Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary cancer in the liver, and its incidence is increasing in developed countries. To discover novel molecular targets for the diagnosis and treatment of ICCs, we earlier analyzed expression profiles of 25 ICCs using a cDNA microarray containing 27,648 genes. In this study, we focused on the RAD51 associating protein-1 (RAD51AP1) gene because its expression was frequently elevated in our microarray data. Quantitative PCR confirmed that RAD51AP1 expression was elevated in the great majority of the ICCs examined. Immunohistochemical analysis with anti-RAD51AP1 antibody further corroborated its accumulation in 14 of 23 ICC tissues (61%). Notably, suppression of RAD51AP1 by short interfering RNA resulted in growth suppression of cholangiocarcinoma cells, suggesting its involvement in the development and/or progression of ICC. Because RAD51AP1 interacts with RAD51, a molecule involved in DNA repair, we investigated whether RAD51AP1 is implicated in DNA strand breaks using gamma-irradiation. As a result, gamma-irradiation augmented RAD51AP1 protein expression and brought a focus formation in the nuclei, where accumulated RAD51AP1 colocalized with phosphorylated histone 2AX (gamma-H2AX) and RAD51. These data suggest that RAD51AP1 may play a role in cell proliferation as well as DNA repair. Our findings may contribute to the better understanding of cholangiocarcinogenesis and open a new avenue to the development of novel therapeutic and/or diagnostic approach to this type of tumor.
Highlights
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary cancer in the liver, and its incidence is increasing in developed countries
By real-time reverse transcription – PCR analysis, we subsequently examined RAD51AP1 expression levels using the RNA samples that had served for the microarray analysis
We observed elevated RAD51AP1 expression (>5-fold) in 17 of 21 tumors compared with a mixture of noncancerous biliary epithelia (Fig. 1A), which corroborated the enhanced RAD51AP1 expression in ICC
Summary
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary cancer in the liver, and its incidence is increasing in developed countries. G-irradiation augmented RAD51AP1 protein expression and brought a focus formation in the nuclei, where accumulated RAD51AP1 colocalized with phosphorylated histone 2AX (g-H2AX) and RAD51 These data suggest that RAD51AP1 may play a role in cell proliferation as well as DNA repair. We carried out a genome-wide analysis of gene expression profiles of 25 ICCs by means of a cDNA microarray representing 27,648 genes [13] These efforts identified 52 genes that were commonly up-regulated in the tumors compared with epithelia of noncancerous intrahepatic bile duct. The panel of commonly up-regulated genes included genes that were reported to be involved in carcinogenesis It is unclear how the remnants play a role in carcinogenesis, these genes may serve for novel diagnostic and/ or therapeutic targets of ICC. We further show evidence that RAD51AP1 is involved in DNA www.aacrjournals.org
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