Journal
ONCOTARGET
Volume 7, Issue 21, Pages 31299-31310Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.8896
Keywords
histamine; H2 receptor; tight junctions-associated proteins; blood-tumor barrier
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Funding
- National Natural Science Foundation of China [81202806]
- Zhejiang Provincial Natural Science Foundation of China [Y2110004]
- General Research Program of Medical Health in Zhejiang Province [2014KYB039]
- Public Welfare Technology Application Studies Program of Zhejiang Province [2015C33286]
- 1022 Talent Training Program of Zhejiang Cancer Hospital
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Blood-tumor barrier (BTB) reduce the permeability for drugs into tumor tissues. We found that histamine might serve as an essential regulator of BTB function. Further, we aim to determine the role of H2 receptor expression in BTB permeability, and elucidate the underlying mechanisms thereof. Transmission electron microscopy showed that histamine disrupted the integrity of tight junctions (TJ) and increased the number of pinosomes in the cytoplasm. Horseradish peroxidase (HRP) and transendothelial resistance detection (TEER) assays revealed that histamine could open BTB and this action was inhibited by cimetidine. Western blot and immunofluorescence assays showed that histamine decreased the expression of tight junction proteins zonula occluden-1(ZO-1), occludin, and claudin-5. Further, quantitative RT-PCR assay showed that the expression of H2 receptor could represent and predicted histamine-induced BTB permeability. In conclusion, histamine opened BTB by down-regulating the TJ-associated proteins. The levels of H2 receptor expression was correlated with the histamine-induced BTB permeability.
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