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The Functions of EP300 in Activated Pancreatic Stellate Cells and the Drug Resistance Problem in Pancreatic Cancer

Liu, Lizhen

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Abstract

Pancreatic stellate cells (PSCs) are generally quiescent in normal conditions, but during inflammation or cancer these cells are activated, differentiate to myofibroblast-like cells, proliferate, migrate and start secreting extracellular matrix protein, which are the main contributors to the stromal formation during the process of cancer. EP300 is an important transcription coactivator and plays an important role in the process of cell proliferation and differentiation. Thus, we hypothesize that targeting EP300 will affect the activation of PSCs and may influence the process of pancreatic cancer, especially for pancreatic ductal adenocarcinoma (PDAC). Transient specific small interfering RNA (SiRNA) knockdown of EP300 resulted in reduced expression of fibronectin (FN) and collagen I (Col-I) in activated PSCs. Stable knockdown of EP300 by CRISPR/Cas9 gRNA plasmid had the same effects. However, the migration of PSCs was increased. And we firstly showed that EP300 manipulated cell migration through ERK pathway. Furthermore, EP300 down regulation in PSCs increased the proliferation effect PSCs had on pancreatic cancer cells and PSCs protected tumor cells from chemotherapy more. Together, the evidences draw the conclusion that EP300 is a tumor suppressor gene, its downregulation increases the migration of PSCs and PSCs becomes more supportive for pancreatic cancer cells, but that reduces the extra cellular matrix production of PSCs.

High resistance to chemotherapy is a frustrating issue in treating pancreatic ductal adenocarcinoma. It is one reason for a 5-year survival rate of PDAC patients lower than 5%. In recent years, researcher showed that the tumor microenvironment might make a great contribution to the drug resistance of pancreatic cancer. PSCs are important cells that exist in the tumor stroma of pancreatic cancer. Gemcitabine is a nucleoside analog, which is currently used as the best standard treatment for pancreatic cancer patients. In the present study, I analyzed how PSCs will affect the drug resistance of different drug sensitive pancreatic cancer cell lines. My results for the first time showed that conditioned medium from PSCs promotes chemo-resistance of Bxpc-3 cells by up regulating RRM1 and RRM2, but has no influence on the drug sensitivity of Panc-1 and Miapaca-2 cells. In addition, I could show that factors that are <100kDa and produced by pancreatic stellate cells are responsible for the effects. These factors are heat insensitive, trypsin and proteinase K insensitive and cannot be degraded by nucleases either, but the exact factor has yet to be determined.

Item Type: Dissertation
Supervisor: Hoheisel, Dr. Jörg
Date of thesis defense: 9 November 2017
Date Deposited: 23 Nov 2017 10:43
Date: 2017
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
Controlled Keywords: EP300, Pancreatic cancer, Drug resistance
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