Notch Signaling Activation in Cervical Cancer Cells Induces Cell Growth Arrest with the Involvement of the Nuclear Receptor NR4A2

Sun, Lichun; Liu, Mingqiu; Sun, Guangchun; Xu, Youzhi; Qian, Qingqing; Feng, Shuyu; Mackey, L. Vienna; Coy, David H.

doi:10.7150/jca.15274

Cited by 39 publications

(41 citation statements)

References 27 publications

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“…Our previous study also showed that NR4A2 stimulated cervical cancer cell growth [11]. Presently, we found that NR4A2 was up-regulated in many primary HCC tissues and immortal HCC cell lines, and co-existed with Notch1.…”

Section: Discussionmentioning

confidence: 52%

“…We also observed the effects of Notch1 on certain genes in cervical cancer Hela cells [11]. NR4A2, as well as VPA, modulated the expression of these genes in HCC HTB-52 cells [9].…”

Section: Resultsmentioning

confidence: 99%

“…In our previous study, the nuclear receptor gene NR4A2 was found to be involved in Notch-mediated downstream signaling pathways in cervical cancer cells [11]. NR4A2 belongs to the NR4A subfamily of the nuclear receptor family of transcription factors [18].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 52%

“…We also observed the effects of Notch1 on certain genes in cervical cancer Hela cells [11]. NR4A2, as well as VPA, modulated the expression of these genes in HCC HTB-52 cells [9].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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“…These pathways are composed of various cytokines and transcription factors and among these pathways, the Notch-Hes signaling transduction pathway is the most important pathway. If there is abnormity of Notch signaling pathway, the cells cannot differentiate normally, thus there is possibility of oncogenesis, and it has been reported that the Notch receptor is abnormally expressed in numerous human solid tumor types including cervical, head and neck, endometrial, kidney, lung and breast cancer, pleural mesothelioma and salivary gland tumors) and hematological malignancies (26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

The cloning and activity of human Hes1 gene promoter

2017

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The aim of the current study was to obtain and analyze the activity of the human Hes1 gene promoter. The genomic DNA of human HeLa cell was used as template, polymerase chain reaction (PCR) was used to amplify the 5' end sequence of Hes1 gene and then the amplified segment was connected to pMD18‑T vector. Subsequently, double enzyme digestion was used for identification and the sequence was detected; the promoter with the correct sequence was inserted into pGL3‑Basic, and the sequence was identified by double enzyme digestion. The recombinant DNA with correct sequence was transiently transfected into cervical cancer cells, and the dual luciferase reporter gene assay system was used to detect the activity of the promoter. The results demonstrated that the human Hes1 gene promoter amplified by PCR was the same as that of the sequence in the gene bank, and the dual luciferase reporter gene assay system demonstrated that there was promoter activity in cervical cancer cells. In conclusion, the Hes1 luciferase reporter recombinant vector was successfully established and transfected into HeLa cells to verify that it has promoter activity, and the core area of the promoter has several tumor‑promoting and tumor suppressor genes. This provides a basis for understanding the regulatory mechanism of Hes1 transcription and translation.

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“…Silencing of Nurr1 was shown to reduce anchorage-independent growth by increasing anoikis, as demonstrated by the increase in DNA fragmentation. Apart from inhibiting apoptosis, Sun et al reported that Nurr1 increases cell proliferation [ 25 ]. Notch activation (by overexpression of four Notch receptors: ICN1, 2, 3, 4) suppresses tumor growth in cervical cancer with ICN1 displaying the most significant antitumor effect.…”

Section: Expression and Function Of Nurr1 In Cancermentioning

confidence: 99%

Role of Nurr1 in Carcinogenesis and Tumor Immunology: A State of the Art Review

Wan

Siu

Leung

et al. 2020

Cancers

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Nuclear receptor related-1 protein (Nurr1), coded by an early response gene, is involved in multiple cellular and physiological functions, including proliferation, survival, and self-renewal. Dysregulation of Nurr1 has been frequently observed in many cancers and is attributed to multiple transcriptional and post-transcriptional mechanisms. Besides, Nurr1 exhibits extensive crosstalk with many oncogenic and tumor suppressor molecules, which contribute to its potential pro-malignant behaviors. Furthermore, Nurr1 is a key player in attenuating antitumor immune responses. It not only potentiates immunosuppressive functions of regulatory T cells but also dampens the activity of cytotoxic T cells. The selective accessibility of chromatin by Nurr1 in T cells is closely associated with cell exhaustion and poor efficacy of cancer immunotherapy. In this review, we summarize the reported findings of Nurr1 in different malignancies, the mechanisms that regulate Nurr1 expression, and the downstream signaling pathways that Nurr1 employs to promote a wide range of malignant phenotypes. We also give an overview of the association between Nurr1 and antitumor immunity and discuss the inhibition of Nurr1 as a potential immunotherapeutic strategy.

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Notch Signaling Activation in Cervical Cancer Cells Induces Cell Growth Arrest with the Involvement of the Nuclear Receptor NR4A2

Cited by 39 publications

References 27 publications

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

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

The cloning and activity of human Hes1 gene promoter

Role of Nurr1 in Carcinogenesis and Tumor Immunology: A State of the Art Review

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