Downregulation of transcription factor SOX2 in cancer stem cells suppresses growth and metastasis of lung cancer

Abstract

Background:The cancer stem cell hypothesis suggests that neoplastic clones are maintained exclusively by a small subpopulation of cells, which have indefinite proliferation and differentiation potentials and give rise to phenotypically diverse cancer cells. Cancer stem cells have been isolated by their ability to efflux Hoechst 33342 dye and are referred to as the ‘side population' (SP).Methods and results:The Hoechst efflux assay was used to isolate and characterize the SP from murine D121 lung carcinoma cells. Here, we demonstrated that D121-SP cells contain cancer stem cell characteristics, that is, upregulation of the transcription factors SOX2 and Oct 4 in D121-SP cells. In addition, the migration of D121-SP was decreased, and apoptosis of D121-SP was upregulated following knocking down of SOX2 in D121 cells. Importantly, downregulation of SOX2 in D121 cells markedly suppressed their metastatic potential in syngeneic mice.Conclusions:These results suggest that the SP is an enriched source of lung tumour cells with stem cell properties and that SOX2 has an important role in maintaining stem cell properties and functions that may be a potential target for effective lung cancer therapy.

Multiple Pluripotent Stem Cell Markers in Human Anaplastic Thyroid Cancer: The Putative Upstream Role of SOX2

“…Indeed, in this model SOX2 was expressed more abundantly than both stem nuclear transcription factors OCT-4 and NANOG. Moreover, SOX2 silencing by RNA interference (siRNA) caused down-regulation not only of the downstream NANOG gene but also of OCT-4, confirming that SOX2 is able to regulate OCT-4 (27,29). In addition, SOX2 down-regulation caused chemosensitization to cisplatin and doxorubicin.…”

Kanserde yeni bir hedef haline gelen çok yönlü Sox2 geni

“…Sox2'nin onkojenik olduğu, aşırı ifade edilmesiyle, fare akciğer kanser modelinde ve gen çoğalmasıyla insan akciğer ve özefajiyal skuamöz hücreli karsinomlarda gösterilmiştir (42,57,58). Kanser kök hücrelerinde Sox2'nin transkripsiyonunun engellenmesiyle akciğer kanserinin gelişimi ve metastazı baskılanmıştır (59). 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).…”

“…EGFR mutasyonlu NSCLC TKI dirençli tümörlerde Sox2'i inhibe etmek için PI3K/Akt inhibitörlerinin kullanılmasının yararlı olabileceği düşünülmektedir (69). Bazı farklılıklar olsa da Sox2'nin farklı tümör modellerinde kanser hücrelerinin antiapoptotik özelliğinin oluşmasına katkı sağladığı açıklanmıştır (38,59,68).…”

Cancer Stem Cells (CSCs) in Lung Cancer

“…Knock-down of Oct-4 expression can significantly inhibit the abilities of tumor invasion and colony formation, increase apoptotic activities, and enhance the treatment effect of chemoradiotherapy (Chen et al, 2008). The downregulation of transcription factor SOX in lung CSCs reportedly suppresses growth and metastasis (Xiang et al, 2011), and the blocking of the SCF/c-kit signaling pathway inhibits CSC proliferation and survival after chemotherapy exposure in human lung cancer cell lines (Levina et al, 2010). Cisplatin treatment eliminated most of the tumor cells, but unlike the blocking of c-kit, it was unsuccessful in eliminating CSCs.…”