SOX2 identified as a target gene for the amplification at 3q26 that is frequently detected in esophageal squamous cell carcinoma

Gen, Yasuyuki; Yasui, Kohichiroh; Zen, Yoh; Zen, Keika; Dohi, Osamu; Endo, Mio; Tsuji, Kazuhiro; Wakabayashi, Naoki; Itoh, Yoshito; Naito, Yuji; Taniwaki, Masafumi; Nakanuma, Yasuni; Okanoue, Takeshi; Yoshikawa, Toshikazu

doi:10.1016/j.cancergencyto.2010.01.023

Cited by 72 publications

(72 citation statements)

References 45 publications

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“…Taken together, these data suggested that exogenous SOX2 expression might promote neuroblastoma tumorigenesis both in vitro and in vivo. These results were consistent with previous studies in which SOX2 was found to be overexpressed and could promote cell proliferation and tumorigenesis (16)(17)(18)(19)(20).…”

Section: Discussionsupporting

confidence: 83%

“…The SOX family of transcription factors is expressed during various phases of embryonic development, which affects cell fate and differentiation (15 and the potential for differentiation. Further studies revealed that SOX2 is required for the self-renewing proliferation of many normal and cancer stem cells (16)(17)(18)(19)(20). Moreover, SOX2 over-expressing mice displayed extensive hyperplasia, and about half of the mice expressing the highest levels of SOX2 also developed carcinoma over a 12-34-week period (21).…”

Section: Introductionmentioning

confidence: 99%

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SOX2 promotes tumorigenicity and inhibits the differentiation of I-type neuroblastoma cells

Yang¹,

Zheng²,

Xiao³

et al. 2014

International Journal of Oncology

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Abstract. SOX2 is a transcription factor associated with the pluripotency, proliferative potential, and self-renewing properties observed with embryonic stem cells and germ cells. SOX2 expression has been reported in several cancers and is implicated in tumorigenesis. We previously found that SOX2 expression was correlated to the clinical stage of neuroblastoma. Recently, we found that SOX2 overexpression occurs in I-type neuroblastoma cells (BE(2)-C cells). To elucidate the tumorigenic function of SOX2, we established a SOX2 overexpressed BE(2)-C cell line. SOX2 overexpressed cells showed higher tumorigenicity than control cells and exhibited decreased expression levels of marker proteins of N-or S-type cells after agent-induced differetiation. By contrast, in cells where SOX2 mRNA expression was knocked down by genespecific siRNA, tumorigenicty was significantly decreased and the expression levels of marker proteins of N-or S-type cells were upregulated. In conclusion, our findings indicate an important function for SOX2 in promoting tumorigenicity of I-type neuroblastoma cells and in inhibiting their differentiation, suggesting that SOX2 might be a potential therapeutic target in neuroblastoma.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

SOX2 promotes tumorigenicity and inhibits the differentiation of I-type neuroblastoma cells

Yang¹,

Zheng²,

Xiao³

et al. 2014

International Journal of Oncology

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“…(13) These findings are consistent with several publications from other groups. (14,15) However, the mechanisms by which SOX2 promotes ESCC remain to be elucidated.…”

supporting

confidence: 83%

SOX2 promotes tumor growth of esophageal squamous cell carcinoma through the AKT/mammalian target of rapamycin complex 1 signaling pathway

et al. 2013

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The transcription factor SOX2 is essential for the maintenance of embryonic stem cells and normal development of the esophagus. Our previous study revealed that the SOX2 gene is an amplification target of 3q26.3 in esophageal squamous cell carcinoma (ESCC), and that SOX2 promotes ESCC cell proliferation in vitro.In the present study, we aimed to identify the mechanisms by which SOX2 promotes proliferation of ESCC cells. Using a phosphoprotein array, we assayed multiple signaling pathways activated by SOX2 and determined that SOX2 activated the AKT ⁄ mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. LY294002, an inhibitor of phosphatidylinositol 3-kinase, and rapamycin, an inhibitor of mTORC1, suppressed the ability of SOX2 to enhance proliferation of ESCC cells in vitro. Effects of SOX2 knockdown, including reduced levels of phosphorylated AKT and decreased ESCC cell proliferation, were reversed with constitutive activation of AKT with knockdown of phosphatase and tensin homolog. In mouse xenografts, SOX2 promoted in vivo tumor growth of ESCC, which was dependent on AKT ⁄ mTORC1 activation. LY294002 suppressed the ability of SOX2 to enhance tumor growth of ESCC by reducing cell proliferation, but not by enhancing apoptosis. Furthermore, tissue microarray analysis of 61 primary ESCC tumors showed a positive correlation between expression levels of SOX2 and phosphorylated AKT. Our findings suggest that SOX2 promotes in vivo tumor growth of ESCC through activation of the AKT ⁄ mTORC1 signaling pathway, which enhances cell proliferation. (Cancer Sci 2013; 104: 810-816) S OX2 is a member of the SOX family of transcription factors.(1-3) SOX2 is critical for the maintenance of pluripotency and self-renewal of embryonic stem cells (4,5) and generation of induced pluripotent stem cells. (6)(7)(8) In the esophagus, SOX2 plays an important role in differentiation and morphogenesis.(9) In the developing foregut endoderm, the highest levels of SOX2 expression occur in the future esophagus and the anterior stomach. (10,11) Mutations in the SOX2 gene cause anophthalmia-esophageal-genital syndrome, a condition that involves esophageal atresia and tracheoesophageal fistula. (12) We previously showed that SOX2 is the amplification target at chromosome 3q26.3 in esophageal squamous cell carcinoma (ESCC), and that SOX2 promotes ESCC cell proliferation in vitro.(13) Furthermore, we showed that the expression of SOX2 is elevated in most primary ESCCs (70%).(13) These findings are consistent with several publications from other groups. (14,15) However, the mechanisms by which SOX2 promotes ESCC remain to be elucidated.In the present study, we aimed to identify the mechanisms by which SOX2 promotes proliferation of ESCC cells. Using a phosphoprotein array, we assayed multiple signaling pathways activated by SOX2. Here we show that SOX2 promotes in vivo tumor growth of ESCC through activation of the AKT ⁄ mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, which promotes cell proliferation. The serin...

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“…We previously investigated 3q amplifications in lung and esophageal SCCs and found in both variants that the focus of amplification lies at the locus of the developmental transcription factor SOX2, which we further demonstrated to serve as an essential SCC oncogene (2). SOX2 amplification and oncogenicity have since been reported in a spectrum of SCCs (3)(4)(5)(6)(7)(8) and, more recently, small-cell lung cancer (9). The most comprehensive SCC genomic characterization effort to date, The Cancer Genome Atlas (TCGA) lung SCC study, identified high-level amplification/overexpression of SOX2 in 21% of tumors, the third most frequent genomic alteration after inactivation of TP53 and CDKN2A (10).…”

Section: Introductionmentioning

confidence: 99%

SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas

Watanabe¹,

Ma²,

Peng³

et al. 2014

J. Clin. Invest.

148

150

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The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology.

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SOX2 identified as a target gene for the amplification at 3q26 that is frequently detected in esophageal squamous cell carcinoma

Cited by 72 publications

References 45 publications

SOX2 promotes tumorigenicity and inhibits the differentiation of I-type neuroblastoma cells

SOX2 promotes tumorigenicity and inhibits the differentiation of I-type neuroblastoma cells

SOX2 promotes tumor growth of esophageal squamous cell carcinoma through the AKT/mammalian target of rapamycin complex 1 signaling pathway

SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas

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