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. 2006 Sep;97(9):861-7.
doi: 10.1111/j.1349-7006.2006.00262.x. Epub 2006 Jun 29.

Plausible linkage of hypoxia inducible factor-1alpha in uterine cervical cancer

Jiro Fujimoto  1 , Syed Mahfuzul Alam, Israt Jahan, Eriko Sato, Hiroshi Toyoki, Bao Li Hong, Hideki Sakaguchi, Teruhiko Tamaya
Affiliations

Plausible linkage of hypoxia inducible factor-1alpha in uterine cervical cancer

Jiro Fujimoto et al. Cancer Sci. 2006 Sep.

Abstract

Angiogenesis is essential for the development, growth and advancement of solid tumors. Angiogenesis is induced by hypoxia with angiogenic transcription factor hypoxia inducible factors (HIF). This prompted us to study the clinical implications of HIF relative to angiogenesis in uterine cervical cancers. Although there was no significant difference in HIF-1alpha histoscores and mRNA levels according to histopathological type or lymph node metastasis, HIF-1alpha histoscores and mRNA levels increased significantly with advancing cancer stages. The prognosis of 30 patients with high HIF-1alpha in uterine cervical cancers was poor (73% survival), whereas the 24-month survival rate of the other 30 patients with low HIF-1alpha was 93%. HIF-1alpha histoscores and mRNA levels were correlated with the levels of the angiogenic factors thymidine phosphorylase and interleukin-8, and HIF-1alpha might be linked with these factors in cervical cancer tissue. HIF-1alpha is a candidate for prognostic indicator as an angiogenic mediator in uterine cervical cancer.

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Figures

Figure 1
Figure 1
Hypoxia inducible factor (HIF)‐1α mRNA levels in uterine cervical cancers classified according to (a) clinical stage, (b) histopathological type and (c) lymph node metastasis. Clinical stages of uterine cervical cancer are in accordance with the International Federation of Obstetrics and Gynecology classification. Each level is the mean of nine determinations. The bar indicates SD. Alive and deceased cases are shown as ○ and •, respectively. AD, adenocarcinoma; SCC, squamous cell carcinoma.
Figure 2
Figure 2
Hypoxia inducible factor (HIF)‐2α mRNA levels in uterine cervical cancers classified according to (a) clinical stage, (b) histopathological type and (c) lymph node metastasis. Clinical stages of uterine cervical cancer are in accordance with the International Federation of Obstetrics and Gynecology classification. Each level is the mean of nine determinations. The bar indicates SD. Alive and deceased cases are shown as ○ and •, respectively. AD, adenocarcinoma; SCC, squamous cell carcinoma.
Figure 3
Figure 3
Hypoxia inducible factor (HIF)‐1β mRNA levels in uterine cervical cancers classified according to (a) clinical stage, (b) histopathological type and (c) lymph node metastasis. Clinical stages of uterine cervical cancer are in accordance with the International Federation of Obstetrics and Gynecology classification. Each level is the mean of nine determinations. The bar indicates SD. Alive and deceased cases are shown as ○ and •, respectively. AD, adenocarcinoma; SCC, squamous cell carcinoma.
Figure 4
Figure 4
Immunohistochemical staining for hypoxia inducible factor (HIF)‐1α in uterine cervical cancer. (a) A case of squamous cell carcinoma of the uterine cervix and (b) negative control. Rabbit antihuman HIF‐1α was used at a dilution of 1 : 20 as the primary antibody (original magnification ×200). Scale bars = 50 µm.
Figure 5
Figure 5
Hypoxia inducible factor (HIF)‐1α histoscores in uterine cervical cancers classified according to (a) clinical stage, (b) histopathological type and (c) lymph node metastasis. Clinical stages of uterine cervical cancer are in accordance with the International Federation of Obstetrics and Gynecology classification. Each level is the mean of nine determinations. The bar indicates SD. Alive and deceased cases are shown as ○ and •, respectively. AD, adenocarcinoma; SCC, squamous cell carcinoma.
Figure 6
Figure 6
Survival rate after curative resection for uterine cervical cancers. Patient prognosis was analyzed with a 24‐month survival rate. High hypoxia inducible factor (HIF)‐1α: histoscore >270 and >3.6 × 108 copies/µg total RNA. Low HIF‐1α: histoscore <270 and <3.6 × 108 copies/µg total RNA.
Figure 7
Figure 7
Correlation between hypoxia inducible factor (HIF)‐1α histoscore and levels of (a) vascular endothelial growth factor (VEGF), (c) thymidine phosphorylase (TP) and (e) interleukin (IL)‐8, and between mRNA level and levels of (b) VEGF, (d) TP and (f) IL‐8 in uterine cervical cancers.
Figure 8
Figure 8
Correlation between microvessel count (MVC) and (a) interleukin (IL)‐8 levels, (b) thymidine phosphorylase (TP) levels and (c) hypoxia inducible factor (HIF)‐1α histoscores in uterine cervical cancers. MVC, indicative of the level of angiogenesis, were evaluated by immunohistochemistry for factor VIII‐related antigen (•) and for CD34 (○) in the same specimens as for immunohistochemistry of HIF‐1α.
Figure 9
Figure 9
Correlation between rate of apoptosis and hypoxia inducible factor (HIF)‐1α histoscores in uterine cervical cancers.
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