Hot TopicThe kisspeptin (KiSS-1)/GPR54 system in cancer biology
Introduction
Metastasis is a complex multistep process, which includes loss of cell–cell adhesion within neoplastic epithelium, invasion of surrounding tissues, angiogenesis and dissemination of cancer cells through vascular and lymphatic vessels, trans passing through vascular endothelium into distant sites (host tissues).1, 2 Nowadays, cancer research is focusing on the blockade of the metastatic process at its early steps.3, 4 Therefore, there is growing interest in identifying metastasis suppressor genes, which may be involved in the control of cancer cell dissemination. In this context, KiSS-1 was initially discovered by Lee et al. (1996) in experiments designed to identify the molecules responsible for the antimetastatic effect of human chromosome 6. Using subtractive hybridization and differential display, the researchers isolated seven cDNA clones that exhibited higher expression in neo6/melanoma hybrids. One of these clones, designated KiSS-1, suppressed metastasis in two human malignant melanoma cell lines.5 So far, data have analyzed the regulation of kisspeptins secretion and have provided strong evidence for the participation for these molecules in several biological processes.
The main kisspeptin functions which have been thoroughly investigated are the following: Kisspeptin and reproductive axis and puberty: The possible connection of kisspeptin system and pubertal development was revealed in 2003, when humans and mice with GPR54 mutations6 were found to suffer from hypogonadotropic hypogonadism, characterized by absence of sexual maturation and decreased levels of sex hormones and gonadotropins. Interestingly, a GPR54-activating mutation was found in a patient with central precocious puberty.7 Polymorphism scans of the KiSS-1 and GPR54 genes in Chinese girls with central precocious puberty revealed a nonsynonymous single nucleotide polymorphism in the KiSS-1 gene and a SNP (nonsynonymous mutation) in the promoter region of the GPR54 gene, that were statistically related to the disease.8, 9 Further evidence, have supported the crucial role of KiSS-1/GPR54 system in reproductive function, which included the stimulation of LH release after in vivo administration of kisspeptin in mammals10, 11 as well as the implication of kisspeptin in mediating the estrogen positive and negative feedback in gonadotropin secretion.12, 13, 14 Moreover, the KiSS-1/GPR54 system has a distinct role in the seasonal (photoperiodic) control of reproduction as well as in the integration between energy status and reproduction (Fig. 1). Revel et al. 2007, have studied the photoneuroendocrine system in Syrian hamsters and concluded that the unknown – so far – link between the melatonin secretion and reproduction is the KiSS-1/GPR54 system.15 As far as the metabolic control of reproduction is concerned, it was observed that while the hypothalamic KiSS-1 gene expression is diminished during states of negative energy balance; kisspeptin administration overcomes the hypogonadotropic state seen in such conditions, an action thought to be mediated by leptin.16, 17, 18
Kisspeptin and placenta/trophoblasts: Kisspeptin was also involved in the procedure of placentation and trophoblast invasion. Recent studies have shown that kisspeptin repressed the invasion of the trophoblast into the maternal deciduas,19, 20 an essential process for fetal development, which so closely mimics the invasion of cancer cells (hence the normal trophoblast has been termed “pseudomalignant”). Measurements throughout pregnancy have revealed a dramatic increase of the circulating kisspeptin levels, which returned to near baseline levels, by day 5 postpartum, suggesting that the placenta produces kisspeptin during pregnancy.21 While the precise role of kisspeptin in pregnancy is still unknown, it is thought that it probably mediates the down regulation of the hypothalamic-pituitary-gonadal (HPG) axis.22 Quantitative polymerase chain reaction (PCR) analysis and laser capture microdissection revealed higher GPR54 expression levels in early placentas (where the invasive capacity of trophoblasts needs to be tightly controlled) as compared to term placentas.23 Moreover, KiSS-1/GPR54 role in the pathogenesis of pre-eclampsia has been recently proposed, but the existing data report rather conflicting results. Thus, according to Qiao et al. 2005 and Zhang et al. 2006, higher kisspeptin levels along with decreased matrix metalloproteinase 9 (MMP-9) are detected in pre-eclampsia while another study has reported decreased KiSS-1 levels in the placental tissues of pre-eclampsia.24, 25, 26
Furthermore, recent data suggested the possible role for these molecules in other previously unsuspected pathologies: Kisspeptin and polycystic ovarian syndrome (PCOS): Panidis et al. 2006, measured the circulating kp-54 (referred also as metastin) levels in 28 obese women with PCOS, 28 normal weight women with the syndrome, and 13 obese controls and found that the obese-PCOS group had the lowest kp-54 levels compared to normal weight women with PCOS and obese controls. However, plasma kp-54 immunoreactive (IR) concentrations were not significantly different in women with PCOS compared to controls. Furthermore, plasma kp-54 levels were found to be negatively correlated with body mass index (BMI), free androgen index, and indices of insulin resistance.27Kisspeptin and cardiovascular system: Mead et al. 2006, described a potent vasoconstrictor action of kisspeptins in isolated rings of coronary artery and umbilical vein.28Kisspeptin and diabetes: Hauge-Evans et al. 2006, detected expression of the KiSS-1/GPR54 system in the endocrine pancreas and reported the stimulation of glucose-induced insulin secretion when human and mouse islets are exposed to kisspeptin.29 Castellano et al. 2006, after conducting experiments in diabetic male rats, propose a role for the KiSS-1/GPR54 system in the altered gonadotropin secretion of type 1 diabetes.30Kisspeptin and menopause: Rometo et al. 2007, observed that menopause is associated with increased hypothalamic kisspeptin expression.31
Section snippets
KiSS-1/GPR54 system in cancer
The KiSS-1 gene is located on chromosome 1 (Fig. 2), with regulatory elements localized in chromosome 6 (to the 40 cM region between D6S468 and D6S314 in 6q16.3–q23).5, 32 KiSS-1 and GPR54 genes are mainly expressed in the placenta but also are found in the central nervous system (CNS), testis, ovary, pancreas and intestine (Table 1). The primary translation product of the KiSS-1 gene is a largely hydrophobic 145 amino acid polypeptide, known as kisspeptin. This peptide produces by proteolytic
Future investigation
There exist strong data to suggest that KiSS-1 is a metastasis suppressor in melanoma, bladder cancer, gastric carcinoma, esophageal cancer, thyroid cancer, epithelial ovarian cancer, endometrial cancer, choriocarcinoma, pancreatic cancer and uveal melanoma. Several studies so far have supported a strong correlation between lack of KiSS-1 expression and poor clinical outcome. However, there are two types of human malignancies, in which high rather than low KiSS-1 expression is associated to
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