Influence of ionizing radiation on ovarian carcinoma SKOV- 3 xenografts in nude mice under hypoxic conditions.
OBJECTIVE
We aimed to detect the expression of HIF-1α, VEGF, HPSE-1 and CD31 in SKOV3 xenografts in nude mice treated with different doses of ionizing radiation, trying to explore the possible mechanism of hypoxia and radioresistance.


METHODS
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, treated with ionizing radiation from low dose to high dose : 50cGy first and 300cGy after 6h interval). The mRNA levels of HIF-1 and VEGF in each group were detected by real time polymerase chain reaction, while HPSE-1 expression was measured by ELISA. The microvessel density (MVD) and hypoxic cells were determined through immunohistochemical (IHC) staining of CD31 and HIF-1a.


RESULTS
Significant differences of HIF-1α mRNA level could be found among the 4 groups (F=74.164, P<0.001): Group C>Group A>Group D> Group B. The mRNA level of VEGF in Group C was significantly higher than in the other three groups (t=-5.267, P=0.000), while no significant difference was observed among Group A, B and D (t=1.528, 1.588; P=0.205, 0.222). In addition, the MVD was shown to be the highest in Group C (t=6.253, P=0.000), whereas the HPSE-1 level in Group A was lower than in Group B (t=14.066, P=0.000) and higher than in Group C (t=-21.919, P=0.000), and similar with Group 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 (+).


CONCLUSIONS
Ionizing radiation with lower- doses might improve tumor hypoxia through inhibiting the expression of HIF-1 and HPSE-1, whereas higher- doses worsen tumor hypoxic conditions by up-regulating HIF-1α, HPSE-1, VEGF and CD31 levels. A protocol of low-dose ionizing radiation followed by a high-dose irradiation might at least partly improve tumor hypoxia and enhance radiosensitivity.
Oncology Department, the Affiliated Hospital of Qingdao University, Qingdao, China E-mail : zuogehaoyisheng@163.com.
Yong-Chun
YC
Zhang
Gang
G
Jiang
Han
H
Gao
Hua-Min
HM
Liu
Jun
J
Liang
D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D005260:Female; D005966:Glucuronidase / Q000235:genetics; D064593:Heterografts; D000860:Hypoxia / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D011829:Radiation Dosage; D011839:Radiation, Ionizing; D015854:Up-Regulation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D000099175:Heparanase
D005966:Glucuronidase; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase; C497443:Hif1a protein, mouse; C467480:vascular endothelial growth factor A, mouse