kiss1-protein--human and Ovarian-Neoplasms

Peritoneal metastasis is a critical feature and clinical challenge in epithelial ovarian cancer (EOC). We previously identified a novel long noncoding RNA (lncRNA, TC0101441) in epithelial ovarian cancer (EOC) using microarrays. However, the impact of TC0101441 on EOC metastasis and prognosis remains unclear. TC0101441 expression in EOC tissues and its correlation with clinicopathological factors and prognosis were examined. A series of in vitro and in vivo assays were performed to elucidate the roles and mechanism of TC0101441 in EOC metastasis. We found that TC0101441 levels were elevated in EOC tissues compared with those in normal controls and significantly correlated with an advanced clinical stage and lymph node metastasis. TC0101441 was determined to be an independent prognostic predictor of overall survival (OS) and disease-free survival (DFS). Furthermore, loss-of-function assays showed that TC0101441 promoted the invasive and metastatic capacities of EOC cells both in vitro and in vivo. Mechanistically, the prometastatic effects of TC0101441 were linked to the induction of epithelial-mesenchymal transition (EMT). Importantly, KiSS1 was identified as a downstream target gene of TC0101441 and was downregulated by TC0101441 in EOC cells. After TC0101441 was silenced, the corresponding phenotypes of EOC cell invasion and EMT were reversed by the overexpression of KiSS1. Taken together, our data suggest that TC0101441 functions as a potential promigratory/invasive oncogene by promoting EMT and metastasis in EOC through downregulation of KiSS1, which may represent a novel prognostic marker and therapeutic target in EOC.

Topics: Animals; Apoptosis; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Kisspeptins; Lymphatic Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Ovarian Neoplasms; Peritoneal Neoplasms; Prognosis; RNA, Long Noncoding; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

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

To evaluate the diagnostic accuracy of peripheral blood kisspeptin (KISS1) mRNA and plasma cancer antigen 125 (CA125) protein of epithelial ovarian cancer (EOC) in previously pregnant patients, we prospectively enrolled 40 EOC patients as cases and 20 uterine fibroids patients with normal ovary as controls. Levels of peripheral blood KISS1 mRNA and plasma CA125 protein was respectively measured by RT-PCR and electrochemiluminescent method, respectively. Receiver operating characteristic curves with area under curve (AUC) were used to evaluate the diagnostic accuracy. Logistic regression analysis was used to obtain a prediction model for combined diagnosis of KISS1 mRNA and CA125 protein. Both KISS1 mRNA and CA125 protein and had good diagnostic accuracy for EOC, early EOC and advanced EOC (AUC > 0.5, P < 0.05). The CA125 protein had higher diagnostic accuracy than KISS1 mRNA for advanced EOC (P = 0.0009). Moreover, the combination of KISS1 mRNA and CA125 protein had higher diagnostic accuracy for EOC than them alone (P 0.05). Peripheral blood KISS1 mRNA was a novel biomarker for detecting EOC in previously pregnant patients. Combination application of KISS1 mRNA and CA125 protein was recommended for the diagnosis of EOC, but not for advanced and early EOC.

Topics: Area Under Curve; Biomarkers, Tumor; CA-125 Antigen; Carcinoma, Ovarian Epithelial; Female; Humans; Kisspeptins; Leiomyoma; Ovarian Neoplasms; Pregnancy; RNA, Messenger

Our study aimed to elucidate the role of Kisspeptin (KISS1) in tumor tissues of patients with epithelial ovarian cancer (EOC) and investigate the prognostic value of this biomarker.Forty EOC patients and 20 uterine fibroids female patients with healthy ovaries undergoing cytoreductive surgery between January 2010 and January 2014 in our hospital were enrolled in this study. KISS1 expression in tumor and normal tissues was detected. Correlations between clinic-pathologic variables and KISS1 expression in EOC tissues and the prognostic value of KISS1 for overall survival were evaluated.During the follow-up of 11.2 to 62.1 months, the overall survival rate and mean survival time were 28.9% (11/38) and 38.35 ± 2.84 months. Preoperative KISS1 mRNA was higher in tumor tissue than in normal tissue (P <0.001), and it was associated with histologic grade of tumor, surgical FIGO stage, metastasis, and residual tumor size (all P <0.05). Multivariate survival analysis indicated significant influence of residual tumor size (HR = 2.357, P = 0.039) and preoperative KISS1 mRNA (HR = 0.0001, P <0.001) on mean survival time. Patients with low KISS1 mRNA expression had shorter survival time than those with high expression (P = 0.001).Preoperative KISS1 mRNA was a potential prognostic biomarker for EOC, and high preoperative KISS1 expression indicated a favorable prognosis.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Female; Humans; Kisspeptins; Middle Aged; Neoplasm Grading; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Prognosis; Survival Rate

The standard treatment of ovarian cancer with chemotherapy often leads to drug resistance and relapse of the disease, and the need for development of novel therapy alternatives is obvious. The MOC31PE immunotoxin binds to the cell surface antigen EpCAM, which is expressed by the majority of epithelial cancers including ovarian carcinomas, and we studied the cytotoxic effects of MOC31PE in ovarian cancer cells.. Investigation of the effects of MOC31PE treatment on protein synthesis, cell viability, proliferation and gene expression of the ovarian cancer cell lines B76 and HOC7.. MOC31PE treatment for 24 h caused a dose-dependent reduction of protein synthesis with ID50 values of less than 10 ng/ml, followed by reduced cell viability. In a gene expression array monitoring the expression of 84 key genes in cancer pathways, 13 of the genes were differentially expressed by MOC31PE treatment in comparison to untreated cells. By combining MOC31PE and the immune suppressor cyclosporin A (CsA) the MOC31PE effect on protein synthesis inhibition and cell viability increased tenfold. Cell migration was also reduced, both in the individual MOC31PE and CsA treatment, but even more when combining MOC31PE and CsA. In tumor metastasis PCR arrays, 23 of 84 genes were differentially expressed comparing CsA versus MOC31PE + CsA treatment. Increased expression of the tumor suppressor KISS1 and the nuclear receptor NR4A3 was observed, and the differential candidate gene expression was confirmed in complementary qPCR analyses. For NR4A3 this was not accompanied by increased protein expression. However, a subcellular fractionation assay revealed increased mitochondrial NR4A3 in MOC31PE treated cells, suggesting a role for this protein in MOC31PE-induced apoptotic cell death.. The present study demonstrates that MOC31PE may become a new targeted therapy for ovarian cancer and that the MOC31PE anti-cancer effect is potentiated by CsA.

Topics: Antineoplastic Agents; Cell Death; Cell Line, Tumor; Cell Movement; Cell Survival; Cyclosporine; DNA-Binding Proteins; Dose-Response Relationship, Drug; Drug Synergism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunoconjugates; Immunotoxins; Inhibitory Concentration 50; Kisspeptins; Oligonucleotide Array Sequence Analysis; Ovarian Neoplasms; Polymerase Chain Reaction; Receptors, Steroid; Receptors, Thyroid Hormone; Time Factors; Up-Regulation

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

To investigate the expression and correlation of KiSS-1, matrix metalloproteinase-9 (MMP-9) and nuclear factor (NF)-kappaBp65 proteins in primary epithelial ovarian tumors.. Expression of KiSS-1, MMP-9, NF-kappaBp65 proteins in primary ovarian epithelial tumors (malignant n = 50, borderline tumor n = 20, benign adenoma n = 20, normal tissue n = 10) was evaluated by immunohistochemical staining.. Expression of metastin protein in primary epithelial ovarian cancers was significantly higher than that in ovarian benign adenoma (P < 0.05) and normal tissues (P < 0.05). Expression of metastin protein in ovarian borderline tumors was significantly higher than that in normal tissues (P < 0.05). Expression of metastin protein in ovarian cancer was significantly correlated with node metastasis (P < 0.05). However, Metastin protein expression was not correlated with different histological classifications (P > 0.05), differentiation grade (P > 0.05) and International Federation of Gynecology and Obstetrics (FIGO) stage (P > 0.05). MMP-9 protein was positive in 68% (34/50) of the epithelial ovarian cancers, significantly higher than that in normal tissues (20%, 2/10; P < 0.05). NF-kappaBp65 protein was positive in 72% (36/50) of the epithelial ovarian cancers, significantly higher than that in ovarian benign adenoma (30%, 6/20; P < 0.05) and normal tissues (10%, 1/10; P < 0.05). The expression of MMP-9 protein in epithelial ovarian cancer was significantly correlated with FIGO stage (P < 0.05) and lymph node metastasis (P < 0.05). However, MMP-9 protein expression was not correlated with different histological classifications (P > 0.05) and differentiation grade (P > 0.05). The expression of NF-kappaBp65 protein in epithelial ovarian cancer was significantly correlated with FIGO stage (P < 0.05), differentiation grade (P < 0.05) and lymph node metastasis (P < 0.05). However, NF-kappaBp65 protein expression was not correlated with different histological classifications (P > 0.05). There was obviously negative correlation between KiSS-1 and MMP-9 expression in ovarian cancer (rs = -0.547, P < 0.05), as well as between KiSS-1 and NF-kappaBp65 expression in ovarian cancer (rs = -0.414, P < 0.05), while there was obviously positive correlation between MMP-9 and NF-kappaBp65 expression in ovarian cancer (rs = 0.695, P < 0.05).. The results indicate that KiSS-1 plays some role in suppression of the metastasis of ovarian epithelial cancers, which may be through inhibiting the expression of MMP-9 and NF-kappaBp65.

Topics: Adolescent; Adult; Aged; Female; Humans; Immunohistochemistry; Kisspeptins; Lymphatic Metastasis; Matrix Metalloproteinase 9; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Ovary; Prognosis; Retrospective Studies; Transcription Factor RelA; Tumor Suppressor Proteins

Metastin, a product of the KiSS-1 gene, is a ligand for a G-protein-coupled receptor (AXOR12) and is a strong suppressant of metastasis. The aim of this study was to evaluate whether metastin and AXOR12 gene expressions affect prognosis of patients with epithelial ovarian cancer.. The expression levels of metastin, AXOR12 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression were analysed by the real-time quantitative reverse transcription-polymerase chain reaction in 76 epithelial ovarian cancer surgical specimens. Their expression (metastin/GAPDH and AXOR12/GAPDH ratios) was correlated with the clinical findings. Furthermore, cellular distribution of metastin and AXOR12 mRNA was examined by in situ hybridisation on tissue sections.. The median and range of mRNA expression for metastin and AXOR12 were 0.047 and 0.01-13.57, and 4.00 and 0.011-135.13, respectively. Patients were dichotomised into two groups having low and high expressions by using the median value as the cutoff. A good agreement was noticed between metastin and AXOR12 gene expression levels (kappa coefficient; 0.74). The presence of residual tumour following resection was negatively associated with metastin (P=0.0084) and AXOR12 (P=0.0148) gene expressions indicating an association of low expression of these genes in more aggressive, and advanced tumours. By univariate Cox regression analysis, the prognosis of the patients with low AXOR12 gene expression was significantly worse than those with high AXOR12 gene expression (P=0.030). The combination of metastin and AXOR12 gene expression level was also significantly associated with the prognosis (P=0.049). Transcripts for both metastin and AXOR12 were detected in the epithelial ovarian carcinoma cells.. These results present a new insight into the understanding of the biological behaviour of epithelial ovarian cancer. Metastin/AXOR12 signalling may suppress the invasive phenotype of epithelial ovarian cancer.

Topics: Adult; Aged; Female; Gene Expression; Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); Humans; Kisspeptins; Middle Aged; Neoplasm Proteins; Ovarian Neoplasms; Prognosis; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survival Analysis; Tumor Suppressor Proteins

Kisspeptins and their G-protein coupled receptor, GPR54 are required for GnRH release and have been associated with anti-metastatic tumour cell behaviour in model systems. The latter might suggest that their overexpression would be associated with a better prognosis in cancer. However, kisspeptin/GPR54 interactions (autocrine, paracrine, and/or endocrine) could also impact tumour behaviour in a negative manner. Here, for the first time, we associate the immunoreactivity of the kisspeptin/GPR54 ligand-receptor pair with favourable prognosis in a large cohort of ovarian carcinomas.. Immunohistochemical analysis for kisspeptin and GPR54 was performed on a tissue microarray (TMA) consisting of 518 early stage ovarian carcinomas, all with linked clinical outcome data. The TMA was scored using a staining intensity scale of 0 (negative), +1 (mild-moderate), and +2 (strong). Strong staining cases were considered either kisspeptin or GPR54 positive and designated as 1, while all other cases were considered negative and designated 0. All statistical analysis was conducted using two-sided tests and a p value equal to or less than 0.05 was considered significant.. Kisspeptin and GPR54 immunoreactive cases show a favourable prognosis in univariable disease specific survival (p = 0.0023, p = 0.0092), as well as in overall survival (p = 0.0006, p = 0.0002). Furthermore, kisspeptin is an independent marker for favourable prognosis as determined by multivariable disease specific (p = 0.0046) and overall survival analysis (p = 0.0170), while GPR54 is an independent marker for overall survival only (p = 0.0303). Both kisspeptin positive and GPR54 positive cases are strongly associated with the ovarian carcinoma clear cell subtype (p < 0.0001, p < 0.0001), and GPR54 is significantly associated with favourable prognosis in overall survival within the clear cell subtype (p = 0.0102).. Kisspeptin and GPR54 immunoreactivity are significantly associated with favourable prognosis in both disease specific and overall survival, as well as being significantly associated with the clear cell ovarian carcinoma subtype, thereby creating the first independent prognostic biomarkers specific for ovarian clear cell carcinomas.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Cohort Studies; Disease; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Kisspeptins; Middle Aged; Ovarian Neoplasms; Prognosis; Proportional Hazards Models; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Tumor Suppressor Proteins

To study the expression and significance of metastasis suppressor gene KiSS-1 and its receptor GPR54 in epithelial ovarian cancer.. The expression and their clinical significance of KiSS-1 and GPR54 were evaluated by RT-PCR in 37 patients with epithelial ovarian cancer, 15 patients with borderline epithelial ovarian tumors, 15 patients with epithelial benign tumors and 11 patients with normal ovarian tissues.. The positivity and relative contents of KiSS-1 mRNA in patients with epithelial ovarian cancer (68%, 0.82 +/- 0.09) and borderline epithelial ovarian tumors (60%, 0.80 +/- 0.10) were all higher than in patients with epithelial benign tumor (20%, 0.65 +/- 0.10) and normal ovarian tissues (18%, 0.66 +/- 0.06; P < 0.05). The positivity and relative contents of KiSS-1 mRNA in patients with epithelial ovarian cancer correlated with their clinical stage and lymph node metastasis (P < 0.05). There was no difference in the positivity and relative contents of GPR54 mRNA between patients with epithelial ovarian cancer (70%, 0.79 +/- 0.07), borderline epithelial ovarian tumor (67%, 0.76 +/- 0.10), benign epithelial ovarian tumor (60%, 0.73 +/- 0.07) and normal ovarian tissues (45%, 0.78 +/- 0.08), respectively (all P > 0.05). The positivity and relative contents of GPR54 mRNA in patients with epithelial ovarian cancer did not correlate with their clinical stage, histology grade, lymph node metastasis and production of ascites (P > 0.05).. KiSS-1 and GPR54 may play an important role in inhibiting the invasion and metastasis of early epithelial ovarian cancer.

Topics: Adult; Aged; Female; Gene Expression Regulation, Neoplastic; Humans; Kisspeptins; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Ovarian Neoplasms; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Suppressor Proteins

Metastasis is a vital target for cancer treatment, since the majority of cancer patients die from metastatic, rather than the primary disease. KiSS1 has been identified as a metastasis suppressor gene in melanoma and breast carcinomas. We show here that KiSS1 is also a metastasis suppressor in human ovarian cancer. Overexpression of KiSS1 in ovarian cancer cells inhibits cell migration induced by serum or lysophosphatidic acid (LPA), and colonization in soft agar, but not cell proliferation, representing the characteristics of a metastasis suppressor gene. Furthermore, using an experimental metastatic mouse model, we show that expression of KiSS1 in SKOV3 ovarian cancer cells suppresses >50% metastatic colonization in mice (P < 0.0001). We find that activating protein kinase C (PKC) reverses about 80% of the inhibited cell migration induced by KiSS1, while down-regulation of PKCalpha with shRNA restores KiSS1 effect, providing evidence that inhibiting PKCalpha may be an important mechanism of the effect of KiSS1. These results suggest that KiSS1 is a metastasis suppressor of ovarian cancer and may be a potential molecular target for the treatment.

Topics: Animals; Cell Movement; Cell Proliferation; Down-Regulation; Female; Humans; Kisspeptins; Lysophospholipids; Mice; Mice, Nude; Neoplasm Metastasis; Ovarian Neoplasms; Protein Kinase C-alpha; Proteins; Transplantation, Heterologous; Tumor Suppressor Proteins