Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.606811
Title: An investigation of CTen signalling and regulation in cancer
Author: AlGhamdi, Saleh Mohammed S.
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2013
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Abstract:
C-terminal Tensin-like (Cten) is a member of the Tensin gene family but lacks the N-terminus actin-binding domain. Cten functions as a tumour suppressor in some cancers while in other cancer types it is recognized to have oncogenic activities. Our group has previously shown that, in colorectal cancer (CRC), Cten is up-regulated and acts as an oncogene which alters several cellular functions including cell migration and invasion. In this project we tried to understand (a) the mechanism through which Cten affects cell function and (b) the mechanisms by which Cten expression may be controlled in cancer. Three cancer models system (colorectal, pancreatic and lung cancer) have been tested to validate our observations. (a) Since Cten is found in complex with integrins at focal adhesions, we hypothesized that it may influence other molecules which are associated with focal adhesion and integrin function. Through a combined approach of forced expression and knockdown experiments, we examined the effect of Cten on ILK and FAK. We found that Cten positively regulates expression of both ILK and FAK and this may be the mechanism through which cell motility is controlled. (b) (i) Activation of the Epidermal Growth Factor Receptor (EGFR) signalling pathway in breast cancer results in up-regulation of Cten accompanied by down-regulation of Tensin 3 (known as the "Tensin switch"). We tested this in CRC and found that stimulation and inhibition of the EGFR using recombinant EGF and the EGFR inhibitor PD135053, resulted in changes in Cten expression (with a tensin switch) and changes in cell motility. Since EGFR classically signals through Kras/Braf we hypothesized that Kras (which is frequently mutated in CRC) may regulate Cten expression. Analysis of CRC cell lines showed an association between Kras/Braf mutation and high Cten expression. Knockdown of Kras in cell lines harbouring Kras mutations resulted in loss of Cten expression while no effect was observed in the cell lines with Braf ,mutations. However Braf knockdown in cell lines with Braf mutation resulted in down-regulation of Cten levels. (ii) CD24 has been shown to be associated with integrins suggesting a possible involvement with Cten at Focal Adhesions. Manipulation of CD24 protein levels in CRC cell lines was mirrored by changes in Cten expression although this effect was not accompanied by a tensin switch. (iii) STAT3 can function as both a tumour suppressor and an oncogene. Modulation of STAT3 levels - either directly through gene knockdown or indirectly through IL-6 stimulation - showed that STAT3 is a negative regulator of Cten. Since around 90% of pancreatic cancers and 60% of lung cancers have Kras mutations we repeated the experiments in these two models. Our data showed that functional activity and regulation of Cten was similar to that seen in CRCs. We can conclude that Cten can regulate cell motility through modulation of FAK and ILK. In addition, Cten is regulated by EGFRKras- Braf signalling and that CD24 and STAT3 are also, respectively, positive and negative regulators of Cten. Finally, Cten activity is broadly consistent in three different cancer models. Future studies should involve further refinement of the signalling pathway and study of other tumour types involving frequent Kras mutations. ..
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.606811  DOI: Not available
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