Nuclear receptor modulators inhibit osteosarcoma cell proliferation and tumour growth by regulating the mTOR signaling pathway.

Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Chemoresistance leads to poor responses to conventional therapy in patients with osteosarcoma. The discovery of novel effective therapeutic targets and drugs is still the main focus of osteosarcoma research. Nuclear receptors (NRs) have shown substantial promise as novel therapeutic targets for various cancers. In the present study, we performed a drug screen using 29 chemicals that specifically target 17 NRs in several different human osteosarcoma and osteoblast cell lines. The retinoic acid receptor beta (RARb) antagonist LE135, peroxisome proliferator activated receptor gamma (PPARg) antagonist T0070907, liver X receptor (LXR) agonist T0901317 and Rev-Erba agonist SR9011 significantly inhibited the proliferation of malignant osteosarcoma cells (U2OS, HOS-MNNG and Saos-2 cells) but did not inhibit the growth of normal osteoblasts. The effects of these NR modulators on osteosarcoma cells occurred in a dose-dependent manner and were not observed in NR-knockout osteosarcoma cells. These NR modulators also significantly inhibited osteosarcoma growth in vivo and enhanced the antitumour effect of doxorubicin (DOX). Transcriptomic and immunoblotting results showed that these NR modulators may inhibit the growth of osteosarcoma cells by regulating the PI3K/AKT/mTOR and ERK/mTOR pathways. DDIT4, which blocks mTOR activation, was identified as one of the common downstream target genes of these NRs. DDIT4 knockout significantly attenuated the inhibitory effects of these NR modulators on osteosarcoma cell growth. Together, our results revealed that modulators of RARb, PPARg, LXRs and Rev-Erba inhibit osteosarcoma growth both in vitro and in vivo through the mTOR signaling pathway, suggesting that treatment with these NR modulators is a novel potential therapeutic strategy.

Prognostic values of the core components of the mammalian circadian clock in prostate cancer.

BACKGROUND: Prostate cancer (PC) is one of the most common malignancies in males. Extensive and complex connections between circadian rhythm and cancer were found. Nonetheless, in PC, the potential role of the core components of the mammalian circadian clock (CCMCCs) in prognosis prediction has not been fully clarified. METHODS: We firstly collected 605 patients with PC from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Survival analysis was carried out for each CCMCC. Then, we investigated the prognostic ability of CCMCCs by Cox regression analysis. Independent prognostic signatures were extracted for the establishment of the circadian clock-based risk score model. We explored the predictive performance of the risk score model in the TCGA training cohort and the independent GEO dataset. Finally, the relationships between risk score and clinicopathological parameters, biological processes, and signaling pathways were evaluated. RESULTS: The expression levels of CCMCCs were widely correlated with age, tumor status, lymph node status, disease-free survival (DFS), progression-free survival (PFS), and overall survival (OS). Nine circadian clock genes, including CSNK1D, BTRC, CLOCK, CSNK1E, FBXL3, PRKAA2, DBP, NR1D2, and RORB, were identified as vital prognostic factors in PC and were used to construct the circadian clock-based risk score model. For DFS, the area under the 3-year or 5-year receiver operating characteristic curves ranged from 0.728 to 0.821, suggesting better predictive performance. When compared with T3-4N1 stage, PC patients at T2N0 stage might be benefited more from the circadian clock-based risk score model. Furthermore, a high circadian clock-based risk score indicated shorter DFS (p < 0.0001), early progression (p < 0.0001), and higher 5-year death rate (p = 0.007) in PC. The risk score was related to tumor status (p < 0.001), lymph node status (p < 0.001), and ribosome-related biogenesis and pathways. CONCLUSIONS: The vital roles of circadian clock genes in clinical outcomes were fully depicted. The circadian clock-based risk score model could reflect and predict the prognosis of patients with PC.

STC1 is a Novel Biomarker Associated with Immune Characteristics and Prognosis of Bladder Cancer.

BACKGROUND: Stanniocalcin-1 (STC1) is a well-studied oncogene that promotes different types of cancer progression. However, the expression status of STC1, the values of STC1 on prognosis, and its immune characteristic in bladder cancer (BLCA) have not been well examined. METHODS: The expression of STC1 and its clinicopathological as well as immune characteristics in BLCA samples were firstly identified in The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Immunohistochemistry (IHC) performed on the tissue microarray (TMA) slide was further used to validate the expression of STC1 and its relationship with immune features in 16 non-muscle invasive bladder cancer (NMIBC) samples and 42 muscle invasive bladder cancer (MIBC) samples. RESULTS: The expression of STC1 was upregulated in higher stage BLCA. High STC1 expression also predicted poor prognosis in BLCA. Subsequently, the TMA validated the expression and prognostic value of STC1 in BLCA. Bioinformatics analysis demonstrated that STC1 and common immune checkpoints as well as immune markers of various immune cells were positively correlated in TCGA. In addition, IHC data from the TMA further validated that tumor cells with higher STC1 level tended to express higher PDL1 as well as increased infiltration of CD3+ T cells. CONCLUSION: To our knowledge, this is the first comprehensive study that investigates the clinical and immune characteristics of STC1 in BLCA. It may provide new insight into the function of STC1 in regulating tumor immune microenvironment. Further studies are warranted to uncover the potential mechanisms that mediate STC1 expression and tumor immunity in BLCA.

Identification of a Novel Ferroptosis-Related Gene Prognostic Signature in Bladder Cancer.

BACKGROUND: Ferroptosis is a newly found non-apoptotic forms of cell death that plays an important role in tumors. However, the prognostic value of ferroptosis-related genes (FRG) in bladder cancer (BLCA) have not been well examined. METHODS: FRG data and clinical information were collected from The Cancer Genome Atlas (TCGA). Then, significantly different FRGs were investigated by functional enrichment analyses. The prognostic FRG signature was identified by univariate cox regression and least absolute shrinkage and selection operator (LASSO) analysis, which was validated in TCGA cohort and Gene Expression Omnibus (GEO) cohort. Subsequently, the nomogram integrating risk scores and clinical parameters were established and evaluated. Additionally, Gene Set Enrichment Analyses (GSEA) was performed to explore the potential molecular mechanisms underlying our prognostic FRG signature. Finally, the expression of three key FRGs was verified in clinical specimens. RESULTS: Thirty-two significantly different FRGs were identified from TCGA-BLCA cohort. Enrichment analyses showed that these genes were mainly related to the ferroptosis. Seven genes (TFRC, G6PD, SLC38A1, ZEB1, SCD, SRC, and PRDX6) were then identified to develop a prognostic signature. The Kaplan-Meier analysis confirmed the predictive value of the signature for overall survival (OS) in both TCGA and GEO cohort. A nomogram integrating age and risk scores was established and demonstrated high predictive accuracy, which was validated through calibration curves and receiver operating characteristic (ROC) curve [area under the curve (AUC) = 0.690]. GSEA showed that molecular alteration in the high- or low-risk group was closely associated with ferroptosis. Finally, experimental results confirmed the expression of SCD, SRC, and PRDX6 in BLCA. CONCLUSION: Herein, we identified a novel FRG prognostic signature that maybe involved in BLCA. It showed high values in predicting OS, and targeting these FRGs may be an alternative for BLCA treatment. Further experimental studies are warranted to uncover the mechanisms that these FRGs mediate BLCA progression.