Influence of Ionizing Radiation on Ovarian Carcinoma SKOV-3 Xenografts in Nude Mice under Hypoxic Conditions

Abstract

Purpose: We aimed to detect the expression of HIF-1α, VEGF, HPSE-1 and CD31 in SKOV3 xenografts innude mice treated with different doses of ionizing radiation, trying to explore the possible mechanism of hypoxiaand radioresistance. <br/><b>Methods</b>: Nude mice bearing SKOV3 xenografts were randomly divided into 4 groups:Group A (control group, no ionizing radiation), Group B (treated with low dose of ionizing radiation: 50cGy),Group C (treated with high dose of ionizing radiation: 300cGy), Group D ( combined ionizing radiation, treatedwith ionizing radiation from low dose to high dose : 50cGy first and 300cGy after 6h interval). The mRNAlevels of HIF-1 and VEGF in each group were detected by real time polymerase chain reaction, while HPSE-1expression was measured by ELISA. The microvessel density (MVD) and hypoxic cells were determined throughimmunohistochemical (IHC) staining of CD31 and HIF-1a. <br/><b>Results</b>: Significant differences of HIF-1α mRNA levelcould be found among the 4 groups (F=74.164, P<0.001): Group C>Group A>Group D> Group B. The mRNAlevel of VEGF in Group C was significantly higher than in the other three groups (t=-5.267, P=0.000), while nosignificant difference was observed among Group A, B and D (t=1.528, 1.588; P=0.205, 0.222). In addition, theMVD was shown to be the highest in Group C (t=6.253, P=0.000), whereas the HPSE-1 level in Group A waslower than in Group B (t=14.066, P=0.000) and higher than in Group C (t=-21.919, P=0.000), and similar withGroup D (t=-2.066, P=0.058). Through IHC staining of HIF-1a, the expression of hypoxic cells in Group A was(++), Group B was (+), Group C was (+++) and Group D was (+). <br/><b>Conclusion</b>: Ionizing radiation with lowerdosesmight improve tumor hypoxia through inhibiting the expression of HIF-1 and HPSE-1, whereas higherdosesworsen tumor hypoxic conditions by up-regulating HIF-1α, HPSE-1, VEGF and CD31 levels. A protocolof low-dose ionizing radiation followed by a high-dose irradiation might at least partly improve tumor hypoxiaand enhance radiosensitivity.