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Bone morphogenetic proteins and their co-receptor, repulsive guidance molecules, signalling pathways in human cancers

Li, Jin 2010. Bone morphogenetic proteins and their co-receptor, repulsive guidance molecules, signalling pathways in human cancers. PhD Thesis, Cardiff University.

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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.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
ISBN: 9781303222290
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:31
URI: http://orca-mwe.cf.ac.uk/id/eprint/55075

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