Hypoxia inducible factors and hypoxia associated factor expression profiles and prognostic significance in renal cell carcinomas

Abstract

Hypoxia Inducible Factor-1 alpha and Hypoxia Inducible Factor-2 alpha (HIF-1α and HIF-2α) are crucial in Renal Cell Carcinoma (RCC) formation. Hypoxia Associated Factor (HAF) prompts HIF-1α degradation regardless of oxygen levels, but no such link exists for HIF-2α. This study encompassed 239 cases, where tissue microarray (TMA) sections were exposed to HIF-1α, HIF-2α, and HAF antibodies. Staining intensity and tumor cell percentage determined scores for HIF-1α, HIF-2α, and HAF, with median histoscore establishing "high" or "low" cutoffs. Among the cases, 64.9% (155 cases) were negative for HIF-1α, 17.6% (42 cases) displayed low, and another 17.6% (42 cases) showed strong HIF-1α expression. HIF-1α expression correlated significantly with histological type and World Health Organization/International Society of Urological Pathology (WHO/ISUP) nuclear grade. Regarding HIF-2α, 15.5% (37 cases) were negative, 23.4% (56 cases) exhibited low, and 61.1% (146 cases) displayed high expression, with larger tumor size in the high HIF-2α group. Among 239 cases, 41.4% (99 cases) were negative for HAF, 36.8% (88 cases) showed low, and 21.8% (52 cases) displayed high HAF scores. HAF expression correlated with WHO/ISUP nuclear grade and metastasis presence. Notably, HIF-2α staining intensity directly correlated with increased HAF intensity (rho=0.146; p=0.024), while HIF-1α intensity decrease corresponded with heightened HAF intensity, showing a statistically significant negative correlation (rho=-0.180; p=0.005). In this rare examination of tumor tissue, a reverse connection between HIF-1α and HAF expression was uncovered, while a linear link emerged between HIF-2α and HAF expression. Overall, this study established that HIF-1α, HIF-2α, and HAF expression are associated with an unfavorable prognosis.