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Osteopontin, a major non-collagenous bone matrix protein, is strikingly upregulated in various tissues under certain pathologic conditions, including cancer. However, the mechanism of upregulation of the osteopontin gene in tumor cells remains unclear. Okadaic acid, a strong non-phorbol ester tumor promoter, is known to stimulate the expression of osteopontin. The aim of the present study was to understand the mechanism by which okadaic acid regulates osteopontin gene expression. Okadaic acid stimulated osteopontin mRNA expression in several cell lines within 3 h, and the increase in osteopontin mRNA was sustained for 24 h. New protein synthesis was required for the okadaic acid-elicited increase in osteopontin mRNA expression. A serial promoter deletion study showed that the okadaic acid-response element is located between positions -265 and -73, a sequence that includes the Runx2, Ets-1, and AP-1 binding sequences. Okadaic acid increased the mRNA expression of AP-1 components but not of Runx2 or Ets-1. Site-directed mutagenesis and electrophoretic mobility shift assays confirmed that protein binding of the AP-1 consensus sequence is necessary for the okadaic acid-mediated osteopontin gene upregulation. These results indicate that de novo induction of the oncoprotein AP-1 is required for okadaic acid-stimulated osteopontin gene upregulation. 相似文献
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Bidder M Shao JS Charlton-Kachigian N Loewy AP Semenkovich CF Towler DA 《The Journal of biological chemistry》2002,277(46):44485-44496
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Liver metastasis is a major cause of mortality from colorectal cancer (CRC). However, mechanisms underlying this process are largely unknown. Osteopontin (OPN) is a secreted phosphorylated glycoprotein that is involved in tumor migration and metastasis. The role of OPN in cancer is currently unclear. In this study, OPN mRNA was examined in tissues from CRC, adjacent normal mucosa, and liver metastatic lesions using quantitative real-time PCR analysis. The protein expression of OPN and its receptors (integrin αv and CD44 v6) was detected by using an immunohistochemical (IHC) method. The role of OPN in liver metastasis was studied in established colon cancer Colo-205 and SW-480 cell lines transfected with sense- or antisense-OPN eukaryotic expression plasmids by flow cytometry and cell adhesion assay. Florescence redistribution after photobleaching (FRAP) was used to study gap functional intercellular communication (GJIC) among OPN-transfected cells. It was found that OPN was highly expressed in metastatic hepatic lesions from CRC compared to primary CRC tissue and adjacent normal mucosa. The expression of OPN mRNA in tumor tissues was significantly related with the CRC stages. OPN expression was also detected in normal hepatocytes surrounding CRC metastatic lesions. Two known receptors of OPN, integrin αv and CD44v6 proteins, were strongly expressed in hepatocytes from normal liver. CRC cells with forced OPN expression exhibited increased heterotypic adhesion with endothelial cells and weakened intercellular communication. OPN plays a significant role in CRC metastasis to liver through interaction with its receptors in hepatocytes, decreased homotypic adhesion, and enhanced heterotypic adhesion. 相似文献
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Francisco Villanueva Hector Araya Pedro Briceño Nelson Varela Andres Stevenson Sofia Jerez Fabian Tempio Jonas Chnaiderman Carola Perez Milena Villarroel Emma Concha Farzaneh Khani Roman Thaler Flavio Salazar-Onfray Gary S Stein Andre J. van Wijnen Mario Galindo 《Journal of cellular physiology》2019,234(8):13659-13679
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Histone deacetylases (HDACs) deacetylate lysine residues of histone and non-histone proteins and thereby regulate the cell-cycle,
gene expression, and several other processes. We have analyzed the effects of HDAC1 on Runx2-mediated regulation of osteopontin
(OPN) promoter activation and gene expression in mesenchymal progenitor C3h10t1/2 cells and show that co-expression of HDAC1
along with Runx2 results in down-regulation of Runx2-induced OPN mRNA expression during both the proliferation and differentiation
stages of C3h10t1/2 cells. Luciferase assay results revealed that HDAC1 efficiently down-regulated Runx2-stimulated OPN promoter
activity in a dose-dependent manner whereas TSA relieved the HDAC1-mediated repression and up-regulated the Runx2-induced
OPN promoter activity and mRNA expression. In vivo HDAC1 co-localized and physically interacted with Runx2 and associated
with the OPN promoter. Thus, HDAC1 not only plays a critical role in regulation of Runx2-stimulated expression of osteogenic
genes, like OPN, but also regulate the proliferation and differentiation stages of mesenchymal progenitor cells, such as C3h10t1/2. 相似文献