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

• Published in: Eye (London) Vol. 32; no. 11; pp. 1772 - 1782
• Main Authors: Lange, Clemens Alexander Klaus, Lehnert, Patrick, Boneva, Stefaniya Konstantinova, Zhang, Peipei, Ludwig, Franziska, Boeker, Martin, Hoffmeier, Klaus, Horres, Ralf, Schlunck, Günther, Reinhard, Thomas, Böhringer, Daniel, Auw-Haedrich, Claudia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2018; Nature Publishing Group
• Subjects: 13/51; 45/91; 631/208/199; 631/61/212; 631/67/1484; Adult; Aged; Angiogenesis; Association analysis; Carcinoma, Squamous Cell - metabolism; Clinical outcomes; Eye Neoplasms - metabolism; Eye Neoplasms - pathology; Female; Frizzled-related protein 1; Gene Expression Profiling; Humans; Hypoxia; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Hypoxia-inducible factors; Immunohistochemistry; Kaplan-Meier Estimate; Laboratory Medicine; Lymphoma; Lymphoma, Non-Hodgkin - metabolism; Male; Medicine; Medicine & Public Health; Melanoma; Melanoma - metabolism; Metastases; Middle Aged; Nevus - metabolism; Ophthalmology; Papilloma - metabolism; Pharmaceutical Sciences/Technology; Prognosis; Squamous cell carcinoma; Surgery; Surgical Oncology; Transcription factors; Tumors; Vascular endothelial growth factor
• ISSN: 0950-222X; 1476-5454; 1476-5454
• DOI: 10.1038/s41433-018-0172-6

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.