Surgery (Austin & Northern Health) - Theses
Permanent URI for this collection
Search Results
1 - 1 of 1
-
ItemFunctions of CXC Ligand Family in Pancreatic Tumour Microenvironment( 2021)Chemoresistance is the major contributor to the low survival of pancreatic cancer (PC). PC progression is a complex process reliant on interactions between tumour and tumour microenvironment (TME). A family of structurally similar inflammatory chemokines, namely CXC ligands (CXCLs), were recently discovered to play important roles in various cancer types, including PC. This thesis aimed to investigate the role of CXCL5 in chemoresistance of PC. In both human and mice PC cell lines tested, CXCL5 expression was dramatically upregulated. The expressions of CXCL5, CXCL10 and selected CSC genes were various in gemcitabine resistant cell lines, and gemcitabine treated cells. However, in mouse xenografted tumour samples, which was generated from a patient-derived cell line, gemcitabine alone or in combination with other chemotherapeutic reagents led to increased CXCL5 protein level while CXCL10 level remained unchanged. These results suggested that expression of CXCL5 may be stimulated upon administration of gemcitabine or other chemotherapeutic reagents. Therefore, CXCL5 has a role in chemoresistance and clinical importance in PC; however, the mechanisms involved deserves a careful investigation. To determine whether CXCL5 mediates chemoresistance in PC, CXCL5 expression in MiaPaCa-2 cells was knocked down by shRNA. To determine whether CXCL5 mediated chemoresistance in vitro, two chemotherapeutic drugs, were used to treat a negative control (NC) and CXCL5 knockdown (KD) clones. In the cell proliferation assays, CXCL5 was found to mediate the resistance to gemcitabine and 5-fluouracil (5- FU). Mice carrying xenografted tumours inoculated by either NC or CXCL5 KD cells II were treated with gemcitabine. CXCL5 KD suppressed tumour growth and enhanced the inhibitory effect of gemcitabine by decreasing proliferation and promoting apoptosis These results indicated that knockdown of CXCL5 sensitized PC cell response to gemcitabine and 5-FU, suggesting that CXCL5 mediates chemoresistance in PC. Finally, the global proteomic analysis showed CXCL5 knockdown resulted in significant changes in expression of several proteins. Each of these proteins had a distinct biological function in cancer as determined with KEGG pathway analysis and NCBI. From the phosphor-proteomic analysis, CXCL5 knockdown induced significant changes of certain phosphorylated proteins. Cross-referencing with the database of NCBI clearly identified the biological functions of these proteins. Although experimental and clinical validation are necessary, CXCL5 serves as a pivotal molecular target in overcoming chemoresistance and eliminating PC tumours in clinical practices. In summary, these studies have revealed that CXCL5 plays an important role in chemoresistance and activates several intracellular pathways that contribute to resistance to therapeutic treatments and PC progression. Therefore, CXCL5 could serve as a potential molecular target in reversing chemoresistance in pancreatic cancer.