Apelin/APJ system and cancer

Yang, Yanjie; Lv, Shuangyu; Ye, Wenling; Zhang, Liang

doi:10.1016/j.cca.2016.04.001

Cited by 72 publications

(56 citation statements)

References 50 publications

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“…Previous studies have shown that hyperplastic and neoplastic cholangiocytes secrete a variety of hormones, peptides, and growth factors that help regulate cell proliferation [36]. Hypoxia appears to be a major factor in tumor angiogenesis by increasing expression of VEGF and hypoxia-inducible factor (HIF) [5,37]. Similarly, Heo et al demonstrated that apelin expression was significantly up regulated under hypoxic conditions in oral squamous cell carcinoma, which correlated with increased cell proliferation and migration [38].…”

Section: Discussionmentioning

confidence: 99%

“…Apelin is a bioactive peptide and endogenous ligand for the APJ receptor (APLNR), a member of the G protein coupled receptor family that shares a similar sequence as the angiotensin type-1 receptor (AT1) [5]. Early studies demonstrated that the apelin/APLNR receptor axis plays a significant role in blood pressure regulation and cardiovascular disease by regulating angiogenesis and the response of endothelial cells to hypoxic injury [6–9].…”

Section: Introductionmentioning

confidence: 99%

“…More recent studies have shown that the apelin/APLNR axis also regulates angiogenesis and growth of certain malignancies, potentially serving as a novel therapeutic target [5,11]. Additionally, apelin has been shown to promote lymphangiogenesis and lymph node metastasis, further emphasizing its importance in cancer physiology [12].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth

et al. 2017

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Purpose Cholangiocarcinoma (CCA) is a malignancy of the biliary epithelium that is associated with low five-year survival. The apelin receptor (APLNR), which is activated by the apelin peptide, has not been studied in CCA. The purpose of this study is to determine if inhibition of the apelin/APLNR axis can inhibit CCA growth. Methods Immunohistochemistry, rtPCR, immunofluorescence, flow cytometry, and ELISA was used to measure APLNR expression in human CCA cells and tissues. Mz-ChA-1 cells were treated with increasing concentrations of apelin and ML221, an APLNR antagonist. Expression of proliferative and angiogenic genes were measured via rtPCR. In vivo, Mz-ChA-1 cells were injected into the flanks of nu/nu mice, which were treated with ML221 (150 μg/kg) via tail vein injection. Results Expression of the apelin/APLNR axis was increased in CCA. In vitro, CCA proliferation and angiogenesis was inhibited by ML221 treatment. ML221 treatment significantly decreased tumor growth in nu/nu mice. Conclusion The apelin/APLNR axis regulates CCA proliferation and angiogenesis. Inhibition of the apelin/APLNR axis decreases tumor growth in our xenograft model. Targeting APLNR signaling has the potential to serve as a novel, tumor directed therapy for CCA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth

et al. 2017

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“…8,18 The role of the APLNR-axis for tumour neo-angiogenesis, especially under hypoxia, regulated by hypoxia-inducible factor (HIF)-1alpha, is well documented. 9,19,20 ccRCC is a highly vascularised tumour with high levels of intratumoural HIF, which accumulates due to inactivation of the von Hippel-Lindau gene. 21 This could explain the generally high vascular expression of the APLNR and APLN in tumour tissues in our study.…”

Section: )mentioning

confidence: 99%

“…5 Since apelin (APLN) and the apelin receptor have long been known to play important roles in vascular physiology, 6,7 emerging evidence of their importance in oncological diseases is not surprising. [8][9][10][11] Given the paucity of data concerning the role of APLN and APLNR in renal cell carcinoma 12 and the importance of immune evasion mechanisms of this tumour, our study aimed to investigate the expression of APLN and APLNR in RCC and its association with clinicopathological parameters and survival.…”

Section: Introductionmentioning

confidence: 99%

Apelin and apelin receptor expression in renal cell carcinoma

et al. 2019

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BACKGROUND: The APLNR (apelin receptor) has been shown to be an essential gene for cancer immunotherapy, with deficiency in APLNR leading to immunotherapy failure. The aim of this study is to investigate the expression of APLN (apelin) and APLNR in patients with renal cell carcinoma (RCC), and its association with clinicopathological parameters and survival. METHODS: Three well-characterised patient cohorts with RCC were used: Study cohort 1 (clear-cell RCC; APLN/APLNR mRNA expression; n = 166); TCGA validation cohort (clear-cell RCC; APLN/APLNR mRNA expression; n = 481); Study cohort 2 (all RCC subtypes; APLNR protein expression/immunohistochemistry; n = 300). Associations between mRNA/protein expression and clinicopathological variables/patients' survival were tested statistically. RESULTS: While APLN showed only very weak association with tumour histological grade (TCGA cohort), APLNR/mRNA protein expression correlate significantly with ccRCC aggressiveness. APLNR is expressed in tumour vasculature and tumour cells at different levels, and these expression levels associate with tumour aggressiveness in opposing directions. APLNR expression was negatively correlated with PD-L1 expression by tumour cells in a subset of patients with ccRCC. APLNR expression in either compartment is an independent prognostic factor for survival of patients with ccRCC. CONCLUSION: The APLNR/APLN-system appears to play an important role in ccRCC, warranting further clinical investigation.

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MicroRNA‐204 deregulation in lung adenocarcinoma controls the biological behaviors of endothelial cells potentially by modulating Janus kinase 2–signal transducer and activator of transcription 3 pathway

et al. 2017

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MicroRNAs (miRNAs) have been implicated in a wide range of biological processes including angiogenesis. MiR-204 was identified as a tumor suppressor in multiple cancer types, including lung adenocarcinoma. However, the function of miR-204 in lung tumor angiogenesis remains unknown. In this study, we found that the miR-204 expression was decreased in lung adenocarcinoma based on the cancer genome atlas (TCGA) analysis and gain-of-function experiment showed that miR-204 promoted cancer cell apoptosis and suppressed cell proliferation, migration in vitro and tumor growth in vivo. Functionally, both the tube formation and migration abilities of human umbilical vein endothelial cells (HUVECs) were suppressed by conditioned media from lung cancer A549 cells with miR-204 overexpression. Meanwhile, these conditioned media inhibited proliferation and promoted apoptosis in HUVECs. The key angiogenesis inducer hypoxia inducible factor-1α (HIF1α) and the pro-angiogenic mediators vascular endothelial growth factor and platelet-derived growth factor were decreased in A549 cells transfected with miR-204 mimics. Mechanistically, miR-204 could target Janus kinase 2 (JAK2) and further impaired signal transducer and activator of transcription 3 both in vitro and in vivo. Inhibition of JAK2 or signal transducer and activator of transcription 3 (STAT3) activity with small chemical inhibitors in A549 cells impaired lung adenocarcinoma angiogenesis in vitro. Meanwhile, conditional media from interleukin 6-treated lung normal epithelial cells significantly promoted tube formation of HUVEC, which was disturbed by miR-204 overexpression. Taken together, our findings demonstrate that miR-204 attenuates angiogenesis in lung adenocarcinoma potentially via JAK2-STAT3 pathway. Clinically, the miR-204/JAK2/STAT3 signaling pathway is a putative therapeutic target in lung adenocarcinoma. © 2017 IUBMB Life, 70(1):81-91, 2018.

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Apelin/APJ system and cancer

Cited by 72 publications

References 50 publications

Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth

Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth

Apelin and apelin receptor expression in renal cell carcinoma

MicroRNA‐204 deregulation in lung adenocarcinoma controls the biological behaviors of endothelial cells potentially by modulating Janus kinase 2–signal transducer and activator of transcription 3 pathway

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