kiss1-protein--human and Colorectal-Neoplasms

KISS1 and KISS1R, a novel pair of metastasis suppressors, are likely to be associated with the prognosis of colorectal cancer (CRC). Here, a meta-analysis was performed to study the role of KISS1 and KISS1R in CRC. Heterogeneity, stability and publication bias were all estimated. Six publications describing a total of 559 CRC patients were included in the present study. Low KISS1 expression predicted 70% higher risk of poor prognosis for general patients (HR, 1.71; 95% CI, 1.28-2.29) and 99% higher risk for East Asian patients (HR, 1.99; 95% CI, 1.46-2.72). Limited evidence indicated that decreased KISS1R expression might predict poor outcome (HR, 2.96; 95% CI, 1.51-5.82). Neither heterogeneity nor publication bias was identified. The current analyses suggest that low KISS1 expression predicts poor overall survival among East Asian patients with CRC. Evidence on other races and KISS1R are still insufficient, and additional studies are required to clarify the risk of CRC associated with KISS1R by race.

Topics: Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Kisspeptins; Prognosis; Receptors, Kisspeptin-1

Topics: Colorectal Neoplasms; Gene Expression Regulation; Gene Silencing; Humans; Kisspeptins; Loss of Heterozygosity; N-Acetylglucosaminyltransferases; Neoplasm Metastasis; Neovascularization, Pathologic; Oligonucleotide Array Sequence Analysis; Proteins; Tumor Suppressor Proteins

Colorectal cancer (CRC) is one of the most common cancers and the fourth leading cause of cancer-related deaths worldwide. We aimed to determine the role of miR-650 in CRC pathogenesis.. In this study, we examined the expression of miR-650 and KISS1 in 80 CRC patients who either received or did not receive chemo agents. For this aim, we assessed the miR-650 and KISS1 expression levels in 80 CRC tissues, 30 of which had no history of chemotherapy. The effect of miR-650 and 5-FU on KISS1 expression was measured using qPCR and Western blotting. Also, the 5- FU effect on miR-650 expression in the CRC cell lines was measured by qRT-PCR. Next, MTT assay and Flowcytometry assays were conducted to determine the role of miR-650 in cell viability and apoptosis.. The results showed that miR-650 was down-regulated in CRC tissues. However, patients who received 5-FU before surgery showed increased expression of miR-650. The results for KISS1 were insignificant while administering 5-FU to patients preoperatively increased its expression. In-vitro studies showed that 5-FU led to the up-regulation of miR-650 in the SW480 CRC cell line. Furthermore, the administration of miR-650 and 5-FU downregulated KISS1, especially when combined. Moreover, miR-650 with 5-FU significantly reduced cell viability in CRC cell lines by inducing apoptosis.. These results indicate that miR-650 has a tumor suppressive function, overcoming 5-FU chemoresistance in CRC, and induces apoptosis probably by alleviating KISS1. These results suggest that miR-650 is a potential contributor to CRC pathogenesis.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Down-Regulation; Drug Resistance, Neoplasm; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Kisspeptins; MicroRNAs

The aim of the present study was to investigate the mechanism through which kisspeptin inhibits colorectal cancer metastasis.. 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.. 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.. Kisspeptin-mediated activation of PKR-PP2A inhibited colorectal cancer cell invasiveness.

Topics: Apoptosis; Cell Movement; Cell Proliferation; Colorectal Neoplasms; eIF-2 Kinase; Humans; Kisspeptins; Neoplasm Invasiveness; Phosphorylation; Protein Phosphatase 2; Tumor Cells, Cultured

Cancers are among the most serious threats of human health worldwide. Survival and mortality rates of colorectal cancer (CRC) strongly depend on the early diagnosis. The aberrant methylation pattern of genes as a diagnostic biomarker can serve as a practical option for timely detection and contribute subsequently to the enhancement of survival rate in CRC patients, since methylation changes are not only frequent but also can occur in initial tumorogenesis stages. It has been indicated that EDNRB and KISS1 genes are hypermethylated through progression and development of CRC. In current study, after extraction of genomic DNA from 45 paired tumor and adjacent non-cancerous tissue samples and treatment with bisulfite conversion, the methylation status of EDNRB and KISS1 CpG rich regions were assessed quantitatively using MS-HRM assay to determine practicability of these aberrant methylations for diagnosis of sporadic CRC and its discrimination from corresponding normal tissues. The results showed that the methylation distribution differences, comparing tumor tissues with their adjacent non-cancerous tissues, were statistically significant in all selected locations within EDNRB gene promoter (P < 0.001); they had also some correlations with tumor stage and grade. Nonetheless, methylation distribution in KISS1 gene CpG rich region revealed no statistically significant differences between CRC and adjacent non-cancerous tissues (P = 0.060). Overall, it can be concluded that aberrant methylated EDNRB can be a promising potential diagnostic biomarker for CRC, while KISS1 is controversial and needs to be more investigated.

Topics: Biomarkers, Tumor; Colorectal Neoplasms; DNA Methylation; Genetic Predisposition to Disease; Humans; Iran; Kisspeptins; Mutation; Polymorphism, Single Nucleotide; Prevalence; Receptor, Endothelin B; Reproducibility of Results; Risk Factors; Sensitivity and Specificity

Metastasis of colorectal cancer (CRC) depends critically on MMP-9. KiSS-1 is a human malignant melanoma metastasis-suppressor gene. Thus, the interaction between MMP-9 and KiSS-1 has drawn considerable attention in recent years. In the present study, it was hypothesized that KiSS-1 gene could repress the metastatic potential of colorectal cancer cells by inhibiting the expression of MMP-9. Stable transfection of KiSS-1 specific siRNA and KiSS-1 expression vector in human CRC cell line HCT-116 was achieved by lentivirus infection. Moreover, the cell proliferation, invasiveness, and apoptosis were evaluated by CCK-8 method, transwell experiment, and fluorescence activated cell sorter, respectively. We also investigated the expression of MMP-9, PI3K, Akt, pAKt, and NF-кB subunit p65 using western blotting. KiSS-1 overexpression significantly decreased the cell proliferation and invasiveness of HCT-119 cells, while apoptosis was enhanced. The result of western blotting showed that synthesis of MMP-9, PI3K, p65, and phosphorylation of Akt were significantly blocked by overexpression of KiSS-1. Concatenated treatment of KiSS-1 overexpression vector with PI3K and Akt agonists attenuated the effect of KiSS-1 on the biological activity of CRC cells and also released the expression of MMP-9, PI3K, p65, and phosphorylation of Akt from the influence of overexpression of KiSS-1. Overexpression of KiSS-1 suppressed the invasiveness of CRC cells, and the gene exerted its function by reducing the expression of MMP-9 via blocking of tge PI3K/Akt/NF-κB pathway.

Topics: Apoptosis; Cell Proliferation; Colorectal Neoplasms; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Kisspeptins; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Transcription Factor RelA

The progression of distant metastasis cascade is a multistep and complicated process, frequently leading to a poor prognosis in cancer patients. Recently, growing evidence has indicated that deregulation of microRNAs (miRNAs) contributes to tumorigenesis and tumor progression in colorectal cancer (CRC). In the present study, by comparing the miRNA expression profiles of CRC tissues and corresponding hepatic metastasis tissues, we established the downregulation of miR-199b in CRC metastasis tissues. The decrease in miR-199b expression was significantly correlated to late TNM stage and distant metastasis. Moreover, Kaplan-Meier curves showed that CRC patients with high expression level of miR-199b had a longer median survival. Functional assays results indicated that the restoration of miR-199b considerably reduced cell invasion and migration in vitro and in vivo, and increased the sensitivity to 5-FU and oxaliplatin. Further dual-luciferase reporter gene assays revealed that SIRT1 was the direct target of miR-199b in CRC. The expression of miR-199b was inversely correlated with SIRT1 in CRC specimens. SIRT1 knockdown produced effects on biological behavior that were similar to those of miR-199b overexpression. Furthermore, through Human Tumor Metastasis PCR Array we discovered KISS1 was one of the downstream targets of SIRT1. Silencing of SIRT1 upregulated KISS1 expression by enhancing the acetylation of the transcription factor CREB. The latter was further activated via binding to the promoter of KISS1 to induce transcription. Thus, we concluded that miR-199b regulates SIRT1/CREB/KISS1 signaling pathway and might serve as a prognosis marker or a novel therapeutic target for patients with CRC.

Topics: Adult; Aged; Animals; Colorectal Neoplasms; Cyclic AMP Response Element-Binding Protein; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Kaplan-Meier Estimate; Kisspeptins; Male; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; Middle Aged; Neoplasm Invasiveness; Prognosis; Sirtuin 1

Angiogenesis is a significant biological mechanism in the progression and metastasis of solid tumors. Vascular endothelial growth factor (VEGF), its receptors and signaling effectors have a central role in tumor-induced angiogenesis. Genetic variation in the VEGF pathway may impact on tumor angiogenesis and, hence, on clinical cancer outcomes. This study evaluates the influence of common genetic variations within the VEGF pathway in the clinical outcomes of 172 metastatic colorectal cancer (mCRC) patients treated with first-line oxaliplatin/5-fluorouracil chemotherapy. A total of 27 single-nucleotide polymorphisms (SNPs) in 16 genes in the VEGF-dependent angionenesis process were genotyped using a dynamic array on the BioMark™ system. After assessing the KRAS mutational status, we found that four SNPs located in three genes (KISS1, KRAS and VEGFR2) were associated with progression-free survival. Five SNPs in three genes (ITGAV, KRAS and VEGFR2) correlated with overall survival. The gene-gene interactions identified in the survival tree analysis support the importance of VEGFR2 rs2071559 and KISS1 rs71745629 in modulating these outcomes. This study provides evidence that functional germline polymorphisms in the VEGF pathway may help to predict outcome in mCRC patients who undergo oxaliplatin/5-fluorouracil chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Genetic Association Studies; Humans; Kisspeptins; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prognosis; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

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.

Topics: Aged; Biomarkers, Tumor; Cell Transformation, Neoplastic; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Intestinal Mucosa; Kisspeptins; Liver Neoplasms; Lymphatic Metastasis; Male; Prognosis; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1

Cancer metastasis is a major contributor to patient death because of its systemic nature and resistance to therapeutic agents. KISS1, originally identified to be a metastasis suppressor, couples to its receptor KISS1R and plays a pivotal role in suppressing cancer metastasis. In this study, we investigated KISS1 and KISS1R expression in colorectal liver metastasis (CRLM), and analyzed their correlation with patients' clinicopathological variables, including prognosis.. Overall, 55 patients with CRLM who underwent hepatectomy between 2003 and 2013 were enrolled in this study. Immunohistochemistry was performed to evaluate the protein expression of KISS1, KISS1R, and matrix metalloproteinase-9 (MMP-9). Clinicopathological variables, including prognosis, were compared between low- and high-expressing groups of KISS1 or KISS1R. We analyzed the correlation of KISS1 or KISS1R protein expression with MMP-9.. Expression of both KISS1 and KISS1R was significantly correlated with overall survival (p = 0.0283 and p = 0.0275, respectively). The 5-year overall survival rate of the KISS1 and KISS1R low groups was 44.3 and 39.3 %, and 73.7 and 67.9 % in the high groups, respectively. Multivariate analysis revealed that KISS1 low expression was an independent prognostic factor (p = 0.037, hazard ratio 0.20). Moreover, KISS1 low-expression patients had more frequent distant metastasis (p < 0.05). Furthermore, KISS1 low-expressing tumor tissues expressed more MMP-9 protein (p = 0.034), which was mainly expressed in neutrophils at the metastatic tumor edge.. KISS1 could be a promising prognostic and therapeutic marker in CRLM. KISS1 low expression may induce high MMP-9 expression in neutrophils.

Topics: Aged; Biomarkers, Tumor; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Kisspeptins; Liver Neoplasms; Male; Matrix Metalloproteinase 9; Neoplasm Staging; Prognosis; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Survival Rate

To investigate the effect of Kiss-1 gene suppression on the metastatic capacity of HCT116 human colorectal carcinoma cells in vitro and the involvement of nuclear factor-κB (NF-κB) signaling pathway.. A recombinant lentiviral vector of Kiss-1 gene pGC-LV-Kiss-1-EGFP or the empty vector was transfected in HCT116 cells. Cell Counting Kit-8 (CCK8) and Transwell chamber assay were used to detect the changes in cell proliferation, invasion and migration ability after the transfection. Western blotting was used to detect the expression of I-κB, the inhibitive protein of NF-κB signal pathway, and the expression of the downstream effector MMP-9 before and after transfection.. In cells over-expressing Kiss-1, I-κB expression increased and MMP-9 expression decreased significantly compared to those in the blank control and vector-transfected cells (P<0.05). Kiss-1 gene over-expression resulted in significant inhibition of HCT116 cell proliferation, invasion, and migration as compared to the control cells (P<0.05).. Lentivirus-mediated Kiss-1 gene over-expression can inhibit the proliferation, invasion, and migration of HCT116 cells via the NF-B signaling pathway.

Topics: Cell Movement; Cell Proliferation; Colorectal Neoplasms; Genetic Vectors; HCT116 Cells; Humans; I-kappa B Kinase; Kisspeptins; Lentivirus; Matrix Metalloproteinase 9; Neoplasm Invasiveness; NF-kappa B; Signal Transduction; Transfection

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.

Topics: Aged; Aged, 80 and over; Apoptosis; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Cytokines; Gene Silencing; Humans; Kisspeptins; Lymphocytes; Middle Aged; Neoplasm Proteins; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; RNA-Binding Proteins

To examine the effect of aberrant methylation of the KISS1 promoter on the development of colorectal cancer (CRC) and to investigate reversing aberrant methylation of the KISS1 promoter as a potential therapeutic target.. KISS1 promoter methylation, mRNA expression and protein expression were detected by methylation-specific polymerase chain reaction (PCR), real-time quantitative PCR and Western blotting, respectively, in 126 CRC tissues and 142 normal colorectal tissues. Human CRC cells with KISS1 promoter hypermethylation and poor KISS1 expression were treated in vitro with 5-aza-2'-deoxycytidine (5-Aza-CdR). After treatment, KISS1 promoter methylation, KISS1 mRNA and protein expression and cell migration and invasion were evaluated.. Hypermethylation of KISS1 occurred frequently in CRC samples (83.1%, 105/126), but was infrequent in normal colorectal tissues (6.34%, 9/142). Moreover, KISS1 methylation was associated with tumor differentiation, the depth of invasion, lymph node metastasis and distant metastasis (P < 0.001). KISS1 methylation was also associated with low KISS1 expression (P < 0.001). Furthermore, we observed re-expression of the KISS1 gene and decreased cell migration after 5-Aza-CdR treatment in a CRC cell line.. These data suggest that KISS1 is down-regulated in cancer tissues via promoter hypermethylation and therefore may represent a candidate target for treating metastatic CRC.

Topics: Aged; Biomarkers, Tumor; Case-Control Studies; Cell Movement; Colorectal Neoplasms; Disease Progression; DNA Methylation; DNA Modification Methylases; Down-Regulation; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Kisspeptins; Male; Middle Aged; Neoplasm Invasiveness; Promoter Regions, Genetic; RNA, Messenger

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.. 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.. 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.. The present study has presented evidence that Kiss-1 may be a putative metastasis suppressor molecule in human colorectal cancer.

Topics: Adenocarcinoma; Cell Line, Tumor; Cell Movement; Chemoradiotherapy; Colon; Colorectal Neoplasms; Gene Expression; Humans; Kaplan-Meier Estimate; Kisspeptins; MAP Kinase Signaling System; Matrix Metalloproteinase 9; Multivariate Analysis; Prognosis; Receptors, G-Protein-Coupled; Receptors, Kisspeptin-1; Treatment Outcome

Cancer research is currently focused on blocking the metastatic process at its early steps. Some particularly attractive targets are metastasis suppressor genes, which control cancer cell dissemination. The aim of this study was to clarify the relationship between the expression of KiSS1, a metastasis suppressor gene, and disease progression in colorectal cancer patients. One-hundred and seventy-five patients who underwent surgery for colorectal cancer were enrolled in this study. We analyzed KiSS1 mRNA expression by real-time reverse transcription PCR in colorectal cancer tissue and paired adjacent normal mucosa. KiSS1 protein expression in early- and advanced-stage colorectal cancer samples was determined by immunohistochemical analysis. Decreased KiSS1 expression was significantly associated with lymph node metastasis and was an independent prognostic factor. Logistic regression analysis revealed that decreased KiSS1 expression was an independent risk factor for lymph node metastasis. Immunohistochemical analysis indicated that KiSS1 was highly expressed in the cell cytoplasm of early-stage colorectal cancer cells. The loss of KiSS1 appears to correlate with the progression of lymph node metastasis. An assessment of KiSS1 expression may assist in the accurate colorectal cancer diagnosis and may contribute to predict clinical outcomes.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Child; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Kisspeptins; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Peritoneal Neoplasms; Prognosis; Prospective Studies; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survival Rate; Young Adult

Kisspeptins, the products of the KISS1 gene, are involved in cancer invasion, migration, metastasis and angiogenesis, while they induce apoptosis in various cancers. Herein, we studied KISS1 expression in colorectal cancer. We analyzed KISS1 expression using immunohistochemistry and image analysis in normal and malignant tissue samples from 60 patients with colorectal adenocarcinoma. The results correlated with various clinicopathological parameters. The expression of KISS1 was much higher in normal than in malignant colonic mucosa. However, among malignant tissues, KISS1 expression was higher in larger tumors (>4 cm) than in smaller ones (≤4 cm) and in stages III and IV than in stages I and II. In addition, it was higher in patients with lymph node metastases. Moreover, KISS1 levels in the normal mucosa and their difference from those in the malignant mucosa were higher in the right part of the large intestine than in the left one. KISS1 expression is reduced during the malignant transformation of the colonic mucosa and there is a difference in the expression pattern between the right and the left part of the large intestine. However, larger and advanced colorectal tumors express higher KISS1 levels than smaller and localized ones.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Cell Transformation, Neoplastic; Colon; Colorectal Neoplasms; Female; Gene Expression; Humans; Intestinal Mucosa; Kisspeptins; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Tumor Burden

KISS1 is a metastasis suppressor lost in several solid malignancies. We evaluated the clinical relevance of KiSS-1 methylation and its protein expression in colorectal cancer. The epigenetic silencing of KiSS-1 by hypermethylation was tested in colon cancer cells (n = 5) before and after azacytidine treatment. KiSS-1 methylation was evaluated by methylation-specific PCR in colorectal cancer cells, and normal, benign, and tumor tissues (n = 352) were grouped in a training set (n = 62) and two independent validation cohorts (n = 100 and n = 190). KiSS-1 protein expression was analyzed by immunohistochemistry on tissue arrays. KiSS-1 hypermethylation correlated with transcript and protein expression loss, being increased in vitro by azacytidine. Methylation rates were 53.1, 70.0, and 80.0 % in the training and validation sets, respectively. In the training set, KiSS-1 methylation rendered a diagnostic accuracy of 72.7 % (p = 0.002). Combination of KiSS-1 methylation and serum CEA (p = 0.001) increased the prognostic utility of CEA alone (p = 0.022). In the first validation set, KiSS-1 methylation correlated with tumor grade (p = 0.011), predicted recurrence (p = 0.009), metastasis (p = 0.004), disease-free (p = 0.034), and overall survival (p = 0.015). In the second validation cohort, KiSS-1 methylation predicted disease-specific survival (p = 0.030). In the training set, cytoplasmic KiSS-1 expression was significantly higher in nonneoplastic biopsies as compared to colorectal tumors (p < 0.0005). In the validation set, loss of cytoplasmic expression correlated with tumor stage (p = 0.007), grade (p = 0.035), recurrence (p = 0.017), and disease-specific survival (p = 0.022). KiSS-1 was revealed epigenetically modified in colorectal cancer. The diagnostic and prognostic utility of KiSS-1 methylation and expression patterns suggests their assessment for the clinical management of colorectal cancer patients.

Topics: Adult; Aged; Aged, 80 and over; Azacitidine; Biomarkers, Tumor; Cell Line, Tumor; Colorectal Neoplasms; Disease Progression; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Humans; Kisspeptins; Male; Middle Aged; Molecular Sequence Data; Prognosis

Recent studies have demonstrated that Kisspeptin, the product of the metastasis suppressor gene KiSS-1, could have a role in tumor progression and invasion. In this pilot study, we investigated the association of plasma Kisspeptin-54 level with colorectal cancer (CRC).. Plasma Kisspeptin-54 levels were quantified using enzyme-immunoassay (EIA) kits from blood samples of 81 patients with CRC at their initial staging and 59 age-matched healthy controls.. Plasma Kisspeptin-54 levels were significantly higher in CRC patients (86.2 ± 20.5) than in controls (49 ± 12.7; p < 0.005). The cutoff value for Kisspeptin-54 detection was determined as 46 ng/ml, and area under curve (AUC) value was 0.766 with sensitivity 63 %, specificity 81.4 %, positive predictive value 82.2 %, negative predictive value 61.5 %, positive likelihood ratio 3.38, and negative likelihood ratio 0.46. Increased plasma Kisspeptin-54 levels were significantly correlated with nodal involvement of CRC (Spearman, rs = 0.345, p = 0.002). Kisspeptin-54 was also found to be an independent predictive marker for lymph node metastases of CRC (p = 0; Exp(B): 2.053; 95 % CI, 1.255-2.851).. Our results reveal that plasma Kisspeptin-54 measurement could be a useful diagnostic and prognostic parameter for CRC. Further prospective evaluation is needed to validate these findings and to establish the clinical usefulness of Kisspeptin-54 for CRC diagnostics.

Topics: Aged; Colorectal Neoplasms; Female; Humans; Kisspeptins; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Pilot Projects; ROC Curve

To investigate the change of expression level of metastasis suppressor gene Kiss-1 in the colorectal cancer cell line SW480 after radiation, and to determine its association with the proliferation and apoptosis of SW480 cells.. SW480 cells were divided into control group (0 Gy) and study groups (2, 4, 6, 8 Gy). Cells in the study groups were irradiated by 6-MV X-ray radiation for 48 hours. Immunohistochemistry and real-time PCR methods were used to investigate the influence of radiation on Kiss-1 gene expression of SW480. Colony formation assay was used to detect the proliferation of SW480. Flow cytometry-Annexin- V/PI assay was used to observe the change of the apoptosis rate.. Compared with the control group, Kiss-1 protein expression increased after radiation of 6, 8 Gy (P<0.05), but no significant changes were observed after radiation of 2, 4 Gy(P>0.05). Kiss-1 gene mRNA level increased after radiation of 2, 4, 6 Gy, while no obvious change was observed for 8 Gy radiation. The apoptosis rates increased for 4, 6, 8 Gy radiation(P<0.05), however, there was no significant difference for 2 Gy radiation (P<0.05).. Radiation may increase Kiss-1 gene expression in SW480 cells, which results in decreases proliferation and increases apoptosis in residual surviving cells.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Humans; Kisspeptins; RNA, Messenger; X-Rays

To study the expression of vascular endothelial growth factor (VEGF) and metastin in colorectal carcinoma and their association with the clinicopathological features of the malignancy.. VEGF and metastin expressions were examined immunohistochemically with SP method in 70 specimens of human colorectal carcinoma tissues and adjacent normal tissues.. VEGF protein overexpression was detected in 48.6% (34/70)of the colorectal carcinoma tissues but in none of the adjacent normal tissues (P<0.01), and for metastin, the overexpression rate was 28.6% (20/70) in the colorectal carcinoma tissues and 70.0% (49/70) in the normal tissues (P<0.01). The expression of both VEGF and metastin was related to the histological grades, infiltration depth, TNM stage and lymph node metastasis of the tumor (P<0.01 and P<0.05, respectively).. Immunohistochemical detection of VEGF and metastin can be of value in assessment of the malignancy and in prognostic evaluation of colorectal carcinoma.

Topics: Adult; Aged; Colorectal Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Kisspeptins; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Tumor Suppressor Proteins; Vascular Endothelial Growth Factor A; Young Adult