kiss1-protein--human and Carcinoma

The present is an overview of recent data that describes the genetic underpinnings of the suppression of cancer metastasis. Despite the explosion of new information about the genetics of cancer, only six human genes have thus far been shown to suppress metastasis functionally. Not all have been shown to be functional in breast carcinoma. Several additional genes inhibit various steps of the metastatic cascade, but do not necessarily block metastasis when tested using in vivo assays. The implications of this are discussed. Two recently discovered metastasis suppressor genes block proliferation of tumor cells at a secondary site, offering a new target for therapeutic intervention.

Topics: Antigens, CD; Breast Neoplasms; Cadherins; Carcinoma; Cell Adhesion; Disease Progression; Female; Forecasting; Genes, Tumor Suppressor; Humans; Kangai-1 Protein; Kisspeptins; MAP Kinase Kinase 4; Membrane Glycoproteins; Mitogen-Activated Protein Kinase Kinases; Monomeric GTP-Binding Proteins; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; NM23 Nucleoside Diphosphate Kinases; Nucleoside-Diphosphate Kinase; Proteins; Proto-Oncogene Proteins; Repressor Proteins; Transcription Factors; Tumor Suppressor Proteins

Recurrence and metastasis are the usual manifestations of treatment failure of epithelial ovarian carcinoma (EOC). Vasculogenic mimicry (VM; blood supply development often seen in highly aggressive cancers), aldehyde dehydrogenase 1 (ALDH1, cancer stem cell biomarker), KiSS-1 (suppressor of tumor metastasis), and metastasis associated in colon cancer-1 (MACC1) are all useful predictive factors for metastasis and prognosis in various cancers. In this study, we analyzed associations among VM, ALDH1, KiSS-1, and MACC1 in EOC, and their respective correlations with clinicopathological characteristics and survival in EOC.. Positive rates of VM, ALDH1, KiSS-1, and MACC1 in 207 whole EOC tissue samples were detected by immunohistochemistry. Patients' clinical data were also collected.. Levels of VM, ALDH1, and MACC1 were significantly higher, and levels of KiSS-1 significantly lower, in EOC tissues than in benign ovary tumors. Levels of VM, ALDH1, KiSS-1, and MACC1 were associated significantly with tumor/lymph node/metastasis (LNM) grade, implantation, and International Federation of Gynecology and Obstetrics (FIGO) stage, and with patients' overall survival (OS); whereas the KiSS-1+ subgroup had significantly longer OS than did the KiSS-1- subgroup. In multivariate analysis, high VM, ALDH1 or MACC1 levels, FIGO stage, implantation and low KiSS-1 levels were independently associated with shorter OS in patients with EOC.. VM and expressions of ALDH1, KiSS-1, and MACC1 represent promising markers for metastasis and prognosis, and potential therapeutic targets for EOC.

Topics: Adult; Aged; Aldehyde Dehydrogenase 1 Family; Biomarkers, Tumor; Carcinoma; Female; Humans; Immunohistochemistry; Isoenzymes; Kisspeptins; Lymphatic Metastasis; Middle Aged; Ovarian Neoplasms; Ovary; Prognosis; Retinal Dehydrogenase; Trans-Activators; Transcription Factors; Young Adult

KiSS1 is a metastasis suppressor gene associated with inhibition of cellular chemotaxis and invasion attenuating the metastasis in melanoma and breast cancer cell lines. Along the KiSS-1 gene at least 294 SNPs have been described; however the association of these polymorphisms as genetic markers for metastasis in breast cancer studies has not been investigated. Here we describe two simple PCR-RFLPs protocols to identify the rs5780218 (9DelT) and the rs12998 (E20K) KiSS1 polymorphisms and the allelic, genotypic, and haplotypic frequencies in Mexican general population (GP) and patients with benign breast disease (BBD) or breast cancer (BC).. The rs5780218 polymorphism was individually associated with breast cancer (P = 0.0332) and the rs12998 polymorphism shows statistically significant differences when GP versus case (BC and BBD) groups were compared (P < 0.0001). The H1 Haplotype (G/-) occurred more frequently in BC group (0.4256) whereas H2 haplotype (G/T) was the most prevalent in BBD group (0.4674).. Our data indicated that the rs5780218 polymorphism individually confers susceptibility for development of breast cancer in Mexican population and a possible role as a genetic marker in breast cancer metastasis for H1 haplotype (Wt/variant) in KiSS1 gene must be analyzed in other populations.

Topics: Adult; Aged; Breast Neoplasms; Carcinoma; Case-Control Studies; Female; Humans; Kisspeptins; Mexico; Middle Aged; Polymorphism, Single Nucleotide

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.. Retrospective study.. 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.. 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.. 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.

Topics: Adult; Aged; Carcinoma; Female; Humans; Immunoenzyme Techniques; Kisspeptins; Male; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Staging; Prognosis; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Retrospective Studies

Topics: Biomarkers, Tumor; Carcinoma; Case-Control Studies; Female; Humans; Kisspeptins; Neoplasm Grading; Ovarian Neoplasms; Pilot Projects

Kisspeptins are hypothalamic neuropeptides encoded by KISS1 and recently described as major regulators of GnRH release from hypothalamic neurons. Although 17beta-estradiol (E2)-induced up-regulation of KISS1 expression has been documented in anteroventral periventricular nucleus neurons, E2 down-regulates KISS1 expression in arcuate nucleus neurons via the estrogen receptor alpha by unknown molecular mechanisms. Because KISS1 was initially described as a metastasis inhibitor, notably in breast tumors, we used the MDA-MB-231 breast cancer cell line, which expresses high levels of KISS1, to characterize the molecular mechanism underlying KISS1 regulation by E2. E2 rapidly down-regulated endogenous KISS1 in a stable ERalpha-expressing MDA-MB-231 cell line. Promoter analysis revealed that E2 down-regulation was determined by a short 93-bp sequence devoid of estrogen response element and Sp1 sites. E2 down-regulation persisted with an ERalpha that was unable to bind DNA and in the presence of histone deacetylase inhibitor. In the absence of E2, unliganded ERalpha and RNA polymerase II (RNAPII) were present on the proximal promoter. E2 stimulation induced recruitment of ERalpha and loss of RNAPII at the proximal promoter. Along the gene body, total RNAPII amounts were similar in E2-treated and untreated cells, whereas the active form was significantly less abundant in E2-treated cells. Thus, E2-induced down-regulation of KISS1 is mediated by a pathway combining RNAPII loss at the proximal promoter and modulation of active RNAPII along the gene body, which is a novel mechanism in the complex process of E2-induced repression of gene expression.

Topics: Binding Sites; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Estradiol; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; Kisspeptins; Promoter Regions, Genetic; Protein Binding; RNA Polymerase II; Signal Transduction; Tumor Suppressor Proteins