Identification of Small RNAs as potential biomarkers and regulators of chemoradiotherapy response in Oesophageal Adenocarcinoma (EAC)

Author: Guoqian Ding

Ding, Guoqian, 2024 Identification of Small RNAs as potential biomarkers and regulators of chemoradiotherapy response in Oesophageal Adenocarcinoma (EAC), Flinders University, College of Medicine and Public Health

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It is reported that neoadjuvant chemoradiotherapy for esophageal cancer can significantly improve overall survival. However, not all patients have a good response to chemoradiotherapy and achieve significant survival improvement. Therefore, it is important to find biomarkers that are associated with chemoradiotherapy response to treat patients individually and adjust the treatment approach in a response-guided manner in neoadjuvant settings. It would be ideal if these biomarkers enabled prediction of response prior to administering of therapy.

Emerging evidence demonstrates that small RNAs, such as miRNAs, piRNAs, snRNAs, and snoRNAs play a pivotal role in the development and progression of numerous cancers. However, there are few studies on the roles of small RNAs in tissue or in blood as biomarkers and regulator of treatment response in oesophageal adenocarcinoma (EAC).

In this thesis, the top differentially expressed tissue small RNAs between EAC neoadjuvant chemoradiotherapy responders and non-responders were identified as potential biomarkers. The potential functions and mechanisms underlying their actions were studied using EAC cell lines. miR-451a was the top biomarker for prediction of responders. The functional study showed that miR-451a enhanced EAC cell proliferation and decreased apoptosis in these cells. miR-451a rendered the EAC cells more resistant to drug treatment. Protein analysis indicated that miR-451a might regulate the treatment response by affecting pAMPK, Thr172/AMPK, 14-3-3 zeta phos Ser58/14-3-3 zeta/delta and pEGFR/EGFR.

Exosomes circulating in peripheral blood contain numerous small RNAs, some of which come from tumor tissues and might be useful biomarkers. Therefore, in this study response based differentially expressed small RNAs were identified using serum exosomes from patients with EAC. Some reports have suggested that circulating exosomes can modulate the local tumor environment to influence tumor response to chemoradiotherapy. Therefore, this study tested the ability of serum exosomes from patients with EAC to modulate the proliferation and/or drug or radiation response behavior of EAC cells. The results showed that the exosomes from non-responders made the cells less resistant to cisplatin while the exosomes from non-responders made the cells more resistant to 5-FU in most experiments.

Collectively, this study identified specific small RNAs as potentially useful biomarkers of response to chemoradiotherapy in EAC and provided information on the potential roles of these small RNAs in regulating the response to chemoradiotherapy.

Keywords: Small RNAs, biomarkers, cheoradiotherapy, exosomes, EAC

Subject: Medicine thesis

Thesis type: Masters
Completed: 2024
School: College of Medicine and Public Health
Supervisor: Damian hussey