Expression Analysis of the Mediators of Epithelial to Mesenchymal Transition and Early Risk Assessment of Therapeutic Failure in Laryngeal Carcinoma.

Nora Kariche,Wahiba Ouahioune,Leila-Sarah Sellam,Mehdi Bourouba,Djamel Djennaoui,Chafia Touil-Boukoffa,Nabila Moulaï,Samir Benyahia

doi:10.1155/2019/5649846

Abstract

Laryngeal squamous cell carcinoma (LSCC) is an aggressive malignancy which lacks early predictors of prognosis. Here, we hypothesized that expression and prognostic characterization of the critical mediators of epithelial to mesenchymal transition (EMT) may provide key information in this regard. Linear regression and multiple correspondence analyses were performed on immunohistochemical data obtained from 20 invasive tumors. Principal component and unsupervised hierarchical clustering were used to analyze the dataset patterns associating with LSCC metastatic profile. Survival and death risk assessments were performed using Kaplan–Meier and hazard ratio tests. Data mining analysis using CHAID decision tree and logistic regression analysis was applied to define the predictive value of the risk factors of tumor aggressiveness. Our analyses showed, that in invasive LSCC tumors, cells associating with a mesenchymal profile were likely to exhibit enhanced NOS2, TGF-β, and IL-17A expression levels, concomitantly to NF-κB nuclear translocation. IHC data deciphering determined that EMT induction was also linked to the enrichment of the tumors with CD68+ populations and IL-10 signal. Strikingly, dataset cluster analysis showed that these signatures could define distinct patterns of invasive tumors, where NOS2 associated with IL-10 expression, and TGF-β and IL-17A signals associated with MMP-9 activation. Decision tree analysis identified IL-17A as a possible predictor of LSCC aggressiveness. Altogether, our results show that distinct immunological patterns would support the acquisition of EMT features in invasive LSCC and suggest that IL-17A may be useful in the early identification of patients “at-risk” of therapeutic failure.

Highlights

Laryngeal squamous cell carcinoma (LSCC) is a highly metastatic malignancy of the head and neck caused by tobacco and alcohol intake [1]. e disease is characterized by a dismal prognosis and to the best of our knowledge, absence of predictors of therapeutic failure which may help in improving disease management [2]. is is mainly due to the complexity of the molecular aspects of resistance to therapy and the difficulties in identifying predictive molecular markers of tumor aggressiveness and lethality by traditional statistical approaches
We examined the expression of epithelial-mesenchymal transition (EMT) markers (E-cadherin, β-catenin, and vimentin) in invasive LSCC (n 20), adjacent in-situ carcinoma (n 9), and normal epithelium (n 10)
To explore if a possible link prevailed between NOS2 with EMT in LSCC, we analyzed the profile of association of NOS2 with EMT by IHC

Summary

Introduction

Laryngeal squamous cell carcinoma (LSCC) is a highly metastatic malignancy of the head and neck caused by tobacco and alcohol intake [1]. e disease is characterized by a dismal prognosis and to the best of our knowledge, absence of predictors of therapeutic failure which may help in improving disease management [2]. is is mainly due to the complexity of the molecular aspects of resistance to therapy and the difficulties in identifying predictive molecular markers of tumor aggressiveness and lethality by traditional statistical approaches.Tumor invasion occurs in the context of smoldering inflammation as a consequence of phenotypical alterations which affect tumor epithelial cells adhesion and attachment to the extracellular matrix (ECM) [3]. is process occurs consecutively to a partial to a full transition of tumor cells from an epithelial to a mesenchymal phenotype, in a process known as epithelial-mesenchymal transition (EMT) [4]. e downregulation of epithelial cadherin (E-cadherin) representsJournal of Oncology a critical step in epithelial tissue architecture disruption [5]. The loss of E-cadherin/β-catenin complex may contribute to cancer progression by modifying a complex network of pathways that tightly regulate fundamental processes as oxidative stress, immune evasion, and cell metabolism [7,8,9]. Despite the fact that EMT in head and neck cancers has recently been associated with metastasis [10], little attention has been given to date to the possible prognostic value of its mediators [11,12,13]. In recent years, a number of soluble mediators of EMT among which, the reactive nitrogen/oxygen intermediates (RNI/ROI), matrix metalloprotease 9, the immunomodulatory cytokine IL-10, and TGF-β, as well as the proinflammatory cytokines IL-6 and IL-17A, have gained increased attention due to their possible value in cancer management [13,14,15,16,17]. We thought to examine through an integrative analysis and their possible association to the acquisition of a mesenchymal profile and determined their possible influence on LSCC lethality risk

Methods

Results

Discussion

Conclusion