Gene Summary

Gene:KISS1R; KISS1 receptor
Aliases: HH8, CPPB1, GPR54, AXOR12, KISS-1R, HOT7T175
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:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:kiSS-1 receptor
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Latest Publications: KISS1R (cancer-related)

Branavan U, Muneeswaran K, Wijesundera WSS, et al.
Association of Kiss1 and GPR54 Gene Polymorphisms with Polycystic Ovary Syndrome among Sri Lankan Women.
Biomed Res Int. 2019; 2019:6235680 [PubMed] Free Access to Full Article Related Publications
Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder affecting women of reproductive age. Its aetiology, though yet unclear, is presumed to have an oligogenic basis interacting with environmental factors. Kisspeptins are peptide products of Kiss1 gene that control the hypothalamic pituitary (HPG) axis by acting via G protein-coupled receptor known as GPR54. There is paucity of data on the role of Kiss1 and GPR54 gene in PCOS. We aimed to identify the polymorphisms in Kiss1 and GPR54 genes and explore their association with serum kisspeptin levels among Sri Lankan women with well-characterized PCOS. Consecutive women with PCOS manifesting from adolescence (n=55) and adult controls (n=110) were recruited. Serum kisspeptin and testosterone levels were determined by ELISA method. Whole gene sequencing was performed to identify the polymorphisms in Kiss1 and GPR54 genes. Serum kisspeptin and testosterone concentrations were significantly higher in women with PCOS than controls: kisspeptin 4.873nmol/L versus 4.127nmol/L; testosterone 4.713nmol/L versus 3.415 nmol/L, p<0.05. Sequencing the GPR54 gene revealed 5 single nucleotide polymorphisms (SNPs), rs10407968, rs1250729403, rs350131, chr19:918686, and chr19:918735, with two novel SNPs (chr19:918686 and chr19:918735), while sequencing the Kiss1 gene revealed 2 SNPs, rs5780218 and rs4889. All identified SNPs showed no significant difference in frequency between patients and controls. GPR54 gene rs350131 polymorphism (G/T) was detected more frequently in our study population. The heterozygous allele (AG) of GPR54 gene novel polymorphism chr19:918686 showed a marginal association with serum kisspeptin levels (p=0.053). Genetic variations in GPR54 and Kiss1 genes are unlikely to be associated with PCOS among Sri Lankan women manifesting from adolescence. Meanwhile the heterozygous allele of chr19:918686 is probably associated with serum kisspeptin concentrations, which suggests a potential role in the aetiology of PCOS.

Corno C, Perego P
KiSS1 in regulation of metastasis and response to antitumor drugs.
Drug Resist Updat. 2019; 42:12-21 [PubMed] Related Publications
Metastatic dissemination of tumor cells represents a major obstacle towards cancer cure. Tumor cells with metastatic capacity are often resistant to chemotherapy. Experimental efforts revealed that the metastatic cascade is a complex process that involves multiple positive and negative regulators. In this respect, several metastasis suppressor genes have been described. Here, we review the role of the metastasis suppressor KiSS1 in regulation of metastasis and in response to antitumor agents. Physiologically, KiSS1 plays a key role in the activation of the hypothalamic-pituitary-gonadal axis regulating puberty and reproductive functions. KiSS1-derived peptides i.e., kisspeptins, signal through the G-protein coupled receptor GPR54. In cancer, KiSS1 signaling suppresses metastases and maintains dormancy of disseminated malignant cells, by interfering with cell migratory and invasive abilities. Besides, KiSS1 modulates glucose and lipid metabolism, by reprogramming energy production towards oxidative phosphorylation and β-oxidation. Loss or reduced expression of KiSS1, in part through promoter hypermethylation, is related to the development of metastases in various cancer types, with some conflicting reports. The poorly understood role of KiSS1 in response to chemotherapeutic agents appears to be linked to stimulation of the intrinsic apoptotic pathway and inhibition of cell defense factors (e.g., glutathione S-transferase-π) as well as autophagy modulation. Deciphering the molecular basis underlying regulation of the metastatic potential is crucial for the establishment of novel treatment strategies.

Stubendorff B, Wilhelm K, Posselt K, et al.
A three-gene methylation marker panel for the nodal metastatic risk assessment of muscle-invasive bladder cancer.
J Cancer Res Clin Oncol. 2019; 145(4):811-820 [PubMed] Related Publications
PURPOSE: In this study, we aimed to identify a DNA methylation pattern suitable for prognosis assessment of muscle-invasive bladder cancer and to investigate metastasis-associated processes regulated by DNA methylation.
METHODS: Genome-wide methylation analysis was performed on 23 muscle-invasive bladder tumors by microarray analysis. Validation was performed by the qAMP technique in two different patient cohorts (n = 32 and n = 100). mRNA expression was analyzed in 12 samples. Protein expression was determined using tissue microarrays of 291 patients. Bladder cancer cell lines T24 and 253JB-V were used for functional analyses.
RESULTS: Microarray analyses revealed KISS1R, SEPT9 and CSAD as putative biomarkers with hypermethylation in node-positive tumors. The combination of the three genes predicted the metastatic risk with sensitivity of 73% and specificity of 71% in cohort 1, and sensitivity of 82% and specificity of 54% in cohort 2. mRNA expression differences were detected for KISS1R (p = 0.04). Protein expression of KISS1R was significantly reduced (p < 0.001). Knockdown of SEPT9v3 resulted in increased cell migration by 28% (p = 0.04) and increased invasion by 22% (p = 0.004). KISS1R overexpression resulted in decreased cell migration (25%, p = 0.1).
CONCLUSIONS: We identified a methylation marker panel suitable to differentiate between patients with positive and negative lymph nodes at time of cystectomy. This enables a risk assessment for patients who potentially benefit from extended lymph node resection as well as from neoadjuvant chemotherapy and could improve the survival rates. Furthermore, we examined the impact of putative markers on tumor behavior. Hence, KISS1R and SEPT9 could represent a starting point for the development of novel therapy approaches.

Blasco V, Pinto FM, Fernández-Atucha A, et al.
Altered expression of the kisspeptin/KISS1R and neurokinin B/NK3R systems in mural granulosa and cumulus cells of patients with polycystic ovarian syndrome.
J Assist Reprod Genet. 2019; 36(1):113-120 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
PURPOSE: The neurokinin B (NKB)/NK
METHODS: A cross-sectional study was performed in 46 healthy women and 43 PCOS women undergoing controlled ovarian stimulation. MGCs and CCs were collected from pre-ovulatory follicles after transvaginal ultrasound-guided oocyte retrieval and the expression of the genes encoding NKB (TAC3), NK3R (TACR3), KISS1, and its receptor (KISS1R) was analyzed using real-time quantitative RT-PCR.
RESULTS: TAC3, TACR3, and KISS1 mRNA levels were decreased in MGCs and CCs of PCOS women. TAC3 positively correlated with KISS1 in MGCs of healthy women and TACR3 was positively associated with KISS1R in CCs from healthy women. These associations were not observed in PCOS women.
CONCLUSION: The NKB/NK3R and KISS1/KISS1R systems are dysregulated in MGCs and CCs of PCOS women. The lower expression of these systems in GCs could contribute to the abnormal follicle development and defective ovulation that characterize the pathogenesis of PCOS.

Kim JN, Kim TH, Yoon JH, Cho SG
Kisspeptin Inhibits Colorectal Cancer Cell Invasiveness by Activating PKR and PP2A.
Anticancer Res. 2018; 38(10):5791-5798 [PubMed] Related Publications
BACKGROUND/AIM: The aim of the present study was to investigate the mechanism through which kisspeptin inhibits colorectal cancer metastasis.
MATERIALS AND METHODS: Colorectal cancer cells were treated with kisspeptin and then subjected to assays for cell viability, migration, invasion and anchorage-independent growth. Kisspeptin receptor (KISS1R) requirement was examined by siRNA-based gene silencing followed by western blot and invasion assays. Kisspeptin regulation of PKR and PP2A was examined by treating cells with inhibitors for PKR or PP2A.
RESULTS: Kisspeptin inhibited colorectal cancer cell invasiveness without affecting cell proliferation. Kisspeptin required activation of KISS1R and resulted in activation of PKR and PP2A. PKR inhibitor blocked kisspeptin-induced PP2A phosphorylation, while PP2A inhibitor failed to block kisspeptin-induced PKR phosphorylation.
CONCLUSION: Kisspeptin-mediated activation of PKR-PP2A inhibited colorectal cancer cell invasiveness.

Albalawi FS, Daghestani MH, Daghestani MH, et al.
rs4889 polymorphism in KISS1 gene, its effect on polycystic ovary syndrome development and anthropometric and hormonal parameters in Saudi women.
J Biomed Sci. 2018; 25(1):50 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: Kisspeptin is involved in female reproduction. This study was designed to i- estimate kisspeptin levels in women with polycystic ovary syndrome (PCOS), in comparison with controls, ii- study the correlations between kisspeptin and PCOS-related reproductive hormones, and iii- investigate the relation between KISS1 gene polymorphisms and hormone levels in women suffering from PCOS.
METHODS: The investigation was a clinically designed study on 28 women with PCOS, and 30 normal, healthy women with no signs of PCOS as controls. Blood samples were collected between day 3 and day 6 of the menstrual cycle in both groups at 8:00 a.m., and circulating levels of LH, FSH and kisspeptin were estimated. DNA was extracted from whole blood and all coding exons of KISS1 gene were sequenced.
RESULTS: Women with PCOS had higher LH levels and BMI compared to controls. Plasma kisspeptin levels were positively correlated with LH levels. There was no statistically significant difference between the groups in terms of kisspeptin and FSH levels. The SNP rs4889 C/G, a non-synonymous SNP, was investigated in the PCOS group. The frequency of GG genotype was significantly higher in the PCOS compared to the controls. These patients were more obese, had higher kisspeptin and FSH levels.
CONCLUSION: The results of the study show that the genetic variation of KISS1 gene may be a factor contributing to PCOS development. The association between the gene and the gene variation and PCOS need further validation in large-scaled and functional studies.

Kostakis ID, Agrogiannis G, Vaiopoulos AG, et al.
KISS1 and KISS1R expression in gastric cancer.
J BUON. 2018 Jan-Feb; 23(1):79-84 [PubMed] Related Publications
PURPOSE: Kisspeptins, which are derived from the gene KISS1, supress tumor progression. We intended to investigate the production of KISS1 and its receptor (KISSR) in gastric cancer.
METHODS: The expression of KISS1 and KISS1R in both normal and cancer tissue was examined with immunohistochemistry in tissue specimens of 40 cases of gastric adenocarcinoma.
RESULTS: KISS1 expression in normal gastric mucosa was much higher than in malignant mucosa. KISS1 expression was higher in early stages (stage I or II) than in advanced stages (stage III or IV), in tumors with intestinal histological type than in those with diffuse histological type, in tumors without lymphovascular invasion than in those with and in cancers of older patients (≥70 years) than in younger patients. No significant differences were found regarding other clinicopathological parameters. There was no KISS1R expression in cancer tissues, while only low levels of KISS1R were detected in normal gastric epithelium.
CONCLUSIONS: KISS1 expression is decreased during carcinogenesis in gastric mucosa. More advanced tumors and more aggressive histological types produce lower KISS1 levels. In addition, no KISS1R is produced in malignant gastric epithelium, while KISS1R is only weakly expressed in normal gastric epithelium.

A P S, Laishram RS
Nuclear Phosphatidylinositol-Phosphate Type I Kinase α-Coupled Star-PAP Polyadenylation Regulates Cell Invasion.
Mol Cell Biol. 2018; 38(5) [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Star-PAP, a nuclear phosphatidylinositol (PI) signal-regulated poly(A) polymerase (PAP), couples with type I PI phosphate kinase α (PIPKIα) and controls gene expression. We show that Star-PAP and PIPKIα together regulate 3'-end processing and expression of pre-mRNAs encoding key anti-invasive factors (

Kim TH, Cho SG
Kisspeptin inhibits cancer growth and metastasis via activation of EIF2AK2.
Mol Med Rep. 2017; 16(5):7585-7590 [PubMed] Related Publications
Kisspeptin is a protein encoded by the KISS1 gene, which has been reported to suppress the metastatic capabilities of various types of cancer cells, through the activation of its G‑protein coupled receptor GPR54. However, the molecular mechanisms underlying the involvement of kisspeptin‑mediated signaling in the inhibition of cancer cell migration and invasion have yet to be elucidated. The present in vitro cell proliferation, migration and invasion assays and in vivo experimental metastasis studies demonstrated that kisspeptin‑induced eukaryotic translation initiation factor 2α kinase 2 (EIF2AK2) activation suppressed the metastatic capabilities of several types of cancer cells. Kisspeptin was revealed to inhibit the migratory and invasive abilities of highly metastatic breast SK‑BR‑3, prostatic PC‑3 and colorectal adenocarcinoma LoVo human cancer cell lines, whereas its inhibitory effects were abolished following the silencing of EIF2AK2 expression using RNA interference. Similarly, kisspeptin failed to inhibit the migration and invasion of mouse embryonic fibroblasts following the deletion of the EIF2AK2 gene. Furthermore, kisspeptin was demonstrated to activate Ras homolog gene family member A (RhoA)‑dependent signaling, and to phosphorylate EIF2AK2 via RhoA‑mediated pathways in various cancer cells. In addition, results obtained from nude mice bearing LoVo‑derived xenograft tumors revealed that kisspeptin inhibited tumor growth through an EIF2AK2‑dependent mechanism, and an in vivo metastasis assay identified kisspeptin‑activated EIF2AK2 signaling as critical for the suppression of distant metastasis. The present study concluded that kisspeptin represses cancer metastasis via EIF2AK2 signaling, thus clarifying the role of kisspeptin signaling in complicated cancer metastasis signaling network. Therefore, kisspeptin treatment may be a choice for blocking metastases.

Blake A, Dragan M, Tirona RG, et al.
G protein-coupled KISS1 receptor is overexpressed in triple negative breast cancer and promotes drug resistance.
Sci Rep. 2017; 7:46525 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor α, progesterone receptor and human epidermal growth factor receptor 2 (HER2). TNBC patients lack targeted therapies, as they fail to respond to endocrine and anti-HER2 therapy. Prognosis for this aggressive cancer subtype is poor and survival is limited due to the development of resistance to available chemotherapies and resultant metastases. The mechanisms regulating tumor resistance are poorly understood. Here we demonstrate that the G protein-coupled kisspeptin receptor (KISS1R) promotes drug resistance in TNBC cells. KISS1R binds kisspeptins, peptide products of the KISS1 gene and in numerous cancers, this signaling pathway plays anti-metastatic roles. However, in TNBC, KISS1R promotes tumor invasion. We show that KISS1 and KISS1R mRNA and KISS1R protein are upregulated in TNBC tumors, compared to normal breast tissue. KISS1R signaling promotes drug resistance by increasing the expression of efflux drug transporter, breast cancer resistance protein (BCRP) and by inducing the activity and transcription of the receptor tyrosine kinase, AXL. BCRP and AXL transcripts are elevated in TNBC tumors, compared to normal breast, and TNBC tumors expressing KISS1R also express AXL and BCRP. Thus, KISS1R represents a potentially novel therapeutic target to restore drug sensitivity in TNBC patients.

Wang H, Schaefer T, Konantz M, et al.
Prominent Oncogenic Roles of EVI1 in Breast Carcinoma.
Cancer Res. 2017; 77(8):2148-2160 [PubMed] Related Publications
Overexpression of the EVI1 oncogene is associated typically with aggressive myeloid leukemia, but is also detectable in breast carcinoma where its contributions are unexplored. Analyzing a tissue microarray of 608 breast carcinoma patient specimens, we documented EVI1 overexpression in both estrogen receptor-positive (ER

Dotterweich J, Tower RJ, Brandl A, et al.
The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease.
PLoS One. 2016; 11(5):e0155087 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R), a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs) and osteoprogenitor cells (OPCs) when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment.

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.

Hu N, Kadota M, Liu H, et al.
Genomic Landscape of Somatic Alterations in Esophageal Squamous Cell Carcinoma and Gastric Cancer.
Cancer Res. 2016; 76(7):1714-23 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Gastric cancer and esophageal cancer are the second and sixth leading causes of cancer-related death worldwide. Multiple genomic alterations underlying gastric cancer and esophageal squamous cell carcinoma (ESCC) have been identified, but the full spectrum of genomic structural variations and mutations have yet to be uncovered. Here, we report the results of whole-genome sequencing of 30 samples comprising tumor and blood from 15 patients, four of whom presented with ESCC, seven with gastric cardia adenocarcinoma (GCA), and four with gastric noncardia adenocarcinoma. Analyses revealed that an A>C mutation was common in GCA, and in addition to the preferential nucleotide sequence of A located 5 prime to the mutation as noted in previous studies, we found enrichment of T in the 5 prime base. The A>C mutations in GCA suggested that oxidation of guanine may be a potential mechanism underlying cancer mutagenesis. Furthermore, we identified genes with mutations in gastric cancer and ESCC, including well-known cancer genes, TP53, JAK3, BRCA2, FGF2, FBXW7, MSH3, PTCH, NF1, ERBB2, and CHEK2, and potentially novel cancer-associated genes, KISS1R, AMH, MNX1, WNK2, and PRKRIR Finally, we identified recurrent chromosome alterations in at least 30% of tumors in genes, including MACROD2, FHIT, and PARK2 that were often intragenic deletions. These structural alterations were validated using the The Cancer Genome Atlas dataset. Our studies provide new insights into understanding the genomic landscape, genome instability, and mutation profile underlying gastric cancer and ESCC development. Cancer Res; 76(7); 1714-23. ©2016 AACR.

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):165-176 [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] Article available free on PMC after 01/01/2020 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, ), 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 ( ). 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] Article available free on PMC after 01/01/2020 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] Article available free on PMC after 01/01/2020 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] Article available free on PMC after 01/01/2020 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.

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