Amplification and overexpression of vinculin are associated with increased tumour cell proliferation and progression in advanced prostate cancer

Christian Ruiz, David R. Holz, Martin Oeggerli, Sandra Schneider, Irma M. Gonzales, Jeffrey M. Kiefer, Tobias Zellweger, Alexander Bachmann, Pasi A. Koivisto, Heikki J. Helin, Spyro Mousses, Michael Barrett, David O. Azorsa, Lukas Bubendorf

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Androgen withdrawal is the standard treatment for advanced prostate cancer. Although this therapy is initially effective, nearly all prostate cancers become refractory to it. Approximately 15% of these castration-resistant prostate cancers harbour a genomic amplification at 10q22. The aim of this study was to explore the structure of the 10q22 amplicon and to determine the major driving genes. Application of high-resolution array-CGH using the 244k Agilent microarrays to cell lines with 10q22 amplification allowed us to narrow down the common amplified region to a region of 5.8 megabases. We silenced each of the genes of this region by an RNAi screen in the prostate cancer cell lines PC-3 and 22Rv1. We selected genes with a significant growth reduction in the 10q22 amplified cell line PC-3, but not in the non-amplified 22Rv1 cells, as putative target genes of this amplicon. Immunohistochemical analysis of the protein expression of these candidate genes on a tissue microarray enriched for 10q22 amplified prostate cancers revealed vinculin as the most promising target of this amplicon. We found a strong association between vinculin gene amplification and overexpression (p < 0.001). Further analysis of 443 specimens from across all stages of prostate cancer progression showed that vinculin expression was highest in castration-resistant prostate cancers, but negative or very low in benign prostatic hyperplasia (p < 0.0001). Additionally, high tumour cell proliferation measured by Ki67 expression was significantly associated with high vinculin expression in prostate cancer (p < 0.0001). Our data suggest that vinculin is a major driving gene of the 10q22 amplification in prostate cancer and that vinculin overexpression might contribute to prostate cancer progression by enhancing tumour cell proliferation.

Original languageEnglish (US)
Pages (from-to)543-552
Number of pages10
JournalJournal of Pathology
Volume223
Issue number4
DOIs
StatePublished - Mar 2011
Externally publishedYes

Fingerprint

Vinculin
Prostatic Neoplasms
Cell Proliferation
Neoplasms
Gene Amplification
Castration
Cell Line
Genes
Prostatic Hyperplasia
RNA Interference
Androgens

Keywords

  • 10q22
  • array-CGH
  • prostate cancer
  • tissue microarray
  • vinculin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Amplification and overexpression of vinculin are associated with increased tumour cell proliferation and progression in advanced prostate cancer. / Ruiz, Christian; Holz, David R.; Oeggerli, Martin; Schneider, Sandra; Gonzales, Irma M.; Kiefer, Jeffrey M.; Zellweger, Tobias; Bachmann, Alexander; Koivisto, Pasi A.; Helin, Heikki J.; Mousses, Spyro; Barrett, Michael; Azorsa, David O.; Bubendorf, Lukas.

In: Journal of Pathology, Vol. 223, No. 4, 03.2011, p. 543-552.

Research output: Contribution to journalArticle

Ruiz, C, Holz, DR, Oeggerli, M, Schneider, S, Gonzales, IM, Kiefer, JM, Zellweger, T, Bachmann, A, Koivisto, PA, Helin, HJ, Mousses, S, Barrett, M, Azorsa, DO & Bubendorf, L 2011, 'Amplification and overexpression of vinculin are associated with increased tumour cell proliferation and progression in advanced prostate cancer', Journal of Pathology, vol. 223, no. 4, pp. 543-552. https://doi.org/10.1002/path.2828
Ruiz, Christian ; Holz, David R. ; Oeggerli, Martin ; Schneider, Sandra ; Gonzales, Irma M. ; Kiefer, Jeffrey M. ; Zellweger, Tobias ; Bachmann, Alexander ; Koivisto, Pasi A. ; Helin, Heikki J. ; Mousses, Spyro ; Barrett, Michael ; Azorsa, David O. ; Bubendorf, Lukas. / Amplification and overexpression of vinculin are associated with increased tumour cell proliferation and progression in advanced prostate cancer. In: Journal of Pathology. 2011 ; Vol. 223, No. 4. pp. 543-552.
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AU - Kiefer, Jeffrey M.

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AU - Bachmann, Alexander

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AU - Helin, Heikki J.

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AB - Androgen withdrawal is the standard treatment for advanced prostate cancer. Although this therapy is initially effective, nearly all prostate cancers become refractory to it. Approximately 15% of these castration-resistant prostate cancers harbour a genomic amplification at 10q22. The aim of this study was to explore the structure of the 10q22 amplicon and to determine the major driving genes. Application of high-resolution array-CGH using the 244k Agilent microarrays to cell lines with 10q22 amplification allowed us to narrow down the common amplified region to a region of 5.8 megabases. We silenced each of the genes of this region by an RNAi screen in the prostate cancer cell lines PC-3 and 22Rv1. We selected genes with a significant growth reduction in the 10q22 amplified cell line PC-3, but not in the non-amplified 22Rv1 cells, as putative target genes of this amplicon. Immunohistochemical analysis of the protein expression of these candidate genes on a tissue microarray enriched for 10q22 amplified prostate cancers revealed vinculin as the most promising target of this amplicon. We found a strong association between vinculin gene amplification and overexpression (p < 0.001). Further analysis of 443 specimens from across all stages of prostate cancer progression showed that vinculin expression was highest in castration-resistant prostate cancers, but negative or very low in benign prostatic hyperplasia (p < 0.0001). Additionally, high tumour cell proliferation measured by Ki67 expression was significantly associated with high vinculin expression in prostate cancer (p < 0.0001). Our data suggest that vinculin is a major driving gene of the 10q22 amplification in prostate cancer and that vinculin overexpression might contribute to prostate cancer progression by enhancing tumour cell proliferation.

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