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MicroRNAs as bile-based biomarkers for pancreatic and biliary-tract cancers

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Title: MicroRNAs as bile-based biomarkers for pancreatic and biliary-tract cancers
Authors: Mato Prado, Mireia
Item Type: Thesis or dissertation
Abstract: Pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancers (BTC) are lethal diseases and have poor survival rates. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. They are commonly deregulated in cancer and are incredibly stable molecules in tissues and biofluids. Therefore, miRNAs have potential as clinical useful biomarkers for the detection of cancer. PDAC and BTC often present with obstruction of the common bile duct leading to painless jaundice. Therefore, finding novel miRNAs in the bile-fluid associated with PDAC and/or BTC would be a considerable discovery, due to its close proximity to the malignant lesion. Exosomes are small extracellular vesicles of endocytic origin, which contain miRNAs. They are secreted into the extracellular space by a variety of cells, including cancer cells. They play a crucial role in cell-cell communication in the tumour microenvironment, transferring information through their cargo, and are implicated in cancer development and metastasis. Here, I develop upon these initial observations and demonstrate that bile miRNAs can discriminate PDAC and BTC from benign disease. Profiling revealed miRNAs are able to differentiate between benign and malignant lesions. These candidates were further validated in an independent cohort of bile samples and three miRNAs (miR-148a, miR-194 and miR-125b) were able to not only differentiate benign from malignant lesions, but also discriminate between PDAC and cholangiocarcinoma (CCA). Furthermore, the expression of these three miRNAs was measured in exosomes from six pancreatic cell lines showing a higher expression of these miRNAs in exosomes compared to the cell pellet. A significantly higher expression of miR-148a was observed in exosomes compared to the cell pellet. Therefore, there is potential to use these bile-based miRNAs to improve diagnosis and stratify patients, thereby informing treatment decisions and improving survival by “personalising” their subsequent therapies.
Content Version: Open Access
Issue Date: Oct-2018
Date Awarded: Feb-2019
URI: http://hdl.handle.net/10044/1/81592
DOI: https://doi.org/10.25560/81592
Copyright Statement: Creative Commons Attribution NonCommercial NoDerivatives Licence
Supervisor: Frampton, Adam
Krell, Jonathan
Stebbing, Justin
Sponsor/Funder: Action Against Cancer
Department: Department of Surgery & Cancer
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Department of Surgery and Cancer PhD Theses



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