Background: Oral epithelial dysplasia (OED) is a potentially malignant condition with a 15% transition rate into oral squamous cell carcinoma (OSCC) (1). Early treatment and eradication of OED offers the potential to transform OSCC rates. Despite this, the key molecular events which lead to the development of OED and its progression to OSCC are still poorly understood making current treatment options limited.
Post-translational modification of proteins by Small Ubiquitin-related MOdifier (SUMO-1, 2/3) regulates many cellular processes. The modification is rapidly reversible by deSUMOylation through the actions of SUMO proteases (SENPs). Specifically, SENP3 is known to be essential to many cellular processes including the oxidative stress response and cell survival (2-5). Recent work by us and others, suggests that SENP3 is upregulated in several cancer types including OSCC (6). However, its specific role in tumourigenesis remain undetermined. Therefore, we hypothesise that SENP3-mediated deSUMOylation plays an important role in the transformation of OED into OSCC and targeted inhibition could lead to chemoprevention. This project aims to identify novel targets for chemoprevention which could lead to new therapeutic strategies to improve oral cancer survival rates.
Objectives: 1. Evaluate SENP3 levels in normal oral epithelia, OED and OSCC cell lines and patient biopsies. 2. Investigate the role of SENP3 in oral cancer transformation. 3. Identify and validate specific deSUMOylating target(s) for therapeutic chemoprevention.
Experimental Approach: SENP3 gene and protein levels will be profiled in cell lines representing normal, OED and OSCC both in monolayer and tissue-engineered constructs that model oral cancer progression using real-time PCR and immunoblotting, and validated against human tissue biopsy. Subsequently, the role of SENP3 on cellular functions including cell proliferation (EdU), migration and invasion (live-cell imaging assays), survival and death (cleaved-caspase 3 & PARP cleavage), mitochondrial functions (Seahorse mitochondrial assays) will be examined by altering SENP3 levels/functions using overexpression or RNAi-knockdown. Finally, deSUMOylation target proteins for SENP3 in OED will be identified and validated with molecular inhibitors delivered topically to demonstrate chemoprevention of OED in tissue-engineered models.
Impact: Through building synergies by combining distinct but complementary areas of expertise in cell and molecular biology (Dr Chun Guo) with tissue-engineering (Dr Helen Colley) underpinned by expert clinical knowledge of OSCC (Professor Keith Hunter), this collaborative project will facilitate translation of the research from basic science through complex tissue-engineered constructs to address an unmet clinical need, ultimately taking the research from ‘bench to bedside’ for direct patient benefit.
Science Graduate School
As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit http://www.sheffield.ac.uk/sgs to learn more.
Continue with Facebook
