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

Overview

Journal Mol Oncol

Specialties Molecular Biology
Oncology

Date 2015 Jun 5

PMID 26040981

Citations 43

Authors

Pilar Bayo

Adriana Jou

Albrecht Stenzinger

Chunxuan Shao

Madeleine Gross

Alexandra Jensen

Niels Grabe

Christel Herold Mende

Pantelis Varvaki Rados

Juergen Debus

Wilko Weichert

Peter K Plinkert

Peter Lichter

Kolja Freier

Jochen Hess

Affiliations

Soon will be listed here.

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.

Citing Articles

Expression analysis of SOX2 and SOX9 in patients with oral squamous cell carcinoma.

Steen S, Horn D, Flechtenmacher C, Hoffmann J, Freier K, Ristow O Head Neck. 2024; 47(2):437-451.

PMID: 39180200 PMC: 11717967. DOI: 10.1002/hed.27925.

DUSP1 and SOX2 expression determine squamous cell carcinoma of the salivary gland progression.

Acero-Riaguas L, Griso-Acevedo A, SanLorenzo-Vaquero A, Ibanez-Herrera B, Fernandez-Diaz S, Mascaraque M Sci Rep. 2024; 14(1):15007.

PMID: 38951654 PMC: 11217270. DOI: 10.1038/s41598-024-65945-x.

The Role of SOX2 and SOX9 in Radioresistance and Tumor Recurrence.

Barbosa S, Laureano N, Wijaya Hadiwikarta W, Visioli F, Bonrouhi M, Pajdzik K Cancers (Basel). 2024; 16(2).

PMID: 38275880 PMC: 10814462. DOI: 10.3390/cancers16020439.

Sox2 and βIII-Tubulin as Biomarkers of Drug Resistance in Poorly Differentiated Sinonasal Carcinomas.

Lopez L, Fernandez-Vanes L, Cabal V, Garcia-Marin R, Suarez-Fernandez L, Codina-Martinez H J Pers Med. 2023; 13(10).

PMID: 37888115 PMC: 10608336. DOI: 10.3390/jpm13101504.

Signet-Ring Cell Squamous Cell Carcinoma: A Biphenotypic Neoplasm of the Gastro-Esophageal Junction with Uncertain Biological Potential: Case Report and Literature Review.

Satala C, Kovacs Z, Bara Jr T, Jung I, Gurzu S Int J Mol Sci. 2023; 24(11).

PMID: 37298485 PMC: 10253756. DOI: 10.3390/ijms24119535.

References

Wang J, Qian J, Hoeksema M, Zou Y, Espinosa A, Rahman S . Integrative genomics analysis identifies candidate drivers at 3q26-29 amplicon in squamous cell carcinoma of the lung. Clin Cancer Res. 2013; 19(20):5580-90. PMC: 3807802. DOI: 10.1158/1078-0432.CCR-13-0594. View

Pai S, Westra W . Molecular pathology of head and neck cancer: implications for diagnosis, prognosis, and treatment. Annu Rev Pathol. 2008; 4:49-70. PMC: 3703474. DOI: 10.1146/annurev.pathol.4.110807.092158. View

Zhang X, Yu H, Yang Y, Zhu R, Bai J, Peng Z . SOX2 in gastric carcinoma, but not Hath1, is related to patients' clinicopathological features and prognosis. J Gastrointest Surg. 2010; 14(8):1220-6. DOI: 10.1007/s11605-010-1246-3. View

Halec G, Holzinger D, Schmitt M, Flechtenmacher C, Dyckhoff G, Lloveras B . Biological evidence for a causal role of HPV16 in a small fraction of laryngeal squamous cell carcinoma. Br J Cancer. 2013; 109(1):172-83. PMC: 3708587. DOI: 10.1038/bjc.2013.296. View

Vanner R, Remke M, Gallo M, Selvadurai H, Coutinho F, Lee L . Quiescent sox2(+) cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma. Cancer Cell. 2014; 26(1):33-47. PMC: 4441014. DOI: 10.1016/j.ccr.2014.05.005. View

Pickering C, Zhang J, Yoo S, Bengtsson L, Moorthy S, Neskey D . Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov. 2013; 3(7):770-81. PMC: 3858325. DOI: 10.1158/2159-8290.CD-12-0537. View

Du L, Yang Y, Xiao X, Wang C, Zhang X, Wang L . Sox2 nuclear expression is closely associated with poor prognosis in patients with histologically node-negative oral tongue squamous cell carcinoma. Oral Oncol. 2011; 47(8):709-13. DOI: 10.1016/j.oraloncology.2011.05.017. View

Ben-Porath I, Thomson M, Carey V, Ge R, Bell G, Regev A . An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 2008; 40(5):499-507. PMC: 2912221. DOI: 10.1038/ng.127. View

Pscherer A, Schliwka J, Wildenberger K, Mincheva A, Schwaenen C, Dohner H . Antagonizing inactivated tumor suppressor genes and activated oncogenes by a versatile transgenesis system: application in mantle cell lymphoma. FASEB J. 2006; 20(8):1188-90. DOI: 10.1096/fj.05-4854fje. View

10.

Schrock A, Bode M, Goke F, Bareiss P, Schairer R, Wang H . Expression and role of the embryonic protein SOX2 in head and neck squamous cell carcinoma. Carcinogenesis. 2014; 35(7):1636-42. DOI: 10.1093/carcin/bgu094. View

11.

Chang C, Hsu W, Wang C, Chou C, Yen-Ping Kuo M, Lin B . Connective tissue growth factor activates pluripotency genes and mesenchymal-epithelial transition in head and neck cancer cells. Cancer Res. 2013; 73(13):4147-57. DOI: 10.1158/0008-5472.CAN-12-4085. View

12.

Li R, Liang J, Ni S, Zhou T, Qing X, Li H . A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell. 2010; 7(1):51-63. DOI: 10.1016/j.stem.2010.04.014. View

13.

Freier K, Knoepfle K, Flechtenmacher C, Pungs S, Devens F, Toedt G . Recurrent copy number gain of transcription factor SOX2 and corresponding high protein expression in oral squamous cell carcinoma. Genes Chromosomes Cancer. 2009; 49(1):9-16. DOI: 10.1002/gcc.20714. View

14.

Rodriguez-Pinilla S, Sarrio D, Moreno-Bueno G, Rodriguez-Gil Y, Martinez M, Hernandez L . Sox2: a possible driver of the basal-like phenotype in sporadic breast cancer. Mod Pathol. 2007; 20(4):474-81. DOI: 10.1038/modpathol.3800760. View

15.

Jensen A, Bergmann Z, Garcia-Huttenlocher H, Freier K, Debus J, Munter M . Cetuximab and radiation for primary and recurrent squamous cell carcinoma of the head and neck (SCCHN) in the elderly and multi-morbid patient: a single-centre experience. Head Neck Oncol. 2010; 2:34. PMC: 3002347. DOI: 10.1186/1758-3284-2-34. View

16.

Schmitt M, Dondog B, Waterboer T, Pawlita M . Homogeneous amplification of genital human alpha papillomaviruses by PCR using novel broad-spectrum GP5+ and GP6+ primers. J Clin Microbiol. 2008; 46(3):1050-9. PMC: 2268381. DOI: 10.1128/JCM.02227-07. View

17.

. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015; 517(7536):576-82. PMC: 4311405. DOI: 10.1038/nature14129. View

18.

Fang X, Yoon J, Li L, Yu W, Shao J, Hua D . The SOX2 response program in glioblastoma multiforme: an integrated ChIP-seq, expression microarray, and microRNA analysis. BMC Genomics. 2011; 12:11. PMC: 3022822. DOI: 10.1186/1471-2164-12-11. View

19.

Wiechert L, Nemeth J, Pusterla T, Bauer C, de Ponti A, Manthey S . Hepatocyte-specific S100a8 and S100a9 transgene expression in mice causes Cxcl1 induction and systemic neutrophil enrichment. Cell Commun Signal. 2012; 10(1):40. PMC: 3533587. DOI: 10.1186/1478-811X-10-40. View

20.

Ge N, Lin H, Xiao X, Guo L, Xu H, Wang X . Prognostic significance of Oct4 and Sox2 expression in hypopharyngeal squamous cell carcinoma. J Transl Med. 2010; 8:94. PMC: 2958910. DOI: 10.1186/1479-5876-8-94. View