Journal of the National Cancer Institute Advance Access published online on July 8, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn214
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Multiple Cellular Mechanisms Related to Cyclin A1 in Prostate Cancer Invasion and Metastasis
Affiliations of authors: Division of Pathology, Department of Laboratory Medicine (BW, LH, EN, JLP), Tumor Biology, Department of Laboratory Medicine (PH), Division of Urological Cancers (BW, AB), Division of Urological Research (ND, MT), Department of Clinical Sciences, Lund University, University Hospital, Malmö, Sweden; Department of Anatomy, University of Turku, Turku, Finland (JT); Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (BW, LEO); Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY (AB)
Correspondence to: Jenny Liao Persson, PhD, Division of Pathology, Department of Laboratory Medicine, Lund University, University Hospital, 205 02 Malmö, Sweden (e-mail: jenny_l.persson{at}med.lu.se).
Background: Cyclin A1 is a cell cycle regulator that has been implicated in the progression of prostate cancer. Its role in invasion and metastasis of this disease has not been characterized.
Methods: Immunohistochemistry and cDNA microarray analyses were used to assess protein and mRNA expression of cyclin A1 and proteins with roles in metastasis, including vascular endothelial growth factor (VEGF), metalloproteinase 2 (MMP2), and MMP9, in human prostate cancer. Transient transfection and infection with viral vectors expressing cyclin A1 and short hairpin RNA (shRNA) targeting cyclin A1 were used to study the effects of altered cyclin A1 expression in PC3 prostate cancer cells. The BrdU assay, annexin V staining, and invasion chambers were used to examine cyclin A1 effects on proliferation, apoptosis, and invasion, respectively. The role of cyclin A1 and androgen receptor (AR) in transcription of VEGF and MMP2 was assessed by promoter mutation and chromatin immunoprecipitation. The effect of cyclin A1 expression on tumor growth and metastasis was analyzed in a mouse model of metastasis. All statistical tests were two-sided.
Results: Cyclin A1 protein and mRNA expression were statistically significantly higher in prostate cancers than in adjacent benign tissues. A statistically significant correlation between expression of cyclin A1 and of MMP2, MMP9, and VEGF was observed in prostate tumors from 482 patients (P values from Spearman rank correlation tests < .001). PC3 cells that overexpressed cyclin A1 showed increased invasiveness, and inhibition of cyclin A1 expression via shRNA expression reduced invasiveness of these cells. Eight of 10 mice (80%) bearing PC3 cells overexpressing cyclin A1 had infiltration of tumor cells in lymph node, liver, and lung, but all 10 mice bearing tumors expressing control vector were free of liver and lung metastases and only one mouse from this group had lymph node metastasis (P values from Fisher exact tests < .001). Cyclin A1, in concert with AR, bound to and increased expression from the VEGF and MMP2 promoters.
Conclusions: Cyclin A1 contributes to prostate cancer invasion by modulating the expression of MMPs and VEGF and by interacting with AR.
| CONTEXT AND CAVEATS Prior knowledge Cyclin A1 is a cell cycle regulatory factor that is highly expressed in human prostate cancers. Study design Cyclin A1 expression was altered in cultured prostate cancer cells by introducing expression vectors or RNA interference. The effect of alterations in cyclin A1 expression was examined in terms of cellular processes relevant to the progression of prostate cancer, including invasion of prostate cancer cells in vitro and in mouse models of tumor growth and metastasis, and regulation at the promoter level of genes that play a role in metastasis. Contribution This work demonstrated, and characterized in some molecular detail, the role of cyclin A1 in promoting invasion and metastasis of prostate cancer cells. Implications A cell cycle regulatory factor may contribute to prostate cancer invasion and metastasis. Limitations The manipulations of cyclin A1 expression were confined to cell lines and animal models that may not recapitulate the process of prostate cancer invasion and metastasis in humans. From the Editors
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Manuscript received February 1, 2008; revised May 2, 2008; accepted May 29, 2008.
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J Natl Cancer Inst 2008 100: 975.
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