Prognostic value of HIF-1α in digestive system malignancies: Evidence from a systematic review and meta-analysis
Gastroenterology and Hepatology from Bed to Bench,
Background/aims: Numerous studies have demonstrated that hypoxia-inducible factor-1α (HIF-1α) is abnormally expressed in various solid tumors. However, the clinicopathological features and prognostic value of HIF-1α expression in patients with digestive system malignancies remain controversial. Accordingly, this meta-analysis was aimed to evaluate the association of HIF-1α expression with clinicopathological features and overall survival (OS) of patients with digestive system malignancies.
Methods: A literature search in PubMed, Web of Science, and Scopus databases was performed to identify all relevant studies published in English until 15 October 2020. Pooled effect was calculated to evaluate the association between HIF-1α expression and clinicopathological features and overall survival in cancer patients. Pooled odds ratios (ORs) or hazard ratios (HRs) with 95% confidence interval (CI) were calculated using either fixed- or random-effects model.
Results: A total of 44 eligible studies with 5,964 patients were included. Pooled results indicated positive correlation of HIF-1α overexpression with poor overall survival (OS) (HR=1.990, 95% CI: 1.615-2.453, P<0.001) and disease free survival (DFS) (HR=1.90, 95% CI: 1.084-3.329, P=0.043). Meta-results showed that HIF-1α level expression was significantly associated with positive lymph node metastasis (OR=1.869, 95% CI: 1.488-2.248, P<0.001), distance metastasis (OR=2.604, 95% CI: 1.500-4.519, P<0.001), tumor stage (OR=1.801, 95% CI: 1.437-2.257, P<0.001) and tumor size (OR=1.392. 95% CI: 1.068-1.815, P=0.014).
Conclusions: This meta-data suggest that HIF-1α expression might serve as an independent prognostic marker and a promising therapeutic target in patients with digestive system malignancies.
- Digestive system
How to Cite
Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin D, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 2019;144:1941-53.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
Haringsma J, van Heel NCM, Kuipers EJ. Are we making progress in diagnosing and preventing gastrointestinal cancers? Therap Adv Gastroenterol 2010;3:213-20.
Arnold M, Abnet CC, Neale RE, Vignat J, Giovannucci EL, McGlynn KA, et al. Global Burden of 5 Major Types of Gastrointestinal Cancer. Gastroenterology 2020;159:335-49.
Mohammadi M, Mianabadi F, Mehrad‐Majd H. Circulating visfatin levels and cancers risk: A systematic review and meta‐analysis. J Cell Physiol 2019;234:5011-22.
Arjmand M-H, Moradi A, Akbari A, Mehrad-Majd H. Clinical significance of circulating omentin levels in various malignant tumors: Evidence from a systematic review and meta-analysis. Cytokine 2020;125:154869.
Banin Hirata BK, Oda JMM, Losi Guembarovski R, Ariza CB, Oliveira CECd, Watanabe MAE. Molecular Markers for Breast Cancer: Prediction on Tumor Behavior. Dis Markers 2014;2014:513158.
Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2002;2:38-47.
Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3:721-32.
Dai C-X, Gao Q, Qiu S-J, Ju M-J, Cai M-Y, Xu Y-F, et al. 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.
Wigerup C, Pahlman S, Bexell D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther 2016;164:152-69.
Ping W, Sun W, Zu Y, Chen W, Fu X. Clinicopathological and prognostic significance of hypoxia-inducible factor-1α in esophageal squamous cell carcinoma: a meta-analysis. Tumor Biol 2014;35:4401-9.
Ogawa K, Chiba I, Morioka T, Shimoji H, Tamaki W, Takamatsu R, et al. Clinical significance of HIF-1α expression in patients with esophageal cancer treated with concurrent chemoradiotherapy. Anticancer Res 2011;31:2351-9.
Ogane N, Yasuda M, Shimizu M, Miyazawa M, Kamoshida S, Ueda A, et al. Clinicopathological implications of expressions of hypoxia-related molecules in esophageal superficial squamous cell carcinoma. Ann Diagn Pathol 2010;14:23-9.
Kuwai T, Kitadai Y, Tanaka S, Onogawa S, Matsutani N, Kaio E, et al. Expression of hypoxia‐inducible factor‐1α is associated with tumor vascularization in human colorectal carcinoma. Int J Cancer 2003;105:176-81.
Kwon HC, Kim SH, Oh SY, Lee S, Kwon KA, Lee JH, et al. Clinicopathological significance of nuclear factor‐kappa B, HIF‐1 alpha, and vascular endothelial growth factor expression in stage III colorectal cancer. Cancer Sci 2010;101:1557-61.
Ma J, Zhang L, Ru G-Q, Zhao Z-S, Xu W-J. Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma. World J Gastroenterol 2007;13:1680.
Hu X, Lin S, Zheng J, Guo R, Li H, You C. Clinicopathological significance of hypoxia-inducible factor-1 alpha polymorphisms in cancers: evidence from a meta-analysis. Tumor Biol 2013;34:2477-87.
Zhang J, Wu Y, Lin Y-H, Guo S, Ning P-F, Zheng Z-C, et al. Prognostic value of hypoxia-inducible factor-1 alpha and prolyl 4-hydroxylase beta polypeptide overexpression in gastric cancer. World J Gastroenterol 2018;24:2381.
Sun H-C, Qiu Z-J, Liu J, Sun J, Jiang T, Huang K-J, et al. Expression of hypoxia-inducible factor-1 alpha and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis. Int J Cancer 2007;30:1359-67.
Xiang Z-L, Zeng Z-C, Fan J, Tang Z-Y, He J, Zeng H-Y, et al. The expression of HIF-1α in primary hepatocellular carcinoma and its correlation with radiotherapy response and clinical outcome. Mol Biol Rep 2012;39:2021-9.
Yang SL, Liu LP, Jiang JX, Xiong ZF, He QJ, Wu C. The correlation of expression levels of HIF-1α and HIF-2α in hepatocellular carcinoma with capsular invasion, portal vein tumor thrombi and patients' clinical outcome. Jpn J Clin Oncol 2014;44:159-67.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603-5.
Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998;17:2815-34.
Williamson PR, Smith CT, Hutton JL, Marson AG. Aggregate data meta‐analysis with time‐to‐event outcomes. Stat Med 2002;21:3337-51.
Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007;8:16.
Galbraith RF. A note on graphical presentation of estimated odds ratios from several clinical trials. Stat Med 1988;7:889-94.
Chen L, Shi Y, Yuan J, Han Y, Qin R, Wu Q, et al. HIF-1 alpha overexpression correlates with poor overall survival and disease-free survival in gastric cancer patients post-gastrectomy. PLoS One 2014;9:e90678.
Lu X-X, Chen Y-T, Feng B, Mao X-B, Yu B, Chu X-Y. Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma. World J Gastroenterol 2013;19:1912.
Isobe T, Aoyagi K, Koufuji K, Shirouzu K, Kawahara A, Taira T, et al. Clinicopathological significance of hypoxia-inducible factor-1 alpha (HIF-1α) expression in gastric cancer. J Cancer Res Clin Oncol 2013;18:293-304.
Qiu M-z, Han B, Luo H-y, Zhou Z-w, Wang Z-q, Wang F-h, et al. Expressions of hypoxia-inducible factor-1α and hexokinase-II in gastric adenocarcinoma: the impact on prognosis and correlation to clinicopathologic features. Tumor Biol 2011;32:159-66.
Oh SY, Kwon H-C, Kim S-H, Jang JS, Kim MC, Kim KH, et al. Clinicopathologic significance of HIF-1α, p53, and VEGF expression and preoperative serum VEGF level in gastric cancer. BMC Cancer 2008;8:123.
KolevY U, TakagiY S. Lactate Dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-Inducible factor (HIF-1a) pathway, angiogenic factors production and poor prognosis. Ann Surg Oncol 2008;15:2336-44.
Griffiths EA, Pritchard S, Valentine HR, Whitchelo N, Bishop P, Ebert M, et al. Hypoxia-inducible factor-1 α expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas. Br J Cancer 2007;96:95-103.
Sumiyoshi Y, Kakeji Y, Egashira A, Mizokami K, Orita H, Maehara Y. Overexpression of hypoxia-inducible factor 1α and p53 is a marker for an unfavorable prognosis in gastric cancer. Clin Cancer Res 2006;12:5112-7.
Urano N, Fujiwara Y, Doki Y, Tsujie M, Yamamoto H, Miyata H, et al. Overexpression of hypoxia-inducible factor-1 alpha in gastric adenocarcinoma. Gastric Cancer 2006;9:44-9.
Mizokami K, Kakeji Y, Oda S, Irie K, Yonemura T, Konishi F, et al. Clinicopathologic significance of hypoxia‐inducible factor 1α overexpression in gastric carcinomas. J Surg Oncol 2006;94:149-54.
Jiang X, Zhang S, Yin Z, Sheng Y, Yan Q, Sun R, et al. The correlation between NEDD4L and HIF-1α levels as a gastric cancer prognostic marker. Int J Med Sci 2019;16:1517-24.
Saka B, Ekinci O, Dursun A, Akyurek N. Clinicopathologic and prognostic significance of immunohistochemical expression of HIF-1α, CXCR4 and CA9 in colorectal carcinoma. Pathol Res Pract 2017;213:783-92.
Shimomura M, Hinoi T, Kuroda S, Adachi T, Kawaguchi Y, Sasada T, et al. Overexpression of hypoxia inducible factor-1 alpha is an independent risk factor for recurrence after curative resection of colorectal liver metastases. Ann Surg Oncol 2013;20:527-36.
Xie YQ, Fu D, He ZH, Tan QD. Prognostic value of Annexin A3 in human colorectal cancer and its correlation with hypoxia‑inducible factor‑1α. Oncol Lett 2013;6:1631-5.
Shioya M, Takahashi T, Ishikawa H, Sakurai H, Ebara T, Suzuki Y, et al. Expression of hypoxia-inducible factor 1α predicts clinical outcome after preoperative hyperthermo-chemoradiotherapy for locally advanced rectal cancer. J Radiat Res 2011;52:821-7.
Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Koike Y, et al. Clinical significance of CD133 and hypoxia inducible factor-1α gene expression in rectal cancer after preoperative chemoradiotherapy. Clin Oncol 2011;23:323-32.
Baba Y, Nosho K, Shima K, Irahara N, Chan AT, Meyerhardt JA, et al. HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. Am J Pathol 2010;176:2292-301.
Cao D, Hou M, Guan Y-s, Jiang M, Yang Y, Gou H-f. Expression of HIF-1alpha and VEGF in colorectal cancer: association with clinical outcomes and prognostic implications. BMC Cancer 2009;9:432.
Jubb A, Turley H, Moeller H, Steers G, Han C, Li J, et al. Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer. Br J Cancer 2009;101:1749-57.
Rajaganeshan R, Prasad R, Guillou P, Scott N, Poston G, Jayne D. Expression patterns of hypoxic markers at the invasive margin of colorectal cancers and liver metastases. Eur J Surg Oncol 2009;35:1286-94.
Rasheed S, Harris A, Tekkis P, Turley H, Silver A, McDonald P, et al. Hypoxia-inducible factor-1α and-2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis. Br J Cancer 2009;100:1666-73.
Lu X-g, Xing C-g, Feng Y-z, Chen J, Deng C. Clinical significance of immunohistochemical expression of hypoxia-inducible Factor–1α as a prognostic marker in rectal adenocarcinoma. Clin Colorectal Cancer 2006;5:350-3.
Theodoropoulos GE, Lazaris AC, Theodoropoulos VE, Papatheodosiou K, Gazouli M, Bramis J, et al. Hypoxia, angiogenesis and apoptosis markers in locally advanced rectal cancer. Int J Colorectal Dis 2006;21:248-57.
Yoshimura H, Dhar DK, Kohno H, Kubota H, Fujii T, Ueda S, et al. Prognostic impact of hypoxia-inducible factors 1α and 2α in colorectal cancer patients: correlation with tumor angiogenesis and cyclooxygenase-2 expression. Clin Cancer Res 2004;10:8554-60.
Kuwai T, Kitadai Y, Tanaka S, Kuroda T, Ochiumi T, Matsumura S, et al. Single nucleotide polymorphism in the hypoxia-inducible factor-1α gene in colorectal carcinoma. Oncol Rep 2004;12:1033-7.
Schmitz KJ, Müller CI, Reis H, Alakus H, Winde G, Baba HA, et al. Combined analysis of hypoxia-inducible factor 1 alpha and metallothionein indicates an aggressive subtype of colorectal carcinoma. Int J Colorectal Dis 2009;24:1287-96.
Chen Y, Lu Y, Lu C, 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)-1α expression. Pathol Oncol Res 2009;15:487.
Tzao C, Lee S-C, Tung H-J, Hsu H-S, Hsu W-H, Sun G-H, et al. Expression of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF)-D as outcome predictors in resected esophageal squamous cell carcinoma. Dis Markers 2008;25:141-8.
Zhang H, Wang Y, Xu N, Zhu S, Liu B. Expression and clinical significance of HIF-1α, VEGF and Survivin in esophageal squamous cell carcinoma. Chin-Germ J Clin Oncol 2007;6:339-44.
Katsuta M, Miyashita M, Makino H, Nomura T, Shinji S, Yamashita K, et al. Correlation of hypoxia inducible factor-1α with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer. Exp Mol Pathol 2005;78:123-30.
Kimura S, Kitadai Y, Tanaka S, Kuwai T, Hihara J, Yoshida K, et al. Expression of hypoxia-inducible factor (HIF)-1α is associated with vascular endothelial growth factor expression and tumour angiogenesis in human oesophageal squamous cell carcinoma. Eur J Cancer 2004;40:1904-12.
Kurokawa T, Miyamoto M, Kato K, Cho Y, Kawarada Y, Hida Y, et al. Overexpression of hypoxia-inducible-factor 1 α (HIF-1 α) in oesophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage. Br J Cancer 2003;89:1042-7.
Munipalle PC, Viswanath YK, Davis PA, Scoones D. Prognostic value of hypoxia inducible factor 1α in esophageal squamous cell carcinoma. Dis Esophagus 2011;24:177-81.
Wang D, Zhang X, Lu Y, Wang X, Zhu L. Hypoxia inducible factor 1α in hepatocellular carcinoma with cirrhosis: Association with prognosis. Pathol Res Pract 2018;214:1987-92.
Dai X, Pi G, Yang S-l, Chen GG, Liu L-p, Dong H-H. Association of PD-L1 and HIF-1α coexpression with poor prognosis in hepatocellular carcinoma. Transl Oncol 2018;11:559-66.
Yang S-L, Liu L-P, Jiang J-X, Xiong Z-F, He Q-J, Wu C. The correlation of expression levels of HIF-1α and HIF-2α in hepatocellular carcinoma with capsular invasion, portal vein tumor thrombi and patients' clinical outcome. Jpn J Clin Oncol 2014;44:159-67.
Bottaro DP, Liotta LA. Out of air is not out of action. Nature 2003;423:593-5.
Bao B, Azmi AS, Ali S, Ahmad A, Li Y, Banerjee S, et al. The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness. Biochim Biophys Acta 2012;1826:272-96.
Lv X, Li J, Zhang C, Hu T, Li S, He S, et al. The role of hypoxia-inducible factors in tumor angiogenesis and cell metabolism. Genes Dis 2016;4:19-24.
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