Prognostic Value of Hypoxia-Inducible Factor 1α in Solid Malignancies: A Meta-Analysis

Prognostic Value of Hypoxia-Inducible Factor 1α in Solid Malignancies: A Meta-Analysis

Loading document ...
Loading page ...


Author(s): Yuewen QI, Shuai Zhang, Zhe Sun, Xiaolu Fang, Hong Yu

Download Full PDF Read Complete Article

DOI: 10.18483/ijSci.1616 86 351 111-120 Volume 7 - Mar 2018


Numerous studies have reported the prognostic role of Hypoxia-Inducible Factor 1α(HIF-1α)and solid malignancies, but the data of different reports remains controversial. To accurately evaluate the prognostic value of HIF-1α expression in solid malignancies, a meta-analysis based on published studies was conducted. Relevant studies from 34 observational articles with 3828 patients were collected via PubMed, Embase. These studies were chosen for the meta-analysis based on requisite criteria and the quality was evaluated using the Newcastle Ottawa Quality Assessment Scale. Hazard ratios (HRs) and 95% confidence interval (CIs) were pooled from studies on overall survival (OS) and disease-free survival (DFS) to estimate the association. The pooled HRs (95% CIs) of HIF-1α for OS and DFS were 1.94 [1.74, 2.16] and 2.16 [1.71, 2.74], respectively. The overall data of the shown meta-analysis suggested that the high expression of HIF-1α is correlated with poor survival outcome in solid malignancies.


Hypoxia-Inducible Factor 1α, Prognostic, Solid Malignancies, Meta-Analysis


  1. Wang GL, Jiang BH, Rue EA and Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proceedings of the National Academy of Sciences of the United States of America. 1995; 92(12):5510-5514.
  2. Wang GL and Semenza GL. Purification and characterization of hypoxia-inducible factor 1. The Journal of biological chemistry. 1995; 270(3):1230-1237.
  3. Birner P, Schindl M, Obermair A, Plank C, Breitenecker G and Oberhuber G. Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer research. 2000; 60(17):4693-4696.
  4. Unruh A, Ressel A, Mohamed HG, Johnson RS, Nadrowitz R, Richter E, Katschinski DM and Wenger RH. The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene. 2003; 22(21):3213-3220.
  5. Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends in pharmacological sciences. 2012; 33(4):207-214.
  6. Kaelin WG, Jr. and Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Molecular cell. 2008; 30(4):393-402.
  7. Parmar MK, Torri V and Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Statistics in medicine. 1998; 17(24):2815-2834.
  8. Tierney JF, Stewart LA, Ghersi D, Burdett S and Sydes MR. Response to: Practical methods for incorporating summary time-to-event data into meta. Authors' reply. Trials. 2013; 14:391.
  9. Malfettone A, Saponaro C, Paradiso A, Simone G and Mangia A. Peritumoral vascular invasion and NHERF1 expression define an immunophenotype of grade 2 invasive breast cancer associated with poor prognosis. BMC cancer. 2012; 12:106.
  10. Isobe T, Aoyagi K, Koufuji K, Shirouzu K, Kawahara A, Taira T and Kage M. Clinicopathological significance of hypoxia-inducible factor-1 alpha (HIF-1alpha) expression in gastric cancer. International journal of clinical oncology. 2013; 18(2):293-304.
  11. Zhan H, Liang H, Liu X, Deng J, Wang B and Hao X. Expression of Rac1, HIF-1alpha, and VEGF in gastric carcinoma: correlation with angiogenesis and prognosis. Onkologie. 2013; 36(3):102-107.
  12. Lu XX, Chen YT, Feng B, Mao XB, Yu B and Chu XY. Expression and clinical significance of CD73 and hypoxia-inducible factor-1alpha in gastric carcinoma. World journal of gastroenterology. 2013; 19(12):1912-1918.
  13. Kolev Y, Uetake H, Takagi Y and Sugihara K. Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1alpha) pathway, angiogenic factors production and poor prognosis. Annals of surgical oncology. 2008; 15(8):2336-2344.
  14. Qiu MZ, Han B, Luo HY, Zhou ZW, Wang ZQ, Wang FH, Li YH and Xu RH. Expressions of hypoxia-inducible factor-1alpha and hexokinase-II in gastric adenocarcinoma: the impact on prognosis and correlation to clinicopathologic features. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2011; 32(1):159-166.
  15. Kim BW, Cho H, Chung JY, Conway C, Ylaya K, Kim JH and Hewitt SM. Prognostic assessment of hypoxia and metabolic markers in cervical cancer using automated digital image analysis of immunohistochemistry. Journal of translational medicine. 2013; 11:185.
  16. Yu L, Wu SW, Zhou L and Song WQ. [Correlation between bacterial L-form infection, expression of HIF-1alpha/MMP-9 and vasculogenic mimicry in epithelial ovarian cancer]. Sheng li xue bao : [Acta physiologica Sinica]. 2012; 64(6):657-665.
  17. Shimogai R, Kigawa J, Itamochi H, Iba T, Kanamori Y, Oishi T, Shimada M, Sato S, Kawaguchi W, Sato S and Terakawa N. Expression of hypoxia-inducible factor 1alpha gene affects the outcome in patients with ovarian cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2008; 18(3):499-505.
  18. Huang M, Chen Q, Xiao J, Yao T, Bian L, Liu C and Lin Z. Overexpression of hypoxia-inducible factor-1alpha is a predictor of poor prognosis in cervical cancer: a clinicopathologic study and a meta-analysis. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2014; 24(6):1054-1064.
  19. Ogane N, Yasuda M, Shimizu M, Miyazawa M, Kamoshida S, Ueda A, Takata K, Sakuma Y, Miyagi Y and Kameda Y. Clinicopathological implications of expressions of hypoxia-related molecules in esophageal superficial squamous cell carcinoma. Annals of diagnostic pathology. 2010; 14(1):23-29.
  20. Chen Y, Lu Y, Lu C and Zhang L. Beclin-1 expression is a predictor of clinical outcome in patients with esophageal squamous cell carcinoma and correlated to hypoxia-inducible factor (HIF)-1alpha expression. Pathology oncology research : POR. 2009; 15(3):487-493.
  21. Tzao C, Lee SC, Tung HJ, Hsu HS, Hsu WH, Sun GH, Yu CP, Jin JS and Cheng YL. Expression of hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF)-D as outcome predictors in resected esophageal squamous cell carcinoma. Disease markers. 2008; 25(3):141-148.
  22. Lee GW, Go SI, Cho YJ, Jeong YY, Kim HC, Duk Lee J, Hwang YS, Ko GH, Lee JH, Kim DC, Yang JW, Oh S and Lee JS. Hypoxia-inducible factor-1alpha and excision repair cross-complementing 1 in patients with small cell lung cancer who received front-line platinum-based chemotherapy: a retrospective study. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2012; 7(3):528-534.
  23. Hung JJ, Yang MH, Hsu HS, Hsu WH, Liu JS and Wu KJ. Prognostic significance of hypoxia-inducible factor-1alpha, TWIST1 and Snail expression in resectable non-small cell lung cancer. Thorax. 2009; 64(12):1082-1089.
  24. Kaira K, Nakagawa K, Ohde Y, Okumura T, Takahashi T, Murakami H, Endo M, Kondo H, Nakajima T and Yamamoto N. Depolarized MUC1 expression is closely associated with hypoxic markers and poor outcome in resected non-small cell lung cancer. International journal of surgical pathology. 2012; 20(3):223-232.
  25. Park S, Ha SY, Cho HY, Chung DH, Kim NR, Hong J and Cho EK. Prognostic implications of hypoxia-inducible factor-1alpha in epidermal growth factor receptor-negative non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands). 2011; 72(1):100-107.
  26. Zhu GH, Huang C, Feng ZZ, Lv XH and Qiu ZJ. Hypoxia-induced snail expression through transcriptional regulation by HIF-1alpha in pancreatic cancer cells. Digestive diseases and sciences. 2013; 58(12):3503-3515.
  27. Matsuo Y, Ding Q, Desaki R, Maemura K, Mataki Y, Shinchi H, Natsugoe S and Takao S. Hypoxia inducible factor-1 alpha plays a pivotal role in hepatic metastasis of pancreatic cancer: an immunohistochemical study. Journal of hepato-biliary-pancreatic sciences. 2014; 21(2):105-112.
  28. Zhang JJ, Wu HS, Wang L, Tian Y, Zhang JH and Wu HL. Expression and significance of TLR4 and HIF-1alpha in pancreatic ductal adenocarcinoma. World journal of gastroenterology. 2010; 16(23):2881-2888.
  29. Liu L, Zhu XD, Wang WQ, Shen Y, Qin Y, Ren ZG, Sun HC and Tang ZY. Activation of beta-catenin by hypoxia in hepatocellular carcinoma contributes to enhanced metastatic potential and poor prognosis. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010; 16(10):2740-2750.
  30. Xia L, Mo P, Huang W, Zhang L, Wang Y, Zhu H, Tian D, Liu J, Chen Z, Zhang Y, Chen Z, Hu H, Fan D, Nie Y and Wu K. The TNF-alpha/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis. Carcinogenesis. 2012; 33(11):2250-2259.
  31. Xiang ZL, Zeng ZC, Fan J, Tang ZY, He J, Zeng HY and Chang JY. The expression of HIF-1alpha in primary hepatocellular carcinoma and its correlation with radiotherapy response and clinical outcome. Molecular biology reports. 2012; 39(2):2021-2029.
  32. Dai CX, Gao Q, Qiu SJ, Ju MJ, Cai MY, Xu YF, Zhou J, Zhang BH and Fan J. Hypoxia-inducible factor-1 alpha, in association with inflammation, angiogenesis and MYC, is a critical prognostic factor in patients with HCC after surgery. BMC cancer. 2009; 9:418.
  33. Zhao H, Wu Y, Chen Y and Liu H. Clinical significance of hypoxia-inducible factor 1 and VEGF-A in osteosarcoma. International journal of clinical oncology. 2015; 20(6):1233-1243.
  34. Hu T, He N, Yang Y, Yin C, Sang N and Yang Q. DEC2 expression is positively correlated with HIF-1 activation and the invasiveness of human osteosarcomas. Journal of experimental & clinical cancer research : CR. 2015; 34:22.
  35. Kim JI, Choi KU, Lee IS, Choi YJ, Kim WT, Shin DH, Kim K, Lee JH, Kim JY and Sol MY. Expression of hypoxic markers and their prognostic significance in soft tissue sarcoma. Oncology letters. 2015; 9(4):1699-1706.
  36. Cao D, Hou M, Guan YS, Jiang M, Yang Y and Gou HF. Expression of HIF-1alpha and VEGF in colorectal cancer: association with clinical outcomes and prognostic implications. BMC cancer. 2009; 9:432.
  37. Yoshimura H, Dhar DK, Kohno H, Kubota H, Fujii T, Ueda S, Kinugasa S, Tachibana M and Nagasue N. Prognostic impact of hypoxia-inducible factors 1alpha and 2alpha in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression. Clinical cancer research : an official journal of the American Association for Cancer Research. 2004; 10(24):8554-8560.
  38. Xie YQ, Fu D, He ZH and Tan QD. Prognostic value of Annexin A3 in human colorectal cancer and its correlation with hypoxia-inducible factor-1alpha. Oncology letters. 2013; 6(6):1631-1635.
  39. Hong A, Zhang M, Veillard AS, Jahanbani J, Lee CS, Jones D, Harnett G, Clark J, Elliott M, Milross C and Rose B. The prognostic significance of hypoxia inducing factor 1-alpha in oropharyngeal cancer in relation to human papillomavirus status. Oral oncology. 2013; 49(4):354-359.
  40. Eckert AW, Lautner MH, Schutze A, Taubert H, Schubert J and Bilkenroth U. Coexpression of hypoxia-inducible factor-1alpha and glucose transporter-1 is associated with poor prognosis in oral squamous cell carcinoma patients. Histopathology. 2011; 58(7):1136-1147.
  41. Sun W, Shen ZY, Zhang H, Fan YZ, Zhang WZ, Zhang JT, Lu XS and Ye C. Overexpression of HIF-1alpha in primary gallbladder carcinoma and its relation to vasculogenic mimicry and unfavourable prognosis. Oncology reports. 2012; 27(6):1990-2002.
  42. Zheng Y, Ni Y, Huang X, Wang Z and Han W. Overexpression of HIF-1alpha indicates a poor prognosis in tongue carcinoma and may be associated with tumour metastasis. Oncology letters. 2013; 5(4):1285-1289.
  43. Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nature reviews Cancer. 2002; 2(1):38-47.
  44. Semenza GL. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends in molecular medicine. 2002; 8(4 Suppl):S62-67.
  45. Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, Rey S, Hammers H, Chang D, Pili R, Dang CV, Liu JO and Semenza GL. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proceedings of the National Academy of Sciences of the United States of America. 2008; 105(50):19579-19586.
  46. Zhang M, Li W, Yu L and Wu S. The suppressive effect of resveratrol on HIF-1alpha and VEGF expression after warm ischemia and reperfusion in rat liver. PloS one. 2014; 9(10):e109589.
  47. Chen T, Ren Z, Ye LC, Zhou PH, Xu JM, Shi Q, Yao LQ and Zhong YS. Factor inhibiting HIF1alpha (FIH-1) functions as a tumor suppressor in human colorectal cancer by repressing HIF1alpha pathway. Cancer biology & therapy. 2015; 16(2):244-252.
  48. Zhu CL, Huang Q, Liu CH, Lin XS and Xie F. Prognostic value of HIF-1alpha expression in patients with gastric cancer. Molecular biology reports. 2013; 40(11):6055-6062.
  49. Cao S, Yang S, Wu C, Wang Y, Jiang J and Lu Z. Protein expression of hypoxia-inducible factor-1 alpha and hepatocellular carcinoma: a systematic review with meta-analysis. Clinics and research in hepatology and gastroenterology. 2014; 38(5):598-603.
  50. Ren W, Mi D, Yang K, Cao N, Tian J, Li Z and Ma B. The expression of hypoxia-inducible factor-1alpha and its clinical significance in lung cancer: a systematic review and meta-analysis. Swiss medical weekly. 2013; 143:w13855.

Cite this Article:

International Journal of Sciences is Open Access Journal.
This article is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) License.
Author(s) retain the copyrights of this article, though, publication rights are with Alkhaer Publications.

Search Articles

Issue June 2023

Volume 12, June 2023

Table of Contents

World-wide Delivery is FREE

Share this Issue with Friends:

Submit your Paper