TR4 Nuclear Receptor Functions as a Tumor Suppressor for Prostate Tumorigenesis via Modulation of DNA Damage/Repair System.

ArticleinCarcinogenesis 35(6) · February 2014with13 Reads
DOI: 10.1093/carcin/bgu052 · Source: PubMed
Testicular nuclear receptor 4 (TR4), a member of the nuclear receptor superfamily, plays important roles in metabolism, fertility and aging. The linkage of TR4 functions in cancer progression, however, remains unclear. Using three different mouse models, we found TR4 could prevent or delay prostate cancer (PCa)/prostatic intraepithelial neoplasia development. Knocking down TR4 in human RWPE1 and mouse mPrE normal prostate cells promoted tumorigenesis under carcinogen challenge, suggesting TR4 may play a suppressor role in PCa initiation. Mechanism dissection in both in vitro cell lines and in vivo mice studies found that knocking down TR4 led to increased DNA damage with altered DNA repair system that involved the modulation of ATM expression at the transcriptional level, and addition of ATM partially interrupted the TR4 small interfering RNA-induced tumorigenesis in cell transformation assays. Immunohistochemical staining in human PCa tissue microarrays revealed ATM expression is highly correlated with TR4 expression. Together, these results suggest TR4 may function as a tumor suppressor to prevent or delay prostate tumorigenesis via regulating ATM expression at the transcriptional level. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] /* */
    • "Lentiviral particles were generated by calcium phosphate transfection of lentiviral expressing, packaging and envelop plasmids into HEK293T cells. Lentiviral particles were collected to infect target cells according to a previous report [16]. "
    [Show abstract] [Hide abstract] ABSTRACT: Early studies indicated that several inflammatory immune cells, including macrophages, mast cells, B and T cells in the tumor microenvironment, might influence cancer progression. Here we found that bladder cancer (BCa) cells could recruit more neutrophils than normal bladder cells. The consequences of recruiting more neutrophils might then increase BCa cell invasion via up-regulating androgen receptor (AR) signals. Mechanism dissection revealed infiltrating neutrophils could up-regulate AR signals via either increased AR mRNA/protein expression or increased AR transactivation. The increased AR signals might then enhance BCa cell invasion via increasing MMP13 expression. Together, these results might provide us a new potential therapeutic approach to better battle BCa metastasis via targeting the newly identified signaling from infiltrating neutrophils to BCa through AR to MMP13 signals.
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    • "However, an early report suggested that continued TZD treatment in diabetic patients might lead to increased bladder cancer risk in some patients [10], which raised a concern whether continued TZD treatment in diabetic patients might also have risks of promoting progression of other cancers. Recent unexpected findings [11] showing TZDs could also function as ligands/activators to activate the TR4 nuclear receptor (TR4, NR2C2)1213141516171819 raised an interesting question about the potential impacts of this newly identified TZD-TR4 signaling on the classic TZD-PPAR signaling. Here, we found 9% of PCa patients had lost one allele of TR4 gene in their tumors compared to their adjacent benign tissues. "
    [Show abstract] [Hide abstract] ABSTRACT: The insulin sensitizers, thiazolidinediones (TZDs), have been used as anti-diabetic drugs since the discovery of their ability to alter insulin resistance through transactivation of peroxisome proliferator-activated receptors (PPARs). However, their side effects in hepatitis, cardiovascular diseases, and bladder cancer resulted in some selling restrictions in the USA and Europe. Here, we found that the potential impact of TZDs on the prostate cancer (PCa) progression might be linked to the TR4 nuclear receptor expression. Clinical surveys found that 9% of PCa patients had one allele TR4 deletion in their tumors. TZD increased cell growth and invasion in PCa cells when TR4 was knocked down. In contrast, TZD decreased PCa progression in PCa cells with wild type TR4. Mechanism dissection found that the Harvey Rat Sarcoma (HRAS) oncogene increased on TZD treatment of the TR4 knocked-down CWR22Rv1 and C4-2 cells, and interruption with HRAS inhibitor resulted in reversal of TZD-induced PCa progression. Together, these results suggest that TZD treatment may promote PCa progression depending on the TR4 expression status that may be clinically relevant since extra caution may be needed for those diabetic PCa patients receiving TZD treatment who have one allele TR4 deletion. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015
    • "Targeting NF-kappaB/miRNA-21/PTEN signaling pathway has also been suggested to alter the chemo- resistance [29]. Early studies indicated that TR4 might play cytoprotective roles [8, 10,[30][31][32][33]that could function through altering the cell survival signals including the TR4-Oct4-IL1Ra axis [11]. Here we found a reverse cytotoxic phenotype in HCC cells that might function through promoting cisplatin-mediated apoptosis, suggesting that the roles of TR4 in mediation of the tumor progression and chemotherapy efficacy is complex, and may depend on cell context or cytotoxicity inducers. "
    [Show abstract] [Hide abstract] ABSTRACT: Early studies indicated that TR4 nuclear receptor (TR4) may play a key role to modulate the prostate cancer progression, its potential linkage to liver cancer progression, however, remains unclear. Here we found that higher TR4 expression in hepatocellular carcinoma (HCC) cells might enhance the efficacy of cisplatin chemotherapy to better suppress the HCC progression. Knocking down TR4 with TR4-siRNA in HCC Huh7 and Hep3B cells increased cisplatin chemotherapy resistance and overexpression of TR4 with TR4-cDNA in HCC LM3 and SNU387 cells increased cisplatin chemotherapy sensitivity. Mechanism dissection found that TR4 might function through altering the ATF3 expression at the transcriptional level to enhance the cisplatin chemotherapy sensitivity, and interrupting ATF3 expression via ATF3-siRNA reversed TR4-enhanced cisplatin chemotherapy sensitivity in HCC cells. The in vivo HCC mouse model using xenografted HCC LM3 cells also confirmed in vitro cell lines data showing TR4 enhanced the cisplatin chemotherapy sensitivity. Together, these results provided a new potential therapeutic approach via altering the TR4-ATF3 signals to increase the efficacy of cisplatin to better suppress the HCC progression.
    Full-text · Article · Nov 2014
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