title: Targeting hypoxia-mediated mucin 2 production as a therapeutic strategy for mucinous tumors.
abstract: Excessive accumulation of mucin 2 (MUC2; a gel-forming secreted mucin) protein in the peritoneal cavity is the major cause of morbidity and mortality in pseudomyxoma peritonei (PMP). Hypoxia (hypoxia-inducible factor-1α; HIF-1α) has been shown to regulate the expression of similar mucins (eg, MUC5AC). We hypothesized that hypoxia (HIF-1α) drives MUC2 expression in PMP and is therefore a novel target to reduce mucinous tumor growth. The regulation of MUC2 by 2% hypoxia (HIF-1α) was evaluated in MUC2-secreting LS174T cells. The effect of BAY 87-2243, an inhibitor of HIF-1α, on MUC2 expression and mucinous tumor growth was evaluated in LS174T cells, PMP explant tissue, and in a unique intraperitoneal murine xenograft model of PMP. In vitro exposure of LS174T cells to hypoxia increased MUC2 messenger RNA (mRNA) and protein expression and increased HIF-1α binding to the MUC2 promoter. Hypoxia-mediated MUC2 protein overexpression was downregulated by transfected HIF-1α small interfering RNA (siRNA) compared with scrambled siRNA in LS174T cells. BAY 87-2243 inhibited hypoxia-induced MUC2 mRNA and protein expression in LS174T cells and PMP explant tissue. In a murine xenograft model of PMP, chronic oral therapy with BAY 87-2243 inhibited mucinous tumor growth and MUC2, HIF-1α expression in the tumor tissue. Our data suggest that hypoxia (HIF-1α) induces MUC2 promoter activity to increase MUC2 expression. HIF-1α inhibition decreases MUC2 production and mucinous tumor growth, providing a preclinical rationale for the use of HIF-1α inhibitors to treat patients with PMP.
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Dilly
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa; Department of Pharmacology and Chemical Biology, University of Pittsburgh Medical Center, Pittsburgh, Pa.
authors.forename: Yong J
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa.
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa.
authors.forename: Zong Sheng
authors.initials: ZS
authors.lastname: Guo
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa.
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.affiliation: Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa. Electronic address: choudrymh@upmc.edu.
authors.forename: Haroon A
authors.initials: HA
authors.lastname: Choudry
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D064593:Heterografts; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D055262:Mucin-2 / Q000096:biosynthesis*; D011553:Pseudomyxoma Peritonei / Q000378:metabolism / Q000628:therapy*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C524626:Muc2 protein, mouse; D055262:Mucin-2; D034741:RNA, Small Interfering