Graduation Date

Summer 8-13-2021

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Biochemistry & Molecular Biology

First Advisor

Ashley Mohr

Second Advisor

Justin Mott

Third Advisor

Laurey Steinke

Fourth Advisor

Robert Lewis

Abstract

Fibroblast growth factor receptor 4 (FGFR4) is over-expressed in many cancers, including cholangiocarcinoma (CCA). FGFR4 is activated by fibroblast growth factor ligand 19 (FGF19) and plays a critical role in CCA progression. An intracellular cleaved product of FGFR4, referred as R4-ICD (FGFR4 intracellular domain) is also overexpressed in CCA. However, the specific role of R4-ICD in CCA is unknown. In this study, we hypothesized that FGFR4 and R4-ICD play a role in cell proliferation, cell survival and metastasis in CCA. To test this, FGFR4 and R4-ICD were cloned into a cholangiocarcinoma cell line (HuCCT-1) that does not endogenously express FGFR4. Two other CCA cell lines, KMCH and Mz-ChA-1, were also utilized that express endogenous FGFR4. To determine the influence of FGFR4 on CCA proliferation, survival, and migration, FGFR4-selective and pan-FGFR inhibitors were used. Expression of FGFR4 increased CCA proliferation, cell survival and migration. Stable knockdown of FGFR4 using shRNA reduced CCA proliferation, cell survival and migration. FGFR4-selective small molecular inhibitors sensitized cells to TRAIL-induced apoptosis and reduced migration. R4-ICD-expressing HuCCT-1 cells (lacking endogenous FGFR4 expression) were protected against TRAIL-induced apoptosis, indicating an underlying role of R4-ICD. This study suggests that, in addition to FGFR4, R4-ICD can be a potential regulator of CCA.

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