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

Purpose To investigate the expression profile of the hypoxia-inducible transcription factor-1 alpha (HIF-1 alpha) 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-1 alpha protein expression by immunohistochemistry and assessed the association between HIF-1 alpha and clinical outcome via Kaplan-Meier analysis. Furthermore, we assessed the expression of HIF-1 alpha downstream factors by transcriptional sequencing using the MACE (massive analysis of cDNA ends) technology. Results SCCs revealed a strong HIF-1 alpha 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-1 alpha expression compared with nevi and RLHs. Transcriptional sequencing and Gene Ontology Cluster analysis demonstrated 37 hypoxia-associated factors, including HIF-1 alpha, VEGF, SFRP1 and LOXL2 that are significantly increased in SCC and may contribute to tumour proliferation, angiogenesis, and metastasis. Association analysis between HIF-1 alpha immunoreactivity and clinical outcome revealed a trend towards an unfavourable prognosis in malignant tumours with increased HIF-1 alpha expression. Conclusions HIF-1 alpha protein is increased in malignant tumours of the ocular adnexa, which is associated with an increase in multiple HIF-1 alpha-downstream factors and a trend towards an unfavourable clinical outcome.