84634

KISS1R

KISS1 receptor;KISS1R;KISS1 receptor

G protein-coupled receptor 54|G-protein coupled receptor OT7T175|hypogonadotropin-1|kiSS-1 receptor|kisspeptins receptor|metastin receptor

19p13.3

protein-coding

Kisspeptins (KPs), peptide products of the KISS1 metastasis-suppressor gene, are endogenous ligands for a G protein-coupled receptor (KISS1R). KISS1 acts as a metastasis suppressor in numerous human cancers. However, recent studies have demonstrated that an increase in KISS1 and KISS1R expression in patient breast tumors correlates with higher tumor grade and metastatic potential. We have shown that KP-10 stimulates invasion of estrogen receptor alpha (ERalpha)-negative MDA-MB-231 breast cancer cells via transactivation of the epidermal growth factor receptor (EGFR). Here, we report that either KP-10 treatment of ERalpha-negative nonmalignant mammary epithelial MCF10A cells or expression of KISS1R in MCF10A cells induced a mesenchymal phenotype and stimulated invasiveness. Similarly, exogenous expression of KISS1R in ERalpha-negative SKBR3 breast cancer cells was sufficient to trigger invasion and induced extravasation in vivo. In contrast, KP-10 failed to transactivate EGFR or stimulate invasiveness in the ERalpha-positive MCF7 and T47D breast cancer cells. This suggested that ERalpha negatively regulates KISS1R-dependent breast cancer cell migration, invasion, and EGFR transactivation. In support of this, we found that these KP-10-induced effects were ablated upon exogenous expression of ERalpha in the MDA-MB-231 cells, by down-regulating KISS1R expression. Lastly, we have identified IQGAP1, an actin cytoskeletal binding protein as a novel binding partner of KISS1R, and have shown that KISS1R regulates EGFR transactivation in breast cancer cells in an IQGAP1-dependent manner. Overall, our data strongly suggest that the ERalpha status of mammary cells dictates whether KISS1R may be a novel clinical target for treating breast cancer metastasis.

KISS-1 is a metastasis-suppressor gene of human melanoma, and encodes metastin, which was identified as the ligand of a G-protein-coupled receptor (metastin receptor). The precursor protein is cleaved to 54 amino acids, which may be further truncated into carboxy-terminal fragments. Previous studies showed that lack of metastin receptor in clear cell renal cell carcinoma (RCC) is associated with tumor progression, but the prediction of metastasis in patients with pT1 clear cell RCC after radical nephrectomy is difficult. The objective of this study was to evaluate the usefulness of metastin receptor immunohistochemistry in predicting metastasis after nephrectomy for pT1 clear cell RCC. After verification of the correlation between immunostaining and mRNA expression, we evaluated the clinical value of metastin receptor immunohistochemistry. Fifty-four patients were enrolled in this study; following radical nephrectomy, seven patients were found to have lung metastasis. The sensitivity, specificity, positive predictive value, and negative predictive value with negative immunostaining of metastin receptor were 85.7, 97.6, 46.2, and 97.6 %, respectively. metastasis-free survival rates were significantly higher in patients with positive staining (97.6 %) than in patients with negative staining (53.8 %) (P < 0.001). In univariate analysis for metastasis-free survival, negative immunostaining of metastin receptor was a significant risk factor for metastasis (P = 0.001). Furthermore, negative immunostaining of metastin receptor was an independent predictor for metastasis in multivariate analysis (hazard ratio, 3.735; 95 %

PURPOSE: Lymph node metastasis is the most important predictor of prognosis in esophageal squamous cell carcinoma (ESCC). Recently, KiSS-1 was cloned as a human metastasis suppressor gene, and an orphan G-protein-coupled receptor (hOT7T175) was identified as the endogenous receptor of the KiSS-1 product. However, the clinical importance of KiSS-1 and hOT7T175 gene expression in ESCC remains unclear. EXPERIMENTAL DESIGN: In this study, total RNA was extracted from tumors and noncancerous epithelia of 71 patients with ESCC who underwent surgical esophageal resection. The expression levels of KiSS-1, hOT7T175, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNAs were analyzed quantitatively by real-time reverse transcription-PCR and compared with the clinical findings. RESULTS: The mean KiSS-1:GAPDH and hOT7T175:GAPDH ratios of the tumors were 1.2 and 0.3 and were at the same levels as those in the noncancerous epithelia. The loss of KiSS-1 and hOT7T175 gene expression was detected in 38% and 61% of tumors. Loss of KiSS-1 and/or hOT7T175 gene expression was not correlated with tumor size or degree of tumor invasion but was found to be a significant predictor of lymph node metastasis. CONCLUSIONS: Loss of KiSS-1 or hOT7T175 gene expression may be an important biomarker for detection of lymph node metastasis in ESCC.