The role of the proline rich homeodomain transcription factor (PRH/Hhex) in cholangiocarcinoma

Lee, Ka Ying (2021). The role of the proline rich homeodomain transcription factor (PRH/Hhex) in cholangiocarcinoma. University of Birmingham. Ph.D.

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Abstract

Cholangiocarcinoma (CCA) is cancer of the bile duct that only has a few treatment options, typically with poor prognostic outcomes. The Proline-Rich Homeodomain protein (PRH), also known as haematopoietically expressed homeobox (Hhex), is a transcription factor that regulates liver and bile duct development. PRH is not expressed in normal bile duct cells but this protein is highly expressed in CCA cells. Using a combination of overexpression and knockdown experiments, PRH was shown to increase cell proliferation, migration and invasion in tumour cell lines. Similar results were obtained in immortalized AKN-1 cells and also in primary biliary epithelial cells. In these cells PRH overexpression also led to the initiation of epithelial to mesenchymal transition (EMT) and anoikis resistance as well as increased cell proliferation and invasion. Gene Ontology and Gene Set Enrichment Analysis of RNA-sequencing data from cells with altered PRH levels reveal that in all cell types PRH regulates multiple
signaling pathways and that key genes involved in the Notch signaling pathway, the cell cycle and EMT are regulated by PRH. CCA cells with elevated PRH expression were found to be more sensitive to the CDK4/6 inhibitor Palbociclib as PRH controls the cell cycle through regulation of multiple cell cycle genes including CCND2. Drug screening with a drug repurposing library was performed to identify novel drug treatments for CCA and several repurposed drugs that show a stronger cytotoxic effect when combined with Palbociclib were identified using
cell viability assays. This thesis therefore reveals that PRH protein is an important oncoprotein in CCA and that this protein may play a role in initiating CCA and in driving cancer progression and identifies new drug treatment options.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):