Dataset Information

SOX1 down-regulates ?-catenin and reverses malignant phenotype in nasopharyngeal carcinoma.

ABSTRACT:

Background

Aberrant activation of the Wnt/?-catenin signaling pathway is an important factor in the development of nasopharyngeal carcinoma (NPC). Previous studies have demonstrated that the developmental gene sex-determining region Y (SRY)-box 1 (SOX1) inhibits cervical and liver tumorigenesis by interfering with the Wnt/?-catenin signaling pathway. However, the role of SOX1 in NPC remains unclear. This study investigates the function of SOX1 in NPC pathogenesis.

Results

Down-regulation of SOX1 was detected in NPC cell lines and tissues. Besides, quantitative methylation-specific polymerase chain reaction revealed that SOX1 promoter was hypermethylated in NPC cell lines. Ectopic expression of SOX1 in NPC cells suppressed colony formation, proliferation and migration in vitro and impaired tumor growth in nude mice. Restoration of SOX1 expression significantly reduced epithelial-mesenchymal transition, enhanced cell differentiation and induced cellular senescence. Conversely, transient knockdown of SOX1 by siRNA in these cells partially restored cell proliferation and colony formation. Notably, SOX1 was found to physically interact with ?-catenin and reduce its expression independent of proteasomal activity, leading to inhibition of Wnt/?-catenin signaling and decreased expression of downstream target genes.

Conclusions

SOX1 decreases the expression of ?-catenin in a proteasome-independent manner and reverses the malignant phenotype in NPC cells.

SUBMITTER: Guan Z

PROVIDER: S-EPMC4326525 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Publications

SOX1 down-regulates β-catenin and reverses malignant phenotype in nasopharyngeal carcinoma.

Guan Zhong Z Zhang Jialiang J Wang Jing J Wang Hefei H Zheng Feimeng F Peng Jieren J Xu Yaodong Y Yan Min M Liu Bing B Cui Bai B Huang Ying Y Liu Quentin Q

Molecular cancer 20141126

<h4>Background</h4>Aberrant activation of the Wnt/β-catenin signaling pathway is an important factor in the development of nasopharyngeal carcinoma (NPC). Previous studies have demonstrated that the developmental gene sex-determining region Y (SRY)-box 1 (SOX1) inhibits cervical and liver tumorigenesis by interfering with the Wnt/β-catenin signaling pathway. However, the role of SOX1 in NPC remains unclear. This study investigates the function of SOX1 in NPC pathogenesis.<h4>Results</h4>Down-reg ...[more]

PMID: 25427424

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Project description:Dysregulated microRNAs (miRNAs) are involved in carcinoma progression, metastasis, and poor prognosis. We demonstrated that in nasopharyngeal carcinoma (NPC), transactivated MIR106A-5p promotes a malignant phenotype by functioning as a macroautophagy/autophagy suppressor by targeting BTG3 (BTG anti-proliferation factor 3) and activating autophagy-regulating MAPK signaling. MIR106A-5p expression was markedly increased in NPC cases based on quantitative real-time PCR, miRNA microarray, and TCGA database analysis findings. Moreover, MIR106A-5p was correlated with advanced stage, recurrence, and poor clinical outcomes in NPC patients. In addition to three-dimensional cell culture assays, zebrafish and BALB/c mouse tumor models revealed that overexpressed MIR106A-5p targeted BTG3 and accelerated the NPC malignant phenotype by inhibiting autophagy. BTG3 promoted autophagy, and its expression was correlated with poor prognosis in NPC. Attenuation of autophagy, mediated by the MIR106A-5p-BTG3 axis, occurred because of MAPK pathway activation. MIR106A-5p overexpression in NPC was due to increased transactivation by EGR1 and SOX9. Our findings may lead to novel insights into the pathogenesis of NPC.Abbreviations: ACTB: actin beta; ATG: autophagy-related; ATG5: autophagy related 5; BLI: bioluminescence; BTG3: BTG anti-proliferation factor 3; CASP3: caspase 3; ChIP: chromatin immunoprecipitation; CQ: chloroquine; Ct: threshold cycle; DAPI: 4',6-diamidino-2-phenylindole; DiL: 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; EBSS: Earle's balanced salt solution; EGR1: early growth response 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GEO: Gene Expression Omnibus; GFP: green fluorescent protein; IF: immunofluorescence; IHC: immunohistochemistry; ISH: in situ hybridization; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MIR106A-5p: microRNA 106a-5p; miRNAs: microRNAs; MKI67: marker of proliferation ki-67; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; NPC: nasopharyngeal carcinoma; qRT-PCR: quantitative real-time PCR; siRNA: small interfering RNA; SOX9: SRY-box transcription factor 9; SQSTM1: sequestosome 1; TCGA: The Cancer Genome Atlas; WB: western blot.