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ASAP1, a Gene at 8q24, Is Associated with Prostate Cancer Metastasis

Departments of ¹ Cancer Endocrinology and ² Cancer Genetics and ³ Genome Sciences Centre, British Columbia Cancer Agency; ⁴ Department of Pathology and ⁵ Prostate Centre at Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada; and ⁶ Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada

Requests for reprints: Yu-Zhuo Wang, Department of Cancer Endocrinology, British Columbia Cancer Agency-Research Center, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3. Phone: 604-675-8013; Fax: 604-675-8019; E-mail: ywang{at}bccrc.ca.

Key Words: prostate cancer • metastasis • ASAP1/AMAP1/DDEF1 gene • SAGE • FISH

Metastatic prostate cancer is a terminal disease, and the development of reliable prognostic tools and more effective therapy is critically important for improved disease survival and management. This study was aimed at identifying genes that are differentially expressed in metastatic and nonmetastatic prostate cancer cells and, as such, could be critical in the development of metastasis. Long-SAGE analysis was used to compare a transplantable human metastatic prostate cancer subline, PCa1-met, with a nonmetastatic counterpart, PCa2. Both sublines were developed from a patient's prostate cancer specimen via subrenal capsule grafting and subsequent orthotopic implantation into SCID mice. Among various differentially expressed genes identified, ASAP1, an 8q24 gene encoding an ADP-ribosylation factor GTPase-activating protein not previously associated with prostate cancer, was up-regulated in the metastatic subline as confirmed by quantitative real-time PCR. Immunohistochemistry of xenograft sections showed that cytoplasmic ASAP1 protein staining was absent or weak in benign tissue, significantly stronger in nonmetastatic PCa2 tissue, and strongest in PCa1-met tissue. In clinical specimens, ASAP1 protein staining was elevated in 80% of primary prostate cancers and substantially higher in metastatic lesions compared with benign prostate tissue. Moreover, additional ASAP1 gene copies were detected in 58% of the primary prostate cancer specimens. Small interfering RNA–induced reduction of ASAP1 protein expression markedly suppressed in vitro PC-3 cell migration (50%) and Matrigel invasion (67%). This study suggests that the ASAP1 gene plays a role in prostate cancer metastasis and may represent a therapeutic target and/or biomarker for metastatic disease. [Cancer Res 2008;68(11):4352–9]

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