Inactivating p53 is essential for nerve growth factor receptor to promote melanoma-initiating cell-stemmed tumorigenesis

Jiang, Leiwei; Huang, Shibo; Wang, Jieqiong; Zhang, Yiwei; Xiong, Yan; Zeng, Shelya X.; Lu, Hua

doi:10.1038/s41419-020-02758-6

Cited by 15 publications

(13 citation statements)

References 32 publications

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“…These receptors are also expressed on nerves, and p75 neurotrophin receptor has recently been reported to act as a chemoattractant for cancer cells (54). Indeed, cancer-derived NGF drives neurite growth and cancer proliferation and migration and is correlated with nervecancer crosstalk (1,(55)(56)(57)(58)(59)(60)(61)(62)(63)(64). One notable study demonstrated an association between expanded enteric nerves and increased NGF expression in gastric cancer and the NGF/Trk signaling regulation of Dclk1+ tuft-cell coordinated crosstalk between nerves and gastric cancer (64,65).…”

Section: Neurogenic Factors Promote Axonogenesis In Cancer Progressionmentioning

confidence: 99%

Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk

et al. 2020

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In this review, we highlight recent discoveries regarding mechanisms contributing to nerve-cancer crosstalk and the effects of nerve-cancer crosstalk on tumor progression and dissemination. High intratumoral nerve density correlates with poor prognosis and high recurrence across multiple solid tumor types. Recent research has shown that cancer cells express neurotrophic markers such as nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor and release axon guidance molecules such as Ephrin B1 to promote axonogenesis. Tumor cells recruit new neural progenitors to the tumor milieu and facilitate their maturation into adrenergic infiltrating nerves. Tumors also rewire established nerves to adrenergic phenotypes via exosomeinduced neural reprogramming by p53-deficient tumors. In turn, infiltrating sympathetic nerves facilitate cancer progression. Intratumoral adrenergic nerves release noradrenaline to stimulate angiogenesis via vascular endothelial growth factor signaling and enhance the rate of tumor growth. Intratumoral parasympathetic nerves may have a dichotomous role in cancer progression and may induce Wnt-β-catenin signals that expand cancer stem cells. Importantly, infiltrating nerves not only influence the tumor cells themselves but also impact other cells of the tumor stroma. This leads to enhanced sympathetic signaling and glucocorticoid production, which influences neutrophil and macrophage differentiation, lymphocyte phenotype, and potentially lymphocyte function. Although much remains unexplored within this field, fundamental discoveries underscore the importance of nerve-cancer crosstalk to tumor progression and may provide the foundation for developing effective targets for the inhibition of tumor-induced neurogenesis and tumor progression.

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Section: Neurogenic Factors Promote Axonogenesis In Cancer Progressionmentioning

confidence: 99%

Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk

et al. 2020

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“…Cancer cells also utilize diverse oncogenic molecules to modulate the MDM2-p53 axis. For instance, NGFR and PHLDB3 that are highly expressed in multiple human cancers were found to undermine the stability and transcriptional activity of p53 by directly interacting with both MDM2 and p53 (14)(15)(16). In our recent attempt to uncover regulators of the MDM2-p53 circuit in colorectal cancer as further described below, we identified a long noncoding RNA (lncRNA) as a player crucial for cancer development and progression.…”

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confidence: 99%

Inactivation of the tumor suppressor p53 by long noncoding RNA RMRP

Chen

Hao

Wang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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p53 inactivation is highly associated with tumorigenesis and drug resistance. Here, we identify a long noncoding RNA, the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), as an inhibitor of p53. RMRP is overexpressed and associated with an unfavorable prognosis in colorectal cancer. Ectopic RMRP suppresses p53 activity by promoting MDM2-induced p53 ubiquitination and degradation, while depletion of RMRP activates the p53 pathway. RMRP also promotes colorectal cancer growth and proliferation in a p53-dependent fashion in vitro and in vivo. This anti-p53 action of RMRP is executed through an identified partner protein, SNRPA1. RMRP can interact with SNRPA1 and sequester it in the nucleus, consequently blocking its lysosomal proteolysis via chaperone-mediated autophagy. The nuclear SNRPA1 then interacts with p53 and enhances MDM2-induced proteasomal degradation of p53. Remarkably, ablation of SNRPA1 completely abrogates RMRP regulation of p53 and tumor cell growth, indicating that SNRPA1 is indispensable for the anti-p53 function of RMRP. Interestingly and significantly, poly (ADP-ribose) polymerase (PARP) inhibitors induce RMRP expression through the transcription factor C/EBPβ, and RMRP confers tumor resistance to PARP inhibition by preventing p53 activation. Altogether, our study demonstrates that RMRP plays an oncogenic role by inactivating p53 via SNRPA1 in colorectal cancer.

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“…Furthermore, nuclear translocation of p75 NTR ‐ICD helps modulate transcriptional events [23–25]. In addition, studies showed that the N terminus of p75 NTR can inactivate p53 by direct binding with its central DNA binding domain [26,27]. However, the knowledge of how p75 NTR proteolytic fragments play their roles in tumorigenesis is still largely unknown.…”

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confidence: 99%

The p75^NTR and its carboxyl‐terminal fragment exert opposing effects on melanoma cell proliferation and apoptosis via modulation of the NF‐κB pathway

et al. 2020

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The p75 neurotrophin receptor (p75 NTR), a member of the tumor necrosis factor superfamily of receptors, is sensitive to proteolysis and has been observed to be expressed in various cancers. However, the roles of p75 NTR and its proteolytic fragments in tumorigenesis remain incompletely understood. Here, we report that the proportion of the p75 NTR carboxyl-terminal fragment (p75 NTR-CTF) is much higher than that of the full-length p75 NTR (p75 NTR-FL) in melanoma cells. While p75 NTR-FL positively regulates apoptosis, p75 NTR-CTF promotes cell proliferation and survival as well as increasing sorafenib resistance in vivo and in vitro. Moreover, p75 NTR-CTF activates the NF-κB pathway and enhances the mRNA and protein levels of its downstream genes c-IAP1/2, FLIP, bFGF, IL8 and VEGF. On the contrary, p75 NTR-FL inhibits these processes. Taken together, these findings demonstrate that p75 NTR-CTF and p75 NTR-FL have opposing

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Inactivating p53 is essential for nerve growth factor receptor to promote melanoma-initiating cell-stemmed tumorigenesis

Cited by 15 publications

References 32 publications

Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk

Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk

Inactivation of the tumor suppressor p53 by long noncoding RNA RMRP

The p75^NTR and its carboxyl‐terminal fragment exert opposing effects on melanoma cell proliferation and apoptosis via modulation of the NF‐κB pathway

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Inactivating p53 is essential for nerve growth factor receptor to promote melanoma-initiating cell-stemmed tumorigenesis

Cited by 15 publications

References 32 publications

Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk

Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk

Inactivation of the tumor suppressor p53 by long noncoding RNA RMRP

The p75NTR and its carboxyl‐terminal fragment exert opposing effects on melanoma cell proliferation and apoptosis via modulation of the NF‐κB pathway

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The p75^NTR and its carboxyl‐terminal fragment exert opposing effects on melanoma cell proliferation and apoptosis via modulation of the NF‐κB pathway