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Feedback regulation loop between bone morphogenetic proteins and their antagonists in prostate cancer and the implication in bone metastasis

Resaul, Jeyna 2018. Feedback regulation loop between bone morphogenetic proteins and their antagonists in prostate cancer and the implication in bone metastasis. PhD Thesis, Cardiff University.
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Bone morphogenetic proteins (BMP) have been heavily implicated in prostate cancer and bone metastasis. With various studies demonstrating a feedback loop between BMPs and their regulators, BMP antagonists, we aimed to investigate the role of this interplay in prostate cancer and osteoblastic bone lesion formation. We assessed the expression of BMPs, their antagonists, and their signalling components in different prostate cancer cell lines in the absence and presence of a bone matrix extract (BME) by RNA-Seq and qPCR. We also analysed GEO data from a prostate cancer cell line expression study, and microarray studies of LNCaP-osteoblast co-cultures and prostate cancer bone metastases. From these, we demonstrated evidence of a BMP/BMP antagonist feedback loop, especially between BMP-2 and Gremlin isoforms, GREM1 and GREM2. BMP antagonists Noggin, Follistatin isoform FST344, and Gremlin were then overexpressed in DU145 using the pEF6/V5- HIS-TOPO® TA vector and the resultant cell lines DU145PEF, DU145NOG, DU145FST344 and DU145GREM were subjected to functional assays examining cell proliferation, invasion, adhesion and migration. Results demonstrated that Noggin and FST344 may have a protective effect against prostate cancer bone metastasis due to their inhibition of cell growth and migration, and stimulation of adhesion, although FST344 also caused an increase in invasion in BME. In contrast, DU145GREM showed an increase in cell growth and migration, with minimal effects from BME. qPCR analyses and the GEO data gave more evidence of a BMP/BMP antagonist relationship affecting EMT status and MMP expression profile of cancer cells, with further indication of a BMP-2/Gremlin interplay. iii Our study demonstrates the importance of a BMP/BMP antagonist interplay in the establishment of prostate cancer bone metastases. While further experimentation is required to decipher the precise molecular mechanisms underlying this interplay, this could present a novel therapeutic target for the prevention or treatment of prostate cancer and its related bone metastasis.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 23 May 2019
Last Modified: 23 May 2020 02:05

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