The Critical Role of Hypoxic Microenvironment and Epigenetic Deregulation in Esophageal Cancer Radioresistance

Abstract

Esophageal cancer (EC) is the seventh most common cancer worldwide and the sixth leading cause of death, according to Globocan 2018. Despite efforts made for therapeutic advances, EC remains highly lethal, portending a five-year overall survival of just 15–20%. Hence, the discovery of new molecular targets that might improve therapeutic efficacy is urgently needed. Due to high proliferative rates and also the limited oxygen and nutrient diffusion in tumors, the development of hypoxic regions and consequent activation of hypoxia-inducible factors (HIFs) are a common characteristic of solid tumors, including EC. Accordingly, HIF-1α, involved in cell cycle deregulation, apoptosis, angiogenesis induction and proliferation in cancer, constitutes a predictive marker of resistance to radiotherapy (RT). Deregulation of epigenetic mechanisms, including aberrant DNA methylation and histone modifications, have emerged as critical factors in cancer development and progression. Recently, interactions between epigenetic enzymes and HIF-1α transcription factors have been reported. Thus, further insight into hypoxia-induced epigenetic alterations in EC may allow the identification of novel therapeutic targets and predictive biomarkers, impacting on patient survival and quality of life.

Hypoxic tumour cell-derived exosomal miR-340-5p promotes radioresistance of oesophageal squamous cell carcinoma via KLF10

“…Therefore, investigating the molecular mechanisms underlying radioresistance may be of great significance for improving OSCC patient outcomes. Hypoxia is a critical cause of radioresistance [27]. Although the radioresistance mechanisms of hypoxic cells have been extensively studied, the complexity of the hypoxic response in the hypoxic TME needs to be defined more clearly.…”

Hypoxic tumour cell-derived exosomal miR-340-5p promotes radioresistance of oesophageal squamous cell carcinoma via KLF10

“…Therefore, investigating the molecular mechanisms underlying radioresistance may be of great signi cance for improving OSCC patient outcomes. Hypoxia is a critical cause of radioresistance (27). Although the radioresistance mechanisms of hypoxic cells themselves have been extensively studied, the complexity of the hypoxic response in the hypoxic TME needs to be de ned more clearly.…”

Hypoxic tumour cell-derived exosomal miR-340-5p promotes radioresistance of oesophageal squamous cell carcinoma via KLF10

“…Therefore, investigating the molecular mechanisms underlying radioresistance may be of great signi cance for improving OSCC patient outcomes. Hypoxia is a critical cause of radioresistance (27). Although the radioresistance mechanisms of hypoxic cells have been extensively studied, the complexity of the hypoxic response in the hypoxic TME needs to be de ned more clearly.…”