Increased expression of hypoxia-inducible factor-1 alpha and its impact on transcriptional changes and prognosis in malignant tumours of the ocular adnexa

Eye (Lond). 2018 Nov;32(11):1772-1782. doi: 10.1038/s41433-018-0172-6. Epub 2018 Jul 31.

Abstract

Purpose: To investigate the expression profile of the hypoxia-inducible transcription factor-1α (HIF-1α) and its downstream targets in malignancies of the ocular adnexa and to determine its relevance as a prognostic factor for clinical outcome.

Methods: We included 49 subjects with malignant tumours (25 squamous cell carcinomas (SCC), 15 non-Hodgkin lymphomas, 9 melanomas) and 30 patients with benign tumours of the ocular adnexa (13 papillomas, 7 reactive lymphoid hyperplasias (RLHs) and 10 nevi) as controls. We quantified HIF-1α protein expression by immunohistochemistry and assessed the association between HIF-1α and clinical outcome via Kaplan-Meier analysis. Furthermore, we assessed the expression of HIF-1α downstream factors by transcriptional sequencing using the MACE (massive analysis of cDNA ends) technology.

Results: SCCs revealed a strong HIF-1α expression in 61% of tumour cells in comparison with only 22% in papillomas (p < 0.0001). In contrast, malignant melanomas and lymphomas revealed a similar HIF-1α expression compared with nevi and RLHs. Transcriptional sequencing and Gene Ontology Cluster analysis demonstrated 37 hypoxia-associated factors, including HIF-1α, VEGF, SFRP1 and LOXL2 that are significantly increased in SCC and may contribute to tumour proliferation, angiogenesis, and metastasis. Association analysis between HIF-1α immunoreactivity and clinical outcome revealed a trend towards an unfavourable prognosis in malignant tumours with increased HIF-1α expression.

Conclusions: HIF-1α protein is increased in malignant tumours of the ocular adnexa, which is associated with an increase in multiple HIF-1α-downstream factors and a trend towards an unfavourable clinical outcome.

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Squamous Cell / metabolism
  • Eye Neoplasms / metabolism*
  • Eye Neoplasms / pathology
  • Female
  • Gene Expression Profiling
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Lymphoma, Non-Hodgkin / metabolism
  • Male
  • Melanoma / metabolism
  • Middle Aged
  • Nevus / metabolism
  • Papilloma / metabolism
  • Prognosis

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit