Nuclear orphan receptor NR4A2 confers chemoresistance and predicts unfavorable prognosis of colorectal carcinoma patients who received postoperative chemotherapy

Han, Yaling; Cai, Hui; Ma, Long; Ding, Yibo; Tan, Xiaojie; Liu, Yan; Su, Tong; Ye, Yu; Chang, Wenjun; Zhang, Hongwei; Fu, Chuangang; Cao, Guangwen

doi:10.1016/j.ejca.2013.06.001

Cited by 27 publications

(30 citation statements)

References 31 publications

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“…Using tissue microarray analysis, these studies also found that NR4A2 expression was increased in colorectal cancer specimens collected from 51 adenomatous colorectal cancers, 14 familial adenomatous polyposis colorectal cancers, 17 stage IV colorectal cancers with adjacent mucosa, and 682 stage I–III colorectal cancers. Increased expression of NR4A2 was related to protein kinase A activation and was correlated with chemoresistance [164]. These data demonstrate that NR4A2 expression predicts poor survival and drug resistance in various cancers, including breast, prostate, bladder and colon cancers.…”

Section: Nr4a2 In Cellular Homeostasis and Diseasementioning

confidence: 96%

“…Small molecules that stimulate the inhibitory effects of NR4A2 may have promise in treating cancer, demonstrated by the effects of the NR4A2-acting compound 1,1-bis(3′-indolyl)-1-( p -chlorophenyl)methane (C-DIM12 or DIM-C-pPhCl) which induced TRAIL protein expression and PARP cleavage in bladder cancer cells that was significantly decreased by inhibition of NR4A2 with RNAi [136]. Interestingly, overexpression of NR4A2 in colorectal cancer cells revealed that ectopic expression of NR4A2 increased resistance to the chemotherapeutic agents 5-fluorouracil and oxaliplatin and attenuated the chemotherapeutic-induced apoptosis [164]. Using tissue microarray analysis, these studies also found that NR4A2 expression was increased in colorectal cancer specimens collected from 51 adenomatous colorectal cancers, 14 familial adenomatous polyposis colorectal cancers, 17 stage IV colorectal cancers with adjacent mucosa, and 682 stage I–III colorectal cancers.…”

Section: Nr4a2 In Cellular Homeostasis and Diseasementioning

confidence: 99%

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Nuclear receptor 4A (NR4A) family – orphans no more

Safe

Jin

Morpurgo

et al. 2016

The Journal of Steroid Biochemistry and Molecular Biology

157

161

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The orphan nuclear receptors NR4A1, NR4A2 and NR4A3 are immediate early genes induced by multiple stressors, and the NR4A1 receptors play an important role in maintaining cellular homeostasis and disease. There is increasing evidence for the role of these receptors in metabolic, cardiovascular and neurological functions and also in inflammation and inflammatory diseases and in immune functions and cancer. Despite the similarities of NR4A1, NR4A2 and NR4A3 and their interactions with common cis-genomic elements, they exhibit unique activities and cell-/tissue-specific functions. Although endogenous ligands for NR4A receptors have not been identified, there is increasing evidence that structurally-diverse synthetic molecules can directly interact with the ligand binding domain of NR4A1 and act as agonists or antagonists, and ligands for NR4A2 and NR4A3 have also been identified. Since NR4A receptors are key factors in multiple diseases, there are opportunities for the future development of NR4A ligands for clinical applications in treating multiple health problems including metabolic, neurologic and cardiovascular diseases, other inflammatory conditions, and cancer.

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Section: Nr4a2 In Cellular Homeostasis and Diseasementioning

confidence: 96%

Section: Nr4a2 In Cellular Homeostasis and Diseasementioning

confidence: 99%

Nuclear receptor 4A (NR4A) family – orphans no more

Safe

Jin

Morpurgo

et al. 2016

The Journal of Steroid Biochemistry and Molecular Biology

157

161

View full text Add to dashboard Cite

show abstract

“…Deficiency of RAD51B has been shown to sensitize to chemotherapy and radiation therapy in in vitro models (83) and has been suggested to contribute to the favourable response to therapy of HPV-associated cancers (21). Overexpression of the oncogene NR4A2 , which has also been identified as a recurrent integration site, has been shown to confer an unfavorable prognosis in colorectal cancer patients (84). PIK3CA alterations have also been reported as therapeutic biomarkers in HNSCC (48).…”

Section: Clinical Perspectivesmentioning

confidence: 99%

Genomic Landscape of Human Papillomavirus–Associated Cancers

Rusan

Hammerman

2015

Clinical Cancer Research

107

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Recent next-generation sequencing studies have generated a comprehensive overview of the genomic landscape of Human Papillomavirus (HPV)-associated cancers. This review summarizes these findings to provide insight into the tumor biology of these cancers and potential therapeutic opportunities for HPV-driven malignancies. In addition to the tumorigenic properties of the HPV oncoproteins, integration of HPV DNA into the host genome is suggested to be a driver of the neoplastic process. Integration may confer a growth and survival advantage via enhanced expression of viral oncoproteins, alteration of critical cellular genes, and changes in global promoter methylation and transcription. Alteration of cellular genes may lead to loss of function of tumor suppressor genes, enhanced oncogene expression, loss of function of DNA repair genes, or other vital cellular functions. Recurrent integrations in RAD51B, NR4A2, and TP63, leading to aberrant forms of these proteins, are observed in both HPV-positive head and neck squamous cell carcinoma (HNSCC) and cervical carcinoma. Additional genomic alterations, independent of integration events, include recurrent PIK3CA mutations (and aberrations in other members of the PI3K pathway), alterations in receptor tyrosine kinases (primarily FGFR2 and FGFR3 in HPV-positive HNSCC, and ERBB2 in cervical squamous cell carcinoma), and genes in pathways related to squamous cell differentiation and immune responses. A number of the alterations identified are potentially targetable, which may lead to advances in the treatment of HPV-associated cancers.

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“…These NR4A family members affect multiple cell functions such as cell cycling, cell apoptosis and proliferation [19–21]. They also were found related to the progression of cancers such as cervical cancer, melanoma, bladder cancer, prostate cancer and lung cancer [18–20, 22]. However, their roles in carcinogenesis are poorly defined.…”

Section: Introductionmentioning

confidence: 99%

Activated Notch signaling augments cell growth in hepatocellular carcinoma via up-regulating the nuclear receptor NR4A2

et al. 2017

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Hepatocellular carcinoma (HCC) is one of the most malignant cancers. Conventional therapies are limited due to the human liver being such a unique organ and easily showing side-effects. The unclear molecular mechanisms are tough challenges for scientists searching for new and effective anti-HCC targeting drugs. We identified that the nuclear receptor NR4A2 is a novel oncogene in HCC progression. In this study, we show that NR4A2 and the notch recceptor Notch1 were expressed highly in primary HCC tissues and immortal HCC cells by using qPCR, western blot and immuno-histochemistry assays. Both genes were observed to stimulate HCC cell proliferation, anti-apoptosis and cell cycle arrest by using cell proliferation assays and FACS assays. We also observed that the four notch receptor subtypes (Notch1-4) displayed different effects on HCC cell growth. The over-expression of Notch1 by transiently transfecting the intracellular domain of Notch1 (ICN1, Notch1 active form) increased the expression of NR4A2, with the knockdown of Notch1 decreasing NR4A2. This indicates that NR4A2 is one of the Notch-mediated downstream genes. Moreover, both NR4A2 and Notch1 suppressed the expression of tumor suppressors p21 and p63. These findings support that Notch1/NR4A2 co-regulate HCC cell functions by playing oncogenic roles and regulating the associated downstream signaling pathways. Novel Notch1/NR4A2-mediated oncogenic signaling may provide us a great opportunity for anti-HCC drug development.

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Nuclear orphan receptor NR4A2 confers chemoresistance and predicts unfavorable prognosis of colorectal carcinoma patients who received postoperative chemotherapy

Cited by 27 publications

References 31 publications

Nuclear receptor 4A (NR4A) family – orphans no more

Nuclear receptor 4A (NR4A) family – orphans no more

Genomic Landscape of Human Papillomavirus–Associated Cancers

Activated Notch signaling augments cell growth in hepatocellular carcinoma via up-regulating the nuclear receptor NR4A2

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