Natriuretic peptide receptor A inhibition suppresses gastric cancer development through reactive oxygen species-mediated G2/M cell cycle arrest and cell death

Li, Zheng; Wang, Jiwei; Wang, Weizhi; Zhi, Xiaofei; Zhang, Qun; Li, Bowen; Wang, Linjun; Xie, Kunling; Tao, Jinqiu; Tang, Jie; Wei, Song; Zhu, Yi; Xu, Hao; Zhang, Dian-Cai; Yang, Li; Xu, Zekuan

doi:10.1016/j.freeradbiomed.2016.08.019

Cited by 26 publications

(23 citation statements)

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“…In addition to the physiological effects of the NP system, recent research has also identified NPRA expression and signalling in a number of cancers. Overexpression of NPRA correlates with tumour size and disease stage in gastric cancer (Li et al 2016), with TNM stages and poor prognosis in oesophageal squamous cell carcinomas (Zhao et al 2014) and the severity of the clinical stage of prostate cancers (Wang et al 2011). It was demonstrated in the mouse that signalling through NPRA plays a key role in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Although these SMG tissues did not show gross morphological changes, ectopic NPRA expression was identified in the glandular stroma of a subset of OSCC cases. Considering NPRA overexpression has been identified in a number of malignancies (Li et al 2016;Zhao et al 2014;Wang et al 2011), this finding warrants further studies to explore a potential link between early OSCC invasion and NPRA overexpression.…”

Section: Introductionmentioning

confidence: 87%

“…NPRA overexpression in a number of malignancies (Li et al 2016;Zhao et al 2014;Wang et al 2011) combined with the requirement for NprA for tumour growth in a murine model (Kong et al 2008) prompted us to study NPRA distribution in SMG tissue in pathological situations. Malignant tumours of SGs are uncommon, with squamous cell carcinoma (SCC) accounting for less than 1% of SG tumours (Kaszuba et al 2007).…”

Section: Ectopic Npra Expression In Submandibular Glands Of Patients mentioning

confidence: 99%

“…Indeed, mice deficient for NprA, the receptor for ANP, exhibit reduced lung inflammation in an injury model for allergic asthma, indicating ANP/NprA signalling plays a significant role in the inflammatory process (Kong et al 2008). Importantly, NP and NPR levels are altered in pathophysiological conditions such as heart failure (Volpe et al 2016) and cancers (Li et al 2016;Zhao et al 2014;Wang et al 2011). Hence understanding the varied physiological effects of NP signalling and the mechanisms at play can help elucidate the role and diagnostic and therapeutic potential of the NP system in pathophysiological conditions.…”

Section: Introductionmentioning

confidence: 99%

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Natriuretic peptide system expression in murine and human submandibular salivary glands: a study of the spatial localisation of ANB, BNP, CNP and their receptors

et al. 2019

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The natriuretic peptide (NP) system comprises of three ligands, the Atrial Natriuretic Peptide (ANP), Brain Natriuretic peptide (BNP) and C-type Natriuretic peptide (CNP), and three natriuretic peptide receptors, NPRA, NPRB and NPRC. Here we present a comprehensive study of the natriuretic peptide system in healthy murine and human submandibular salivary glands (SMGs). We show CNP is the dominant NP in mouse and human SMG and is expressed together with NP receptors in ducts, autonomic nerves and the microvasculature of the gland, suggesting CNP autocrine signalling may take place in some of these glandular structures. These data suggest the NP system may control salivary gland function during homeostasis through the regulation of electrolyte re-absorption, neural stimulation and/or blood vessel wall contraction/relaxation. We also show abnormal expression of NPRA in the stroma of a subset of human SMGs resected from patients diagnosed with oral squamous cell carcinoma (OSCC) of non-salivary gland origin. This finding warrants further research to investigate a possible correlation between early OSCC invasion and NPRA overexpression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

Section: Ectopic Npra Expression In Submandibular Glands Of Patients mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Natriuretic peptide system expression in murine and human submandibular salivary glands: a study of the spatial localisation of ANB, BNP, CNP and their receptors

et al. 2019

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“…For detection of cell viability, cells were seeded into 96-well plates (5,000 cells/well) and incubated for 6 h to allow static adherence for reducing the effects of proliferation resulting from alterations in miR-584-5p expression. Cells were incubated in RPMI-1640 medium without FBS for 48 h as described previously [19]. Cell proliferation and viability were assessed by measurement of the optical density measured at 450 nm.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of miR-584-5p inhibits proliferation and induces apoptosis by targeting WW domain-containing E3 ubiquitin protein ligase 1 in gastric cancer

Zheng

Wei

et al. 2017

J Exp Clin Cancer Res

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BackgroundMicroRNAs are endogenously expressed, small non-coding RNAs that modulate gene expression by targeting specific mRNAs, resulting in translational repression or mRNA degradation. Although miR-584-5p has been reported to play a vital role in various malignancies, its role and the molecular mechanisms underlying the effects of miR-584-5p in gastric cancer (GC) remain to be clarified. In this study, we investigated the role of miR-584-5p in GC.MethodsThe expression of miR-584-5p and its specific target gene were determined in human GC specimens and cell lines by microRNA real-time polymerase chain reaction (RT-PCR), quantitative RT-PCR (qRT-PCR) and Western blot. The effects of miR-584-5p depletion or ectopic expression on GC proliferation were evaluated in vitro using CCK-8 proliferation assays, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, colony formation assays and cell-cycle assays and the in vivo effects were investigated using a mouse tumorigenicity model. Cell apoptosis was evaluated by in vitro flow cytometric analysis, cell viability assays and in vivo TUNEL assays. Luciferase reporter assays were employed to identify interactions between miR-584-5p and its specific target gene.ResultsA series of in vitro and in vivo gain- and loss-of-function assays revealed that miR-584-5p inhibited GC cell proliferation, while apoptosis was induced. Luciferase reporter assays and Western blot analysis revealed WWP1 to be a direct target of miR-584-5p. The effects of miR-584-5p-mimic were rescued by WWP1 overexpression. In contrast, the effects of the miR-584-5p-inhibitor were impaired by WWP1-shRNA. Furthermore, miR-584-5p expression levels correlated negatively with WWP1 protein expression in GC tissues and GC cell lines. A series of investigations indicated that miR-584-5p promoted senescence and activated the TGFβ signaling pathway by downregulation of WWP1.ConclusionTaken together, these results suggest that downregulation of miR-584-5p contributes to tumor progression by downregulation of WWP1, thus, highlighting the potential of miR-584-5p as a therapeutic target for human GC.

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Therapeutic antibody targeting natriuretic peptide receptor 1 inhibits gastric cancer growth viaBCL‐2‐mediated intrinsic apoptosis

Sasahara,

Kanda,

Tanaka

et al. 2023

Intl Journal of Cancer

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Despite recent advances in the development of therapeutic antibodies, the prognosis of unresectable or metastatic gastric cancer (GC) remains poor. Here, we searched for genes involved in the malignant phenotype of GC and investigated the potential of one candidate gene to serve as a novel therapeutic target. Analysis of transcriptome datasets of GC identified natriuretic peptide receptor 1 (NPR1), a plasma membrane protein, as a potential target. We employed a panel of human GC cell lines and gene‐specific small interfering RNA‐mediated NPR1 silencing to investigate the roles of NPR1 in malignancy‐associated functions and intracellular signaling pathways. We generated an anti‐NPR1 polyclonal antibody and examined its efficacy in a mouse xenograft model of GC peritoneal dissemination. Associations between NPR1 expression in GC tissue and clinicopathological factors were also evaluated. NPR1 mRNA was significantly upregulated in several GC cell lines compared with normal epithelial cells. NPR1 silencing attenuated GC cell proliferation, invasion, and migration, and additionally induced the intrinsic apoptosis pathway associated with mitochondrial dysfunction and caspase activation via downregulation of BCL‐2. Administration of anti‐NPR1 antibody significantly reduced the number and volume of GC peritoneal tumors in xenografted mice. High expression of NPR1 mRNA in clinical GC specimens was associated with a significantly higher rate of postoperative recurrence and poorer prognosis. NPR1 regulates the intrinsic apoptosis pathway and plays an important role in promoting the GC malignant phenotype. Inhibition of NPR1 with antibodies may have potential as a novel therapeutic modality for unresectable or metastatic GC.

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Natriuretic peptide receptor A inhibition suppresses gastric cancer development through reactive oxygen species-mediated G2/M cell cycle arrest and cell death

Cited by 26 publications

References 50 publications

Natriuretic peptide system expression in murine and human submandibular salivary glands: a study of the spatial localisation of ANB, BNP, CNP and their receptors

Natriuretic peptide system expression in murine and human submandibular salivary glands: a study of the spatial localisation of ANB, BNP, CNP and their receptors

Overexpression of miR-584-5p inhibits proliferation and induces apoptosis by targeting WW domain-containing E3 ubiquitin protein ligase 1 in gastric cancer

Therapeutic antibody targeting natriuretic peptide receptor 1 inhibits gastric cancer growth viaBCL‐2‐mediated intrinsic apoptosis

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