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2006 Abstracts: Overexpression of Geminin in Pancreatic Cancer tissue and its down-regulation by Apigenin
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Overexpression of Geminin in Pancreatic Cancer tissue and its down-regulation by Apigenin
Mohammad R. Salabat1, Xian Z. Ding1, Laleh Golkar1, Michael B. Ujiki1, Sambasiva M. Rao2, Richard H. Bell1, Thomas E. Adrian1, Jill C. Pelling2, Mark S. Talamonti1, David J. Bentrem1; 1Surgery, Northwestern University, Chicago, IL; 2Pathology, Northwestern Surgery, Chicago, IL

Background and Aim: Geminin is a novel cell cycle regulatory protein. Complex formation of several genes on chromatin during the G1 phase of the cell cycle followed by replication firing at the beginning of the S phase lead to DNA replication initiation and any disruption in this process can result in genomic instability, promoting cancer or cell death. Geminin blocks loading of the MCM complex on chromatin, hence inhibiting yet another replication. In human cancer cell lines, (HCT116 colorectal and H1299 lung carcinoma cells) depletion of geminin by siRNA results in G2/M phase arrest. Geminin has been shown to be overexpressed in 60% of breast and colon cancer tissues. Overexpression of geminin has been shown to increase cell proliferation. Apigenin is a dietary flavonoids that has been shown to have antiproliferative effects in several cancer cell lines. It has been shown that apigenin induces G2/M arrest in mutant p53 HT-29 colorectal adenocarcinoma cells and CD18 human pancreatic cancer cells. We sought to identify the expression of geminin in pancreatic cancer tissue and to investigate the effect of apigenin on geminin expression in pancreatic cancer cells. Methods: We investigated the expression of geminin in pancreatic tissues by immunohistochemistry (IHC). Expression of geminin was also evaluated by western blotting and real time RT-PCR. Immunofluorescence staining was used to localize geminin by confocal microscopy. Results : Our results show that there is a significant increase in staining of geminin in the nucleus of ductal cancer cells in pancreatic tumor tissue compared to normal pancreatic tissue. In the fifteen samples of cancer tissues and their corresponding adjacent normal tissue that were stained with a geminin antibody, geminin stained positive in more than 20% of the ductal cancer cells in 10 of 15 (75%) samples, between 10 and 20% positive in 3 of 15 (20%) samples and less than 10% in only 2 of 15 (5%) samples. None of the normal tissue samples stained for geminin. Geminin mRNA and protein expression levels were significantly reduced by 50μM apigenin in pancreatic cancer cell lines, S2013 and CD18 cells, by real time RT-PCR (p<0.05 and p<0.01, respectively) and western blotting. Immunofluorescence staining in the S2013 pancreatic cancer cell line, localized geminin to the nucleus and cells treated with 50 μM apigenin demonstrated decreased levels of geminin after 4 and 24 hours compared to the control levels. Conclusion: Geminin is upregulated in human pancreatic cancer tissue. Geminin is downregulated by apigenin which may contribute to its antiproliferative effect in human pancreatic cancer cells.


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