Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.585011
Title: Bone morphogenetic proteins and their co-receptor, repulsive guidance molecules, signalling pathways in human cancers
Author: Li, Jin
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2010
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Abstract:
RGMs (repulsive guidance molecules) are a group of recently identified GPI (glycosylphosphatidylinositol)-linked cell-membrane-associated proteins, comprising three family members, which have been implicated in BMPs (Bone morphogenetic proteins) signalling. BMPs have been shown to play profound roles in bone metastases from breast cancer and prostate cancer. This study aims to investigate the implication of RGMs in prostate cancer and breast cancer and their role in coordinating signal transduction by BMPs during disease progression of cancer. The aberrant expression of RGMs was found in breast cancer which was associated with prognosis of breast cancer patients. RGMA, B and C were detected in prostate cancer cell lines and only RGMB was expressed in breast cancer cell lines which allowed for the knockdown study of RGMs in PC-3 and RGMB in MDA-MB-231 using ribozyme transgenes. The knockdown of RGMB in breast cancer cells resulted in an increase of cellular proliferation, adhesion, motility and migration in vitro, which contributed to a tumour's growth and metastasis. Furthermore, an inhibition of caspase-3 was seen in cells after knockdown of RGMB which indicated RGMB as a regulator of cell survival. Up-regulation of FAK and Paxillin were also seen in the cancer cells after loss of RGMB expression, together with an evident induction of EMT (epithelial-mesenchymal transition) which may contribute to the promoted cell-matrix adhesion and cell mobility. The knockdown of RGMs in prostate cancer cells also lead to an increase of cell ability to grow, adhere and move, in which differentiated response of ID-1, a BMPs target gene was seen. As RGMs were reported to be involved in BMP signalling, knockdown of RGMB was found to induce promotion on Smad-dependent pathways (especially Smad-1/5/8 pathway) and inhibition on BMP Smad-independent pathways (MAPK JNK pathway). It suggests that RGMs are important partners to fine-tune responses of cells to BMPs stimuli, particularly during the progression and dissemination of cancer cells, and are potential targets for developing a novel cancer therapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.585011  DOI: Not available
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