Clinical Cancer Research Holland
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ikeguchi, M.
Right arrow Articles by Kaibara, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ikeguchi, M.
Right arrow Articles by Kaibara, N.
Clinical Cancer Research Vol. 10, 1379-1383, February 2004
© 2004 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Clinical Significance of the Loss of KiSS-1 and Orphan G-Protein–Coupled Receptor (hOT7T175) Gene Expression in Esophageal Squamous Cell Carcinoma

Masahide Ikeguchi1, Ken-ichi Yamaguchi2 and Nobuaki Kaibara2

Divisions of1 Operating Room and 2 Surgical Oncology, Faculty of Medicine, Tottori University, Yonago, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Esophageal squamous cell carcinoma (ESCC) is one of the most difficult tumors to treat. Even at an early stage of the cancer, many patients develop lymph node metastasis soon after surgery (1 , 2) . If we have suitable biomarkers to identify tumors with high metastatic potential, it should be possible to start effective chemo-radiotherapy soon after surgery for such patients.

Recently, the KiSS-1 gene has been reported to be a novel metastasis suppressor gene in human melanoma and breast carcinoma cells (3 , 4) . The KiSS-1 gene encodes a 54-amino acid peptide that is the endogenous ligand of an orphan G-protein-coupled receptor (hOT7T175). The metastasis suppressor function of the KiSS-1 gene product is reported to act after binding with hOT7T175. After binding with hOT7T175, the KiSS-1 gene product inhibits the chemotaxis, invasion, and metastasis of cells (5) . However, the clinical importance of the expression of these genes remains unclear.

In the present study, we analyzed the quantitative expression levels of KiSS-1 and hOT7T175 mRNAs in esophageal tissues (tumors and noncancerous epithelia) using the real-time reverse transcription-PCR (RT-PCR) method. Moreover, we evaluated whether or not the KiSS-1 gene and hOT7T175 gene expressions may be new biological markers for the malignant potential of ESCC.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
Surgical esophageal resection was performed on 71 patients between 1993 and 2001 [67 men and 4 women; age at time of surgery (mean ± SE), 65.1 ± 1 years; range, 45–84 years]. None of the patients received preoperative chemotherapy or radiation therapy. To identify KiSS-1 and hOT7T175 gene expression in the tissues, we enrolled these patients. Informed consent was obtained from all patients for the subsequent use of their resected tissues. The present study conformed to the ethical standards of the World Medical Association Declaration of Helsinki. Tumors were staged according to the tumor-node-metastasis (TNM) system: stage I; tumor invades lamina propria or submucosa with no lymph node metastasis (n = 12); stage II, tumor invades muscularis propria or adventitia with no lymph node metastasis, or tumor invades lamina propria or submucosa with regional lymph node metastasis (n = 23); stage III, tumor invades adventitia with lymph node metastasis, or tumor invades adjacent structures with or without lymph node metastasis (n = 31); and stage IV; tumor with distant metastasis (n = 5). Curative surgery was performed on 57 patients, and noncurative surgery was performed on 14 patients (1 patient had liver metastasis, 5 patients had extended lymph node metastasis, and 8 patients had local invasion). All of the patients were followed until October 2002. The mean follow-up was 29.9 months (range, 1–106 months). Causes of death were determined from clinical findings. Twenty-five patients were alive in October 2002, and a total of 46 patients had died. Eleven patients died from diseases other than esophageal cancer (6 died from operative complications, and the in-hospital mortality rate was 8.5%), whereas 35 died from recurrence or relapse of ESCC. The sites of recurrence were identified by computed tomography and ultrasonography.

Tissues.
We obtained tumors and noncancerous esophageal epithelium samples, sufficiently distant from the tumors, from 71 patients immediately after resection of the esophagus. Each tissue sample was stored at -80°C until use.

Real-Time RT-PCR Assay.
Total RNA was isolated from the tissues using RNeasy Mini Kits (Qiagen, Hilden, Germany), and cDNA was synthesized from 1 µg of total RNA with Ready-to-Go You-Prime First-Strand Beads (Amersham Pharmacia Biotech Inc., Piscataway, NJ). Primers and the TaqMan probes for KiSS-1, hOT7T175, and glyceraldehyde-3- phosphate dehydrogenase (GAPDH) were synthesized (5) : (a) KiSS-1, 5'-ACTCACTGGTTTCTTGGCAGC-3' (forward primer), 5'-ACCTTTTCTAATGGCTCCCCA-3' (reverse primer), and 5'-6-carboxy-fluorescein (FAM)-ACTGCTTTCCTCTGTGCCACCCACT-6-carboxy-tetramethyl-rhodamine (TAMRA)-3' (probe); (b) hOT7T175, 5'-CGACTTCATGTGCAAGTTCGTC-3' (forward primer), 5'-CACACTCAATGGCGGTCAGAG-3' (reverse primer), and 5'-FAM-ACTACATCCAGCAGGTCTCGGTGCAGG-TAMRA-3' (probe); and (c) GAPDH, 5'-GAAGGTGAAGGTCGGAGTC-3' (forward primer), 5'-GAAGATGGTGATGGGATTTC-3' (reverse primer), and 5'-FAM-CAAGCTTCCCGTTCTCAGCC-TAMRA-3' (probe). The TaqMan probes were labeled with a fluorescent reporter dye (FAM) at the 5' end and a fluorescent quencher dye (TAMRA) at the 3' end.

Quantification of gene expression was performed by real-time quantitative RT-PCR [Gene Amp 5700 Sequence Detection System (Perkin-Elmer Applied Biosystems, Foster City, CA)], which uses the 5' nuclease activity of Taq polymerase to detect PCR amplicons (6 , 7) . The threshold line was set at an Rn of 0.05 (6) . The point at which the amplification plot crossed this threshold was defined as Ct, which represented the cycle number at this point. Standard curves for KiSS-1, hOT7T175, and GAPDH were generated using serial dilutions (containing 160, 80, 40, 20, and 10 ng) of total RNA derived from the normal esophageal epithelium from one case with ESCC. The plots represent the log of the input amount (log ng of total starting RNA) as the X axis and Ct as the Y axis. Equations were derived from the calibration curves (6) . The formulas for KiSS-1, hOT7T175, and GAPDH were as follows: KiSS-1, y = 36.5 - 4.6x (r2 = 0.997); hOT7T175, y = 42.2 - 3.6x (r2 = 0.999); GAPDH, y = 36.4 - 5.8x (r2 = 0.999). The amounts of KiSS-1, hOT7T175, and GAPDH mRNAs of samples were determined from the standard curves. The amounts of KiSS-1 and hOT7T175 mRNAs were determined by dividing the amount of KiSS-1 and hOT7T175 mRNAs by the amount of GAPDH mRNA, and the KiSS-1:GAPDH ratio and hOT7T175:GAPDH ratio were evaluated.

Statistical Analysis.
The {chi}2 and Fisher’s exact probability tests were used to compare the distribution of individual variables among the patient groups. Differences in the numerical data between two groups were evaluated using the Mann-Whitney U test. Survival rates were calculated using the Kaplan-Meier method. The log-rank test was used for comparisons of two survival curves. A multivariate survival analysis was performed using Cox’s proportional-hazard model. The influence of each variable on the mode of lymph node metastasis was assessed by multivariate logistic regression analysis. A P of <0.05 was considered statistically significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The KiSS-1:GAPDH and hOT7T175:GAPDH Ratios of Tumors and Noncancerous Esophageal Tissues.
The KiSS-1:GAPDH ratio of 71 carcinomas (mean ± SE, 1.2 ± 0.3; range, 0–17.5; median, 0.3) was not different from that of 71 noncancerous esophageal epithelium samples sufficiently distant from the tumors (mean ± SE, 1.2 ± 0.4; range, 0–24.4; P = 0.383). In addition, the hOT7T175:GAPDH ratio of carcinomas (mean ± SE, 0.3 ± 0.1; range, 0–3.9) was not different from that of noncancerous tissues (mean ± SE, 0.3 ± 0.1; range, 0–6.7; P = 0.705). Fig. 1Citation shows the relative expression levels of KiSS-1 and hOT7T175 genes in noncancerous epithelia and tumors. The cases with loss of KiSS-1 or hOT7T175 gene expression in tumors were decided based on the levels of the KiSS-1:GAPDH and hOT7T175:GAPDH ratios in 71 noncancerous tissues (mean - 2xSE; Ref. 8 ). The calculated cutoff values of the KiSS-1:GAPDH and hOT7T175:GAPDH ratios of tumors were 0.4 and 0.1, respectively. Loss of KiSS-1 expression (tumor KiSS-1:GAPDH < 0.4) was detected in 27 cases (38%), and loss of hOT7T175 expression (tumor hOT7T175:GAPDH < 0.1) was detected in 44 cases (61%).



View larger version (24K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. The relative expression levels of KiSS-1 and hOT7T175 genes in 71 noncancerous esophageal epithelia and esophageal tumors.

 
Loss of KiSS-1 and hOT7T175 Gene Expression and the Clinicopathological Findings of Patients.
The loss of both KiSS-1 and hOT7T175 gene expression was found in 16 cases. Preservation of both gene expressions was found in 18 (25%) cases. Table 1Citation shows the correlation between the expression patterns of the KiSS-1 and hOT7T175 genes and the clinicopathological findings of the tumors. Loss of KiSS-1 or hOT7T175 gene expression did not correlate with depth of tumor invasion or lymphatic invasion of cancer cells. However, cases with preserved expression of both genes showed lower incidence of lymph node metastasis than cases with loss of KiSS-1 or hOT7T175 gene expression. Loss of KiSS-1 or hOT7T175 gene expression was found by multivariate logistic regression analysis to be a significantly important factor for lymph node metastasis among factors that were thought to be affecting lymph node metastasis (Table 2)Citation . Correlation among depth of tumor invasion, lymph node metastasis, and loss of expression of one or both genes (KiSS-1 and hOT7T175) is indicated in Table 3Citation . Even in T1 cancer, 20% of cases showed lymph node metastasis. Despite the depth of tumor invasion, loss of KiSS-1 and/or hOT7T175 gene expression was detected in 86–100% of primary tumors in cases with lymph node metastasis.


View this table:
[in this window]
[in a new window]

  		Table 1 Correlation between the clinicopathological findings in the patients and the KiSS-1 and hOT7T175 gene expression levels in ESCCa

 

View this table:
[in this window]
[in a new window]

  		Table 2 Multivariate logistic regression analysis of factors affecting lymph node metastasis

 

View this table:
[in this window]
[in a new window]

  		Table 3 Correlation among the depth of tumor invasion, lymph node metastasis, and loss of KiSS-1 and hOT7T175 gene expressions

 
Prognostic Significance of the Loss of KiSS-1 and/or hOT7T175 Gene Expression in ESCC.
In the 65 patients surviving surgery (excluding the 6 patients who died from surgical complications), disease-specific survivals were compared among three groups (group A, 17 patients with tumors with preserved expression of both KiSS-1 and hOT7T175 genes; group B, 34 patients with tumors with loss of one of the two genes; and group C, 14 patients with tumors with loss of both genes). The disease-specific 5-year survival rates were as follows: group A, 68%; group B, 31%; and group C, 32%. The disease-specific survival curves of groups B and C were same, thus we compared the difference in survival curves between group A and group B + C (Fig. 2)Citation . Depth of tumor invasion and lymph node metastasis were detected as strong prognostic factors in multivariate survival analysis (P = 0.005 and P = 0.044). On the other hand, tumor size and gene expressions of KiSS-1 and hOT7T175 were not detected as prognostic factors (P = 0.217 and P = 0.687) independent from the depth of tumor invasion or lymph node metastasis.



View larger version (18K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Disease-specific survival curves of 65 surviving patients. A, survival curve of 17 patients with tumors with preserved expression of both the KiSS-1 and hOT7T175 genes. The disease-specific 5-year survival rate of these patients was 68%. B + C, survival curve of 48 patients who had tumors with loss of one of the two genes (B; n = 34) or loss of both genes (C; n = 14). The disease-specific 5-year survival rate was 32%. A significant difference was detected between the two survival curves (P = 0.035).

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Lee et al. (3 , 4) transfected full-length human KiSS-1 cDNA into human melanoma and breast cancer cells with high metastasis. After i.v. injection of the cells (with or without KiSS-1 transfection) into the tail vein of athymic nude mice, they found that the number of lung metastases was significantly suppressed in the KiSS-1-transfected mice. This result strongly suggests that KiSS-1 is a novel metastasis suppressor. Furthermore, a recent investigation has shown that KiSS-1 encodes a peptide that is a ligand of a novel human G-protein-coupled receptor [GPCR; named hOT7T175, AXOR12, or GPR54, respectively (5) ]. Ohtaki et al. (5) named this peptide encoded from the KiSS-1 gene "metastin." Recently, Stafford et al. (9) found that activation of the receptor by the KiSS-1 peptide leads to activation of G-protein-activated phospholipase C, which suggests a direct coupling of the KiSS-1 peptide to the G{alpha}q-mediated phospholipase C-Ca2+ signaling pathway. Stimulation of this pathway induces the inhibition of cell proliferation and cell migration. These findings indicate that the metastasis suppressor function of the KiSS-1 gene product may act after binding with hOT7T175.

High expression levels of KiSS-1 mRNA and hOT7T175 mRNA were observed in placenta and in pancreatic tissues (5 , 10 , 11) . In many normal tissues, the expression level of KiSS-1 mRNA was recognized to be 2- to 10,000-fold higher than that of hOT7T175 mRNA (5 , 11) . However, significantly high hOT7T175 mRNA expression levels with low KiSS-1 mRNA expression levels were detected in some ovarian cancers (5) . Ohtaki et al. (5) proposed metastin treatment for patients who have tumors with a high expression level of hOT7T175 mRNA. The expression levels of KiSS-1 and hOT7T175 genes in esophageal epithelia and esophageal cancers have not been reported previously. In the present study, we found that the average expression level of KiSS-1 mRNA was 4-fold higher than that of hOT7T175 mRNA in both normal epithelia and ESCCs. However, in 10 cases, high tumor hOT7T175 mRNA and low tumor KiSS-1 mRNA expression were observed. In such cases, metastin treatment may have some prognostic benefit.

Lymph node metastasis is the principal negative prognostic factor in patients with ESCC. It is difficult to determine whether lymph node metastasis has occurred preoperatively, despite new imaging techniques such as positron emission tomography (12) . Moreover, good biological markers for the detection of lymph node metastasis have not been reported previously in ESCC. If we can obtain information about this metastasis from small preoperative bioptic samples, we can perform radical lymphadenectomy even in patients with early-stage ESCC and start chemo-radiotherapy soon after surgery in patients with a high risk of lymph node metastasis. From our study, we found that loss of KiSS-1 or hOT7T175 gene expression in tumors showed significant and close correlation with high incidence of lymph node metastasis and unfavorable patient prognosis. This phenomenon was detected in cases with loss of one or both of the genes. Furthermore, tumors with preserved expression of both genes suppressed lymph node metastasis regardless of the depth of tumor invasion. These findings strongly suggest that expression of both the KiSS-1 and hOT7T175 genes is essential for inhibition of tumor metastasis and indicate that the loss of expression of one or both genes (KiSS-1 or hOT7T175) may play an important role in ESCC metastasis. Shirasaki et al. (13) noted the importance of KiSS-1 down-regulation in the progression of melanoma. Sanchez-Carbayo et al. (14) demonstrated that loss of KiSS-1 gene expression correlated with poor patient survival in bladder cancer. Thus, in other malignant tumors, investigation of the clinical importance of KiSS-1 and hOT7T175 gene expressions has been started.

In the present study, we used real-time RT-PCR to evaluate the quantitative expression levels of the target genes in esophageal tissues. The recent development of real-time RT-PCR technology has made reliable and accurate PCR quantification possible (15) . This technology can monitor the entire PCR reaction from a small volume of tissues, such as bioptic specimens. Thus, analysis of the expression levels of the KiSS-1 and hOT7T175 genes in preoperative bioptic samples by real-time RT-PCR may provide useful information about the existence of lymph node metastasis in patients with ESCC.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Masahide Ikeguchi, Division of Operating Room, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan. Phone: 81-859-34-8111; Fax: 81-859-34-8095; E-mail: masaike{at}grape.med.tottori-u.ac.jp

Received 12/12/02; revised 12/ 2/03; accepted 12/10/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Tachibana M., Kinugasa S., Dhar D. K., Tabara H., Masunaga R., Kotoh T., Kubota H., Nagasue N. Prognostic factors in T1 and T2 squamous cell carcinoma of the thoracic esophagus. Arch. Surg., 134: 50-54, 1999.[Abstract/Free Full Text]
  2. Hosch S. B., Stoecklein N. H., Pichlmeier U., Rehders A., Scheunemann P., Niendorf A., Knoefel W. T., Izbicki J. R. Esophageal cancer: the mode of lymphatic tumor cell spread and its prognostic significance. J. Clin. Oncol., 19: 1970-1975, 2001.[Abstract/Free Full Text]
  3. Lee J. H., Welch D. R. Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1. Cancer Res., 57: 2384-2387, 1997.[Abstract/Free Full Text]
  4. Lee J. H., Welch D. R. Identification of highly expressed genes in metastasis-suppressed chromosome 6/human malignant melanoma hybrid cells using subtractive hybridization and differential display. Int. J. Cancer, 71: 1035-1044, 1997.[CrossRef][Medline]
  5. Ohtaki T., Shintani Y., Honda S., Matsumoto H., Hori A., Kanehashi K., Terao Y., Kumano S., Takatsu Y., Masuda Y., Ishibashi Y., Watanabe T., Asada M., Yamada T., Suenaga M., Kitada C., Usuki S., Kurokawa T., Onda H., Nishimura O., Fujino M. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature (Lond.), 411: 613-617, 2001.[CrossRef][Medline]
  6. Yajima T., Yagihashi A., Kameshima H., Kobayashi D., Furuya D., Hirata K., Watanabe N. Quantitative reverse transcription-PCR assay of the RNA component of human telomerase using the TaqMan fluorogenic detection system. Clin. Chem., 44: 2441-2445, 1998.[Abstract/Free Full Text]
  7. Mitas M., Mikhitarian K., Walters C., Baron P. L., Elliott B. M., Brothers T. E., Robinson J. G., Metcalf J. S., Palesch Y. Y., Zhang Z., Gillanders W. E., Cole D. J. Quantitative real-time RT-PCR detection of breast cancer micrometastasis using a multigene marker panel. Int. J. Cancer, 93: 162-171, 2001.[CrossRef][Medline]
  8. Cheung I. Y., Cheung N-K. V. Quantitation of marrow disease in neuroblastoma by real-time reverse transcription-PCR. Clin. Cancer Res., 7: 1698-1705, 2001.[Abstract/Free Full Text]
  9. Stafford L. J., Xia C., Ma W., Cai Y., Liu M. Identification and characterization of mouse metastasis-suppressor KiSS1 and its G-protein-coupled receptor. Cancer Res., 62: 5399-5404, 2002.[Abstract/Free Full Text]
  10. Kotani M., Detheux M., Vandenbogaerde A., Communi D., Vanderwinden J. M., Le Poul E., Brézillon S., Tyldesley R., Suarez-Huerta N., Vandeput F., Blanpain C., Schiffmann S. N., Vassart G., Parmentier M. The metastasis suppressor gene KiSS-1 encodes Kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J. Biol. Chem., 276: 34631-34636, 2001.[Abstract/Free Full Text]
  11. Muir A. I., Chamberlain L., Elshourbagy N. A., Michalovich D., Moore D. J., Calamari A., Szekeres P. G., Sarau H. M., Chambers J. K., Murdock P., Steplewski K., Shabon U., Miller J. E., Middleton S. E., Darker J. G., Larminie C. G. C., Wilson S., Bergsma D. J., Emson P., Faull R., Philpott K. L., Harrison D. C. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J. Biol. Chem., 276: 28969-28975, 2001.[Abstract/Free Full Text]
  12. Kim K., Park S. J., Kim B. T., Lee K. S., Shim Y. M. Evaluation of lymph node metastases in squamous cell carcinoma of the esophagus with positron emission tomography. Ann. Thorac. Surg., 71: 290-294, 2001.[Abstract/Free Full Text]
  13. Shirasaki F., Takata M., Hatta N., Takehara K. Loss of expression of the metastasis suppressor gene KiSS1 during melanoma progression and its association with LOH of chromosome 6q16.3-q23. Cancer Res., 61: 7422-7425, 2001.[Abstract/Free Full Text]
  14. Sanchez-Carbayo M., Capodieci P., Cordon-Cardo C. Tumor suppressor role of KiSS-1 in bladder cancer: loss of KiSS-1 expression is associated with bladder cancer progression and clinical outcome. Am. J. Pathol., 162: 609-691, 2003.[Abstract/Free Full Text]
  15. Ikeguchi M., Hirooka Y., Kaibara N. Quantitative analysis of apoptosis-related gene expression in hepatocellular carcinoma. Cancer (Phila.), 95: 1938-1945, 2002.



This article has been cited by other articles:


Home page
 ReproductionHome page
E. Gianetti and S. Seminara
Kisspeptin and KISS1R: a critical pathway in the reproductive system
Reproduction, September 1, 2008; 136(3): 295 - 301.
[Abstract] [Full Text] [PDF]

Home page
 Endocr Relat CancerHome page
D. Marot, I. Bieche, C. Aumas, S. Esselin, C. Bouquet, S. Vacher, G. Lazennec, M. Perricaudet, F. Kuttenn, R. Lidereau, et al.
High tumoral levels of Kiss1 and G-protein-coupled receptor 54 expression are correlated with poor prognosis of estrogen receptor-positive breast tumors
Endocr. Relat. Cancer, September 1, 2007; 14(3): 691 - 702.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. K. Dissanayake, M. Wade, C. E. Johnson, M. P. O'Connell, P. D. Leotlela, A. D. French, K. V. Shah, K. J. Hewitt, D. T. Rosenthal, F. E. Indig, et al.
The Wnt5A/Protein Kinase C Pathway Mediates Motility in Melanoma Cells via the Inhibition of Metastasis Suppressors and Initiation of an Epithelial to Mesenchymal Transition
J. Biol. Chem., June 8, 2007; 282(23): 17259 - 17271.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
G Nicolle, E Comperat, N Nicolaiew, G Cancel-Tassin, and O Cussenot
Metastin (KISS-1) and metastin-coupled receptor (GPR54) expression in transitional cell carcinoma of the bladder
Ann. Onc., March 1, 2007; 18(3): 605 - 607.
[Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
K. T. Nash, P. A. Phadke, J.-M. Navenot, D. R. Hurst, M. A. Accavitti-Loper, E. Sztul, K. S. Vaidya, A. R. Frost, J. C. Kappes, S. C. Peiper, et al.
Requirement of KISS1 Secretion for Multiple Organ Metastasis Suppression and Maintenance of Tumor Dormancy
J Natl Cancer Inst, February 21, 2007; 99(4): 309 - 321.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
W. S. Dhillo, P. Savage, K. G. Murphy, O. B. Chaudhri, M. Patterson, G. M. Nijher, V. M. Foggo, G. S. Dancey, H. Mitchell, M. J. Seckl, et al.
Plasma kisspeptin is raised in patients with gestational trophoblastic neoplasia and falls during treatment
Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E878 - E884.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. M. Castellano, M. Gaytan, J. Roa, E. Vigo, V. M. Navarro, C. Bellido, C. Dieguez, E. Aguilar, J. E. Sanchez-Criado, A. Pellicer, et al.
Expression of KiSS-1 in Rat Ovary: Putative Local Regulator of Ovulation?
Endocrinology, October 1, 2006; 147(10): 4852 - 4862.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
M. Tena-Sempere
GPR54 and kisspeptin in reproduction
Hum. Reprod. Update, September 1, 2006; 12(5): 631 - 639.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. C. Mitchell, M. Abdelrahim, J. Weng, L. J. Stafford, S. Safe, M. Bar-Eli, and M. Liu
Regulation of KiSS-1 Metastasis Suppressor Gene Expression in Breast Cancer Cells by Direct Interaction of Transcription Factors Activator Protein-2{alpha} and Specificity Protein-1
J. Biol. Chem., January 6, 2006; 281(1): 51 - 58.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
N. Stathatos, I. Bourdeau, A. V. Espinosa, M. Saji, V. V. Vasko, K. D. Burman, C. A. Stratakis, and M. D. Ringel
KiSS-1/G Protein-Coupled Receptor 54 Metastasis Suppressor Pathway Increases Myocyte-Enriched Calcineurin Interacting Protein 1 Expression and Chronically Inhibits Calcineurin Activity
J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5432 - 5440.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
V. M. Navarro, J. M. Castellano, R. Fernandez-Fernandez, S. Tovar, J. Roa, A. Mayen, R. Nogueiras, M. J. Vazquez, M. L. Barreiro, P. Magni, et al.
Characterization of the Potent Luteinizing Hormone-Releasing Activity of KiSS-1 Peptide, the Natural Ligand of GPR54
Endocrinology, January 1, 2005; 146(1): 156 - 163.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ikeguchi, M.
Right arrow Articles by Kaibara, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ikeguchi, M.
Right arrow Articles by Kaibara, N.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online