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Title: Elucidating functional mechanisms of OPCML : a tumour suppressor gene lost in epithelial ovarian cancer
Author: Okon, Imoh S.
ISNI:       0000 0004 2690 8922
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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Opioid binding protein cell adhesion molecule-like (OPCML) is a tumour suppressor gene (TSG), originally found to be silenced in epithelial ovarian cancer. Initial functional analysis highlighted both in vitro and in vivo suppression of tumour growth upon constitutive OPCML expression the SKOV-3 ovarian cancer cell line. Increased cell-to-cell adhesion and reduced chemotactic migration was also demonstrated. However, evidence demonstrating possible mechanisms by which OPCML mediates these functions was non-existent. Stable transfection of OPCML into SKOV-3 cells resulted in the inhibition of phospho-ERK1&2 proteins. This result, in addition to earlier observations, provided further clues of possible upstream signal attenuation by OPCML. Subsequent experiments demonstrated upregulation of OPCML (mRNA and protein levels) upon EGF stimulation. Upregulation of OPCML expression correlated with the inhibition of EGFR and ErbB2 proteins, suggesting a negative feedback modulatory mechanism. Ablation of ErbB2 protein level on Western blots was further supported by confocal microscopy in OPCML expressing lines. OPCML expression correlated with increased ErbB2 poly-ubiquitination and proteasomal degradation. Further experiments employing GST-OPCML fusion protein confirmed a direct interaction between the third Ig-domain of OPCML and ErbB2 (but not EGFR). Specific inhibitors directed against the receptors (EGFR/ErbB2) were used to explore the therapeutic potential of OPCML. Results demonstrated increased sensitisation of OPCML-transfected SKOV-3 cells to lapatinib and trastuzumab. In summary, OPCML acts as a 'signalling modulator' that co-ordinately regulates a specific repertoire of receptor tyrosine kinases (RTKs) (mainly ErbB2) resulting in the negative regulation of specific downstream signalling pathways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available