title: MUC1 enhances hypoxia-driven angiogenesis through the regulation of multiple proangiogenic factors.
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.
authors.affiliation: Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kitamoto
authors.forename: S
authors.initials: S
authors.lastname: Yokoyama
authors.forename: M
authors.initials: M
authors.lastname: Higashi
authors.forename: N
authors.initials: N
authors.lastname: Yamada
authors.forename: S
authors.initials: S
authors.lastname: Takao
authors.forename: S
authors.initials: S
authors.lastname: Yonezawa
mesh_terms: D042501:Angiogenic Proteins / Q000096:biosynthesis* / Q000235:genetics; D002277:Carcinoma / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology / Q000556:secondary; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018396:Mucin-1 / Q000502:physiology*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D010446:Peptide Fragments / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D042501:Angiogenic Proteins; C526317:CCN2 protein, human; D017077:Culture Media, Conditioned; C060192:MUC1 protein, human; D018396:Mucin-1; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D055513:Connective Tissue Growth Factor