Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth

Hall, Chad; Ehrlich, Laurent; Venter, Julie; O’Brien, April; White, Tori; Zhou, Tianhao; Dang, Tien; Meng, Fanyin; Invernizzi, Pietro; Bernuzzi, Francesca; Alpini, Gianfranco; Lairmore, Terry C.; Glaser, Shannon

doi:10.1016/j.canlet.2016.11.025

Cited by 46 publications

(43 citation statements)

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“…11 In a cholangiocarcinoma cell model and in in vitro/in vivo experiments with glioblastoma cells, inhibition of the APLN/APLNR axis has resulted in decreased proliferation and angiogenesis. 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.…”

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%

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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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confidence: 99%

Section: Introductionmentioning

confidence: 99%

Apelin and apelin receptor expression in renal cell carcinoma

et al. 2019

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“…APJ/apelin expression is elevated in many malignant tissues (4), indicating that its misexpression/activation may be crucial in tumorigenesis. Studies have also shown that increased expression and/or activation of this axis in the cancer cells as well as in the stroma, contributes to cancer progression mainly by increasing tumor-related angiogenesis (5-7) and proliferation (8)(9)(10). However, the extent of APJ expression by cancer cells and its pathophysiologic roles in human cancers remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Multifunctional APJ Pathway Promotes Ovarian Cancer Progression and Metastasis

Neelakantan

Dogra

Devapatla

et al. 2019

Molecular Cancer Research

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High mortality rates in ovarian cancer are due to late-stage diagnosis when extensive metastases are present, coupled with the eventual development of resistance to standard chemotherapy. There is, thus, an urgent need to identify targetable pathways to curtail this deadly disease. In this study, we show that the apelin receptor, APJ, is a viable target that promotes tumor progression of high-grade serous ovarian cancer (HGSOC). APJ is specifically overexpressed in tumor tissue, and is elevated in metastatic tissues compared with primary tumors. Importantly, increased APJ expression significantly correlates with decreased median overall survival (OS) by 14.7 months in patients with HGSOC. Using various ovarian cancer model systems, we demonstrate that APJ expression in cancer cells is both necessary and sufficient to increase prometastatic phenotypes in vitro, including proliferation, cell adhesion to various molecules of the extracellular matrix (ECM), anoikis resistance, migration, and invasion; and these phenotypes are efficiently inhibited by the APJ inhibitor, ML221. Overexpression of APJ also increases metastasis of ovarian cancer cells in vivo. Mechanistically, the prometastatic STAT3 pathway is activated downstream of APJ, and in addition to the ERK and AKT pathways, contributes to its aggressive phenotypes. Our findings suggest that the APJ pathway is a novel and viable target, with potential to curb ovarian cancer progression and metastasis. Implications: The APJ pathway is a viable target in HGSOC.

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“…Many studies have shown that APLNR also plays an important role in tumors. Hall et al (15) reported that inhibition of APLNR decreases cholangiocarcinoma proliferation and angiogenesis, and overexpression of the apelin-APLNR axis induces tumor arteriogenesis in hepatocellular carcinoma (16).…”

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confidence: 99%

APLNR is involved in ATRA‐induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K‐Akt‐mTOR signaling

Liu¹,

Liu²,

Chen³

et al. 2019

The FASEB Journal

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The apelin receptor (APLNR) is a GPCR involved in many pathophysiological processes; however, the correlation between APLNR expression and nasopharyngeal carcinoma (NPC) has not been reported. In this study, we used cDNA microarray data to determine APLNR expression levels in NPC tissues. We found that APLNR expression was reduced in NPC tissues compared with noncancerous nasopharyngeal epithelial tissues. Subsequently, a large‐scale sample of 1015 tissues was used to validate this discovery and explore the relationship between APLNR expression and prognosis of NPC. Expression levels of APLNR in NPC tissues were indeed down‐regulated. Furthermore, positive expression of APLNR in NPC predicted a better prognosis (disease‐free survival: P = 0.001; overall survival: P < 0.001). Moreover, ingenuity pathway analysis revealed that an indirect interaction existed between APLNR and retinoic acid (RA) in the cancer regulatory network. Consistently, after treatment with all‐trans‐RA (ATRA), we found that APLNR was significantly up‐regulated in NPC cell lines (5‐8F and HNE1), and proliferation of NPC cells was inhibited. Cell cycle arrest occurred in the G0/G1 phase. In contrast, knockdown of APLNR diminished ATRA‐induced growth inhibition of NPC cells. In addition, we surprisingly found that APLNR also played an important role in migration and invasion of NPC. Wound‐healing and Transwell assays revealed that APLNR overexpression led to reduced migratory and invasive properties in 2 NPC cell lines. Western blot results revealed that hallmarks of epithelial‐mesenchymal transition (EMT) were altered as well, suggesting that APLNR was capable of inhibiting EMT in NPC cells. Our study further demonstrated that low expression of APLNR promoted EMT in NPC cells by activating the PI3K‐protein kinase B‐mammalian target of rapamycin signaling pathway. Taken together, our data suggest that APLNR could potentially predict prognosis for patients with NPC and inhibit proliferation, migration, invasion, and EMT in nasopharyngeal cancer cells.—Liu, Y., Liu, Q., Chen, S., Liu, Y., Huang Y., Chen, P., Li, X., Gao, G., Xu, K., Fan, S., Zeng Z., Xiong W., Tan, M., Li, G., Zhang W. APLNR is involved in ATRA‐induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K‐Akt‐mTOR signaling. FASEB J. 33, 11959‐11972 (2019). http://www.fasebj.org

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Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth

Cited by 46 publications

References 61 publications

Apelin and apelin receptor expression in renal cell carcinoma

Apelin and apelin receptor expression in renal cell carcinoma

Multifunctional APJ Pathway Promotes Ovarian Cancer Progression and Metastasis

APLNR is involved in ATRA‐induced growth inhibition of nasopharyngeal carcinoma and may suppress EMT through PI3K‐Akt‐mTOR signaling

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