GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer

Sawada, Yuichiro; Kikugawa, Tadahiko; Iio, Hiroyuki; Sakakibara, Iori; Yoshida, Shuhei; Ikedo, Aoi; Yanagihara, Yoshio; Saeki, Noritaka; Győrffy, Balázs; Kishida, Takeshi; Okubo, Yoichiro; Nakamura, Yoshiyasu; Miyagi, Yohei; Sakaguchi, Takashi; Imai, Yuuki

doi:10.1002/ijc.32554

Cited by 37 publications

(31 citation statements)

References 49 publications

(95 reference statements)

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“…In our study, increased GPRC5A expression was associated with a shorter survival. This is in agreement with results from prostate cancer, where GPRC5A expression also predicts a worse OS and was shown to be involved in metastasis since knock-down of this molecule limited bone metastasis 27 .…”

Section: Discussionsupporting

confidence: 92%

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A multi-layered systems approach for renal cell carcinoma

Rudewicz

Souleyreau

et al. 2020

Preprint

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Acknowledgments:This work was supported by grants from the PlanCancer («Systems Biology of Renal Cell Carcinoma using an Experimental RCC model» (C18005GS, SystemsRCC)) and from the university Bordeaux (G2P project) to AB. LC and AE were supported by post-doctoral fellowships from the Region "Nouvelle Aquitaine". The Crispr/cas9 construct was gratefully provided by Michel Tremblay (Goodman Cancer Center, McGill, University). The authors would like to thank the lentiviral production plateform Vect'UB for EGFP lentivirus, the "service commun des animaleries" for animal production and housing, and the Bordeaux Imaging Center (BIC). 2 AbstractIn order to discover molecular pathways and players in renal cancer development and metastasis, we developed a mouse model to generate sequentially more aggressive and specialized cell lines. Multiple cell lines for primary tumor growth, survival in the blood circulation and lung metastasis or metastatic spread from the primary tumor were generated and analyzed using a multi-layered approach which includes large-scale transcriptome, genome and methylome analyses. Transcriptome and methylome analyses demonstrated distinct clustering in three different groups. Remarkably, DNA sequencing did not show significant genomic variations in the different groups which indicates absence of clonal selection during the in vivo amplification process. Transcriptome analysis revealed several markers and signatures of tumor aggressiveness which were validated, at the mRNA and protein level, in patient cohorts from TCGA, local biobanks and clinical trials. This also includes soluble markers. In particular, SAA2 and CFB were highly predictive for survival and tumor progression. Methylome analysis of full-length DNA allowed clustering of the same groups and revealed clinically predictive signatures. We also uncovered IL34 as a key regulator of renal cell carcinoma (RCC) progression which was also functionally validated in vivo, and a mathematical model of IL34-dependent primary tumor growth and metastasis development was provided. These results indicate that such multilayered analysis in a RCC animal model leads to meaningful results that are of translational significance. 3

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Section: Discussionsupporting

confidence: 92%

“…GPRC5a is involved in epithelial cancers 27 and is proposed to be an emerging biomarker in several human cancers 28 . It was upregulated in all 3 conditions (K, L, T) ( Supplementary Fig.…”

Section: G Protein-coupled Receptor Class C Group 5 Member a (Gprc5a)mentioning

confidence: 99%

A multi-layered systems approach for renal cell carcinoma

Rudewicz

Souleyreau

et al. 2020

Preprint

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“…Among these thousands of candidates, GPRC5A was of interest in the current research because its expression had been found to be up-regulated in GC and the elevated expression of GPRC5A predicted advanced clinical features and poor prognosis [28,29]. GPRC5A was also reported to act as a potential oncogene in prostate cancer and pancreatic ductal adenocarcinoma [30,31]. Moreover, GPRC5A was involved in GC cell malignant progression through acting as a direct target of miR-204 and miR-195 [32,33].…”

Section: Discussionmentioning

confidence: 99%

Circ_0000144 functions as a miR-623 sponge to enhance gastric cancer progression via up-regulating GPRC5A

Lei

Yin

et al. 2020

Bioscience Reports

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Background: Gastric cancer (GC) remains one of the most common malignancies worldwide. Increasing evidence has demonstrated that circRNAs serve as critical roles in human cancer, including GC. In the current study, we focused on the detailed function and mechanism of circ_0000144 on GC progression. Methods: The levels of circ_0000144, miR-623 and G protein-coupled receptor, family C, group 5, member A (GPRC5A) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Targeted relationships among circ_0000144, miR-623 and GPRC5A were confirmed using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Cell proliferation, colony formation, apoptosis, migration and invasion were evaluated by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, flow cytometry and transwell assays. Measurement of glutamine and α-ketoglutarate (α-KG) levels was performed using a corresponding assay kit. GPRC5A protein expression was detected using western blot. Results: Our data indicated that circ_0000144 was up-regulated and miR-623 was down-regulated in GC tissues and cells. Circ_0000144 interacted with miR-623 through directly binding to miR-623. Moreover, the knockdown of circ_0000144 weakened GC cell proliferation, colony formation, migration, invasion and glutaminolysis and accelerated cell apoptosis by up-regulating miR-623. GPRC5A was a direct target of miR-623 and circ_0000144 protected against GPRC5A repression through sponging miR-623. Furthermore, miR-623-mediated regulation on GC cell progression was reversed by the stored expression of GPRC5A. Additionally, circ_0000144 depletion inhibited tumor growth in vivo. Conclusion: Our study indicated that circ-0000144 knockdown repressed GC progression at least partly by regulating GPRC5A expression via sponging miR-623, illumining a novel therapeutic target for GC treatment.

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“…Many observations have highlighted a strong connection between alterations in GPRC5A and several human cancers (Jiang et al, 2018), and in particular with the presence of more aggressive and metastatic phenotypes through the induction of the EMT Sawada et al, 2020;Liu et al, 2017). EMT takes place physiologically during embryonic development, tissue regeneration, organ fibrosis, and wound healing.…”

Section: Discussionmentioning

confidence: 99%

Autoregulatory circuit regulating basolateral cargo export from the TGN: role of the orphan receptor GPRC5A in PKD signaling and cell polarity

Martino

Capalbo

Sticco

et al. 2020

Preprint

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The membrane transport apparatus comprises a series of separate membrane bound compartments, or transport stations, that are responsible for the synthesis, processing, transport, sorting and delivery to their final cellular destinations of most transmembrane and soluble lumenal proteins. Over the last decades the membrane transport system has been shown to be extensively regulated both by environmental inputs and by internal homeostatic signalling systems, or control systems, that operate to maintain the homeostasis and optimal functionality of the main transport stations, such as the endoplasmic reticulum and the Golgi, in the face of internal and external perturbations. The trans-Golgi network (TGN) is a major transport and processing station and the main sorting compartment of the transport apparatus. However, the mechanisms that control cargo export and sorting at the TGN have so far remained elusive. Here we focus on the sorting of basolateral cargo proteins and show that these proteins bind to the TGN localized orphan receptor GPRC5A. The cargo-GPRC5A complex triggers the activation of a signaling pathway that involves the Gβγ subunits dependent activation of the phospholipase C beta 3 (PLCβ3), which inturn induces diacyl glycerol (DAG) production. DAG recruits and activates protein kinase D (PKD) and the phosphorylation of its substrates. This step results in the formation of basolateral carriers for delivery of these cargoes to the basolateral plasma membrane domain. We term this mechanism "ARTG" (AutoRegulation of TGN export). Remarkably, the impairment of ARTG pathway components, and in particular of GPRC5A, causes defects in the polarized organization of epithelial cells.

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GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer

Cited by 37 publications

References 49 publications

A multi-layered systems approach for renal cell carcinoma

A multi-layered systems approach for renal cell carcinoma

Circ_0000144 functions as a miR-623 sponge to enhance gastric cancer progression via up-regulating GPRC5A

Autoregulatory circuit regulating basolateral cargo export from the TGN: role of the orphan receptor GPRC5A in PKD signaling and cell polarity

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