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

Abstract

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...

Sex-determining region Y-related high mobility group box (SOX)-2 is overexpressed in cervical squamous cell carcinoma and contributes cervical cancer cell migration and invasion in vitro

“…An earlier study detailing that SOX-2 enhances tumor growth of esophageal SCC in vivo through activation of the Akt pathway [22] promotes us to explore whether SOX-2 functions through this signaling pathway in cervical SCC. In accordance with the abovementioned study, our study revealed an Fig.…”

Downregulation of miR‐638 promotes invasion and proliferation by regulating SOX2 and induces EMT in NSCLC

“…Prior reports indicated that aberrant SOX2 expression is related to development, progression, and prognosis of multiple tumors by regulation of various cell signaling pathways. In esophageal squamous cell carcinoma, SOX2 could promote tumor growth through the AKT/mammalian target of rapamycin complex 1 signaling pathway [25]. In addition, SOX2 could promote cancer cell invasion by activating Slug in hepatocellular cancer [26].…”

Kanserde yeni bir hedef haline gelen çok yönlü Sox2 geni

“…Örneğin, özefajiyal skuamöz hücreli karsinomda AKT sinyal yolağını kullanarak büyümeyi ve hepatosellüler kanserde invazyonu uyarırken, akciğer kanserinde MAP4K4-sürvivin sinyal yolağı üzerinden hücreleri apoptoza götürmüştür (36)(37)(38). Ayrıca Sox2, WNT/β-catenin sinyal ağını düzenleyerek epitelyal-mezenşimal geçişi uyarmış ve metastaza neden olmuştur (39).…”

“…Akciğer kanserinin önemli bir alt tipi olan, küçük hücreli dışı akciğer kanseri (KHDAK) hastalarında myc ve Sox2 genlerini içeren farklı DNA bölgelerinde işlev kazandıran mutasyonlar ve gen amplifikasyonları belirlenmiştir (60). İnsan KHDAK hücrelerinde Sox2 geni sessizleştirildiğinde, ölüm reseptör yolağı ve mitokondrial sinyal yolağı aktive edilerek apoptozis indüklenmiştir (36). Ayrıca, KHDAK'de Sox2 amplifikasyonu, FGFR1 ve PIK3CA gen kopya sayısının artışı ile ilişkilendirilmiştir (61).…”