Factor-inhibiting hypoxia-inducible factor expression in patients with high-risk locally advanced renal cell carcinoma and its relationship with tumor progression

Abstract

Hypoxia-inducible factor (HIF) plays an important role in renal cell carcinoma (RCC) associated with angiogenesis. Factor-inhibiting HIF (FIH), which is the upstream mediator protein of HIF, is receiving more attention today. In the present study, the role of FIH expression in high-risk locally advanced renal cell carcinoma (LARCC) was explored. Eighty-eight high-risk LARCC cases were divided into two groups based on their prognosis. Using immunohistochemical staining, the correlations of FIH expression along with clinicopathological factors, progression-free survival (PFS), and overall survival (OS) were analyzed. FIH was mainly located in the cytoplasm (34/88) and nucleus (31/88) of the renal tumor cell. Nuclear negative expression or cytoplasmic positive expression of FIH were associated with an increased risk of disease progression (p = 0.007 and p < 0.001, respectively) and worse OS (p = 0.020 and p = 0.008, respectively). Using the group with nuclear and cytoplasmic FIH negative expression as reference, further stratified analysis found that the exclusive nuclear FIH expression group had a better PFS and OS [hazard ratio (HR) = 0.153, p = 0.07 and HR = 0, p = 0.961, respectively], and the exclusive cytoplasmic FIH positive group experienced the worst PFS and OS (HR = 2.876, p = 0.005 and HR = 2.799, p = 0.034, respectively). In addition, nuclear negative expression of FIH was associated with a significant negative predictive value for the effect of interferon-alpha (IFN-α) on PFS (p = 0.045). The nuclear negative and cytoplasmic positive expressions of FIH were identified not only as risk factors for disease progression in high-risk LARCC postoperative patients, but also to be associated with poor OS. Furthermore, the nuclear negative expression of FIH may be a promising biomarker for postoperative adjuvant therapy.