In this study, we analyzed the clinical significance of ferroptosis-related genes (FRGs) in 32 cancer types in the GSCA database. We detected a 2-82% mutation rate among 36 FRGs. In clear cell renal cell carcinoma (ccRCC; n=539) tissues from the The Cancer Genome Atlas database, 30 of 36 FRGs were differentially expressed (up- or down-regulated) compared to normal kidney tissues (n=72). Consensus clustering analysis identified two clusters of FRGs based on similar co-expression in ccRCC tissues. We then used LASSO regression analysis to build a new survival model based on five risk-related FRGs ( CARS, NCOA4, FANCD2, HMGCR, and SLC7A11 ). Receiver operating characteristic curve analysis confirmed good prognostic performance of the new survival model with an area under the curve of 0.73. High FANCD2, CARS, and SLC7A11 expression and low HMGCR and NCOA4 expression were associated with high-risk ccRCC patients. Multivariate analysis showed that risk score, age, stage, and grade were independent risk factors associated with prognosis in ccRCC. These findings demonstrate that this five risk-related FRG-based survival model accurately predicts prognosis in ccRCC patients, and suggest FRGs are potential prognostic biomarkers and therapeutic targets in several cancer types.

Growing evidence indicates that clear cell renal cell carcinoma (ccRCC) is a metabolism-related disease. Changes in fatty acid (FA) and cholesterol metabolism play important roles in ccRCC development. As a nuclear transcription factor receptor, Liver X receptor (LXR) regulates a variety of key molecules associated with FA synthesis and cholesterol transport. Therefore, targeting LXR may provide new therapeutic targets for ccRCC. However, the potential regulatory effect and molecular mechanisms of LXR in ccRCC remain unknown. In the present study, we found that both an LXR agonist and an XLR inverse agonist could inhibit proliferation and colony formation and induce apoptosis in ccRCC cells. We observed that the LXR agonist LXR623 downregulated the expression of the low-density lipoprotein receptor (LDLR) and upregulated the expression of ABCA1, which resulted in reduced intracellular cholesterol and apoptosis. The LXR inverse agonist SR9243 downregulated the FA synthesis proteins sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthase (FASN) and stearoyl-coA desaturase 1 (SCD1), causing a decrease in intracellular FA content and inducing apoptosis in ccRCC cells. SR9243 and LXR623 induced apoptosis in ccRCC cells but had no killing effect on normal renal tubular epithelial HK2 cells. We also found that SRB1-mediated high-density lipoprotein (HDL) in cholesterol influx is the cause of high cholesterol in ccRCC cells. In conclusion, our data suggest that an LXR inverse agonist and LXR agonist decrease the intracellular FA and cholesterol contents in ccRCC to inhibit tumour cells but do not have cytotoxic effects on non-malignant cells. Thus, LXR may be a safe therapeutic target for treating ccRCC patients.

Emerging evidence has indicated that long non‑coding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP) regulates cell growth, differentiation, apoptosis and cancer progression. However, the expression and function of HOTTIP in the progression of renal cell carcinoma (RCC) remain largely unknown. In this study, we investigated the role of the lncRNA HOTTIP in RCC. The expression levels of HOTTIP in RCC tissues and cell lines were determined by RT‑qPCR. The association between HOTTIP expression and clinicopathological characteristics and prognosis was analyzed in patients with RCC from the TCGA database. Loss‑of‑ function assays were designed and conducted to verify the oncogenic function of HOTTIP in RCC progression. Luciferase assay was performed to explore the mechanisms of the miRNA‑lncRNA sponge. The results revealed that HOTTIP expression was upregulated in RCC. An increased HOTTIP expression in RCC was associated with a larger tumor size and a higher clinical stage, lymph node metastasis and vascular invasion. Additionally, patients RCC with a high HOTTIP expression had a significantly shorter overall survival (OS) and disease‑free survival (DFS). HOTTIP knockdown significantly inhibited cell proliferation, migration and invasion, and increased the apoptosis of RCC cells in vitro. Mechanistic analyses revealed that HOTTIP functioned as a competing endogenous RNA (ceRNA) for hsa‑miR‑615‑3p, and led to the derepression of its endogenous target, insulin‑like growth factor-2 (IGF‑2), which is a protein hormone that exerts a stimulatory effect on tumor cell growth. miR‑615 inhibition reversed the suppressive effects of HOTTIP knockdown on RCC cell progression. HOTTIP regulated IGF‑2 expression in a miR‑615‑dependent manner in RCC cells. In addition, IGF‑2 expression was significantly upregulated in the RCC specimens and a positive association between the expression of HOTTIP and IGF‑2 in RCC tissues was detected. The effect of HOTTIP was abolished by the siRNA‑mediated silencing of IGF-2 in RCC cells. On the whole, this study demonstrates, for the first time, at least to the best of our knowledge, that the HOTTIP/miR‑615/IGF‑2 axis plays an important role in RCC progression and potentially contributes to the improvement of RCC diagnosis and therapy.