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The Role of epithelial to mesenchymal transition (EMT) as Biomarker for Radioresistance in HNSCC

Kurth, I.; Digomann, D.; Hein, L.; Linge, A.; Koi, L.; Loeck, S.; Maebert, K.; Stephan, H.; Peitzsch, C.; Krause, M.; Baumann, M.; Dubrovska, A.

Abstract

Purpose or Objective
It is described that epithelial – to -mesenchymal transition (EMT) plays an important role in head and neck squamous carcinomas (HNSCC) progression and resistance to therapy. Recent studies suggest that for instance the expression of EMT related microRNAs may cause intrinsic radioresistance in HNSCC. During the process of EMT epithelial cancer cells obtain a more mesenchymal –like motile and invasive phenotype, which has been argued to sustain survival and therapy resistance of those tumor cells and facilitate cancer progression. Radiotherapy is one of the main approaches to treat HNSCC. However, tumor radioresistance often impedes the success of radiotherapy and has been found to drive tumor aggressiveness and expansion. In this study we asked the question, if radioresistant HNSCC populations display EMT features on a molecular as well as on a functional level and whether we can correlate those characteristics to treatment outcome.
Material and Methods
We used multiple irradiated HNSCC lines (IR) as an established model to investigate the traits of radioresistance. Global gene expression analysis in vitro and on xenograft models and functional radiobiological analyis was applied.
Results
Interestingly, global gene expression analysis revealed a negative correlation of genes associated with cell motility and migration in the IR derivatives of two HNSCC cell lines, namely Cal33, FaDu. We functionally validated those findings and screened for known EMT marks from literature by functional migration assays and EMT-related protein expression in several HNSCC model cell lines and established xenografts as well as in their IR derivatives in order to correlate the acquired findings to radiotherapy outcome. The only positive correlation was found for the initial before therapy protein expression in vitro and in vivo for Slug, a zinc - finger protein encoded by the SNAI2 gene and c-Met, a receptor tyrosine kinase encoded by the MET gene. Functional knockdown of Slug or c-Met expression let to radiosensitization in 3-D clonogenic survival assays of several HNSCC cell lines.
Conclusion
Currently the expression of these molecules is scored for clinical outcome to better understand the context of EMT biomarkers for HNSCC progression and the development of a potential well-directed combinational radiochemotherapy.

Keywords: EMT; radiotherapy; HNSCC; migration

Permalink: https://www.hzdr.de/publications/Publ-26992