The role of MUC4 in the radioresistance of pancreatic ductal adenocarcinoma

Résumé

BACKGROUND – Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by a very low survival rate because of a lack of early diagnostic markers and efficient therapies. This cancer represents the most chemo- and radio-resistant cancer. Mucins are part of a heterogenous family of large O-glycoproteins and are classified into two categories: secreted and membrane-bound mucins. In epithelial cancers, the mucin expression is strongly modified in different types of tumors, which suggests their implication in regulating tumor growth. In the context of pancreatic cancer, several mucins have been shown to be overexpressed. Most studies have focused on the involvement of MUC1 in chemo- and radio-resistances of PDAC. Moreover, it has been demonstrated that the high expression of MUC4 in pancreatic cancer cells conferred resistance to chemotherapy. To our knowledge, the role of MUC4 in the radioresistance of PDAC does not appear to have been studied. AIMS – The purpose of this study was to determine the role of MUC4, a membrane-bound mucin, in pancreatic cancer resistance to radiotherapy. METHODS – In this project, three pancreatic cancer cell lines (Capan-1, AsPC-1 and HPAF-II) were used. These three cell lines were irradiated with increasing doses of X-rays. The mRNA expression of MUC4 and of other membrane-bound mucins was studied post-irradiation by RT-qPCR. To determine the role of MUC4 in radioresistance, a knockdown of MUC4 was performed with short hairpin RNAs. The transduced cells were then irradiated and cell survival was measured using propidium iodide. RESULTS – It was first shown that the three chosen pancreatic cancer cell lines express MUC4. The three cell lines were irradiated with X-rays. The results showed that the survival fraction of the cell lines decreased with increasing doses of irradiation. The most radiosensitive cells, Capan-1, showed a decrease in the expression of MUC4, whereas in the radioresistant cells, HPAF-II, the expression of MUC4 was increased, 72 hours post-irradiation. Then, to identify if MUC4 is implicated in the radioresistance, a knockdown of MUC4 was performed in Capan-1 and AsPC-1 cells. The knockdown was confirmed at mRNA level. Nonetheless, the post-irradiation cell survival was assessed and showed that the number of viable Capan-1 and AsPC-1 transduced cells did not appear to be affected when MUC4 expression was decreased. CONCLUSION – The first results suggest that MUC4 may not be implicated in the radioresistance of PDAC. However, these results are to be taken with caution as they will have to be repeated, and the knockdown of MUC4 will have to be confirmed at protein level.

la date de réponse	17 janv. 2023
langue originale	Anglais
L'institution diplômante	Universite de Namur
Superviseur	Carine Michiels (Promoteur)