title: Prognostic Significance of Hypoxia-Inducible Factor Expression in Renal Cell Carcinoma: A PRISMA-compliant Systematic Review and Meta-Analysis.
abstract: The prognostic value of hypoxia-inducible factor (HIF) in renal cell carcinoma (RCC) has been evaluated in a large number of studies, but the reports were inconsistent and remained inconclusive. Therefore, we conducted a systematic review and meta-analysis to clarify the significance of HIF expression in RCC prognosis. PubMed, Embase, Web of Science, Cochrane Library, EBSCO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Biological Abstracts were searched for eligible studies. Hazard ratio (HR) data for overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) with 95% confidence interval (CI) related to the expression status of HIF-1α or HIF-2α detected by immunohistochemistry were all extracted. Data were combined using a random- or fixed-effects model based on the corresponding inter-study heterogeneity. Subgroup analyses were also performed. A total of 14 studies composed of 1258 patients for HIF-1α evaluation and 619 patients for HIF-2α evaluation were included for further analysis. When initially analyzed as a whole, the HIF-1α expression was not significantly correlated with OS (HR 1.637, 95% CI 0.898-2.985, P = 0.108), CSS (HR 1.110, 95% CI 0.595-2.069, P = 0.744), and PFS (HR 1.113, 95% CI 0.675-1.836, P = 0.674). Similarly, HIF-2α expression was not significantly correlated with CSS (HR 1.597, 95% CI 0.667-3.824, P = 0.293) and PFS (HR 0.847, 95% CI 0.566-1.266, P = 0.417). However, subgroup analyses concerning subcellular localization of HIFs revealed that the high nuclear expression of HIF-1α was significantly associated with poor OS (HR 2.014, 95% CI 1.206-3.363, P = 0.007) and the high cytoplasmic expression of HIF -2α was significantly associated with poor CSS (HR 2.356, 95% CI 1.629-3.407, P = 0.000). The increased nuclear expression of HIF-1α and cytoplasmic expression of HIF-2α indicate unfavorable prognosis in RCC patients, which may serve as biomarkers for disease management.
authors.affiliation: From the State Key Laboratory of Kidney Diseases, Department of Urology, Military Postgraduate Medical College, Chinese People's Liberation Army General Hospital, Beijing, People's Republic of China (YF, HL, XM, LC, XL, QD, YZ, XZ); and Medical School, Nankai University, Tianjin, People's Republic of China (XB).
authors.forename: Yang
authors.initials: Y
authors.lastname: Fan
authors.forename: Hongzhao
authors.initials: H
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Ma
authors.forename: Yu
authors.initials: Y
authors.lastname: Gao
authors.forename: Luyao
authors.initials: L
authors.lastname: Chen
authors.forename: Xintao
authors.initials: X
authors.lastname: Li
authors.forename: Xu
authors.initials: X
authors.lastname: Bao
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Du
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D020033:Protein Isoforms / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020033:Protein Isoforms; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human