Ferroportin and FBXL5 as Prognostic Markers in Advanced Stage Clear Cell Renal Cell Carcinoma

Abstract

PurposeAdvanced stage clear cell renal cell carcinoma (ccRCC) involves a poor prognosis. Several studies have reported that dysfunctions in iron metabolism‒related proteins may cause tumor progression and metastasis of this carcinoma. In this study, we investigated the impact of the expression of iron metabolism‒related proteins on patient prognoses in advanced stage ccRCCs. Materials and MethodsAll of 143 advanced stage ccRCC specimens were selected following validation with double blind reviews. Several clinicopathological parameters including nuclear grade, perirenal fat invasion, renal sinus fat invasion, vascular invasion, necrosis, and sarcomatoid/rhabdoid differentiation were compared with the expression of ferroportin (FPN), and F-Box and leucine rich repeat protein 5 (FBXL5), by immunohistochemistry. FPN and FBXL5 mRNA level of ccRCC from The Cancer Genome Atlas database were also analyzed for validation.ResultsFPN and FBXL5 immunohistochemistry showed membrane and cytoplasmic expression, respectively. Based on the H-score, cases were classified as low or high expression with a cutoff value of 20 for FPN and 15 for FBXL5, respectively. Low expression of FPN and FBXL5 were significantly associated with patient death (p=0.022 and p=0.005, respectively). In survival analyses, low expression of FPN and FBXL5 were significantly associated with shorter overall survival (p=0.003 and p=0.004, respectively). On multivariate analysis, low expression of FBXL5 (hazard ratio, 2.001; p=0.034) was significantly associated with shorter overall survival.ConclusionFPN and FBXL5 can be used as potential prognostic markers and therapeutic targets for advanced stage ccRCC.

The Role of Iron in Cancer Progression

“…And FPN1 mRNA and protein expression are significantly downregulated, and patients with a low FPN1 expression have a poor prognosis in lung cancer and adrenocortical carcinoma (ACC) (178,183). Additionally, a similar effect was observed in multiple myeloma and ccRCC (43,184). Furthermore, STEAP3 is highly expressed in glioblastoma and is closely related to the decreased overall survival rate (39); however, a survival analysis showed that breast cancer patients with high levels of STEAP1, STEAP2, and STEAP4 had an overall good prognosis (185).…”

Loss of F-Box and Leucine Rich Repeat Protein 5 (FBXL5) Expression Is Associated With Poor Survival in Patients With Hepatocellular Carcinoma After Curative Resection: A Two-institute Study

“…Previous studies using FBXL5 knockout mice revealed iron accumulation in the liver and steatohepatitis (18), higher HCC incidence, and increased tumor size compared to FBXL5 intact mice, indicating that deficiency of FBXL5 is involved in hepatic carcinogenesis (19). Alterations in iron metabolism-related proteins seem to be related with the prognosis of diverse cancers, such as prostate, breast, pancreatic and esophageal cancer, and renal cell carcinoma (20)(21)(22)(23)(24). However, FBXL5 expression and its clinical implications have not yet been reported in samples from patients with HCC.…”