Prognostic Value of HIFs Expression in Head and Neck Cancer: A Systematic Review

Abstract

BackgroundTumor hypoxia plays a fundamental role in resistance to therapy and disease progression. A number of studies have assessed the prognostic role of HIFs expression in head and neck cancer (HNC), but no consistent outcomes are reported.MethodologyA systematical search was performed to search relevant literatures in PubMed, Web of Science and ISI Web of Knowledge databases. The patients’ clinical characteristics and survival outcome were extracted. The correlation between HIFs expression and prognosis was analyzed.Principal FindingsA total of 28 studies assessed the association between HIFs and HNC survival, the result showed that overexpressed HIFs was significantly associated with increase of mortality risk (HR = 2.12; 95% CI: 1.52–2.94; I2 74%). Subgroup analysis on different HIF isoforms with OS indicated that both HIF-1α and HIF-2α were associated with worse prognosis. The pooled HRs were 1.72(95% CI 1.34–2.20; I2 70.7%) and 1.79(95% CI: 1.42–2.27, I2 0%). Further subgroup analysis was performed by different geographical locations, disease subtype, stage, types of variate analysis and cut-off value. The results revealed that overexpressed HIF-1α was significantly associated with poor prognosis in Asian patients (HR = 2.34; 95% CI: 1.76–3.1; I2 48.9%), but not in European patients (HR = 1.13; 95% CI: 0.77–1.66; I2 78.3%). Furthermore, HIF-1α overexpression was significantly associated with worse OS in oral carcinoma(HR = 2.1; 95% CI: 1.11–3.97; I2 81.7%), nasopharyngeal carcinoma(HR = 2.07; 95% CI:1.23–3.49; I2 22.5%) and oropharynx carcinoma(HR = 1.76; 95% CI:1.05–2.97; I2 61%), but not in laryngeal carcinoma(HR = 1.38; 95% CI: 0.87–2.19; I2 62.5%). We also found that the prognostic value of HIF-1α overexpression existed only when using staining and percentage as positive definition (HR = 1.82; 95% CI 1.42–2.33; I2 9.9%).ConclusionsThis study showed that overexpressed HIFs were significantly associated with increase of mortality risk. Subgroup analysis revealed that overexpressed HIF-1α was significantly associated with worse prognosis of HNC in Asian countries. Additionally, HIF-1α had different prognostic value in different HNC disease subtypes.

Progress on hypoxia-inducible factor-3: Its structure, gene regulation and biological function (Review)

“…HIF-3α has been investigated to a lesser degree compared with HIF-1 and HIF-2. HIF-1α and HIF-2α are often overexpressed in cancer tissue, leading to progression of aggressive tumors, tumor resistance to chemotherapy and radiation, and poor prognosis of the disease (14)(15)(16)(17). The role of HIF-3α in tumors types remains to be elucidated, however, previous studies have indicated that HIF-3α may suppress the expression of genes, which are typically inducible by HIF-1α and HIF-2α in tumor cells (13,18).…”

Clinical significance of hypoxia in nasopharyngeal carcinoma with a focus on existing and novel hypoxia molecular imaging

“…Furthermore, its prognostic significance was lost after adjusting for confounding factors in multivariate analyses. Nonetheless, the prognostic values of HIF-1α and HIF-2α in head and neck cancers were supported in a recent systematic review (48). A subset analysis included five studies (n=445) which looked solely at HIF-1α expression in NPC.…”

Hypoxia in oral squamous cell carcinoma: A breath of fresh air in cancer research?

“…[3] Thus, persistent hypoxia leads to selection of genotypes promoting tumor angiogenesis, epithelialto-mesenchymal transition (EMT), invasiveness and metastasis, as well as suppressing immune reactivity. [7] Assessing Tumor Hypoxia Most widely used method for direct measurement of PO 2 in human cancers is direct polarographic (needle-electrode) measurements. Its main drawback is that it cannot distinguish necrosis with low O 2 from severe hypoxia in viable tumor areas.…”

“…Currently, the most widely used tracer for hypoxia imaging by means of PET is (18F)-labeled fluoromisonidazole [3,5] Evaluation of hypoxia is now shifting to monitoring of endogenous markers. [7] These include markers such as HIF-1, carbonic anhydrase IX (CA-IX), erythropoietin, glucose transporter type-1 (GLUT-1), and VEGF. [3] In this review, we will be concentrating on HIF, the master transcriptional regulator of genes regulating oxygen homeostasis.…”

“…In addition, HIF-1α overexpression was significantly associated with worse overall survival in oral carcinoma, nasopharyngeal carcinoma and oropharynx carcinoma, but not in laryngeal carcinoma. [7] Contradicting the above findings were Beasley et al who observed increased HIF-1α and improved prognosis in a group of 79 surgically treated patients with HNSCC. [11] Fillies et al too showed an improved 5 years survival and improved diseasefree period in 85 cases of squamous cell carcinoma of floor of the mouth.…”