Identifying the Molecular Mechanisms of Radiation-Induced Epithelial-Mesenchymal Plasticity in Human Oral Squamous Carcinoma Cells under Glucose Stress

Abstract

Remodelling along the epithelial-mesenchymal (E-M) axis is crucial in carcinomas and is strongly linked to tumour invasion, metastasis, and radiation resistance. Research indicates hyperglycaemia, which refers to chronic exposure to high glucose levels, significantly increases cancer risk and impacts key features of tumour development, including the epithelial-mesenchymal transition (EMT). This research seeks to explore the effects of hyperglycaemia on the phenotypic remodelling of oral squamous cell carcinoma (OSCC) in the context of metabolic stress and ionising radiation, while investigating the potential molecular mechanisms involved.

In this study, we utilised the 3D tumour spheroid models generated from the OSCC cells subjected to a 7-day hyperglycaemic stress and performed different cellular, molecular, and high-level transcriptome analyses to investigate the cellular and molecular dynamics of hyperglycaemia and its effects on the tumour remodelling as part of the response to ionising radiation.

The immunohistochemical analysis of epithelial and mesenchymal markers, E-cadherin and Vimentin, revealed a notably higher abundance of both hybrid EMT and mesenchymal-like subpopulations in OSCC spheroids subjected to hyperglycaemic stress. This phenotypic remodelling, triggered by metabolic stress and ionising radiation, is shown to be influenced by the regulation and transition among different EMT transcription factors. Transcriptional profiling and pathway analyses have pinpointed several molecular components that may link hyperglycaemia, EMT, and radioresistance in OSCC spheroids, including integrins, MMPs, and laminins.

This study provides a better understanding of the intricate dynamics involved in OSCC progression and treatment responses, offering essential knowledge for future therapeutic approaches. It may also enlighten new therapeutic possibilities for radioresistant carcinomas, thus enriching the ongoing advancements in cancer research.