MUC1 enhances hypoxia-driven angiogenesis through the regulation of multiple proangiogenic factors
MUC1 enhances hypoxia-driven angiogenesis through the regulation of multiple proangiogenic factors
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DOI：
10.1038/onc.2012.478
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发表时间：
2013-09-26
期刊：
影响因子：
8
通讯作者：
Yonezawa, S.
中科院分区：
文献类型：
--
作者：
Kitamoto, S.;Yokoyama, S.;Yonezawa, S.
胰腺癌因其侵袭性生长和迅速发展的远处转移而成为最致命的恶性肿瘤之一。在这种情况下，粘蛋白1(MUC1)的过度表达和缺氧是经常观察到的事件。然而，它们的功能关系在很大程度上仍然不为人知。本研究提供了MUC1在低氧条件下过度表达的证据，并有助于低氧驱动的血管生成。利用MUC1siRNAs处理低氧应激AsPC1细胞获得的条件培养液，我们证明MUC1siRNAs能增强低氧条件培养液(HCM)诱导的内皮管形成、增殖和迁移能力。此外，低氧可显著诱导胰腺癌细胞(AsPC1、HPAF2或Capan1)产生MUC1，MUC1-胞浆尾巴(MUC1-CT)在低氧条件下聚集于胞核。正如以前的报道所指出的，MUC1-CT被招募到结缔组织生长因子(CTGF)的上游基因组区域，伴随着β-连环素和P53，导致CTGF的低氧诱导。此外，低氧诱导的MUC1部分调节另外两个低氧诱导的促血管生成因子，包括血管内皮生长因子-A和血小板衍生生长因子-B。中和实验表明，抗这三种因子的抗体能明显抑制HCM诱导的血管内皮细胞的形成，提示这些因子在缺氧诱导的血管生成中具有重要作用。综上所述，这是第一个表明MUC1在胰腺癌中通过调节多种促血管生成因子控制缺氧驱动的血管生成的关键作用的报告。我们的发现为理解胰腺癌细胞和肿瘤微环境之间的复杂相互作用提供了新的见解。
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 beta-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.