Recent advances in the study of testicular nuclear receptor 4

Ding, Xiaoyan; Yu, Shicheng; Chen, Bide; Lin, Shin-Jen; Chang, Chawnshang; Li, Gong-hui

doi:10.1631/jzus.b1200357

Cited by 11 publications

(19 citation statements)

References 42 publications

(42 reference statements)

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Section: Introductionmentioning

confidence: 99%

“…Testicular nuclear receptor 4 (TR4), also known as NR2C2 (nuclear receptor subfamily 2, group C, member 2), is a transcriptional factor and a member of the nuclear receptor family. [4][5][6] Earlier studies from TR4 knockout (TR4KO) mice revealed that TR4 might play important roles in fertility, bone formation, neural development and metabolism. [7][8][9][10][11] Recent studies also found TR4 might play a negative role to suppress prostate cancer (PCa) initiation, yet played a positive role to promote PCa metastasis, [12][13][14] which is opposite the androgen receptor that promotes PCa initiation and suppresses PCa metastases.…”

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confidence: 99%

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Preclinical studies using miR‐32‐5p to suppress clear cell renal cell carcinoma metastasis via altering the miR‐32‐5p/TR4/HGF/Met signaling

Wang

Sun

et al. 2018

Intl Journal of Cancer

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While testicular nuclear receptor 4 (TR4) may promote prostate cancer (PCa) metastasis, its role in the clear cell renal cell carcinoma (ccRCC) remains unclear. Here we found a higher expression of TR4 in ccRCC tumors from patients with distant metastases than those from metastasis-free patients, suggesting TR4 may play positive roles in the ccRCC metastasis. Results from multiple in vitro ccRCC cell lines also confirmed TR4's positive roles in promoting ccRCC cell invasion/migration via altering the microRNA (miR-32-5p)/TR4/HGF/Met/MMP2-MMP9 signaling. Mechanism dissection revealed that miR-32-5p could suppress TR4 protein expression levels via direct binding to the 3'UTR of TR4 mRNA, and TR4 might then alter the HGF/Met signaling at the transcriptional level via direct binding to the TR4-response-elements (TR4RE) on the HGF promoter. Then the in vitro data also demonstrated the efficacy of Sunitinib, a currently used drug to treat ccRCC, could be increased after targeting this newly identified miR-32-5p/TR4/HGF/Met signaling. The preclinical study using the in vivo mouse model with xenografted ccRCC cells confirmed the in vitro cell lines data. Together, these findings suggest that TR4 is a key player to promote ccRCC metastasis and targeting this miR-32-5p/TR4/HGF/Met signaling with small molecules including TR4-shRNA or miR-32-5p may help to develop a new therapy to better suppress the ccRCC metastasis.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Preclinical studies using miR‐32‐5p to suppress clear cell renal cell carcinoma metastasis via altering the miR‐32‐5p/TR4/HGF/Met signaling

Wang

Sun

et al. 2018

Intl Journal of Cancer

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“…Testicular nuclear receptor 4 (TR4) is a member of the nuclear receptor superfamily. 4 As an important transcription factor, TR4 can interact with several nuclear receptors and influence intracellular reactive oxygen species (ROS), oxidative stress resistance 5,6 and DNA damage reparation via its various down stream target genes. 7,8 In vivo studies of TR4 gene knockout mice (TR4 − / − ) demonstrated that they display impaired oxidative stress defense, 5 subfertility 9 and premature aging.…”

Section: Introductionmentioning

confidence: 99%

The role of testicular nuclear receptor 4 in chemo-resistance of docetaxel in castration-resistant prostate cancer

Chen

Ding

et al. 2014

Cancer Gene Ther

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Docetaxel-based therapy is one of the first-line options for castration-resistant prostate cancer (CRPC). However, a large proportion of CRPC patients show different extents of docetaxel resistance. The current study aims to investigate the role of testicular nuclear receptor 4 (TR4) in docetaxel resistance in CRPC. TR4 expression level in prostate biopsy samples from CRPC patients treated with docetaxel was measured by immunohistochemistry (IHC). Alternation of TR4 expression in prostate cancer (PCa) cell line PC3 was applied to find out the influence of TR4 on half-maximal inhibitory concentration (IC50), cell viability and cell apoptosis. Patients who failed to achieve prostate-specific antigen (PSA) response (<50% PSA reduction from baseline) after docetaxel-based chemotherapy had a comparatively higher TR4 expression than those who achieved PSA response (⩾50% PSA reduction from baseline). Knocking down TR4 in PC3 cells led to a lower IC50 dose, poorer cell viability and more cell apoptosis when treated with docetaxel, whereas overexpression of TR4 in PC3 led to a higher IC50 dose, better cell viability and less cell apoptosis. TR4 enhances the chemo-resistance of docetaxel in CRPC. It may serve as a biomarker to determine the prognosis of docetaxel-based therapy and as a potential therapy target to combine with docetaxel to better suppress CRPC.

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“…Early studies indicated that many compounds could function as TR4 ligands/activators, including polyunsaturated fatty acids and the thiazolidinedione, rosiglitazone, which could transactivate TR4 target genes. It will be interesting to see if transactivation by any of those ligands/activators can result in similar effects like targeting TR4 protein via TR4‐cDNA or TR4‐siRNA to alter TR4 expression to influence the PCa metastasis.…”

Section: Discussionmentioning

confidence: 99%

TR4 nuclear receptor promotes prostate cancer metastasis via upregulation of CCL2/CCR2 signaling

Ding

Yang

Lee

et al. 2014

Intl Journal of Cancer

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Testicular nuclear receptor 4 (TR4) plays protective roles against oxidative stress and DNA damage and might contribute to aging. Our recent clinical tumor tissue staining results showed higher expression of TR4 in prostate cancer (PCa) patients with high Gleason scores compared to the tissues with the low Gleason scores. In vitro migration/invasion assays after manipulation of the TR4 expression in PCa cells showed that TR4 promoted PCa cells migration/invasion. Mechanism dissection found that the CCL2/CCR2 signal plays the key role in the mediation of TR4-promoted PCa cells migration/invasion. Chromatin immunoprecipitation and Luciferase assays further confirmed TR4 modulation of CCL2 at the transcriptional level and addition of the CCR2 antagonist led to interruption of the TR4-enhanced PCa cells migration/ invasion. Finally, the orthotopic xenografted mice studies using the luciferase expressing CWR22Rv1 cells found that TR4 enhanced PCa metastasis and this increased metastasis was reversed when the CCR2 antagonist was injected into the mice. Together, these in vitro and in vivo results revealed a positive role of TR4 in PCa metastasis and demonstrated CCL2/CCR2 signaling as an important mediator in exerting TR4 action. This finding suggests that TR4 may represent a biomarker related to PCa metastasis and targeting the TR4-CCL2/CCR2 axis may become a new therapeutic approach to battle PCa metastasis.Prostate cancer (PCa) is the second leading cause of cancer related deaths among men in the United States. Since PCa cells depend on androgen/androgen receptor (AR) signaling for their growth, 1 the androgen deprivation therapy (ADT), through either chemical or surgical castration, has been an effective therapy that leads to a regression of androgendependent PCa.2 However, almost all patients eventually relapse with recurrent (castration resistant) PCa and metastases, which respond to few treatments. In this study, we investigated the TR4 role in PCa metastasis using in vitro migration/invasion assays and in vivo metastasis mouse model and demonstrated the positive role of TR4 in promoting PCa metastasis. The mechanism dissection studies further proved that TR4 might function via modulation of the CCL2/CCR2 signaling.

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Recent advances in the study of testicular nuclear receptor 4

Cited by 11 publications

References 42 publications

Preclinical studies using miR‐32‐5p to suppress clear cell renal cell carcinoma metastasis via altering the miR‐32‐5p/TR4/HGF/Met signaling

Preclinical studies using miR‐32‐5p to suppress clear cell renal cell carcinoma metastasis via altering the miR‐32‐5p/TR4/HGF/Met signaling

The role of testicular nuclear receptor 4 in chemo-resistance of docetaxel in castration-resistant prostate cancer

TR4 nuclear receptor promotes prostate cancer metastasis via upregulation of CCL2/CCR2 signaling

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