Induction of plasminogen activator inhibitor type-1 PAI-1 by hypoxia and irradiation in human head and neck carcinoma cell linesReportar como inadecuado

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BMC Cancer

, 7:143

First Online: 30 July 2007Received: 20 December 2006Accepted: 30 July 2007DOI: 10.1186-1471-2407-7-143

Cite this article as: Schilling, D., Bayer, C., Geurts-Moespot, A. et al. BMC Cancer 2007 7: 143. doi:10.1186-1471-2407-7-143


BackgroundSquamous cell carcinoma of the head and neck SCCHN often contain highly radioresistant hypoxic regions, nonetheless, radiotherapy is a common treatment modality for these tumours. Reoxygenation during fractionated radiotherapy is desired to render these hypoxic tumour regions more radiosensitive. Hypoxia additionally leads to up-regulation of PAI-1, a protein involved in tumour progression and an established prognostic marker for poor outcome. However, the impact of reoxygenation and radiation on PAI-1 levels is not yet clear. Therefore, we investigated the kinetics of PAI-1 expression and secretion after hypoxia and reoxygenation, and determined the influence of ionizing radiation on PAI-1 levels in the two human SCCHN cell lines, BHY and FaDu.

MethodsHIF-1α immunoblot was used to visualize the degree of hypoxia in the two cell lines. Cellular PAI-1 expression was investigated by immunofluorescence microscopy. ELISA was used to quantify relative changes in PAI-1 expression cell lysates and secretion cell culture supernatants in response to various lengths 2 – 4 h of hypoxic exposure < 0.66 % O2, reoxygenation 24 h, 20 % O2, and radiation 0, 2, 5 and 10 Gy.

ResultsHIF-1α expression was induced between 2 and 24 h of hypoxic exposure. Intracellular PAI-1 expression was significantly increased in BHY and FaDu cells as early as 4 h after hypoxic exposure. A significant induction in secreted PAI-1 was seen after 12 to 24 h BHY and 8 to 24 h FaDu hypoxia, as compared to the normoxic control. A 24 h reoxygenation period caused significantly less PAI-1 secretion than a 24 h hypoxia period in FaDu cells. Irradiation led to an up-regulation of PAI-1 expression and secretion in both, BHY and FaDu cells.

ConclusionOur data suggest that both, short-term ~4 – 8 h and long-term ~20 – 24 h hypoxic exposure could increase PAI-1 levels in SCCHN in vivo. Importantly, radiation itself could lead to PAI-1 up-regulation in head and neck tumours, whereas reoxygenation of hypoxic tumour cells during fractionated radiotherapy could counteract the increased PAI-1 levels.


ECMextracellular matrix

ELISAenzyme-linked immunosorbent assay

HIFhypoxia inducible factor

HREhypoxia responsive element

PAI-1plasminogen activator inhibitor type-1 PAI-1

uPAurokinase-type plasminogen activator

SCCHNsquamous cell carcinoma of the head and neck

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-7-143 contains supplementary material, which is available to authorized users.

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Autor: Daniela Schilling - Christine Bayer - Anneke Geurts-Moespot - Fred CGJ Sweep - Martin Pruschy - Karin Mengele - Lisa D Sp


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