KISS1R

Gene Summary

Gene:KISS1R; KISS1 receptor
Aliases: HH8, CPPB1, GPR54, AXOR12, KISS-1R, HOT7T175
Location:19p13.3
Summary:The protein encoded by this gene is a galanin-like G protein-coupled receptor that binds metastin, a peptide encoded by the metastasis suppressor gene KISS1. The tissue distribution of the expressed gene suggests that it is involved in the regulation of endocrine function, and this is supported by the finding that this gene appears to play a role in the onset of puberty. Mutations in this gene have been associated with hypogonadotropic hypogonadism and central precocious puberty. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:kiSS-1 receptor
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: KISS1R (cancer-related)

Jabeen S, Qureshi MZ, Javed Z, et al.
Kisspeptin Mediated Signaling in Cancer.
Curr Top Med Chem. 2016; 16(22):2471-6 [PubMed] Related Publications
Research over the years has gradually and sequentially highlighted contributory role of hypothalamic- based kisspeptin-signaling axis as a major positive modulator of the neuroendocrinological reproductive axis in mammals. However, a series of landmark studies provided convincing evidence of role of this signaling in regulation of cancer development and progression. It is becoming progressively more understandable that loss or reduction of KISS1 expression in different human cancers correlates inversely with progression of tumor, metastasizing potential and survival. In this review we have attempted to provide an overview highlight of the most recent updates addressing metastasis- suppressing role of KISS1. We also summarize interplay of microRNA and KISS1 in cancer. The miRNA regulation of different genes is a rapidly expanding area of research however, the community lacks a deep understanding of miRNA regulation of KISS1. Recently, emerging laboratory findings have shown that KISS1 is transcriptionally controlled by TCF21 that is in turn regulated by miR-21. Therefore, there is an urgent need for further study of how miRNA directly or indirectly influences KISS1 at the posttranscriptional level. There is also a lack of evidence regarding natural agents that mediate upregulation or downregulation of KISS1. Increasing the knowledge of the KISS1/KISS1R signaling axis will be helpful in achieving personalized medicine.

Uno M, Kokuryo T, Yokoyama Y, et al.
α-Bisabolol Inhibits Invasiveness and Motility in Pancreatic Cancer Through KISS1R Activation.
Anticancer Res. 2016; 36(2):583-9 [PubMed] Related Publications
α-Bisabolol is a plant-derived, oily sesquiterpene alcohol that induces apoptosis of various cancer cells. We previously reported the antiproliferative effects of α-bisabolol on pancreatic cancer cell lines using in vitro and in vivo experiments. However, the effects of α-bisabolol on tumor invasiveness and motility are still unknown. In this study, demonstrated that α-bisabolol suppressed the invasiveness and motility of a pancreatic cancer cell line. Although Early growth response 1 (EGR1) was involved in antiproliferative effects of α-bisabolol, it had no relationship with the inhibitory effect of α-bisabolol on cellular invasiveness and motility. Polymerase chain reaction analysis revealed that α-bisabolol induced Kisspeptin 1 receptor (KISS1R) in pancreatic cancer cell lines. The inhibition of KISS1R weakened the inhibitory effect of α-bisabolol on invasiveness of pancreatic cancer cells. The results also implied that the inhibitory effects of α-bisabolol on tumor invasiveness and motility are at least partly associated with the activation of KISS1R. However, there is a possibility that other molecular mechanisms of α-bisabolol regulate invasiveness and motility in pancreatic cancer cells. Further investigations are necessary to clarify the precise mechanisms of α-bisabolol activity for clinical application as a novel treatment for pancreatic cancer.

Goertzen CG, Dragan M, Turley E, et al.
KISS1R signaling promotes invadopodia formation in human breast cancer cell via β-arrestin2/ERK.
Cell Signal. 2016; 28(3):165-76 [PubMed] Related Publications
Kisspeptins (KPs), peptide products of the KISS1 gene are endogenous ligands for the kisspeptin receptor (KISS1R), a G protein-coupled receptor. In numerous cancers, KISS1R signaling plays anti-metastatic roles. However, we have previously shown that in breast cancer cells lacking the estrogen receptor (ERα), kisspeptin-10 stimulates cell migration and invasion by cross-talking with the epidermal growth factor receptor (EGFR), via a β-arrestin-2-dependent mechanism. To further define the mechanisms by which KISS1R stimulates invasion, we determined the effect of down-regulating KISS1R expression in triple negative breast cancer cells. We found that depletion of KISS1R reduced their mesenchymal phenotype and invasiveness. We show for the first time that KISS1R signaling induces invadopodia formation and activation of key invadopodia proteins, cortactin, cofilin and membrane type I matrix metalloproteases (MT1-MMP). Moreover, KISS1R stimulated invadopodia formation occurs via a new pathway involving a β-arrestin2 and ERK1/2-dependent mechanism, independent of Src. Taken together, our findings suggest that targeting the KISS1R signaling axis might be a promising strategy to inhibit invasiveness and metastasis.

Wang CH, Qiao C, Wang RC, Zhou WP
KiSS‑1‑mediated suppression of the invasive ability of human pancreatic carcinoma cells is not dependent on the level of KiSS‑1 receptor GPR54.
Mol Med Rep. 2016; 13(1):123-9 [PubMed] Free Access to Full Article Related Publications
The onset of local invasion and lymphatic metastasis in pancreatic cancer limits survival following surgical intervention and additional therapies. Reduced expression of KiSS‑1 in pancreatic cancer is associated with cancer metastasis. Previous studies have indicated that kisspeptin, the KiSS‑1 peptide, is able to bind to its receptor‑GPR54 (hOT7T175) and suppress the migration of PANC‑1 pancreatic cancer cells. Whether the metastatic suppression of KiSS‑1 is dependent on the levels of GPR54 in pancreatic cancer cell lines remains unclear. Human BxPC‑3 pancreatic carcinoma cells are highly differentiated without exhibiting metastasis, however PANC‑1 pancreatic carcinoma cells are poorly differentiated and exhibit local and lymph node metastasis. Compared with primary cultured trophoblasts, BxPc‑3 and PANC‑1 cells were observed to express low levels of KiSS‑1 mRNA and protein, measured using reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. However, greater mRNA and protein expression levels of GPR54 were observed in PANC‑1 cells compared with BxPc‑3 cells. An MTT assay was used to investigate the effect of KiSS‑1 on BxPc‑3 and PANC‑1 cell proliferation. There were no significant differences in proliferation following transfection with KiSS‑1 in BxPc‑3 and PANC‑1 cells compared with the controls (P>0.05). A Transwell assay with chambers coated with Matrigel was used to evaluate the in vitro invasive ability of BxPc‑3 and PANC‑1 cells, with the invasion index of BxPc‑3 and PANC‑1 cells significantly reduced following 48 h of KiSS‑1 overexpression (P<0.05). The mRNA and protein expression levels of KiSS‑1 were significantly increased in BxPc‑3 and PANC‑1 cells 48 h subsequent to transfection with KiSS‑1 (P<0.05), while GPR54 expression was not altered (P>0.05). KiSS‑1 is a metastasis suppressor gene of pancreatic cancer, and this suppression is not dependent on the expression levels of GPR54. Therefore, KiSS‑1 is potentially a novel target for gene therapy.

Kostakis ID, Agrogiannis G, Vaiopoulos AG, et al.
A clinicopathological analysis of KISS1 and KISS1R expression in colorectal cancer.
APMIS. 2015; 123(7):629-37 [PubMed] Related Publications
Kisspeptins, the products of the KISS1 gene have tumor suppressing and antimetastatic properties. We aimed to study KISS1 and KISS1R expression in colorectal cancer. We analyzed KISS1 and KISS1R expression using immunohistochemistry and image analysis in normal and malignant tissue samples from 111 patients with colorectal adenocarcinoma. KISS1 expression was much higher in the normal than in the malignant colonic mucosa. Regarding malignant tissues, KISS1 levels were higher in larger tumors, in stage III and IV cancers, in cancers with lymph node metastasis and in tumors located in the distal part of the large intestine. Patients with greater KISS1 levels had worse prognosis. No KISS1R expression was detected in normal or malignant tissues or in liver metastases. KISS1 expression is reduced during the malignant transformation of the colonic mucosa. However, larger and advanced colorectal cancers express more KISS1, without reaching the former normal levels, and increased KISS1 levels are associated with worse prognosis. Finally, neither the normal nor the malignant colonic epithelial cells produce KISS1R.

Wang X, Zhang Y, Nilsson CL, et al.
Association of chromosome 19 to lung cancer genotypes and phenotypes.
Cancer Metastasis Rev. 2015; 34(2):217-26 [PubMed] Related Publications
The Chromosome 19 Consortium, a part of the Chromosome-Centric Human Proteome Project (C-HPP, http://www.C-HPP.org ), is tasked with the understanding chromosome 19 functions at the gene and protein levels, as well as their roles in lung oncogenesis. Comparative genomic hybridization (CGH) studies revealed chromosome aberration in lung cancer subtypes, including ADC, SCC, LCC, and SCLC. The most common abnormality is 19p loss and 19q gain. Sixty-four aberrant genes identified in previous genomic studies and their encoded protein functions were further validated in the neXtProt database ( http://www.nextprot.org/ ). Among those, the loss of tumor suppressor genes STK11, MUM1, KISS1R (19p13.3), and BRG1 (19p13.13) is associated with lung oncogenesis or remote metastasis. Gene aberrations include translocation t(15, 19) (q13, p13.1) fusion oncogene BRD4-NUT, DNA repair genes (ERCC1, ERCC2, XRCC1), TGFβ1 pathway activation genes (TGFB1, LTBP4), Dyrk1B, and potential oncogenesis protector genes such as NFkB pathway inhibition genes (NFKBIB, PPP1R13L) and EGLN2. In conclusion, neXtProt is an effective resource for the validation of gene aberrations identified in genomic studies. It promises to enhance our understanding of lung cancer oncogenesis.

Cheng S, Castillo V, Eliaz I, Sliva D
Honokiol suppresses metastasis of renal cell carcinoma by targeting KISS1/KISS1R signaling.
Int J Oncol. 2015; 46(6):2293-8 [PubMed] Free Access to Full Article Related Publications
Renal cell carcinoma (RCC) is a common urological cancer worldwide and is known to have a high risk of metastasis, which is considered responsible for more than 90% of cancer associated deaths. Honokiol is a small-molecule biphenol isolated from Magnolia spp. bark and has been shown to be a potential anticancer agent involved in multiple facets of signal transduction. In this study, we demonstrated that honokiol inhibited the invasion and colony formation of highly metastatic RCC cell line 786-0 in a dose-dependent manner. DNA-microarray data showed the significant upregulation of metastasis-suppressor gene KISS1 and its receptor, KISS1R. The upregulation was confirmed by qRT-PCR analysis. Overexpression of KISS1 and KISS1R was detected by western blotting at the translation level as well. Of note, the decreased invasive and colonized capacities were reversed by KISS1 knockdown. Taken together, the results first indicate that activation of KISS1/KISS1R signaling by honokiol suppresses multistep process of metastasis, including invasion and colony formation, in RCC cells 786-0. Honokiol may be considered as a natural agent against RCC metastasis.

Ji K, Ye L, Ruge F, et al.
Implication of metastasis suppressor gene, Kiss-1 and its receptor Kiss-1R in colorectal cancer.
BMC Cancer. 2014; 14:723 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Kiss-1 and Kiss-1R have been suggested as a novel pair of metastasis suppressors for several human solid tumours, however, their role in colorectal cancer remains largely unknown. Therefore, the aim of this study was to investigate the role and signal transduction of Kiss-1 and Kiss-1R in colorectal cancer.
METHODS: Ribozyme transgenes were used to knockdown high expression of Kiss-1 and Kiss-1R in HT115 and HRT18 cells. The stabilized transfected cells were then used to deduce the influence of Kiss-1 and Kiss-1R on the function of colorectal cancer cells by in vitro assays and ECIS assay. The effect of Kiss-1 on MMPs related to tumour metastasis was also deleted by zymography. The mRNA and protein expression of Kiss-1 and Kiss-1R, and their correlation to the clinical outcome in human colorectal cancer were investigated using real-time PCR and IHC respectively.
RESULTS: Knocking down Kiss-1 resulted in increased invasion and migration of colorectal cancer cells. Kisspeptin-10 decreased cellular migration of colorectal cancer cells and required ERK signaling as shown during the ECIS based analyses. Reduction of MMP-9 was caused by Kisspeptin-10 and ERK inhibitor, shown by zymography. In human colorectal cancer tissues, the mRNA expression level of Kiss-1 had a negative correlation with Dukes staging, TNM staging, tumour size and lymph node involvement. Reduction of Kiss-1R was also linked to poor prognosis for the patients.
CONCLUSIONS: The present study has presented evidence that Kiss-1 may be a putative metastasis suppressor molecule in human colorectal cancer.

Baba T, Kang HS, Hosoe Y, et al.
Menstrual cyclic change of metastin/GPR54 in endometrium.
Med Mol Morphol. 2015; 48(2):76-84 [PubMed] Related Publications
Metastin/kisspeptin is encoded by KISS1 and functions as an endogenous ligand of GPR54. Interaction of metastin with GPR54 suppresses metastasis and also regulates release of gonadotropin-releasing hormone, which promotes secretion of estradiol (E2) and progesterone (P4). We have previously demonstrated epigenetic regulation of GPR54 in endometrial cancer and the potent role of metastin peptides in inhibiting metastasis in endometrial cancer. However, little is known about how the metastin-GPR54 axis is regulated in the endometrium, the precursor tissue of endometrial cancer. Endometrial stromal cells (ESCs) and endometrial glandular cells (EGCs) within the endometrium show morphological changes when exposed to E2 and P4. In this study, we show that metastin expression is induced in ESCs through decidualization, but is repressed in glandular components of atypical endometrial hyperplasia (AEH) and endometrial cancer relative to EGCs. The promoter of GPR54 is unmethylated in normal endometrium and in AEH. These results indicate metastin may function in decidualized endometrium to prepare for adequate placentation but this autocrine secretion of metastin is deregulated during oncogenesis to enable tumor cells to spread.

Tan K, Cho SG, Luo W, et al.
KiSS1-induced GPR54 signaling inhibits breast cancer cell migration and epithelial-mesenchymal transition via protein kinase D1.
Curr Mol Med. 2014; 14(5):652-62 [PubMed] Related Publications
The metastasis suppressor protein Kisspeptin regulates cancer cell proliferation and motility through its receptor, GRP54. However, the critical downstream effectors remain unclear. In this study, we investigated GPR54 signaling in breast cancer cells. Kisspeptin stimulation caused a decrease in migration of multiple breast cancer cell lines. Also, Kisspeptin inhibited MDA-MB-231 cell colony formation in 3D matrigel culture and in soft agar. Kisspeptin treatment elevated phosphorylated PKD1 in a PKC-dependent manner. However, knockdown of either GPR54 or PKD1 increased breast cancer cell migration and invasion. Furthermore, GPR54 knockdown blocked Kisspeptin-induced phosphorylation of PKD1. Finally, Kisspeptin stimulation induced a PKD1 phosphorylation-dependent decrease in expression of Slug, a transcription factor that drives epithelial-mesenchymal transition (EMT), and a concomitant increase in E-cadherin expression. Therefore, KiSS1/GPR54 signaling through PKD1 acts to maintain the epithelial state and to inhibit breast cancer cell invasiveness, and exerts functions associated with its role as a metastasis suppressor.

Yaron M, Renner U, Gilad S, et al.
KISS1 receptor is preferentially expressed in clinically non-functioning pituitary tumors.
Pituitary. 2015; 18(3):306-11 [PubMed] Related Publications
OBJECTIVE: KISS1 is a metastasis suppressor gene involved in cancer biology. Given the high expression levels of KISS1 and KISS1R in the hypothalamus and the pituitary respectively, we hypothesized that this system could possibly affect tumor invasiveness and clinical behavior of pituitary tumors.
METHODS: Expression levels of KISS1 and KISS1R mRNA were evaluated by RT-PCR. Clinical information pertaining tumor characteristics was extracted from patients' charts.
RESULTS: Tumors from 39 patients (21 females, mean age 47.5 years) were examined. KISS1R was expressed in 26 (67%) of samples (94% of NFPA, 42% of GH-, 67% of ACTH-, and 25% of PRL-secreting adenomas) and was found more often in female patients (81 vs. 50% males, p < 0.05); and in NFPA (94 vs. 45.5% in secreting tumors; p = 0.003). Patients expressing KISS1R were older at presentation (50.5 ± 1.4 vs. 38.1 ± 1.3 years; p = 0.008). In the multivariate analysis, factors significantly associated with KISS1R expression included female gender (OR 13.8, 95 % CI 1.22-155.9; p = 0.03) and having a NFPA (OR 24.7, 95% CI 1.50-406.4; p = 0.02). Tumor size, invasiveness and age at presentation were not independently associated with KISS1R expression. Pituitary tumors and normal pituitary were negative for KISS1 mRNA expression.
CONCLUSIONS: The majority of human NFPA expressed KISS1R with lower rates of expression in other types of pituitary tumors. KISS1R expression did not impart a clinical beneficial tumor phenotype, as it was not associated with tumor size or invasiveness. Additional studies are required to elucidate the role of KISS1 receptor in pituitary gland physiology and pathology.

Papaoiconomou E, Lymperi M, Petraki C, et al.
Kiss-1/GPR54 protein expression in breast cancer.
Anticancer Res. 2014; 34(3):1401-7 [PubMed] Related Publications
BACKGROUND: Numerous studies have shown that the Kiss-1 gene countervails the metastatic aptitude of several cancer cell lines and solid-tumor neoplasias. However, there still remains ambiguity regarding its role in breast cancer and literature has arisen asserting that Kiss-1 expression may be linked to an aggressive phenotype and malignant progression. Herein, we investigated the protein expression of Kiss-1 and its receptor GPR54 in breast cancer tissues compared to non-cancerous mammary tissues.
MATERIALS AND METHODS: Paraffin-fixed cancer tissues from 43 women with resected breast adenocarcinomas and 11 specimens derived from women suffering from fibrocystic disease, serving as controls, were immunostained with Kiss-1 and GPR54 antibodies.
RESULTS: Kiss-1 and GPR54 protein expression levels were significantly higher in breast cancer compared to fibrocystic tissues (p<0.05). No significant correlation was established between Kiss-1 or GRP54 expression and tumor grade, tumor size, lymph node positivity, histological type or ER status. Kiss-1 expression significantly and positively correlated with GPR54 expression in both breast cancer and fibrocystic disease specimens.
CONCLUSION: Kiss-1/GPR54 expression was found to be significantly higher in breast cancer compared to non-malignant mammary tissues.

Pasquier J, Kamech N, Lafont AG, et al.
Molecular evolution of GPCRs: Kisspeptin/kisspeptin receptors.
J Mol Endocrinol. 2014; 52(3):T101-17 [PubMed] Related Publications
Following the discovery of kisspeptin (Kiss) and its receptor (GPR54 or KissR) in mammals, phylogenetic studies revealed up to three Kiss and four KissR paralogous genes in other vertebrates. The multiplicity of Kiss and KissR types in vertebrates probably originated from the two rounds of whole-genome duplication (1R and 2R) that occurred in early vertebrates. This review examines compelling recent advances on molecular diversity and phylogenetic evolution of vertebrate Kiss and KissR. It also addresses, from an evolutionary point of view, the issues of the structure-activity relationships and interaction of Kiss with KissR and of their signaling pathways. Independent gene losses, during vertebrate evolution, have shaped the repertoire of Kiss and KissR in the extant vertebrate species. In particular, there is no conserved combination of a given Kiss type with a KissR type, across vertebrate evolution. The striking conservation of the biologically active ten-amino-acid C-terminal sequence of all vertebrate kisspeptins, probably allowed this evolutionary flexibility of Kiss/KissR pairs. KissR mutations, responsible for hypogonadotropic hypogonadism in humans, mostly occurred at highly conserved amino acid positions among vertebrate KissR. This further highlights the key role of these amino acids in KissR function. In contrast, less conserved KissR regions, notably in the intracellular C-terminal domain, may account for differential intracellular signaling pathways between vertebrate KissR. Cross talk between evolutionary and biomedical studies should contribute to further understanding of the Kiss/KissR structure-activity relationships and biological functions.

Stathaki M, Armakolas A, Dimakakos A, et al.
Kisspeptin effect on endothelial monocyte activating polypeptide II (EMAP-II)-associated lymphocyte cell death and metastases in colorectal cancer patients.
Mol Med. 2014; 20:80-92 [PubMed] Free Access to Full Article Related Publications
Kisspeptin is an antimetastatic agent in some cancers that has also been associated with lymphoid cell apoptosis, a phenomenon favoring metastases. Our aim was to determine the association of kisspeptin with lymphocyte apoptosis and the presence of metastases in colorectal cancer patients. Blood was drawn from 69 colon cancer patients and 20 healthy volunteers. Tissue specimens from healthy and pathological tissue were immunohistochemically analyzed for kisspeptin and endothelial monocyte activating polypeptide II (EMAP-II) expression. Blood EMAP-II and soluble Fas ligand (sFasL) levels were examined by an enzyme-linked immunosorbent assay method. The kisspeptin and EMAP-II expression and secretion levels in the DLD-1 and HT-29 colon cancer cell lines were examined by quantitative real-time polymerase chain reaction, Western analysis and enzyme-linked immunosorbent assay, whereas lymphocyte viability was assessed by flow cytometry. The effect of kisspeptin on the viability of colon cancer cells was examined by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]. Exogenous, synthetic and naturally produced, kisspeptin induces through the G-protein-coupled receptor 54 (GPR54; also known as the kisspeptin receptor) the EMAP-II expression and secretion in colon cancer cell lines, inducing in vitro lymphocyte apoptosis, as verified by the use of an anti-EMAP-II antibody. These results were reversed with the use of kisspeptin inhibitors and by kisspeptin-silencing experiments. Tumor kisspeptin expression was associated with the tumor EMAP-II expression (p < 0.001). Elevated kisspeptin and EMAP-II expression in colon cancer tissues was associated with lack of metastases (p < 0.001) in colon cancer patients. These data indicate the antimetastatic effect of tumor-elevated kisspeptin in colon cancer patients that may be mediated by the effect of kisspeptin on EMAP-II expression in colon cancer tumors in patients with normal serum EMAP-II levels. These findings provide new insight into the role of kisspeptin in the context of metastases in colon cancer patients.

Prabhu VV, Sakthivel KM, Guruvayoorappan C
Kisspeptins (KiSS-1): essential players in suppressing tumor metastasis.
Asian Pac J Cancer Prev. 2013; 14(11):6215-20 [PubMed] Related Publications
Kisspeptins (KPs) encoded by the KiSS-1 gene are C-terminally amidated peptide products, including KP- 10, KP-13, KP-14 and KP-54, which are endogenous agonists for the G-protein coupled receptor-54 (GPR54). Functional analyses have demonstrated fundamental roles of KiSS-1 in whole body homeostasis including sexual differentiation of brain, action on sex steroids and metabolic regulation of fertility essential for human puberty and maintenance of adult reproduction. In addition, intensive recent investigations have provided substantial evidence suggesting roles of Kisspeptin signalling via its receptor GPR54 in the suppression of metastasis with a variety of cancers. The present review highlights the latest studies regarding the role of Kisspeptins and the KiSS-1 gene in tumor progression and also suggests targeting the KiSS-1/GPR54 system may represent a novel therapeutic approach for cancers. Further investigations are essential to elucidate the complex pathways regulated by the Kisspeptins and how these pathways might be involved in the suppression of metastasis across a range of cancers.

Yuan TZ, Zhang HH, Tang QF, et al.
Prognostic value of kisspeptin expression in nasopharyngeal carcinoma.
Laryngoscope. 2014; 124(5):E167-74 [PubMed] Related Publications
OBJECTIVES/HYPOTHESIS: The KiSS-1 gene has been reported to serve as a metastasis suppressor gene in various human malignancies. However, no information is available regarding the role of the KiSS-1 gene or its gene product kisspeptin in nasopharyngeal carcinoma.
STUDY DESIGN: Retrospective study.
METHODS: Kisspeptin and its receptor AXOR12 expression were assessed using immunohistochemistry in paraffin-embedded tumor tissues from 140 patients diagnosed with nasopharyngeal carcinoma. Immunoreactivity was quantified, and its relationships with patients' clinical parameters and survival were analyzed.
RESULTS: Using a 50% cutoff level, the immunoreactivities of kisspeptin and AXOR12 were divided into low and high expression. The expression levels of kisspeptin and AXOR12 in nasopharyngeal carcinoma were well correlated with each other (rs = 19.31, P < 0.01). Low expression of kisspeptin in nasopharyngeal carcinoma was correlated with clinical stage (P = 0.01), N stage (P = 0.03), and metastasis (P = 0.02). Patients with low kisspeptin expression had poorer distant metastasis-free survival than those with high kisspeptin expression (75.32% vs. 83.79%, P = 0.02). Although neither kisspeptin nor AXOR12 were found to be prognostic factors for overall survival, kisspeptin was determined to be an independent prognostic factor for distant metastasis-free survival (P = 0.03) using multivariate analysis.
CONCLUSION: In this study, we report for the first time that low kisspeptin expression in nasopharyngeal carcinoma is correlated with poor clinical outcome; kisspeptin could serve as an independent prognostic marker for metastasis in nasopharyngeal carcinoma.

Ji K, Ye L, Mason MD, Jiang WG
The Kiss-1/Kiss-1R complex as a negative regulator of cell motility and cancer metastasis (Review).
Int J Mol Med. 2013; 32(4):747-54 [PubMed] Related Publications
Metastasis is a complex multistep process that involves the impairment of cell-cell adhesion in the neoplastic epithelium, invasion into adjacent tissues and the dissemination of cancer cells through the lymphatic and haematogenous routes. The inhibition of the metastatic process at an early stage has become a hot topic in cancer research. The Kiss-1 gene, initially described as a suppressor of metastasis in malignant melanoma, encodes the Kiss-1 protein which can be processed to other peptides, e.g., Kisspeptin-10, Kisspeptin-13, Kisspeptin-14 and Kisspeptin-54. These peptides are endogenous ligands of the Kiss‑1 receptor (Kiss-1R), a G protein-coupled receptor (GPR) also known as hOT7T175, AXOR12 or GPR54. The Kiss-1 gene has been suggested as a suppressor of metastasis in a various types of cancer, including gastric cancer, oesophageal carcinoma, pancreatic, ovarian, bladder and prostate cancer, through the regulation of cellular migration and invasion. In the current review, we summarise the current understanding of the role of Kiss‑1 and Kiss‑1R in cancer and cancer metastasis.

Witchel SF, Tena-Sempere M
The Kiss1 system and polycystic ovary syndrome: lessons from physiology and putative pathophysiologic implications.
Fertil Steril. 2013; 100(1):12-22 [PubMed] Related Publications
Polycystic ovary syndrome (PCOS) is a highly prevalent heterogeneous disease characterized by ovulatory dysfunction, hyperandrogenism, and metabolic alterations. Women with PCOS commonly display dysregulated gonadotropin secretion with higher LH pulsatility and perturbed LH-FSH ratios, which likely contributes to the ovarian phenotype and might be indicative of disrupted GnRH secretory activity. Although the involvement of altered androgen and insulin levels in the pathogenesis of the neuroendocrine alterations of PCOS has been explored in various experimental and clinical settings, the ultimate mechanisms whereby such neurohormonal perturbations take place remain partially unknown. In recent years, kisspeptins, the products of the Kiss1 gene that operate via the surface receptor Gpr54, have emerged as essential elements of the reproductive brain that play an indispensable role in the control of gonadotropin secretion and ovulation. In addition, Kiss1 neurons in the brain are targets and transmitters of the regulatory actions of sex steroids and metabolic cues on the reproductive axis during early organizing periods and adulthood. Furthermore, Kiss1/kisspeptin expression has been documented in the ovary in various species, including humans; yet clear evidence for the involvement of kisspeptin signaling in the control of ovulation, or its alterations, is still pending. Based on these physiologic features, we discuss the putative pathophysiologic implications of alterations of the Kiss1 system in the generation of PCOS and summarize the scarce experimental and clinical evidence that might support such a role.

Sun YB, Xu S
Expression of KISS1 and KISS1R (GPR54) may be used as favorable prognostic markers for patients with non-small cell lung cancer.
Int J Oncol. 2013; 43(2):521-30 [PubMed] Related Publications
Lung cancer is the most commonly diagnosed cancer worldwide. Loss of KISS1 expression has been associated with progression and poor prognosis of various cancers, however, the precise role of KISS1 expression in non-small cell lung cancer (NSCLC) is not well defined. KISS1 receptor (KISS1R, also named GPR54) coupled to KISS1, has been shown to play a pivotal role in suppressing cancer metastasis. In this study, 56 NSCLC specimens were divided into stage IIIB (locally advanced) and stage IV (metastatic). The mRNA and protein levels of KISS1 and KISS1R in cancer tissues were found to be lower compared to that in normal tissues using RT-PCR and western blot analysis, respectively. In addition, the expression of both KISS1 and KISS1R in stage IV NSCLC was lower compared to that in stage IIIB stage NSCLC. The cumulative survival rate of the patients with KISS1 or KISS1R expression was significantly higher compared to that without expression. KISS1 or KISS1R expression in NSCLC can be used to indicate favorable prognosis for disease outcome. Metastin, the product of the KISS1 gene, was lower in the serum of patients with stage IV NSCLC compared to that in stage IIIB NSCLC.

Rodríguez-Rodero S, Fernández AF, Fernández-Morera JL, et al.
DNA methylation signatures identify biologically distinct thyroid cancer subtypes.
J Clin Endocrinol Metab. 2013; 98(7):2811-21 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to determine the global patterns of aberrant DNA methylation in thyroid cancer.
RESEARCH DESIGN AND METHODS: We have used DNA methylation arrays to determine, for the first time, the genome-wide promoter methylation status of papillary, follicular, medullary, and anaplastic thyroid tumors.
RESULTS: We identified 262 and 352 hypermethylated and 13 and 21 hypomethylated genes in differentiated papillary and follicular tumors, respectively. Interestingly, the other tumor types analyzed displayed more hypomethylated genes (280 in anaplastic and 393 in medullary tumors) than aberrantly hypermethylated genes (86 in anaplastic and 131 in medullary tumors). Among the genes indentified, we show that 4 potential tumor suppressor genes (ADAMTS8, HOXB4, ZIC1, and KISS1R) and 4 potential oncogenes (INSL4, DPPA2, TCL1B, and NOTCH4) are frequently regulated by aberrant methylation in primary thyroid tumors. In addition, we show that aberrant promoter hypomethylation-associated overexpression of MAP17 might promote tumor growth in thyroid cancer.
CONCLUSIONS: Thyroid cancer subtypes present differential promoter methylation signatures, and nondifferentiated subtypes are characterized by aberrant promoter hypomethylation rather than hypermethylation. Additional studies are needed to determine the potential clinical interest of the tumor subtype-specific DNA methylation signatures described herein and the role of aberrant promoter hypomethylation in nondifferentiated thyroid tumors.

Cvetkovic D, Dragan M, Leith SJ, et al.
KISS1R induces invasiveness of estrogen receptor-negative human mammary epithelial and breast cancer cells.
Endocrinology. 2013; 154(6):1999-2014 [PubMed] Related Publications
Kisspeptins (KPs), peptide products of the KISS1 metastasis-suppressor gene, are endogenous ligands for a G protein-coupled receptor (KISS1R). KISS1 acts as a metastasis suppressor in numerous human cancers. However, recent studies have demonstrated that an increase in KISS1 and KISS1R expression in patient breast tumors correlates with higher tumor grade and metastatic potential. We have shown that KP-10 stimulates invasion of estrogen receptor α (ERα)-negative MDA-MB-231 breast cancer cells via transactivation of the epidermal growth factor receptor (EGFR). Here, we report that either KP-10 treatment of ERα-negative nonmalignant mammary epithelial MCF10A cells or expression of KISS1R in MCF10A cells induced a mesenchymal phenotype and stimulated invasiveness. Similarly, exogenous expression of KISS1R in ERα-negative SKBR3 breast cancer cells was sufficient to trigger invasion and induced extravasation in vivo. In contrast, KP-10 failed to transactivate EGFR or stimulate invasiveness in the ERα-positive MCF7 and T47D breast cancer cells. This suggested that ERα negatively regulates KISS1R-dependent breast cancer cell migration, invasion, and EGFR transactivation. In support of this, we found that these KP-10-induced effects were ablated upon exogenous expression of ERα in the MDA-MB-231 cells, by down-regulating KISS1R expression. Lastly, we have identified IQGAP1, an actin cytoskeletal binding protein as a novel binding partner of KISS1R, and have shown that KISS1R regulates EGFR transactivation in breast cancer cells in an IQGAP1-dependent manner. Overall, our data strongly suggest that the ERα status of mammary cells dictates whether KISS1R may be a novel clinical target for treating breast cancer metastasis.

Shoji S, Nakano M, Tomonaga T, et al.
Value of metastin receptor immunohistochemistry in predicting metastasis after radical nephrectomy for pT1 clear cell renal cell carcinoma.
Clin Exp Metastasis. 2013; 30(5):607-14 [PubMed] Related Publications
KISS-1 is a metastasis-suppressor gene of human melanoma, and encodes metastin, which was identified as the ligand of a G-protein-coupled receptor (metastin receptor). The precursor protein is cleaved to 54 amino acids, which may be further truncated into carboxy-terminal fragments. Previous studies showed that lack of metastin receptor in clear cell renal cell carcinoma (RCC) is associated with tumor progression, but the prediction of metastasis in patients with pT1 clear cell RCC after radical nephrectomy is difficult. The objective of this study was to evaluate the usefulness of metastin receptor immunohistochemistry in predicting metastasis after nephrectomy for pT1 clear cell RCC. After verification of the correlation between immunostaining and mRNA expression, we evaluated the clinical value of metastin receptor immunohistochemistry. Fifty-four patients were enrolled in this study; following radical nephrectomy, seven patients were found to have lung metastasis. The sensitivity, specificity, positive predictive value, and negative predictive value with negative immunostaining of metastin receptor were 85.7, 97.6, 46.2, and 97.6 %, respectively. Metastasis-free survival rates were significantly higher in patients with positive staining (97.6 %) than in patients with negative staining (53.8 %) (P < 0.001). In univariate analysis for metastasis-free survival, negative immunostaining of metastin receptor was a significant risk factor for metastasis (P = 0.001). Furthermore, negative immunostaining of metastin receptor was an independent predictor for metastasis in multivariate analysis (hazard ratio, 3.735; 95 % CI 0.629-22.174; P = 0.002). In conclusion, our study suggests that negative expression of metastin receptor in clear cell RCC is significantly related to metastasis.

Ziegler E, Olbrich T, Emons G, Gründker C
Antiproliferative effects of kisspeptin‑10 depend on artificial GPR54 (KISS1R) expression levels.
Oncol Rep. 2013; 29(2):549-54 [PubMed] Related Publications
Kisspeptins are peptides derived from the metastasis suppressor gene KISS1 interacting with GPR54 as their corresponding receptor. The KISS1/GPR54 system is one regulator of cellular motility mechanisms leading to decreased migration and invasion. Its role in cell proliferation processes is not clearly understood. In this study, breast cancer cell lines, T47D, ZR75-1, MDA‑MB‑231, MDA‑MB‑435s, MDA‑MB‑453, HCC 70, HCC 1806, HCC 1937 and MCF‑7, were investigated for their endogenous GPR54 expression by immunocytochemistry, RT‑PCR and western blot analysis. The effect of kisspeptin‑10 on proliferation was measured in MDA‑MB‑231, MDA‑MB‑435s, HCC 1806 and MCF‑7 cells. Further experiments on proliferation were carried out with cells transfected with GPR54. All of the tested breast cancer cell lines expressed GPR54 in different amounts. No effects on proliferation were detected in the breast cancer cells expressing the receptor endogenously. In transfected neuronal cells overexpressing GPR54, proliferation was significantly inhibited by kisspeptin‑10. The results indicate that the antiproliferative action of kisspeptin depends on the nature of GPR54 expression. The effect was detected in an artificial system of cells transfected with GPR54 and not in cells expressing the receptor endogenously. Thus, the antiproliferative action of kisspeptin seems not to be important for pathophysiological processes.

Takeda T, Kikuchi E, Mikami S, et al.
Prognostic role of KiSS-1 and possibility of therapeutic modality of metastin, the final peptide of the KiSS-1 gene, in urothelial carcinoma.
Mol Cancer Ther. 2012; 11(4):853-63 [PubMed] Related Publications
The KiSS-1 gene has been reported to be a metastasis suppressor gene in human melanoma. The gene product was isolated from human placenta as the ligand of GPR54, a G protein-coupled receptor, and the C-terminally amidated peptide of 54 amino acids is called metastin. The binding of metastin to GPR54 has been shown to inhibit tumor metastasis in some tumor cells; however, its function remains unclear in urothelial carcinoma. We first evaluated KiSS-1 expression and GPR54 expression in 151 patients with upper urinary tract urothelial carcinoma to determine their prognostic significance. Next, we examined the role of metastin in the invasiveness and lung metastasis of MBT-2 variant (MBT-2V), which is a highly metastatic murine bladder cancer cell. Multivariate analysis revealed that KiSS-1 expression was an independent predictor of metastasis and overall survival. However, GPR54 expression was not selected. Hematogeneous metastasis had a significantly lower level of KiSS-1 expression compared with lymph node metastasis. Metastin treatment significantly reduced the invasiveness of MBT-2V cells and inhibited the DNA-binding activity of NF-κB by blocking its nuclear translocation, leading to a reduction in the expression and activity of matrix metalloproteinase-9. Metastin treatment dramatically prevented the occurrence of lung metastatic nodules (6.3 ± 2.3, n = 15) compared with controls (30.4 ± 5.1, n = 15; P < 0.01), as well as had survival benefit. KiSS-1 plays an important role in the prognosis of upper tract urothelial carcinoma and metastin may be an effective inhibitor of metastasis in urothelial carcinoma through its blockade of NF-κB function.

Cho SG, Wang Y, Rodriguez M, et al.
Haploinsufficiency in the prometastasis Kiss1 receptor Gpr54 delays breast tumor initiation, progression, and lung metastasis.
Cancer Res. 2011; 71(20):6535-46 [PubMed] Free Access to Full Article Related Publications
Activation of KISS1 receptor (KISS1R or GPR54) by its ligands (Kisspeptins) regulates a diverse function both in normal physiology and pathophysiology. In cancer, KISS1R has been implicated in tumor angiogenesis and metastasis, but a broader evaluation of KISS1R in tumorigenesis and tumor progression is yet to be conducted. In this study, we used mouse models of Kiss1r gene knockout and mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT)-induced breast cancer to conduct such an evaluation. Kiss1r heterozygosity in MMTV-PyMT mice was sufficient to attenuate breast cancer initiation, growth, latency, multiplicity, and lung metastasis. To confirm these effects and assess possible contributions of endogenous ligands, we isolated primary tumor cells from PyMT/Kiss1r(+/+) and PyMT/Kiss1r(+/-) mice and compared their phenotypes by in vitro and in vivo assays. Kiss1r loss attenuated in vitro tumorigenic properties as well as tumor growth in vivo in immunocompromised NOD.SCID/NCr mice. Kiss1r activation in these cells, resulting from the addition of its ligand Kisspeptin-10, resulted in RhoA activation and RhoA-dependent gene expression through the Gαq-p63RhoGEF signaling pathway. Anchorage-independent growth was tightly linked to dose-dependent regulation of RhoA by Kiss1r. In support of these results, siRNA-mediated knockdown of KISS1R or inactivation of RhoA in human MCF10A breast epithelial cells overexpressing H-RasV12 was sufficient to reduce Ras-induced anchorage-independent growth. In summary, we concluded that Kiss1r attenuation was sufficient to delay breast tumor initiation, progression, and metastasis through inhibitory effects on the downstream Gαq-p63RhoGEF-RhoA signaling pathway.

Zajac M, Law J, Cvetkovic DD, et al.
GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness.
PLoS One. 2011; 6(6):e21599 [PubMed] Free Access to Full Article Related Publications
Kisspeptins (Kp), peptide products of the Kisspeptin-1 (KISS1) gene are endogenous ligands for a G protein-coupled receptor 54 (GPR54). Previous findings have shown that KISS1 acts as a metastasis suppressor in numerous cancers in humans. However, recent studies have demonstrated that an increase in KISS1 and GPR54 expression in human breast tumors correlates with higher tumor grade and metastatic potential. At present, whether or not Kp signaling promotes breast cancer cell invasiveness, required for metastasis and the underlying mechanisms, is unknown. We have found that kisspeptin-10 (Kp-10), the most potent Kp, stimulates the invasion of human breast cancer MDA-MB-231 and Hs578T cells using Matrigel-coated Transwell chamber assays and induces the formation of invasive stellate structures in three-dimensional invasion assays. Furthermore, Kp-10 stimulated an increase in matrix metalloprotease (MMP)-9 activity. We also found that Kp-10 induced the transactivation of epidermal growth factor receptor (EGFR). Knockdown of the GPCR scaffolding protein, β-arrestin 2, inhibited Kp-10-induced EGFR transactivation as well as Kp-10 induced invasion of breast cancer cells via modulation of MMP-9 secretion and activity. Finally, we found that the two receptors associate with each other under basal conditions, and FRET analysis revealed that GPR54 interacts directly with EGFR. The stability of the receptor complex formation was increased upon treatment of cells by Kp-10. Taken together, our findings suggest a novel mechanism by which Kp signaling via GPR54 stimulates breast cancer cell invasiveness.

Kang HS, Baba T, Mandai M, et al.
GPR54 is a target for suppression of metastasis in endometrial cancer.
Mol Cancer Ther. 2011; 10(4):580-90 [PubMed] Related Publications
Invasion into deep myometrium and/or lymphovascular space is a well-known risk factor for endometrial cancer metastasis, resulting in poor prognosis. It is therefore clinically important to identify novel molecules that suppress tumor invasion. Reduced expression of the metastasis suppressor, kisspeptin (KISS1), and its endogenous receptor, GPR54, has been reported in several cancers, but the significance of the KISS1/GPR54 axis in endometrial cancer metastasis has not been clarified. Metastin-10 is the minimal bioactive sequence of genetic products of KISS1. Clinicopathological analysis of 92 endometrial cancers revealed overall survival is improved in cancers with high expression of GPR54 (P < 0.05) and that GPR54 expression is associated with known prognostic factors including FIGO stage, grade, and deep myometrial invasion. Through RNAi and microarray analyses, metastin-10 was predicted to suppress metastasis of GPR54-expressing endometrial cancers in vivo. Methylation analysis revealed GPR54 is epigenetically regulated. Metastin-GPR54 axis function was restored following treatment with the DNA hypomethylating agent 5-aza-DC. These data suggest that metastin-10 may be effective at inhibiting the metastatic spread of endometrial cancers in combination with demethylating agents to induce GPR54 expression.

Martínez-Fuentes AJ, Molina M, Vázquez-Martínez R, et al.
Expression of functional KISS1 and KISS1R system is altered in human pituitary adenomas: evidence for apoptotic action of kisspeptin-10.
Eur J Endocrinol. 2011; 164(3):355-62 [PubMed] Related Publications
CONTEXT: KISS1 was originally identified as a metastasis-suppressor gene able to inhibit tumor progression. KISS1 gene products, the kisspeptins, bind to a G-protein-coupled receptor (KISS1R, formerly GPR54), which is highly expressed in placenta, pituitary, and pancreas, whereas KISS1 mRNA is mainly expressed in placenta, hypothalamus, striatum, and pituitary.
OBJECTIVE AND DESIGN: KISS1/KISS1R pituitary expression profile, coupled to their anti-tumoral capacities, led us to hypothesize that this system may be involved in the biology of pituitary tumors. To explore this notion, expression levels of KISS1R and KISS1 were evaluated in normal and adenomatous pituitaries. Additionally, functionality of this system was assessed by treating dispersed pituitary adenoma cells in primary culture with kisspeptin-10 and evaluating intracellular calcium kinetics and apoptotic rate.
RESULTS: Both KISS1 and KISS1R were expressed in normal pituitary, whereas this simultaneous expression was frequently lost in pituitary tumors, where diverse patterns of KISS1/KISS1R expression were observed that differed among distinct types of pituitary adenomas. Measurement of calcium kinetics revealed that kisspeptin-10 elicits a remarkable increase in [Ca(2+)](i) in individual cells from four out of the five GH-producing adenomas studied, whereas cells derived from non-functioning pituitary adenomas (NFPA, n=45) did not respond. In contrast, kisspeptin-10 treatment increased the apoptotic rate in cells derived from both GH-producing and NFPA.
CONCLUSIONS: These results provide primary evidence that KISS1 and KISS1R expression can be differentially lost in pituitary tumor subtypes, where this system can exert functional, proapoptotic actions, and thereby offer novel insights to investigate the biology and therapeutic options to treat these tumors.

Chen Y, Yusenko MV, Kovacs G
Lack of KISS1R expression is associated with rapid progression of conventional renal cell carcinomas.
J Pathol. 2011; 223(1):46-53 [PubMed] Related Publications
The mortality of patients with conventional renal cell carcinomas (RCC) correlates directly with the development of metastasis, which cannot be reliably predicted simply by TNM classification. The aim of this study was to identify genes associated with the tumour progression. We have analysed the global gene expression in conventional RCCs, including those with and without progression by Affymetrix GeneChip and selected the genes by gene set enrichment analysis. The expression and function of KISS1R was validated by RT-PCR, western blotting and immunohistochemistry and by in vitro experiments. An immunohistochemical and clinical follow-up study showed that lack of KISS1R expression is associated with rapid progression of tumours. In vitro studies showed that activation of KISS1/KISS1R signalling by kisspeptin treatment decreases the motility and invasive capacity of tumour cells. The kisspeptin treatment also induces the expression of KISS1R in tumour cells in vitro and activates signalling in cases without constitutional expression of the receptor. Expression of the KISS1R protein can be used for estimating the prognosis of conventional RCCs. Confirming the activation of KISS1R signalling in vivo may open a way for kisspeptin treatment of patients with conventional RCCs.

Olbrich T, Ziegler E, Türk G, et al.
Kisspeptin-10 inhibits bone-directed migration of GPR54-positive breast cancer cells: Evidence for a dose-window effect.
Gynecol Oncol. 2010; 119(3):571-8 [PubMed] Related Publications
OBJECTIVES: The KiSS-1 gene product is absent or expressed at low level in metastatic breast cancer compared with their nonmetastatic counterparts. A deca-peptide derived from the KiSS-1 gene product, designated kisspeptin-10 (Kp-10), activates a receptor coupled to Gαq subunits (GPR54 or KiSS-1R). In this study we have analyzed whether Kp-10 treatment affects bone-directed migration of GPR54-positive breast cancer cells.
METHODS: GPR54 expression was analyzed using immune cytochemistry. Bone-directed breast cancer cell invasion was measured by assessment of the breast cancer cell migration rate through an artificial basement membrane. Chemokine receptor CXCR4 and stromal cell-derived factor-1 (SDF-1) mRNA expression was quantified using semi-quantitative RT-PCR. CXCR4 protein expression and SDF-1 protein secretion were measured using the western blot technique.
RESULTS: Breast cancer cell invasion was increased when cocultured with MG63 osteoblast-like cells. Treatment with KP-10 reduced the ability to invade a reconstituted basement membrane and to migrate in response to the cellular stimulus. This effect was significant in a dose-window of 10⁻⁹ M to 10⁻¹¹ M. Searching for the molecular mechanisms we found that KP-10 treatment significantly reduces expression of the chemokine receptor CXCR4 by the breast cancer cells. In addition, expression and secretion of its ligand SDF-1 by the MG63 cells were significantly reduced. Furthermore, SDF-1-induced CXCR4 signaling was down-regulated.
CONCLUSIONS: These data represent the first report that KP-10 inhibits bone-directed migration of GPR54-positive breast cancer cells. In addition, we found evidence for a KP-10 dose-window effect. Furthermore, the SDF-1/CXCR4 system seems to be involved in the anti-migratory action of KP-10.

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