Published: 2019-06-28

Hypoxia-inducible factor 1 alpha expression is an indicator of invasiveness in uterine cervical tumors

Duygu Ayaz, Gülden Diniz, Dudu Solakoğlu Kahraman, Sevil Sayhan, Duygu Kahraman, Tuğba Karadeniz


Background: Hypoxia is a common feature of cancers. Hypoxia-inducible factor 1A (HIF1A) is a causative agent that changes the transcriptional response of tumors under hypoxia. Some alterations lead to an increase in HIF1A activity and this supports other critical pathways leading to angiogenesis, metabolic adaptation and tumor progression. This retrospective study was designed to evaluate the differences of tissue expressions of HIF1A in a spectrum of cervical neoplasms.

Methods: Tissue expression of HIF1A was studied in a total of 107 formalin-fixed, paraffin-embedded uterine cervical tumors specimens and its association with different clinicopathologic parameters was evaluated.

Results: In this series, there were 30 low and 29 high grade cervical intraepithelial neoplasms (CINs), 27 squamous cell carcinomas, 15 adenosquamous carcinomas and 6 adenocarcinomas. Strong and diffuse nuclear staining was evaluated as positive HIF1A expression. Positive HIF-1 alpha expression was detected in 7 (25.9%) of squamous cell carcinomas, 1 of adenocarcinomas (16.7%) and only 1 of HGSILs (3.4%). Statistically it was determined that the positivity rate of strong nuclear HIF1A expression was significantly higher in invasive carcinomas when compared with in non-invasive squamous cell carcinomas (p=0.07). Contrary, there was no statistically significant difference according to the subtypes of carcinomas due to scarce number of cases with adenocarcinoma (p=0.188).

Conclusions: Our findings were demonstrated to link of nuclear HIF1A expression and the invasive characters of uterine neoplasms. As a result, HIF-1 alpha expression may be important in foreseeing of the invasion and tumor progression.


Adenosquamous carcinoma, Adenocarcinoma, HIF 1A, SCC, Uterine cervix

Full Text:



Adams J, Difazio L, Rolandelli RH, Lujan J, Hasko GY, Csoka B, et al. HIF-1: A key mediator in hypoxia. Acta Physiol Hung 2009;96(1):19-28.

Ajduković J. HIF-1-a big chapter in the cancer tale. Exp Oncol. 2016;38(1):9-12.

Ellingsen C, Andersen LMK, Galappathi K, Rofstad EK. Hypoxia biomarkers in squamous cell carcinoma of the uterine cervix. BMC Cancer. 2015;15:805.

Solakoglu Kahraman D, Diniz G, Sayhan S, Ayaz D, Uncel M, Karadeniz T, et al. Differences in the ARID-1 alpha expressions in squamous and adenosquamous carcinomas of uterine cervix. APMIS. 123(10):847-50.

Smith HO, Tiffany MF, Qualls CR, Key CR. The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States-a 24-year population-based study. Gynecol Oncol. 2000;78(2):97-105.

Contag SA, Gostout BS, Clayton AC, Dixon MH, McGovern RM, Calhoucle ES. Comparison of gene expression in squamous cell carcinoma and adenocarcinoma of the uterine cervix. Gynecol Oncol. 2004;95(3):610-7.

Kurman RJ, Ellenson LH, Ronnet BM. Bleustein’s Pathology of the Female Genital Tract. Sixth Ed. Springer 2011 New York; 2011:286-287.

Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 1999;59(22):5830-5.

Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G. Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res. 2000;60:4693-6.

Havre PA, Yuan J, Hedrick L, Cho KR, Glazer PM. p53 inactivation by HPV16 E6 results in increased mutagenesis in human cells. Cancer Res. 1995;55:4420-4.

Tang X, Zhang Q, Nishitani J, Brown J, Shi S, Le AD. Overexpression of human papillomavirus type 16 oncoproteins enhances hypoxia-inducible factor 1 alpha protein accumulation and vascular endothelial growth factor expression in human cervical carcinoma cells. Clin Cancer Res. 2007;13:2568-76.

Nam SY, Ko YS, Jung J, Yoon J, Kim YH, Choi YJ, et al. A hypoxia-dependent upregulation of hypoxia-inducible factor-1 by nuclear factor-κB promotes gastric tumour growth and angiogenesis. Br J Cancer. 2011;104:166-174.

Batmunkh E, Shimada M, Morine Y, Imura S, Kanemura H, Arakawa Y, et al. Expression of hypoxia-inducible factor-1 alpha (HIF-1alpha) in patients with the gallbladder carcinoma. Int J Clin Oncol. 2010;15:59-64.

Coulon C, Georgiadou M, Roncal C, De Bock K, Langenberg T, Carmeliet P. From vessel sprouting to normalization: role of the prolyl hydroxylase domain protein/hypoxia-inducible factor oxygen-sensing machinery. Arterioscler Thromb Vasc Biol. 2010; 30:2331-61.

Brat DJ, Kaur B, Van Meir EG. Genetic modulation of hypoxia induced gene expression and angiogenesis: relevance to brain tumors. Front Biosci. 2003;8:D100-D116.

Bárdos JI, Ashcroft M. Negative and positive regulation of HIF-1: a complex network. Biochim Biophys Acta. 2005;1755:107-20.

Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Sci STKE. 2005;306: re12.

Dales JP, Beaufils N, Silvy M, et al: Hypoxia inducible factor 1alpha gene (HIF-1alpha) splice variants: potential prognostic biomarkers in breast cancer. J BMC Med. 2010;8:44.

Henze AT, Acker T. Feedback regulators of hypoxiainducible factors and their role in cancer biology. Cell Cycle. 2010;14:2749-63.

Rasheed S, Harris AL, Tekkis PP. Hypoxia-inducible factor- 1alpha and -2 alpha are expressed in most rectal cancers but only hypoxia-inducible factor-1alpha is associated with prognosis. Br J Cancer. 2008;100:1666-1673.

Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist. 2005;9(Suppl 5):10-7.

Brökers N, Le-Huu S, Vogel S, Hagos Y, Katschinski DM, Kleinschmidt M. Increased chemoresistance induced by inhibition of HIF-prolyl-hydroxylase domain enzymes. Cancer Sci. 2010;101:129-36.

DeClerck K, Elble RC. The role of hypoxia and acidosis in promoting metastasis and resistance to chemotherapy. Front Biosci. 2010;15:213-25.

Bruick RK, McKnight SL. A conserved family of prolyl- 4-hydroxylases that modify HIF. Science. 2001;5545:1337-40.

Hirsilä M, Koivunen P, Günzler V, Kivirikko KI and Myllyharju J. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J Biol Chem. 2003;278:30772-80.

Tuckerman JR, Zhao Y, Hewitson KS, Tian YM, Pugh CW, Ratcliffe PJ, et al. Determination and comparison of specific activity of the HIF-prolyl hydroxylases. FEBS Lett. 2004;576:145-50.

Roszak A, Kędzia W, Malkowska-Walczak B, Pawlik P, Kędzia H, Łuczak M, et al. Reduced expression of PHD2 prolyl hydroxylase gene in primary advanced uterine cervical carcinoma. Biomed Pharmacother. 2011 Jul 1;65(4):298-302.

Fujimoto J, Alam SM, Jahan I, Sato E, Toyoki H, Hong BL, et al. Plausible linkage of hypoxia inducible factor-1alpha in uterine cervical cancer. Cancer Sci. 2006;97:861-7.

Fyles A, Milosevic M, Hedley D, Pintilie M, Levin W, Manchul L, et al. Tumor hypoxia has independent predictor impact only in patients with node-negative cervix cancer. J Clin Oncol. 2002;20:680-7.

Rofstad EK, Sundfor K, Lyng H, Trope CG. Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis. Br J Cancer. 2000;83:354-9.

Dellas K, Bache M, Pigorsch SU, Taubert H, Kappler M, Holzapfel D, et al. Prognostic impact of HIF- 1alpha expression in patients with definitive radiotherapy for cervical cancer. Strahlenther Onkol. 2008;184:169-74.

Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G. Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res. 2000;60:4693-6.

Ishikawa H, Sakurai H, Hasegawa M, et al. Expression of hypoxic-inducible factor 1alpha predicts metastasis-free survival after radiation therapy alone in stage IIIB cervical squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2004;60:513-21.

Hutchison GJ, Valentine HR, Loncaster JA, Davidson SE, Hunter RD, Roberts SA, et al. Hypoxia-inducible factor 1alpha expression as an intrinsic marker of hypoxia: correlation with tumor oxygen, pimonidazole measurements, and outcome in locally advanced carcinoma of the cervix. Clin Cancer Res. 2004;10:8405-12.

Mayer A, Wree A, Hoeckel M, Leo C, Pilch H, Vaupel P. Lack of correlation between expression of HIF-1alpha protein and oxygenation status in identical tissue areas of squamous cell carcinomas of the uterine cervix. Cancer Res. 2004;64:5876-81.