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Ndrg1 Deficiency is associated with Regional Metastasis in Oral Cancer by inducing Epithelial-Mesenchymal transition


de Lima, Jefferson Muniz; Morand, Grégoire B; Macedo, Carolina Carneiro Soares; Diesel, Luciana; Hier, Michael P; Mlynarek, Alex; Kowalski, Luiz P; Maschietto, Mariana; Alaoui-Jamali, Moulay A; da Silva, Sabrina Daniela (2020). Ndrg1 Deficiency is associated with Regional Metastasis in Oral Cancer by inducing Epithelial-Mesenchymal transition. Carcinogenesis, 41(6):769-777.

Abstract

Regional metastasis is the single most important prognostic factor in oral squamous cell carcinoma (OSCC). Abnormal expression of N-myc downstream-regulated genes (NDRGs) has been identified to occur in several tumor types and to predict poor prognosis. In OSCC, the clinical significance of deregulated NDRG expression has not been fully established. In this study, NDRG1 relevance was assessed at gene and protein level in 100 OSCC patients followed-up by at least 10 years. Survival outcome was analyzed using a multivariable analysis. Tumor progression and metastasis was investigated in preclinical model using oral cancer cell lines (HSC3, SCC25) treated with EGF and orthotopic mouse model of metastatic murine OSCC (AT84). We identified NDRG1 expression levels to be significantly lower in patients with metastatic tumors compared to patients with local disease only (P=0.001). NDRG1 expression was associated with MMP-2, -9, -10 (P=0.022, P=0.002, P=0.042, respectively), and BCL2 (P=0.035). NDRG1 lower expression was able to predict recurrence and metastasis (log-rank test, P=0.001). In multivariable analysis, the expression of NDRG1 was an independent prognostic factor (Cox regression, P=0.013). In invasive OSCC cells, NDRG1 expression is diminished in response to EGF and this was associated with a potent induction of epithelial-mesenchymal transition (EMT) phenotype. This result was further confirmed in an orthotopic OSCC mouse model. Together, this data support that NDRG1 down-regulation is a potential predictor of metastasis and approaches aimed at NDRG1 signaling rescue can serve as potential therapeutic strategy to prevent oral cancer progression to metastasis.

Abstract

Regional metastasis is the single most important prognostic factor in oral squamous cell carcinoma (OSCC). Abnormal expression of N-myc downstream-regulated genes (NDRGs) has been identified to occur in several tumor types and to predict poor prognosis. In OSCC, the clinical significance of deregulated NDRG expression has not been fully established. In this study, NDRG1 relevance was assessed at gene and protein level in 100 OSCC patients followed-up by at least 10 years. Survival outcome was analyzed using a multivariable analysis. Tumor progression and metastasis was investigated in preclinical model using oral cancer cell lines (HSC3, SCC25) treated with EGF and orthotopic mouse model of metastatic murine OSCC (AT84). We identified NDRG1 expression levels to be significantly lower in patients with metastatic tumors compared to patients with local disease only (P=0.001). NDRG1 expression was associated with MMP-2, -9, -10 (P=0.022, P=0.002, P=0.042, respectively), and BCL2 (P=0.035). NDRG1 lower expression was able to predict recurrence and metastasis (log-rank test, P=0.001). In multivariable analysis, the expression of NDRG1 was an independent prognostic factor (Cox regression, P=0.013). In invasive OSCC cells, NDRG1 expression is diminished in response to EGF and this was associated with a potent induction of epithelial-mesenchymal transition (EMT) phenotype. This result was further confirmed in an orthotopic OSCC mouse model. Together, this data support that NDRG1 down-regulation is a potential predictor of metastasis and approaches aimed at NDRG1 signaling rescue can serve as potential therapeutic strategy to prevent oral cancer progression to metastasis.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Otorhinolaryngology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Cancer Research, General Medicine
Language:English
Date:10 July 2020
Deposited On:10 Mar 2020 14:19
Last Modified:04 Sep 2020 15:17
Publisher:Oxford University Press
ISSN:0143-3334
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/carcin/bgaa017
PubMed ID:32112078

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