50807

ASAP1

ArfGAP with SH3 domain, ankyrin repeat and PH domain 1;ASAP1;ArfGAP with SH3 domain, ankyrin repeat and PH domain 1

130 kDa phosphatidylinositol 4,5-biphosphate-dependent ARF1 GTPase-activating protein|130 kDa phosphatidylinositol 4,5-bisphosphate-dependent ARF1 GTPase-activating protein|ADP-ribosylation factor-directed GTPase-activating protein 1|ARF GTPase-activating

8q24.1-q24.2

protein-coding

Angiogenesis and cancer invasiveness greatly contribute to cancer malignancy.Arf6 and its effector, AMAP1, are frequently overexpressed in breast cancer, and constitute a central pathway to induce the invasion and metastasis. In this pathway, Arf6 is activated by EGFR via GEP100. Arf6 is highly expressed also in human umbilical vein endothelial cells (HUVECs) and is implicated in angiogenesis. Here, we found that HUVECs also highly express AMAP1, and that vascular endothelial growth factor receptor-2 (VEGFR2) recruits GEP100 to activate Arf6. AMAP1 functions by binding to cortactin in cancer invasion and metastasis. We demonstrate that the same GEP100-Arf6-AMAP1-cortactin pathway is essential for angiogenesis activities, including cell migration and tubular formation, as well as for the enhancement of cell permeability and VE-cadherin endocytosis of VEGF-stimulated HUVECs. Components of this pathway are highly expressed in pathologic angiogenesis, and blocking of this pathway effectively inhibits VEGF- or tumor-induced angiogenesis and choroidal neovascularization. The GEP100-Arf6-AMAP1-cortactin pathway, activated by receptor tyrosine kinases, appears to be common in angiogenesis and cancer invasion and metastasis, and provides their new therapeutic targets.

Angiogenesis and cancer invasiveness greatly contribute to cancer malignancy.Arf6 and its effector, AMAP1, are frequently overexpressed in breast cancer, and constitute a central pathway to induce the invasion and metastasis. In this pathway, Arf6 is activated by EGFR via GEP100. Arf6 is highly expressed also in human umbilical vein endothelial cells (HUVECs) and is implicated in angiogenesis. Here, we found that HUVECs also highly express AMAP1, and that vascular endothelial growth factor receptor-2 (VEGFR2) recruits GEP100 to activate Arf6. AMAP1 functions by binding to cortactin in cancer invasion and metastasis. We demonstrate that the same GEP100-Arf6-AMAP1-cortactin pathway is essential for angiogenesis activities, including cell migration and tubular formation, as well as for the enhancement of cell permeability and VE-cadherin endocytosis of VEGF-stimulated HUVECs. Components of this pathway are highly expressed in pathologic angiogenesis, and blocking of this pathway effectively inhibits VEGF- or tumor-induced angiogenesis and choroidal neovascularization. The GEP100-Arf6-AMAP1-cortactin pathway, activated by receptor tyrosine kinases, appears to be common in angiogenesis and cancer invasion and metastasis, and provides their new therapeutic targets.

AIMS: This study was conducted to analyze the clinical significance of ASAP1 in epithelial ovarian cancer (EOC). METHODS: A total of 95 patients with EOC were included in the study. The expression profile of ASAP1 in 10 pairs of ovarian cancer and normal ovary tissues were detected by Real-time PCR. The expression level of ASAP1 in 95 paraffin-embedded EOC specimens was measured by immunohistochemistry staining. Statistical analysis was performed to evaluate the clinicopathologic significance of ASAP1. RESULTS: Levels of ASAP1 mRNA were higher in EOC than in normal ovary tissues. Patients with higher ASAP1 expression had shorter overall (P=0.019) and recurrence-free (P=0.030) survival time, whereas those with lower ASAP1 expression survived longer. In addition, high expression of ASAP1 was correlated with poor overall (P=0.044) and recurrence-free (P=0.006) survival in patients with advanced carcinomas. Moreover, statistical analysis displayed a significant correlation in ASAP1 expression with pelvic metastasis (P=0.015). Multivariate analysis revealed that an elevated ASAP1 expression was a significant independent prognostic factor for the overall (P=0.039) and recurrence-free (P=0.028) survival of EOC patients. CONCLUSION: These results indicated that elevated expression of ASAP1 plays an important role in the progression and metastasis of ovarian cancer, and that ASAP1 may be used as a biomarker in predicting patient outcome in EOC patients.

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 (approximately 50%) and Matrigel invasion (approximately 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.