Matriptase-2 and the biological behaviours of prostate cancer cells: a possible role for β-catenin

Webb, Siobhan Louise 2011. Matriptase-2 and the biological behaviours of prostate cancer cells: a possible role for β-catenin. PhD Thesis, Cardiff University.

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Abstract

The type II transmembrane serine proteases (TTSP) are cell surface proteolytic enzymes that mediate a diverse range of cellular functions, including tumour invasion and metastasis. Matriptase-2 is a relatively newly identified member of the TTSP family whose role in cancer is currently poorly understood. Sanders et al 2008 investigated the effect of matriptase-2 in PC3 and DU145 prostate cancer cells. This study aims to further elucidate the role of matriptase-2 in cancer development and progression. The relationship between matriptase-2 and β-catenin was examined as previous preliminary data (unpublished) showed P-catenin to be a protein of interest from a screen of molecules associated with cell.cell and cell:matrix adhesion performed during previous studies. To build on the data gained from Sanders et al. 2008, normal prostate cell lines PZHPV7 and PNT2C2 had matriptase-2 stably knocked down and were used in assays to assess cell functionality. Knock-down of matriptase-2 did not alter the growth or adhesion of PZHPV7 or PNT2C2 cells but did however cause a significant reduction in their motile and invasive capabilities. HECV cells were also used to examine the effect of matriptase-2 on angiogenesis. The over-expression of matriptase-2 in these cells had no effect on growth and adhesion but significantly reduced the motile and tubule formation abilities of the HECV cells. This is a similar effect to that seen in the PZHPV7 and PNT2C2 cells. PC3 and DU145 cells over-expressing matriptase-2 were also used to examine possible mechanisms of matriptase-2 action. Examination into the possible relationship between matriptase-2 and β-catenin revealed that a knockdown of matriptase-2 increased the β-catenin levels and conversely, over-expression decreased the β-catenin levels in PC3 cells. In DU145 cells the β-catenin levels increased. This may be due to the differing expression levels of key molecules such as E-cadherin. The HECV cells appeared to show no change in β-catenin levels. Angiogenesis factor MMP-7 was found to be altered in response to β-catenin levels. Additionally matritpase-2 over-expression was found to reduce uPA and the converse with matriptase-2 knockdown in all cell lines examined. These results indicate that matriptase-2 may have a regulatory function over β-catenin and uPA in prostate cells. This is possibly two mechanisms by which matriptase-2 protects against cancer metastasis and angiogenesis in normal cells and tissues. However, due to the differences seen in the p-catenin experiments, there are obviously other possible mechanisms to be considered. This study provides a valuable insight into how this poorly understood protease functions in prostate cancer.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
ISBN:	9781303196584
Date of First Compliant Deposit:	30 March 2016
Last Modified:	19 Mar 2016 23:30
URI:	https://orca.cardiff.ac.uk/id/eprint/54470

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