Abstract
Pancreatic cancer is one of the most lethal malignancies due to its aggressive growth and rapid development of distant metastases. In this context, mucin 1 (MUC1) overexpression and hypoxia are frequently observed events. However, their functional relationship remains largely unknown. This study provides evidence that MUC1 is overexpressed by hypoxia and contributes to hypoxia-driven angiogenesis. Using the conditioned medium obtained from hypoxia-stressed AsPC1 cells treated with MUC1 siRNAs, we demonstrated that MUC1 enhanced the endothelial tube formation, proliferation and migration ability, which induced by hypoxia-conditioned medium (HCM). In addition, MUC1 was significantly induced by hypoxia, especially in the pancreatic cancer cells derived from metastatic tumors (AsPC1, HPAF2 or Capan1), and MUC1-cytoplasmic tail (MUC1-CT) accumulated in the nucleus under hypoxia. As noted in a previous report, MUC1-CT was recruited to genomic regions upstream of the connective tissue growth factor (CTGF) accompanied with β-catenin and p53, resulting in the hypoxic induction of CTGF. Moreover, hypoxia-induced MUC1 partially regulated two other hypoxia-inducible proangiogenic factors including vascular endothelial growth factor-A and platelet-derived growth factor-B. The neutralization assay revealed that endothelial tube formation induced by HCM was clearly suppressed by antibodies against these three factors, suggesting the importance of these factors in hypoxia-driven angiogenesis. In summary, this is the first report demonstrating a pivotal role of MUC1 in controlling the hypoxia-driven angiogenesis through the regulation of multiple proangiogenic factors in pancreatic cancer. Our findings provide the novel insights into the understanding of complex interactions between pancreatic cancer cells and tumor microenvironments.
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Acknowledgements
This work was supported by the Princess Takamastu Cancer Research Fund (11-24319; S Yonezawa); by the Scientific Research on Priority Areas 20014022 and Scientific Research (B) 23390085 (S Yonezawa) and Scientific Research (C) 20590399 (M Higashi) grants from the Ministry of Education, Science, Sports, Culture and Technology, Japan; by an International Educational Research Support Project for Islands, Environment and Medicine (S Yokoyama); by a JSPS Fellowship Grant-in-Aid (no. 239349; S Kitamoto); by a Pancreas Reserch Foundation of Japan (S Yokoyama) and Kodama Memorial Foundation, Japan (S Kitamoto, S Yokoyama and M Higashi). We would like to express our gratitude to Dr Ming-Sound Tsao for providing us with the immortalized human pancreatic duct epithelial cells. We also thank Mses Izumi Houjou and Yukari Nishimura for their excellent technical assistance.
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Kitamoto, S., Yokoyama, S., Higashi, M. et al. MUC1 enhances hypoxia-driven angiogenesis through the regulation of multiple proangiogenic factors. Oncogene 32, 4614–4621 (2013). https://doi.org/10.1038/onc.2012.478
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DOI: https://doi.org/10.1038/onc.2012.478
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