Targeting hypoxia-mediated mucin 2 production as a therapeutic strategy for mucinous tumors

Ashok K. Dilly, Yong J. Lee, Herbert J. Zeh, Zong Sheng Guo, David L. Bartlett, Haroon A. Choudry

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)19-30.e1
JournalTranslational Research
Volume169
DOIs
StatePublished - Mar 2016
Externally publishedYes

Fingerprint

Mucin-2
Pseudomyxoma Peritonei
Tumors
Mucins
Neoplasms
Tissue
Heterografts
Small Interfering RNA
Proteins
Growth
Therapeutics
Hypoxia-Inducible Factor 1
Messenger RNA
Cell Hypoxia
Peritoneal Cavity
Gels
Hypoxia
Down-Regulation
Morbidity
1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Biochemistry, medical
  • Physiology (medical)

Cite this

Targeting hypoxia-mediated mucin 2 production as a therapeutic strategy for mucinous tumors. / Dilly, Ashok K.; Lee, Yong J.; Zeh, Herbert J.; Guo, Zong Sheng; Bartlett, David L.; Choudry, Haroon A.

In: Translational Research, Vol. 169, 03.2016, p. 19-30.e1.

Research output: Contribution to journalArticle

Dilly, Ashok K. ; Lee, Yong J. ; Zeh, Herbert J. ; Guo, Zong Sheng ; Bartlett, David L. ; Choudry, Haroon A. / Targeting hypoxia-mediated mucin 2 production as a therapeutic strategy for mucinous tumors. In: Translational Research. 2016 ; Vol. 169. pp. 19-30.e1.
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