Loss of SOX2 expression induces cell motility via vimentin up‐regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma

Abstract

Recurrent gain on chromosome 3q26 encompassing the gene locus for the transcription factor SOX2 is a frequent event in human squamous cell carcinoma, including head and neck squamous cell carcinoma (HNSCC). Numerous studies demonstrated that SOX2 expression and function is related to distinct aspects of tumor cell pathophysiology. However, the underlying molecular mechanisms are not well understood, and the correlation between SOX2 expression and clinical outcome revealed conflicting data. Transcriptional profiling after silencing of SOX2 expression in a HNSCC cell line identified a set of up-regulated genes related to cell motility (e.g. VIM, FN1, CDH2). The inverse regulation of SOX2 and aforementioned genes was validated in 18 independent HNSCC cell lines from different anatomical sites. The inhibition of cell migration and invasion by SOX2 was confirmed by constant or conditional gene silencing and accelerated motility of HNSCC cells after SOX2 silencing was partially reverted by down-regulation of vimentin. In a retrospective study, SOX2 expression was determined by immunohistochemical staining on tissue microarrays containing primary tumor specimens of two independent HNSCC patient cohorts. Low SOX2 expression was found in 19.3% and 44.9% of primary tumor specimens, respectively. Univariate analysis demonstrated a statistically significant correlation between low SOX2 protein levels and reduced progression-free survival (Cohort I 51 vs. 16 months; Cohort II 33 vs. 12 months) and overall survival (Cohort I 150 vs. 37 months; Cohort II 33 vs. 16 months). Multivariate Cox proportional hazard model analysis confirmed that low SOX2 expression serves as an independent prognostic marker for HNSCC patients. We conclude that SOX2 inhibits tumor cell motility in HNSCC cells and that low SOX2 expression serves as a prognosticator to identify HNSCC patients at high risk for treatment failure.

Association between periostin and epithelial-mesenchymal transition in esophageal squamous cell carcinoma and its clinical significance

“…The present study therefore demonstrated that POSTN expression was elevated in the ESCC tissues with poor differentiation, lymphatic metastasis, venous invasion and thus a severe TNM stage. In terms of the mechanism, POSTN was previously reported to be able to combine to multiple integrin receptors including αvβ3, αvβ5, and α6β4, partially regulating the intracellular signaling pathways linked to phosphatidylinositol 3 kinase (PI3K) /AKT as well as FAK, and sequentially induce the proliferation, metastasis and invasion of cancer cells, and alter tumor microenvironment (11,16,28). The results of the present study validate the negative influences on the ESCC tissue due to the increased POSTN expression in cancer cells.…”

“…EMT may be directly or indirectly mediated by various factors including snail, slug and twist. Signaling of transforming growth factor-β is considered to exert a pivotal function in triggering and promoting EMT (11 initiation of EMT triggered by twist in prostate cancer (11). As such, POSTN is considered as a key proteins involved in EMT.…”

Epidemiology and Molecular Biology of Head and Neck Cancer

“…Moreover, the expression and function of key regulators of stemness is context-dependent and might be different in tumor cells as compared to embryonic or adult stem cells. As an example, transcriptional profiling after silencing of Sox2 expression in a HNSCC cell line with amplification of the 3q26 locus (encompassing the Sox2 coding region) revealed a set of upregulated genes related to cell motility and a mesenchymal-like phenotype [56]. Accordingly, silencing of Sox2 accelerated tumor cell migration and invasion, and low Sox2 expression served as a prognosticator to identify HNSCC patients at high risk of treatment failure [56].…”

Kanserde yeni bir hedef haline gelen çok yönlü Sox2 geni

“…Aynı şekilde osteosarkomda Sox2 bir sağkalım faktörüdür ve kendini yenilemede yeni bir biyobelirteç olabileceği önerilmektedir (49). Öte yandan, insan baş-boyun kanser örneklerinde azalmış Sox2 ifadesi vimentin proteinini upregüle ederek, tümör hücre göçünü arttırmıştır (50). Baş-boyun kanserleriyle ilgili meta-analiz sonuçları göstermiştir ki, Sox2 ifadesi, tümör TNM evreleme, invazyon derinliği ve lenf nodül metastazı gibi klinik parametrelerle ilişkilidir (51).…”