical staining in 30 colorectal cancer tissues and 30 normal adjacent tissues. We observed positive immunoreactivities in colorectal cancer with nucleus staining pattern in 46%(14/30) of cancer tissues, compared to only 7% in the adjacent mucosa tissue cells. Statistical analysis using Pearson Chi-Square (df=1, two-sided) indicates that the difference in SOX2 expression between cancer and adjacent tissues is significant (P<0.01).
2. SOX2 knockdown decreased cell colony formation on soft agar and in vivo tumorigenesis potential.
We knocked down the expression of SOX2 in colorectal cancer cell and gliomas cell, and found that reduced expression of SOX2 correlates with decreased growth rates, colony formation and migration abilities of cancer cells. In addition, knocking down of SOX2 resulted in an accumulation of cells in the G0/G1 phases and a decrease of cells in S and G2/M phases. Using in vivo mouse models, we showed that SOX2 knockdown cells had reduced tumor sizes compared with the MOCK known down cells. Taking together, these data suggested functional important roles of SOX2 in colorectal carcinogenesis.
3. Identification of SOX2 regulated genes by microarrays.
We used Affymetrix array U133 plus 2 to identify genes regulated by SOX2 by comparing expression profiles of parental SW620 cells and SOX2-knockdown SW620 cells. We found that the expression of 1,205 genes was decreased by 2 fold or more in the SOX2 knockdown SW620 cells comparing with the mock control cells.Gene Ontology analysis of down regulated genes by SOX2 knockdown revealed that the GO terms cell surface receptor linked signal transduction (GO:0007166), BMP signaling pathway (GO:0030509). However, there were no significantly (FDR＜0.05) enriched GO terms for the genes that were up regulated by SOX2 knowndown.
4. Identification of DNA binding consensus and SOX2 collaborating TFs in the SOX2 binding regions.
To see whether the human SOX2 binding regions in GBM cells and colon cancer cells have their own unique and enriched binding motif, we used the MotifSampler program to identify binding consensus sequences enriched in the SOX2 binding regions. We found a consensus sequence wwTGywTT and wwTGnwTw in colon cancer cells and glioma cells. We then wondered whether known TFs could bind to the SOX2 binding regions and act as SOX2 cooperators for the regulation of gene expression. In order to systematically search for potential bindings of other transcription factors, we used the MotifScanner program and scanned all TF motif matrices using the human transcription factor subset of the Transfac professional 7.0. Matched matrices with likelihood (LR) ratios of 500 or higher were tabulated and frequencies calculated. Among the top known TF matrices identified with SOX2 in the SOX2-binding region include the known OCT family and some new unknown families such as the FOX family, the HNF family, the GATA family and several others.
5. IP-MS/MS analysis of SOX2 interacting proteins revealed that SOX2 interacts with heterogeneous nuclear ribonucleoproteins.
We carried out IP-MS/MS analysis to determine the interacting protein partners of SOX2 in cancer cells. We identified SOX2 as a protein in the HnRNP complex because it interacts with many heterogeneous nuclear ribonucleoproteins. Comparing the SOX2 interactome and the HNRPNK interactome, we identified 16 proteins that are common interacting proteins for SOX2 and HNRNPK. suggesting that SOX2 is part of the HNRNP complex, interacting with other HNRNP proteins. Protein-protein interaction analysis revealed that HNRNPK interacts with multiple proteins involved in multiple steps in the gene expression including chromatin remodeling, transcription, RNA processing and translation. Gene Ontology analysis of the SOX2 interacting proteins suggested that SOX2 also interacts with proteins involved in multiple steps in regulating gene expression including chromatin remodeling, transcription, RNA processing and translation. This is not surprising in light of SOX2's essential role in development and in conferring sternness property of cells.
引文
1. Bowles, J., Schepers, G, and Koopman, P. (2000) Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators. Dev Biol 227, Page.
2. Schepers, G. E., Teasdale, R. D., and Koopman, P. (2002) Twenty pairs of sox: extent, homology, and nomenclature of the mouse and human sox transcription factor gene families. Dev Cell 3, Page.
3. Wegner, M. (1999) From head to toes:the multiple facets of Sox proteins. Nucleic Acids Res 27, Page.
4. Avilion, A. A., Nicolis, S. K., Pevny, L. H., Perez, L., Vivian, N., and Lovell-Badge, R. (2003) Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17, Page.
5. Cai, J., Wu, Y., Mirua, T., Pierce, J. L., Lucero, M. T., Albertine, K. H., Spangrude, G. J., and Rao, M. S. (2002) Properties of a fetal multipotent neural stem cell (NEP cell). Dev Biol 251, Page.
6. Graham, V., Khudyakov, J., Ellis, P., and Pevny, L. (2003) SOX2 functions to maintain neural progenitor identity. Neuron 39, Page.
7. Takahashi, K., and Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, Page.
8. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, Page.
9. Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., Slukvin, II, and Thomson, J. A. (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318, Page.
10. Wegner, M., and Stolt, C. C. (2005) From stem cells to neurons and glia:a Soxist's view of neural development. Trends Neurosci 28, Page.
11. Schmitz, M., Temme, A., Senner, V., Ebner, R., Schwind, S., Stevanovic, S., Wehner, R., Schackert, G, Schackert, H. K., Fussel, M., Bachmann, M., Rieber, E. P., and Weigle, B. (2007) Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy. Br J Cancer 96, Page.
12. Phi, J. H., Park, S. H., Kim, S. K., Paek, S. H., Kim, J. H., Lee, Y. J., Cho, B. K., Park, C. K., Lee, D. H., and Wang, K. C. (2008) Sox2 expression in brain tumors:a reflection of the neuroglial differentiation pathway. Am J Surg Pathol 32, Page.
13. Li, X. L., Eishi, Y., Bai, Y. Q., Sakai, H., Akiyama, Y, Tani, M., Takizawa, T., Koike, M., and Yuasa, Y. (2004) Expression of the SRY-related HMG box protein SOX2 in human gastric carcinoma. Int J Oncol 24, Page.
14. Park, E. T., Gum, J. R., Kakar, S., Kwon, S. W., Deng, G., and Kim, Y. S. (2008) Aberrant expression of SOX2 upregulates MUC5AC gastric foveolar mucin in mucinous cancers of the colorectum and related lesions. Int J Cancer 122, Page.
15. Rodriguez-Pinilla, S. M., Sarrio, D., Moreno-Bueno, G., Rodriguez-Gil, Y., Martinez, M. A., Hernandez, L., Hardisson, D., Reis-Filho, J. S., and Palacios, J. (2007) Sox2:a possible driver of the basal-like phenotype in sporadic breast cancer. Mod Pathol 20, Page.
16. Chen, Y, Shi, L., Zhang, L., Li, R., Liang, J., Yu, W., Sun, L., Yang, X., Wang, Y, Zhang, Y, and Shang, Y. (2008) The molecular mechanism governing the oncogenic potential of SOX2 in breast cancer. J Biol Chem 283, Page.
18. Sanada, Y, Yoshida, K., Ohara, M., Oeda, M., Konishi, K., and Tsutani, Y. (2006) Histopathologic evaluation of stepwise progression of pancreatic carcinoma with immunohistochemical analysis of gastric epithelial transcription factor SOX2: comparison of expression patterns between invasive components and cancerous or nonneoplastic intraductal components. Pancreas 32, Page.
19. Sholl, L. M., Long, K. B., and Hornick, J. L. (2009) Sox2 Expression in Pulmonary Non-small Cell and Neuroendocrine Carcinomas. Appl Immunohistochem Mol Morphol, Page.
20. Wang, Q., He, W, Lu, C., Wang, Z., Wang, J., Giercksky, K. E., Nesland, J. M., and Suo, Z. (2009) Oct3/4 and Sox2 are significantly associated with an unfavorable clinical outcome in human esophageal squamous cell carcinoma. Anticancer Res 29, Page.
21. Saigusa, S., Tanaka, K., Toiyama, Y., Yokoe, T., Okugawa, Y, Ioue, Y, Miki, C., and Kusunoki, M. (2009) Correlation of CD133, OCT4, and SOX2 in Rectal Cancer and Their Association with Distant Recurrence After Chemoradiotherapy. Ann Surg Oncol, Page.
22. Barski, A., Cuddapah, S., Cui, K., Roh, T. Y, Schones, D. E., Wang, Z., Wei, G, Chepelev, I., and Zhao, K. (2007) High-resolution.profiling of histone methylations in the human genome. Cell 129, Page.
23. Jothi, R., Cuddapah, S., Barski, A., Cui, K., and Zhao, K. (2008) Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Res 36, Page.
24. Chen, Y, Shi, L., Zhang, L., Li, R., Liang, J., Yu, W., Sun, L., Yang, X., Wang, Y, Zhang, Y, and Shang, Y (2008) The molecular mechanism governing the oncogenic potential of SOX2 in breast cancer. J Biol Chem 283, Page.
25. Li, X. L., Eishi, Y, Bai, Y Q., Sakai, H., Akiyama, Y, Tani, M., Takizawa, T., Koike, M., and Yuasa, Y. (2004) Expression of the SRY-related HMG box protein SOX2 in human gastric carcinoma. Int J Oncol 24, Page.
26. Park, E. T., Gum, J. R., Kakar, S., Kwon, S. W., Deng, G., and Kim, Y S. (2008) Aberrant expression of SOX2 upregulates MUC5AC gastric foveolar mucin in mucinous cancers of the colorectum and related lesions. Int J Cancer 122, Page.
27. Schmitz, M., Temme, A., Senner, V., Ebner, R., Schwind, S., Stevanovic, S., Wehner, R., Schackert, G, Schackert, H. K., Fussel, M., Bachmann, M., Rieber, E. P., and Weigle, B. (2007) Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy. Br J Cancer 96, Page.
28. Phi, J. H., Park, S. H., Kim, S. K., Paek, S. H., Kim, J. H., Lee, Y J., Cho, B. K., Park, C. K., Lee, D. H., and Wang, K. C. (2008) Sox2 expression in brain tumors:a reflection of the neuroglial differentiation pathway. Am J Surg Pathol 32, Page.
29. Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Ioue Y, Miki C, Kusunoki M. Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol 2009; 16:3488-98.
30. Cho SJ, Kim JS, Kim JM, Lee JY, Jung HC, Song IS. Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. Int J Cancer 2008;123:951-7.
31. Foltz G, Ryu GY, Yoon JG, Nelson T, Fahey J, Frakes A, Lee H, Field L, Zander K, Sibenaller Z, Ryken TC, Vibhakar R, et al. Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma. Cancer Res 2006;66:6665-74.
32. Lin B, Wang J, Hong X, Yan X, Hwang D, Cho JH, Yi D, Utleg AG, Fang X, Schones DE, Zhao K, Omenn GS, et al. Integrated expression profiling and ChIP-seq analyses of the growth inhibition response program of the androgen receptor. PLoS One 2009;4:e6589.
33. Halder SK, Rachakonda G, Deane NG, Datta PK. Smad7 induces hepatic metastasis in colorectal cancer. Br J Cancer 2008;99:957-65.
34. Sekharam M, Zhao H, Sun M, Fang Q, Zhang Q, Yuan Z, Dan HC, Boulware D, Cheng JQ, Coppola D. Insulin-like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/Bcl-x(L) pathway. Cancer Res 2003;63:7708-16.
35. O'Dwyer P J, Benson AB,3rd. Epidermal growth factor receptor-targeted therapy in colorectal cancer. Semin Oncol 2002;29:10-7.
36. Hu Q, Zhang L, Wen J, Wang S, Li M, Feng R, Yang X, Li L. The EGF receptor-sox2-EGF receptor feedback loop positively regulates the self-renewal of neural precursor cells. Stem Cells;28:279-86.
37.Fei T, Xia K, Li Z, Zhou B, Zhu S, Chen H, Zhang J, Chen Z, Xiao H, Han JD, Chen YG. Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination.Genome Res.2010, 20(1):36-44
38.Sieber C, Kopf J, Hiepen C, Knaus P.Recent advances in BMP receptor signaling.Cytokine Growth Factor Rev.2009,20:343-55.
39. Kang MH, Kang HN, Kim JL, Kim JS, Oh SC, Yoo YA.Inhibition of PⅠ3 kinase/Akt pathway is required for BMP2-induced EMT and invasion.Oncol Rep.2009, 22:525-34.
40. Alarmo EL, Parssinen J, Ketolainen JM, Savinainen K, Karhu R, Kallioniemi, A.BMP7 influences proliferation, migration, and invasion of breast cancer cells. Cancer Lett.2009,275(1):35-43.
41. Motoyama K, Tanaka F, Kosaka Y, Mimori K, Uetake H, Inoue H, Sugihara K, Mori M.Clinical significance of BMP7 in human colorectal cancer. Ann Surg Oncol. 2008 15:1530-7.
42. Buijs JT, Henriquez NV, van Overveld PG, van der Horst G, ten Dijke P, van der Pluijm GTGF-beta and BMP7 interactions in tumour progression and bone metastasis.Clin Exp Metastasis.2007,24:609-17
43. Barski, A., Cuddapah, S., Cui, K., Roh, T. Y., Schones, D. E., Wang, Z., Wei, G., Chepelev, I., and Zhao, K. (2007) High-resolution profiling of histone methylations in the human genome. Cell 129, Page.
44. Jothi, R., Cuddapah, S., Barski, A., Cui, K., and Zhao, K. (2008) Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Res 36, Page.
45. Johnson, D. S., Mortazavi, A., Myers, R. M., and Wold, B. (2007) Genome-wide mapping of in vivo protein-DNA interactions. Science 316, Page.
46. Okumura-Nakanishi, S., Saito, M., Niwa, H., and Ishikawa, F. (2005) Oct-3/4 and Sox2 regulate Oct-3/4 gene in embryonic stem cells. J Biol Chem 280, Page.
47. Williams, D. C., Jr., Cai, M., and Clore, G. M. (2004) Molecular basis for synergistic transcriptional activation by Octl and Sox2 revealed from the solution structure of the 42-kDa Octl.Sox2.Hoxbl-DNA ternary transcription factor complex. J Biol Chem 279, Page.
48. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nussbaum C, Myers RM, Brown M, Li W, Liu XS. Model-based analysis of ChIP-Seq (MACS). Genome Biol 2008;9:R137.
49. Thijs G, Marchal K, Lescot M, Rombauts S, De Moor B, Rouze P, Moreau Y. A Gibbs sampling method to detect overrepresented motifs in the upstream regions of coexpressed genes. J Comput Biol 2002;9:447-64.
50. Thijs G, Moreau Y, De Smet F, Mathys J, Lescot M, Rombauts S, Rouze P, De Moor B, Marchal K. INCLUSive:integrated clustering, upstream sequence retrieval and motif sampling. Bioinformatics 2002;18:331-2.
51. Sandelin A, Alkema W, Engstrom P, Wasserman WW, Lenhard B. JASPAR:an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res 2004;32:D91-4.
52. Beckstette M, Homann R, Giegerich R, Kurtz S. Fast index based algorithms and software for matching position specific scoring matrices. BMC Bioinformatics 2006;7:389.
53. Wilson, M., and Koopman, P. Matching SOX:partner proteins and co-factors of the SOX family of transcriptional regulators. Curr Opin Genet Dev, (2002) 12, Page.
54. Mertin, S., McDowall, S. G, and Harley, V. R. The DNA-binding specificity of SOX9 and other SOX proteins. Nucleic Acids Res, (1999)27, Page.
55. Kamachi, Y, Uchikawa, M., and Kondoh, H. Pairing SOX off:with partners in the regulation of embryonic development. Trends Genet,(2000) 16, Page.
56. Marson, A., Levine, S. S., Cole, M. F., Frampton, G. M., Brambrink, T., Johnstone, S., Guenther, M. G., Johnston, W. K., Wernig, M., Newman, J., Calabrese, J. M., Dennis, L. M., Volkert, T. L., Gupta, S., Love, J., Hannett, N., Sharp, P. A., Bartel, D. P., Jaenisch, R., and Young, R. A. (2008) Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134, Page.
57. Boyer, L. A., Lee, T. I., Cole, M. F., Johnstone, S. E., Levine, S. S., Zucker, J. P., Guenther, M. G, Kumar, R. M., Murray, H. L., Jenner, R. G, Gifford, D. K. Melton, D. A., Jaenisch, R., and Young, R. A. (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, Page.
58. Chen, X., Xu, H., Yuan, P., Fang, F., Huss, M., Vega, V. B., Wong, E., Orlov, Y. L, Zhang, W., Jiang, J., Loh, Y. H., Yeo, H. C., Yeo, Z. X., Narang, V., Govindarajan, K. R., Leong, B., Shahab, A., Ruan, Y, Bourque, G., Sung, W. K., Clarke, N. D., Wei, C. L., and Ng, H. H. (2008) Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133, Page
59.Petrie K, Guidez F, Howell L, Healy L, Waxman S, Greaves M, Zelent A.The histone deacetylase 9 gene encodes multiple protein isoforms. J Biol Chem. 2003,278:16059-72.
60. Wilson AJ, Byun DS, Nasser S, Murray LB, Ayyanar K, Arango D, Figueroa M, Melnick A, Kao GD, Augenlicht LH, Mariadason JM. HDAC4 Promotes Growth of Colon Cancer Cells via Repression of p21. Mol Biol Cell.2008,19:4062-4075.
61. Lucio-Eterovic AK, Cortez MA, Valera ET, Motta FJ, Queiroz RG, Machado HR, Carlotti CG Jr, Neder L, Scrideli CA, Tone LG.Differential expression of 12 histone deacetylase (HDAC) genes in astrocytomas and normal brain tissue:class II and IV are hypoexpressed in glioblastomas. BMC Cancer.2008,8:243.
62. Oji Y, Yamamoto H, Nomura M, Nakano Y, Ikeba A, Nakatsuka S, Abeno S, Kiyotoh E, Jomgeow T, Sekimoto M, Nezu R, Yoshikawa Y, Inoue Y, Hosen N, Kawakami M, Tsuboi A, Oka Y, Ogawa H, Souda S, Aozasa K, Monden M, Sugiyama H. Overexpression of the Wilms' tumor gene WT1 in colorectal adenocarcinoma. Cancer Sci.2003 94:712-7.
63. Koesters R, Linnebacher M, Coy JF, Germann A, Schwitalle Y, Findeisen P, von Knebel Doeberitz M.WT1 is a tumor-associated antigen in colon cancer that can be recognized by in vitro stimulated cytotoxic T cells. Int J Cancer.2004 109:385-92.
64. Wiesner GL, Daley D, Lewis S, Ticknor C, Platzer P, Lutterbaugh J, MacMillen M, Baliner B, Willis J, Elston RC, Markowitz SD. A subset of familial colorectal neoplasia kindreds linked to chromosome 9q22.2-31.2. Proc Natl Acad Sci U S A 2003;100:12961-5.
65. Lee HJ, Chattopadhyay S, Yoon WH, Bahk JY, Kim TH, Kang HS, Lee K. Overexpression of hepatocyte nuclear factor-3alpha induces apoptosis through the upregulation and accumulation of cytoplasmic p53 in prostate cancer cells. Prostate;70:353-61.
66. Dhawan P, Singh AB, Deane NG, No Y, Shiou SR, Schmidt C, Neff J, Washington MK, Beauchamp RD. Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. J Clin Invest 2005:115:1765-76.
67. Sekharam M, Zhao H, Sun M, Fang Q, Zhang Q, Yuan Z,. Dan HC, Boulware D, Cheng JQ, Coppola D. Insulin-like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/Bcl-x(L) pathway. Cancer Res 2003;63:7708-16.
68 O'Dwyer P J, Benson AB. Epidermal growth factor receptor-targeted therapy in colorectal cancer. Semin Oncol 2002;29:10-7.
69. Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J, Loh YH, Yeo HC, et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 2008;133:1106-17.
70. Esteller M. Cancer epigenomics:DNA methylomes and histone-modification maps. Nat Rev Genet 2007;8:286-98.
71. Ishihama K, Yamakawa M, Semba S, Takeda H, Kawata S, Kimura S, Kimura W. Expression of HDAC1 and CBP/p300 in human colorectal carcinomas. J Clin Pathol 2007;60:1205-10.
72. Flis S, Gnyszka A, Splawinski J. HDAC inhibitors, MS275 and SBHA, enhances cytotoxicity induced by oxaliplatin in the colorectal cancer cell lines. Biochem Biophys Res Commun 2009;387:336-41.
73. Chen X, Wong P, Radany E, Wong JY. HDAC inhibitor, valproic acid, induces p53-dependent radiosensitization of colon cancer cells. Cancer Biother Radiopharm 2009;24:689-99.
74. Wai PY, Mi Z, Gao C, Guo H, Marroquin C, Kuo PC:Ets-1 and runx2 regulate transcription of a metastatic gene, osteopontin, in murine colorectal cancer cells. J Biol Chem 2006;281:18973-82.
75. Baserga R, Hongo A, Rubini M, Prisco M, Valentinis B. The IGF-Ⅰ receptor in cell growth, transformation and apoptosis. Biochim Biophys Acta 1997;1332:F105-26.
76. Hakam A, Yeatman TJ, Lu L, Mora L, Marcet G, Nicosia SV, Karl RC, Coppola D. Expression of insulin-like growth factor-1 receptor in human colorectal cancer. Hum Pathol 1999;30:1128-33.
77. Donovan EA, Kummar S. Role of insulin-like growth factor-1R system in colorectal carcinogenesis. Crit Rev Oncol Hematol 2008;66:91-8.
78.Nahor I, Abramovitch S, Engeland K, Werner H. The p53-family members p63 and p73 inhibit insulin-like growth factor-I receptor gene expression in colon cancer cells. Growth Horm IGF Res 2005;15:388-96.
79 Werner H, Karnieli E, Rauscher FJ, LeRoith D. Wild-type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene. Proc Natl Acad Sci U S A 1996;93:8318-23.
78. Zeeberg, B. R., Qin, H., Narasimhan, S., Sunshine, M., Cao, H., Kane, D. W., Reimers, M., Stephens, R. M., Bryant, D., Burt, S. K., Elnekave, E., Hari, D. M., Wynn, T. A., Cunningham-Rundles, C., Stewart, D. M., Nelson, D., and Weinstein, J. N. (2005) High-Throughput GoMiner, an 'industrial-strength' integrative gene ontology tool for interpretation of multiple-microarray experiments, with application to studies of Common Variable Immune Deficiency (CVID). BMC Bioinformatics 6, Page.
79 Mikula, M., Dzwonek, A., Karczmarski, J., Rubel, T., Dadlez, M., Wyrwicz, L. S., Bomsztyk, K., and Ostrowski, J. (2006) Landscape of the hnRNP K protein-protein interactome. Proteomics 6, Page.
80. Wilson, M., and Koopman, P. (2002) Matching SOX:partner proteins and co-factors of the SOX family of transcriptional regulators. Curr Opin Genet Dev 12, Page.
81. Ostrowski, J., Kawata, Y., Schullery, D. S., Denisenko, O. N., and Bomsztyk, K. (2003) Transient recruitment of the hnRNP K protein to inducibly transcribed gene loci. Nucleic Acids Res 31, Page.
82 Bomsztyk, K., Denisenko, O., and Ostrowski, J. (2004) hnRNP K:one protein multiple processes. Bioessays 26, Page.
83. P.Y. Wai, Z. Mi, C. Gao, H. Guo, C. Marroquin, P.C. Kuo, Ets-1 and runx2 regulate transcription of a metastatic gene, osteopontin, in murine colorectal cancer cells. J Biol Chem 281 (2006) 18973-18982.
1. Aasen, T., Raya, A., Barrero, M.J., Garreta, E., Consiglio, A., Gonzalez, F., Vassena, R., Bilic, J., Pekarik, V., Tiscornia, G., et al. (2008). Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 26, 1276-1284.
2. Bass, A.J., Watanabe, H., Mermel, C.H., Yu, S., Perner, S., Verhaak, R.G., Kim, S.Y., Wardwell, L., Tamayo, P., Gat-Viks, I., et al. (2009). SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 41,1238-1242.
3. Chen, Y., Shi, L., Zhang, L., Li, R., Liang, J., Yu, W., Sun, L., Yang, X., Wang, Y, Zhang, Y, and Shang, Y (2008). The molecular mechanism governing the oncogenic potential of SOX2 in breast cancer. J Biol Chem 283,17969-17978.
4. Cowan, C.A., Atienza, J., Melton, D.A., and Eggan, K. (2005). Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science 309,1369-1373.
5. Ebert, A.D., Yu, J., Rose, F.F., Jr., Mattis, V.B., Lorson, C.L., Thomson, J.A., and Svendsen, C.N. (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457,277-280.
6. Fantes, J., Ragge, N.K., Lynch, S.A., McGill, N.I., Collin, J.R., Howard-Peebles, P.N., Hayward, C., Vivian, A.J., Williamson, K., van Heyningen, V., and FitzPatrick, D.R. (2003). Mutations in SOX2 cause anophthalmia. Nat Genet 33, 461-463.
7. Hamm, C.A., Xie, H., Costa, F.F., Vanin, E.F., Seftor, E.A., Sredni, S.T., Bischof, J., Wang, D., Bonaldo, M.F., Hendrix, M.J., and Soares, M.B. (2009). Global demethylation of rat chondrosarcoma cells after treatment with 5-aza-2'-deoxycytidine results in increased tumorigenicity. PLoS One 4, e8340.
8. Huangfu, D., Maehr, R., Guo, W., Eijkelenboom, A., Snitow, M., Chen, A.E., and Melton, D.A. (2008a). Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol 26,795-797.
9. Huangfu, D., Osafune, K., Maehr, R., Guo, W., Eijkelenboom, A., Chen, S., Muhlestein, W., and Melton, D.A. (2008b). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 26, 1269-1275.
10. Ikushima, H., Todo, T., Ino, Y., Takahashi, M., Miyazawa, K., and Miyazono, K. (2009). Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 5, 504-514.
11. Kaji, K., Norrby, K., Paca, A., Mileikovsky, M., Mohseni, P., and Woltjen, K. (2009). Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458,771-775.
12 Kamachi, Y., Cheah, K.S., and Kondoh, H. (1999). Mechanism of regulatory target selection by the SOX high-mobility-group domain proteins as revealed by comparison of SOX1/2/3 and SOX9. Mol Cell Biol 19,107-120.
13. Kamachi, Y, Uchikawa, M., Tanouchi, A., Sekido, R., and Kondoh, H. (2001). Pax6 and SOX2 form a co-DNA-binding partner complex that regulates initiation of lens development. Genes Dev 15,1272-1286.
14. Loh, Y.H., Agarwal, S., Park, I.H., Urbach, A., Huo, H., Heffner, G.C., Kim, K., Miller, J.D., Ng, K., and Daley, G.Q. (2009). Generation of induced pluripotent stem cells from human blood. Blood 113,5476-5479.
15. Long, K.B., and Hornick, J.L. (2009). SOX2 is highly expressed in squamous cell carcinomas of the gastrointestinal tract. Hum Pathol 40,1768-1773.
16. Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., Okita, K., Mochiduki, Y., Takizawa, N., and Yamanaka, S. (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26,101-106.
17. Nishii, T., Yashiro, M., Shinto, O., Sawada, T., Ohira, M., and Hirakawa, K. (2009). Cancer stem cell-like SP cells have a high adhesion ability to the peritoneum in gastric carcinoma. Cancer Sci 100,1397-1402.
18. Otsubo, T., Akiyama, Y, Yanagihara, K., and Yuasa, Y. (2008). SOX2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis. Br J Cancer 98,824-831.
20. Saigusa, S., Tanaka, K., Toiyama, Y., Yokoe, T., Okugawa, Y., Ioue, Y., Miki, C., and Kusunoki, M. (2009). Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol 16,3488-3498.
21. Schmitz, M., Temme, A., Senner, V., Ebner, R., Schwind, S., Stevanovic, S., Wehner, R., Schackert, G., Schackert, H.K., Fussel, M., et al. (2007). Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy. Br J Cancer 96,1293-1301.
22. Sholl, L.M., Long, K.B., and Hornick, J.L. Sox2 expression in pulmonary non-small cell and neuroendocrine carcinomas. Appl Immunohistochem Mol Morphol 18, 55-61.
23. Soullier, S., Jay, P., Poulat, F., Vanacker, J.M., Berta, P., and Laudet, V. (1999). Diversification pattern of the HMG and SOX family members during evolution. J Mol Evol 48,517-527.
24. Stevanovic, M., Zuffardi, O., Collignon, J., Lovell-Badge, R., and Goodfellow, P. (1994). The cDNA sequence and chromosomal location of the human SOX2 gene. Mamm Genome 5,640-642.
25. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131,861-872.
26. Taura, D., Noguchi, M., Sone, M., Hosoda, K., Mori, E., Okada, Y, Takahashi, K., Homma, K., Oyamada, N., Inuzuka, M., et al. (2009). Adipogenic differentiation of human induced pluripotent stem cells:comparison with that of human embryonic stem cells. FEBS Lett 583,1029-1033.
27. Tung, C.L., Hou, P.H., Kao, Y.L., Huang, Y.W., Shen, C.C., Cheng, Y.H., Wu,S.F., Lee, M.S., and Li, C. SOX2 modulates alternative splicing in transitional cell carcinoma. Biochem Biophys Res Commun 393,420-425.
28. Wellner, U., Schubert, J., Burk, U.C., Schmalhofer, O., Zhu, F., Sonntag, A.
Waldvogel, B., Vannier, C., Darling, D., zur Hausen, A., et al. (2009). The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 11,1487-1495.
29. Williamson, K.A., Hever, A.M., Rainger, J., Rogers, R.C., Magee, A., Fiedler, Z., Keng, W.T.,Sharkey, F.H., McGill, N., Hill, C.J., et al. (2006). Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. Hum Mol Genet 15, 1413-1422.
30. Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920.
31. Yuan, P., Kadara, H., Behrens, C., Tang, X., Woods, D., Solis, L.M., Huang, J., Spinola, M., Dong, W., Yin, G., et al. Sex determining region Y-Box 2 (SOX2) is a potential cell-lineage gene highly expressed in the pathogenesis of squamous cell carcinomas of the lung. PLoS One 5, e9112.
32. Chen, Y, Shi, L., Zhang, L., Li, R., Liang, J., Yu, W., Sun, L., Yang, X., Wang, Y, Zhang, Y, and Shang, Y. (2008). The molecular mechanism governing the oncogenic potential of SOX2 in breast cancer. J Biol Chem 283,17969-17978.
2. Schepers, G. E., Teasdale, R. D., and Koopman, P. (2002) Twenty pairs of sox: extent, homology, and nomenclature of the mouse and human sox transcription factor gene families. Dev Cell 3, Page.
3. Wegner, M. (1999) From head to toes:the multiple facets of Sox proteins. Nucleic Acids Res 27, Page.
4. Avilion, A. A., Nicolis, S. K., Pevny, L. H., Perez, L., Vivian, N., and Lovell-Badge, R. (2003) Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 17, Page.
5. Cai, J., Wu, Y., Mirua, T., Pierce, J. L., Lucero, M. T., Albertine, K. H., Spangrude, G. J., and Rao, M. S. (2002) Properties of a fetal multipotent neural stem cell (NEP cell). Dev Biol 251, Page.
6. Graham, V., Khudyakov, J., Ellis, P., and Pevny, L. (2003) SOX2 functions to maintain neural progenitor identity. Neuron 39, Page.
7. Takahashi, K., and Yamanaka, S. (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, Page.
8. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, Page.
9. Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., Slukvin, II, and Thomson, J. A. (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318, Page.
10. Wegner, M., and Stolt, C. C. (2005) From stem cells to neurons and glia:a Soxist's view of neural development. Trends Neurosci 28, Page.
11. Schmitz, M., Temme, A., Senner, V., Ebner, R., Schwind, S., Stevanovic, S., Wehner, R., Schackert, G, Schackert, H. K., Fussel, M., Bachmann, M., Rieber, E. P., and Weigle, B. (2007) Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy. Br J Cancer 96, Page.
12. Phi, J. H., Park, S. H., Kim, S. K., Paek, S. H., Kim, J. H., Lee, Y. J., Cho, B. K., Park, C. K., Lee, D. H., and Wang, K. C. (2008) Sox2 expression in brain tumors:a reflection of the neuroglial differentiation pathway. Am J Surg Pathol 32, Page.
13. Li, X. L., Eishi, Y., Bai, Y. Q., Sakai, H., Akiyama, Y, Tani, M., Takizawa, T., Koike, M., and Yuasa, Y. (2004) Expression of the SRY-related HMG box protein SOX2 in human gastric carcinoma. Int J Oncol 24, Page.
14. Park, E. T., Gum, J. R., Kakar, S., Kwon, S. W., Deng, G., and Kim, Y. S. (2008) Aberrant expression of SOX2 upregulates MUC5AC gastric foveolar mucin in mucinous cancers of the colorectum and related lesions. Int J Cancer 122, Page.
15. Rodriguez-Pinilla, S. M., Sarrio, D., Moreno-Bueno, G., Rodriguez-Gil, Y., Martinez, M. A., Hernandez, L., Hardisson, D., Reis-Filho, J. S., and Palacios, J. (2007) Sox2:a possible driver of the basal-like phenotype in sporadic breast cancer. Mod Pathol 20, Page.
16. Chen, Y, Shi, L., Zhang, L., Li, R., Liang, J., Yu, W., Sun, L., Yang, X., Wang, Y, Zhang, Y, and Shang, Y. (2008) The molecular mechanism governing the oncogenic potential of SOX2 in breast cancer. J Biol Chem 283, Page.
18. Sanada, Y, Yoshida, K., Ohara, M., Oeda, M., Konishi, K., and Tsutani, Y. (2006) Histopathologic evaluation of stepwise progression of pancreatic carcinoma with immunohistochemical analysis of gastric epithelial transcription factor SOX2: comparison of expression patterns between invasive components and cancerous or nonneoplastic intraductal components. Pancreas 32, Page.
19. Sholl, L. M., Long, K. B., and Hornick, J. L. (2009) Sox2 Expression in Pulmonary Non-small Cell and Neuroendocrine Carcinomas. Appl Immunohistochem Mol Morphol, Page.
20. Wang, Q., He, W, Lu, C., Wang, Z., Wang, J., Giercksky, K. E., Nesland, J. M., and Suo, Z. (2009) Oct3/4 and Sox2 are significantly associated with an unfavorable clinical outcome in human esophageal squamous cell carcinoma. Anticancer Res 29, Page.
21. Saigusa, S., Tanaka, K., Toiyama, Y., Yokoe, T., Okugawa, Y, Ioue, Y, Miki, C., and Kusunoki, M. (2009) Correlation of CD133, OCT4, and SOX2 in Rectal Cancer and Their Association with Distant Recurrence After Chemoradiotherapy. Ann Surg Oncol, Page.
22. Barski, A., Cuddapah, S., Cui, K., Roh, T. Y, Schones, D. E., Wang, Z., Wei, G, Chepelev, I., and Zhao, K. (2007) High-resolution.profiling of histone methylations in the human genome. Cell 129, Page.
23. Jothi, R., Cuddapah, S., Barski, A., Cui, K., and Zhao, K. (2008) Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Res 36, Page.
24. Chen, Y, Shi, L., Zhang, L., Li, R., Liang, J., Yu, W., Sun, L., Yang, X., Wang, Y, Zhang, Y, and Shang, Y (2008) The molecular mechanism governing the oncogenic potential of SOX2 in breast cancer. J Biol Chem 283, Page.
25. Li, X. L., Eishi, Y, Bai, Y Q., Sakai, H., Akiyama, Y, Tani, M., Takizawa, T., Koike, M., and Yuasa, Y. (2004) Expression of the SRY-related HMG box protein SOX2 in human gastric carcinoma. Int J Oncol 24, Page.
26. Park, E. T., Gum, J. R., Kakar, S., Kwon, S. W., Deng, G., and Kim, Y S. (2008) Aberrant expression of SOX2 upregulates MUC5AC gastric foveolar mucin in mucinous cancers of the colorectum and related lesions. Int J Cancer 122, Page.
27. Schmitz, M., Temme, A., Senner, V., Ebner, R., Schwind, S., Stevanovic, S., Wehner, R., Schackert, G, Schackert, H. K., Fussel, M., Bachmann, M., Rieber, E. P., and Weigle, B. (2007) Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy. Br J Cancer 96, Page.
28. Phi, J. H., Park, S. H., Kim, S. K., Paek, S. H., Kim, J. H., Lee, Y J., Cho, B. K., Park, C. K., Lee, D. H., and Wang, K. C. (2008) Sox2 expression in brain tumors:a reflection of the neuroglial differentiation pathway. Am J Surg Pathol 32, Page.
29. Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Ioue Y, Miki C, Kusunoki M. Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol 2009; 16:3488-98.
30. Cho SJ, Kim JS, Kim JM, Lee JY, Jung HC, Song IS. Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. Int J Cancer 2008;123:951-7.
31. Foltz G, Ryu GY, Yoon JG, Nelson T, Fahey J, Frakes A, Lee H, Field L, Zander K, Sibenaller Z, Ryken TC, Vibhakar R, et al. Genome-wide analysis of epigenetic silencing identifies BEX1 and BEX2 as candidate tumor suppressor genes in malignant glioma. Cancer Res 2006;66:6665-74.
32. Lin B, Wang J, Hong X, Yan X, Hwang D, Cho JH, Yi D, Utleg AG, Fang X, Schones DE, Zhao K, Omenn GS, et al. Integrated expression profiling and ChIP-seq analyses of the growth inhibition response program of the androgen receptor. PLoS One 2009;4:e6589.
33. Halder SK, Rachakonda G, Deane NG, Datta PK. Smad7 induces hepatic metastasis in colorectal cancer. Br J Cancer 2008;99:957-65.
34. Sekharam M, Zhao H, Sun M, Fang Q, Zhang Q, Yuan Z, Dan HC, Boulware D, Cheng JQ, Coppola D. Insulin-like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/Bcl-x(L) pathway. Cancer Res 2003;63:7708-16.
35. O'Dwyer P J, Benson AB,3rd. Epidermal growth factor receptor-targeted therapy in colorectal cancer. Semin Oncol 2002;29:10-7.
36. Hu Q, Zhang L, Wen J, Wang S, Li M, Feng R, Yang X, Li L. The EGF receptor-sox2-EGF receptor feedback loop positively regulates the self-renewal of neural precursor cells. Stem Cells;28:279-86.
37.Fei T, Xia K, Li Z, Zhou B, Zhu S, Chen H, Zhang J, Chen Z, Xiao H, Han JD, Chen YG. Genome-wide mapping of SMAD target genes reveals the role of BMP signaling in embryonic stem cell fate determination.Genome Res.2010, 20(1):36-44
38.Sieber C, Kopf J, Hiepen C, Knaus P.Recent advances in BMP receptor signaling.Cytokine Growth Factor Rev.2009,20:343-55.
39. Kang MH, Kang HN, Kim JL, Kim JS, Oh SC, Yoo YA.Inhibition of PⅠ3 kinase/Akt pathway is required for BMP2-induced EMT and invasion.Oncol Rep.2009, 22:525-34.
40. Alarmo EL, Parssinen J, Ketolainen JM, Savinainen K, Karhu R, Kallioniemi, A.BMP7 influences proliferation, migration, and invasion of breast cancer cells. Cancer Lett.2009,275(1):35-43.
41. Motoyama K, Tanaka F, Kosaka Y, Mimori K, Uetake H, Inoue H, Sugihara K, Mori M.Clinical significance of BMP7 in human colorectal cancer. Ann Surg Oncol. 2008 15:1530-7.
42. Buijs JT, Henriquez NV, van Overveld PG, van der Horst G, ten Dijke P, van der Pluijm GTGF-beta and BMP7 interactions in tumour progression and bone metastasis.Clin Exp Metastasis.2007,24:609-17
43. Barski, A., Cuddapah, S., Cui, K., Roh, T. Y., Schones, D. E., Wang, Z., Wei, G., Chepelev, I., and Zhao, K. (2007) High-resolution profiling of histone methylations in the human genome. Cell 129, Page.
44. Jothi, R., Cuddapah, S., Barski, A., Cui, K., and Zhao, K. (2008) Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Res 36, Page.
45. Johnson, D. S., Mortazavi, A., Myers, R. M., and Wold, B. (2007) Genome-wide mapping of in vivo protein-DNA interactions. Science 316, Page.
46. Okumura-Nakanishi, S., Saito, M., Niwa, H., and Ishikawa, F. (2005) Oct-3/4 and Sox2 regulate Oct-3/4 gene in embryonic stem cells. J Biol Chem 280, Page.
47. Williams, D. C., Jr., Cai, M., and Clore, G. M. (2004) Molecular basis for synergistic transcriptional activation by Octl and Sox2 revealed from the solution structure of the 42-kDa Octl.Sox2.Hoxbl-DNA ternary transcription factor complex. J Biol Chem 279, Page.
48. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nussbaum C, Myers RM, Brown M, Li W, Liu XS. Model-based analysis of ChIP-Seq (MACS). Genome Biol 2008;9:R137.
49. Thijs G, Marchal K, Lescot M, Rombauts S, De Moor B, Rouze P, Moreau Y. A Gibbs sampling method to detect overrepresented motifs in the upstream regions of coexpressed genes. J Comput Biol 2002;9:447-64.
50. Thijs G, Moreau Y, De Smet F, Mathys J, Lescot M, Rombauts S, Rouze P, De Moor B, Marchal K. INCLUSive:integrated clustering, upstream sequence retrieval and motif sampling. Bioinformatics 2002;18:331-2.
51. Sandelin A, Alkema W, Engstrom P, Wasserman WW, Lenhard B. JASPAR:an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res 2004;32:D91-4.
52. Beckstette M, Homann R, Giegerich R, Kurtz S. Fast index based algorithms and software for matching position specific scoring matrices. BMC Bioinformatics 2006;7:389.
53. Wilson, M., and Koopman, P. Matching SOX:partner proteins and co-factors of the SOX family of transcriptional regulators. Curr Opin Genet Dev, (2002) 12, Page.
54. Mertin, S., McDowall, S. G, and Harley, V. R. The DNA-binding specificity of SOX9 and other SOX proteins. Nucleic Acids Res, (1999)27, Page.
55. Kamachi, Y, Uchikawa, M., and Kondoh, H. Pairing SOX off:with partners in the regulation of embryonic development. Trends Genet,(2000) 16, Page.
56. Marson, A., Levine, S. S., Cole, M. F., Frampton, G. M., Brambrink, T., Johnstone, S., Guenther, M. G., Johnston, W. K., Wernig, M., Newman, J., Calabrese, J. M., Dennis, L. M., Volkert, T. L., Gupta, S., Love, J., Hannett, N., Sharp, P. A., Bartel, D. P., Jaenisch, R., and Young, R. A. (2008) Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134, Page.
57. Boyer, L. A., Lee, T. I., Cole, M. F., Johnstone, S. E., Levine, S. S., Zucker, J. P., Guenther, M. G, Kumar, R. M., Murray, H. L., Jenner, R. G, Gifford, D. K. Melton, D. A., Jaenisch, R., and Young, R. A. (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, Page.
58. Chen, X., Xu, H., Yuan, P., Fang, F., Huss, M., Vega, V. B., Wong, E., Orlov, Y. L, Zhang, W., Jiang, J., Loh, Y. H., Yeo, H. C., Yeo, Z. X., Narang, V., Govindarajan, K. R., Leong, B., Shahab, A., Ruan, Y, Bourque, G., Sung, W. K., Clarke, N. D., Wei, C. L., and Ng, H. H. (2008) Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 133, Page
59.Petrie K, Guidez F, Howell L, Healy L, Waxman S, Greaves M, Zelent A.The histone deacetylase 9 gene encodes multiple protein isoforms. J Biol Chem. 2003,278:16059-72.
60. Wilson AJ, Byun DS, Nasser S, Murray LB, Ayyanar K, Arango D, Figueroa M, Melnick A, Kao GD, Augenlicht LH, Mariadason JM. HDAC4 Promotes Growth of Colon Cancer Cells via Repression of p21. Mol Biol Cell.2008,19:4062-4075.
61. Lucio-Eterovic AK, Cortez MA, Valera ET, Motta FJ, Queiroz RG, Machado HR, Carlotti CG Jr, Neder L, Scrideli CA, Tone LG.Differential expression of 12 histone deacetylase (HDAC) genes in astrocytomas and normal brain tissue:class II and IV are hypoexpressed in glioblastomas. BMC Cancer.2008,8:243.
62. Oji Y, Yamamoto H, Nomura M, Nakano Y, Ikeba A, Nakatsuka S, Abeno S, Kiyotoh E, Jomgeow T, Sekimoto M, Nezu R, Yoshikawa Y, Inoue Y, Hosen N, Kawakami M, Tsuboi A, Oka Y, Ogawa H, Souda S, Aozasa K, Monden M, Sugiyama H. Overexpression of the Wilms' tumor gene WT1 in colorectal adenocarcinoma. Cancer Sci.2003 94:712-7.
63. Koesters R, Linnebacher M, Coy JF, Germann A, Schwitalle Y, Findeisen P, von Knebel Doeberitz M.WT1 is a tumor-associated antigen in colon cancer that can be recognized by in vitro stimulated cytotoxic T cells. Int J Cancer.2004 109:385-92.
64. Wiesner GL, Daley D, Lewis S, Ticknor C, Platzer P, Lutterbaugh J, MacMillen M, Baliner B, Willis J, Elston RC, Markowitz SD. A subset of familial colorectal neoplasia kindreds linked to chromosome 9q22.2-31.2. Proc Natl Acad Sci U S A 2003;100:12961-5.
65. Lee HJ, Chattopadhyay S, Yoon WH, Bahk JY, Kim TH, Kang HS, Lee K. Overexpression of hepatocyte nuclear factor-3alpha induces apoptosis through the upregulation and accumulation of cytoplasmic p53 in prostate cancer cells. Prostate;70:353-61.
66. Dhawan P, Singh AB, Deane NG, No Y, Shiou SR, Schmidt C, Neff J, Washington MK, Beauchamp RD. Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. J Clin Invest 2005:115:1765-76.
67. Sekharam M, Zhao H, Sun M, Fang Q, Zhang Q, Yuan Z,. Dan HC, Boulware D, Cheng JQ, Coppola D. Insulin-like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/Bcl-x(L) pathway. Cancer Res 2003;63:7708-16.
68 O'Dwyer P J, Benson AB. Epidermal growth factor receptor-targeted therapy in colorectal cancer. Semin Oncol 2002;29:10-7.
69. Chen X, Xu H, Yuan P, Fang F, Huss M, Vega VB, Wong E, Orlov YL, Zhang W, Jiang J, Loh YH, Yeo HC, et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 2008;133:1106-17.
70. Esteller M. Cancer epigenomics:DNA methylomes and histone-modification maps. Nat Rev Genet 2007;8:286-98.
71. Ishihama K, Yamakawa M, Semba S, Takeda H, Kawata S, Kimura S, Kimura W. Expression of HDAC1 and CBP/p300 in human colorectal carcinomas. J Clin Pathol 2007;60:1205-10.
72. Flis S, Gnyszka A, Splawinski J. HDAC inhibitors, MS275 and SBHA, enhances cytotoxicity induced by oxaliplatin in the colorectal cancer cell lines. Biochem Biophys Res Commun 2009;387:336-41.
73. Chen X, Wong P, Radany E, Wong JY. HDAC inhibitor, valproic acid, induces p53-dependent radiosensitization of colon cancer cells. Cancer Biother Radiopharm 2009;24:689-99.
74. Wai PY, Mi Z, Gao C, Guo H, Marroquin C, Kuo PC:Ets-1 and runx2 regulate transcription of a metastatic gene, osteopontin, in murine colorectal cancer cells. J Biol Chem 2006;281:18973-82.
75. Baserga R, Hongo A, Rubini M, Prisco M, Valentinis B. The IGF-Ⅰ receptor in cell growth, transformation and apoptosis. Biochim Biophys Acta 1997;1332:F105-26.
76. Hakam A, Yeatman TJ, Lu L, Mora L, Marcet G, Nicosia SV, Karl RC, Coppola D. Expression of insulin-like growth factor-1 receptor in human colorectal cancer. Hum Pathol 1999;30:1128-33.
77. Donovan EA, Kummar S. Role of insulin-like growth factor-1R system in colorectal carcinogenesis. Crit Rev Oncol Hematol 2008;66:91-8.
78.Nahor I, Abramovitch S, Engeland K, Werner H. The p53-family members p63 and p73 inhibit insulin-like growth factor-I receptor gene expression in colon cancer cells. Growth Horm IGF Res 2005;15:388-96.
79 Werner H, Karnieli E, Rauscher FJ, LeRoith D. Wild-type and mutant p53 differentially regulate transcription of the insulin-like growth factor I receptor gene. Proc Natl Acad Sci U S A 1996;93:8318-23.
78. Zeeberg, B. R., Qin, H., Narasimhan, S., Sunshine, M., Cao, H., Kane, D. W., Reimers, M., Stephens, R. M., Bryant, D., Burt, S. K., Elnekave, E., Hari, D. M., Wynn, T. A., Cunningham-Rundles, C., Stewart, D. M., Nelson, D., and Weinstein, J. N. (2005) High-Throughput GoMiner, an 'industrial-strength' integrative gene ontology tool for interpretation of multiple-microarray experiments, with application to studies of Common Variable Immune Deficiency (CVID). BMC Bioinformatics 6, Page.
79 Mikula, M., Dzwonek, A., Karczmarski, J., Rubel, T., Dadlez, M., Wyrwicz, L. S., Bomsztyk, K., and Ostrowski, J. (2006) Landscape of the hnRNP K protein-protein interactome. Proteomics 6, Page.
80. Wilson, M., and Koopman, P. (2002) Matching SOX:partner proteins and co-factors of the SOX family of transcriptional regulators. Curr Opin Genet Dev 12, Page.
81. Ostrowski, J., Kawata, Y., Schullery, D. S., Denisenko, O. N., and Bomsztyk, K. (2003) Transient recruitment of the hnRNP K protein to inducibly transcribed gene loci. Nucleic Acids Res 31, Page.
82 Bomsztyk, K., Denisenko, O., and Ostrowski, J. (2004) hnRNP K:one protein multiple processes. Bioessays 26, Page.
83. P.Y. Wai, Z. Mi, C. Gao, H. Guo, C. Marroquin, P.C. Kuo, Ets-1 and runx2 regulate transcription of a metastatic gene, osteopontin, in murine colorectal cancer cells. J Biol Chem 281 (2006) 18973-18982.
1. Aasen, T., Raya, A., Barrero, M.J., Garreta, E., Consiglio, A., Gonzalez, F., Vassena, R., Bilic, J., Pekarik, V., Tiscornia, G., et al. (2008). Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 26, 1276-1284.
2. Bass, A.J., Watanabe, H., Mermel, C.H., Yu, S., Perner, S., Verhaak, R.G., Kim, S.Y., Wardwell, L., Tamayo, P., Gat-Viks, I., et al. (2009). SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 41,1238-1242.
3. Chen, Y., Shi, L., Zhang, L., Li, R., Liang, J., Yu, W., Sun, L., Yang, X., Wang, Y, Zhang, Y, and Shang, Y (2008). The molecular mechanism governing the oncogenic potential of SOX2 in breast cancer. J Biol Chem 283,17969-17978.
4. Cowan, C.A., Atienza, J., Melton, D.A., and Eggan, K. (2005). Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science 309,1369-1373.
5. Ebert, A.D., Yu, J., Rose, F.F., Jr., Mattis, V.B., Lorson, C.L., Thomson, J.A., and Svendsen, C.N. (2009). Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature 457,277-280.
6. Fantes, J., Ragge, N.K., Lynch, S.A., McGill, N.I., Collin, J.R., Howard-Peebles, P.N., Hayward, C., Vivian, A.J., Williamson, K., van Heyningen, V., and FitzPatrick, D.R. (2003). Mutations in SOX2 cause anophthalmia. Nat Genet 33, 461-463.
7. Hamm, C.A., Xie, H., Costa, F.F., Vanin, E.F., Seftor, E.A., Sredni, S.T., Bischof, J., Wang, D., Bonaldo, M.F., Hendrix, M.J., and Soares, M.B. (2009). Global demethylation of rat chondrosarcoma cells after treatment with 5-aza-2'-deoxycytidine results in increased tumorigenicity. PLoS One 4, e8340.
8. Huangfu, D., Maehr, R., Guo, W., Eijkelenboom, A., Snitow, M., Chen, A.E., and Melton, D.A. (2008a). Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol 26,795-797.
9. Huangfu, D., Osafune, K., Maehr, R., Guo, W., Eijkelenboom, A., Chen, S., Muhlestein, W., and Melton, D.A. (2008b). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol 26, 1269-1275.
10. Ikushima, H., Todo, T., Ino, Y., Takahashi, M., Miyazawa, K., and Miyazono, K. (2009). Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 5, 504-514.
11. Kaji, K., Norrby, K., Paca, A., Mileikovsky, M., Mohseni, P., and Woltjen, K. (2009). Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458,771-775.
12 Kamachi, Y., Cheah, K.S., and Kondoh, H. (1999). Mechanism of regulatory target selection by the SOX high-mobility-group domain proteins as revealed by comparison of SOX1/2/3 and SOX9. Mol Cell Biol 19,107-120.
13. Kamachi, Y, Uchikawa, M., Tanouchi, A., Sekido, R., and Kondoh, H. (2001). Pax6 and SOX2 form a co-DNA-binding partner complex that regulates initiation of lens development. Genes Dev 15,1272-1286.
14. Loh, Y.H., Agarwal, S., Park, I.H., Urbach, A., Huo, H., Heffner, G.C., Kim, K., Miller, J.D., Ng, K., and Daley, G.Q. (2009). Generation of induced pluripotent stem cells from human blood. Blood 113,5476-5479.
15. Long, K.B., and Hornick, J.L. (2009). SOX2 is highly expressed in squamous cell carcinomas of the gastrointestinal tract. Hum Pathol 40,1768-1773.
16. Nakagawa, M., Koyanagi, M., Tanabe, K., Takahashi, K., Ichisaka, T., Aoi, T., Okita, K., Mochiduki, Y., Takizawa, N., and Yamanaka, S. (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 26,101-106.
17. Nishii, T., Yashiro, M., Shinto, O., Sawada, T., Ohira, M., and Hirakawa, K. (2009). Cancer stem cell-like SP cells have a high adhesion ability to the peritoneum in gastric carcinoma. Cancer Sci 100,1397-1402.
18. Otsubo, T., Akiyama, Y, Yanagihara, K., and Yuasa, Y. (2008). SOX2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis. Br J Cancer 98,824-831.
20. Saigusa, S., Tanaka, K., Toiyama, Y., Yokoe, T., Okugawa, Y., Ioue, Y., Miki, C., and Kusunoki, M. (2009). Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol 16,3488-3498.
21. Schmitz, M., Temme, A., Senner, V., Ebner, R., Schwind, S., Stevanovic, S., Wehner, R., Schackert, G., Schackert, H.K., Fussel, M., et al. (2007). Identification of SOX2 as a novel glioma-associated antigen and potential target for T cell-based immunotherapy. Br J Cancer 96,1293-1301.
22. Sholl, L.M., Long, K.B., and Hornick, J.L. Sox2 expression in pulmonary non-small cell and neuroendocrine carcinomas. Appl Immunohistochem Mol Morphol 18, 55-61.
23. Soullier, S., Jay, P., Poulat, F., Vanacker, J.M., Berta, P., and Laudet, V. (1999). Diversification pattern of the HMG and SOX family members during evolution. J Mol Evol 48,517-527.
24. Stevanovic, M., Zuffardi, O., Collignon, J., Lovell-Badge, R., and Goodfellow, P. (1994). The cDNA sequence and chromosomal location of the human SOX2 gene. Mamm Genome 5,640-642.
25. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131,861-872.
26. Taura, D., Noguchi, M., Sone, M., Hosoda, K., Mori, E., Okada, Y, Takahashi, K., Homma, K., Oyamada, N., Inuzuka, M., et al. (2009). Adipogenic differentiation of human induced pluripotent stem cells:comparison with that of human embryonic stem cells. FEBS Lett 583,1029-1033.
27. Tung, C.L., Hou, P.H., Kao, Y.L., Huang, Y.W., Shen, C.C., Cheng, Y.H., Wu,S.F., Lee, M.S., and Li, C. SOX2 modulates alternative splicing in transitional cell carcinoma. Biochem Biophys Res Commun 393,420-425.
28. Wellner, U., Schubert, J., Burk, U.C., Schmalhofer, O., Zhu, F., Sonntag, A.
Waldvogel, B., Vannier, C., Darling, D., zur Hausen, A., et al. (2009). The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 11,1487-1495.
29. Williamson, K.A., Hever, A.M., Rainger, J., Rogers, R.C., Magee, A., Fiedler, Z., Keng, W.T.,Sharkey, F.H., McGill, N., Hill, C.J., et al. (2006). Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. Hum Mol Genet 15, 1413-1422.
30. Yu, J., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920.
31. Yuan, P., Kadara, H., Behrens, C., Tang, X., Woods, D., Solis, L.M., Huang, J., Spinola, M., Dong, W., Yin, G., et al. Sex determining region Y-Box 2 (SOX2) is a potential cell-lineage gene highly expressed in the pathogenesis of squamous cell carcinomas of the lung. PLoS One 5, e9112.
32. Chen, Y, Shi, L., Zhang, L., Li, R., Liang, J., Yu, W., Sun, L., Yang, X., Wang, Y, Zhang, Y, and Shang, Y. (2008). The molecular mechanism governing the oncogenic potential of SOX2 in breast cancer. J Biol Chem 283,17969-17978.