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Title: Investigating the role of factor inhibiting HIF (FIH) in tumourigenesis
Author: Ma, Jingyi
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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The tumour microenvironment (TME) is frequently hypoxic and inflammatory, leading to the activation of the Hypoxia-Inducible Factor (HIF) family of transcription factors. HIF has been shown to exert broad, and sometimes controversial, effects on tumour progression through the induction of over 70 effector genes. Factor Inhibiting HIF (FIH), an oxygen-dependent hydroxylase of HIF, inhibits the transcription of selective HIF target genes, and is hence a potential therapeutic target to fine-tune HIF activity. However, how FIH may affect tumourigenesis has not been comprehensively investigated. By monitoring the spontaneous tumour formation in mice, it was found that a lack of FIH expression does not profoundly affect the lifespan but accelerates the development of low-grade B cell lymphomas. To investigate whether FIH could suppress tumourigenesis via modulating the TME, syngeneic tumour models were employed on FIH-deficient animals. Reduced FIH expression in the host promotes tumour growth, which is recapitulated by FIH deletion only in the myeloid compartment. Tumours in mice deficient of myeloid FIH exhibit an altered immune profile, reflected by the increased expression of programmed death-ligand 1 (PD-L1) and Arginase 1 (ARG1) in tumour-associated macrophages (TAMs) and a reduced CD4 T cell population. In vitro characterisation of FIH-deficient macrophages reveals that FIH suppresses cell migration to C5a and CCL5, and affects the expression of several inflammatory mediators including PD-L1 and ARG1. Importantly, the transcription of FIH is upregulated in macrophages by tumour cell-conditioned media as well as bacterial infection. Altogether, this study provides the genetic evidence for the role of FIH in tumour suppression, which may result from its influence on the myeloid-mediated immune response. Therefore, FIH represents a new candidate regulator of the TME and can be implicated in other inflammatory conditions such as infection.
Supervisor: Ratcliffe, Peter J. ; Lu, Xin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available