KiSS-1, a novel human malignant melanoma metastasis-suppressor gene

Jeong Hyung Lee, Mary Beth Miele, Deana J. Hicks, Karen K. Phillips, Jeffery M. Trent, Bernard E. Weissman, Danny R. Welch

Research output: Contribution to journalArticle

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Abstract

Background: Microcell-mediated transfer of chromosome 6 into human C8161 and MelJuSo melanoma cells suppresses their ability to metastasize by at least 95% without affecting their tumorigenicity. This observation demonstrates that the ability to metastasize is a phenotype distinct from tumor formation and suggests that tumorigenic cells acquire metastatic capability only after accumulating additional genetic defects. These results also imply that mutations of genes on chromosome 6 are among those late genetic changes responsible for metastatic potential. They further suggest that a melanoma metastasis-suppressor gene(s) is encoded on chromosome 6 or is regulated by genes on chromosome 6. Purpose: Our objective was to identify the gene(s) responsible for the suppression of metastasis in chromosome 6/melanoma cell hybrids. Methods: A modified subtractive hybridization technique was used to compare the expression of messenger RNAs (mRNAs), via an analysis of complementary DNAs (cDNAs), in metastatic cells (C8161 or MelJuSo) and nonmetastatic hybrid clones (neo6/C8161 or neo6/MelJuSo). Results: A novel cDNA, designated KiSS-1, was isolated from malignant melanoma cells that had been suppressed for metastatic potential by the introduction of human chromosome 6. Northern blot analyses comparing mRNAs from a panel of human melanoma cells revealed that KiSS-1 mRNA expression occurred only in nonmetastatic melanoma cells. Expression of this mRNA in normal heart, brain, liver, lung, and skeletal muscle was undetectable by northern blot analysis. Weak expression was found in the kidney and pancreas, but the highest expression was observed in the placenta. The KiSS-1 cDNA encodes a predominantly hydrophilic, 164 amino acid protein with a polyproline-rich domain indicative of an SH3 ligand (binds to the homology 3 domain of the oncoprotein Src) and a putative protein kinase C-α phosphorylation site. Transfection of a full-length KiSS-1 cDNA into C8161 melanoma cells suppressed metastasis in an expression-dependent manner. Conclusions: These data strongly suggest that KiSS-1 expression may suppress the metastatic potential of malignant melanoma cells. Implications: KISS-1 may be a useful marker for distinguishing metastatic melanomas from nonmetastatic melanomas.

Original languageEnglish (US)
Pages (from-to)1731-1737
Number of pages7
JournalJournal of the National Cancer Institute
Volume88
Issue number23
DOIs
StatePublished - Jan 1 1996

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Tumor Suppressor Genes
Melanoma
Chromosomes, Human, Pair 6
Complementary DNA
Messenger RNA
Northern Blotting
Neoplasm Metastasis
Genes
src Homology Domains
Hybrid Cells
Oncogene Proteins
Human Chromosomes
Protein Kinase C
Placenta
Transfection
Pancreas
Skeletal Muscle
Clone Cells
Phosphorylation
Ligands

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lee, J. H., Miele, M. B., Hicks, D. J., Phillips, K. K., Trent, J. M., Weissman, B. E., & Welch, D. R. (1996). KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. Journal of the National Cancer Institute, 88(23), 1731-1737. https://doi.org/10.1093/jnci/88.23.1731
Lee, Jeong Hyung ; Miele, Mary Beth ; Hicks, Deana J. ; Phillips, Karen K. ; Trent, Jeffery M. ; Weissman, Bernard E. ; Welch, Danny R. / KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. In: Journal of the National Cancer Institute. 1996 ; Vol. 88, No. 23. pp. 1731-1737.
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abstract = "Background: Microcell-mediated transfer of chromosome 6 into human C8161 and MelJuSo melanoma cells suppresses their ability to metastasize by at least 95{\%} without affecting their tumorigenicity. This observation demonstrates that the ability to metastasize is a phenotype distinct from tumor formation and suggests that tumorigenic cells acquire metastatic capability only after accumulating additional genetic defects. These results also imply that mutations of genes on chromosome 6 are among those late genetic changes responsible for metastatic potential. They further suggest that a melanoma metastasis-suppressor gene(s) is encoded on chromosome 6 or is regulated by genes on chromosome 6. Purpose: Our objective was to identify the gene(s) responsible for the suppression of metastasis in chromosome 6/melanoma cell hybrids. Methods: A modified subtractive hybridization technique was used to compare the expression of messenger RNAs (mRNAs), via an analysis of complementary DNAs (cDNAs), in metastatic cells (C8161 or MelJuSo) and nonmetastatic hybrid clones (neo6/C8161 or neo6/MelJuSo). Results: A novel cDNA, designated KiSS-1, was isolated from malignant melanoma cells that had been suppressed for metastatic potential by the introduction of human chromosome 6. Northern blot analyses comparing mRNAs from a panel of human melanoma cells revealed that KiSS-1 mRNA expression occurred only in nonmetastatic melanoma cells. Expression of this mRNA in normal heart, brain, liver, lung, and skeletal muscle was undetectable by northern blot analysis. Weak expression was found in the kidney and pancreas, but the highest expression was observed in the placenta. The KiSS-1 cDNA encodes a predominantly hydrophilic, 164 amino acid protein with a polyproline-rich domain indicative of an SH3 ligand (binds to the homology 3 domain of the oncoprotein Src) and a putative protein kinase C-α phosphorylation site. Transfection of a full-length KiSS-1 cDNA into C8161 melanoma cells suppressed metastasis in an expression-dependent manner. Conclusions: These data strongly suggest that KiSS-1 expression may suppress the metastatic potential of malignant melanoma cells. Implications: KISS-1 may be a useful marker for distinguishing metastatic melanomas from nonmetastatic melanomas.",
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Lee, JH, Miele, MB, Hicks, DJ, Phillips, KK, Trent, JM, Weissman, BE & Welch, DR 1996, 'KiSS-1, a novel human malignant melanoma metastasis-suppressor gene', Journal of the National Cancer Institute, vol. 88, no. 23, pp. 1731-1737. https://doi.org/10.1093/jnci/88.23.1731

KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. / Lee, Jeong Hyung; Miele, Mary Beth; Hicks, Deana J.; Phillips, Karen K.; Trent, Jeffery M.; Weissman, Bernard E.; Welch, Danny R.

In: Journal of the National Cancer Institute, Vol. 88, No. 23, 01.01.1996, p. 1731-1737.

Research output: Contribution to journalArticle

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T1 - KiSS-1, a novel human malignant melanoma metastasis-suppressor gene

AU - Lee, Jeong Hyung

AU - Miele, Mary Beth

AU - Hicks, Deana J.

AU - Phillips, Karen K.

AU - Trent, Jeffery M.

AU - Weissman, Bernard E.

AU - Welch, Danny R.

PY - 1996/1/1

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N2 - Background: Microcell-mediated transfer of chromosome 6 into human C8161 and MelJuSo melanoma cells suppresses their ability to metastasize by at least 95% without affecting their tumorigenicity. This observation demonstrates that the ability to metastasize is a phenotype distinct from tumor formation and suggests that tumorigenic cells acquire metastatic capability only after accumulating additional genetic defects. These results also imply that mutations of genes on chromosome 6 are among those late genetic changes responsible for metastatic potential. They further suggest that a melanoma metastasis-suppressor gene(s) is encoded on chromosome 6 or is regulated by genes on chromosome 6. Purpose: Our objective was to identify the gene(s) responsible for the suppression of metastasis in chromosome 6/melanoma cell hybrids. Methods: A modified subtractive hybridization technique was used to compare the expression of messenger RNAs (mRNAs), via an analysis of complementary DNAs (cDNAs), in metastatic cells (C8161 or MelJuSo) and nonmetastatic hybrid clones (neo6/C8161 or neo6/MelJuSo). Results: A novel cDNA, designated KiSS-1, was isolated from malignant melanoma cells that had been suppressed for metastatic potential by the introduction of human chromosome 6. Northern blot analyses comparing mRNAs from a panel of human melanoma cells revealed that KiSS-1 mRNA expression occurred only in nonmetastatic melanoma cells. Expression of this mRNA in normal heart, brain, liver, lung, and skeletal muscle was undetectable by northern blot analysis. Weak expression was found in the kidney and pancreas, but the highest expression was observed in the placenta. The KiSS-1 cDNA encodes a predominantly hydrophilic, 164 amino acid protein with a polyproline-rich domain indicative of an SH3 ligand (binds to the homology 3 domain of the oncoprotein Src) and a putative protein kinase C-α phosphorylation site. Transfection of a full-length KiSS-1 cDNA into C8161 melanoma cells suppressed metastasis in an expression-dependent manner. Conclusions: These data strongly suggest that KiSS-1 expression may suppress the metastatic potential of malignant melanoma cells. Implications: KISS-1 may be a useful marker for distinguishing metastatic melanomas from nonmetastatic melanomas.

AB - Background: Microcell-mediated transfer of chromosome 6 into human C8161 and MelJuSo melanoma cells suppresses their ability to metastasize by at least 95% without affecting their tumorigenicity. This observation demonstrates that the ability to metastasize is a phenotype distinct from tumor formation and suggests that tumorigenic cells acquire metastatic capability only after accumulating additional genetic defects. These results also imply that mutations of genes on chromosome 6 are among those late genetic changes responsible for metastatic potential. They further suggest that a melanoma metastasis-suppressor gene(s) is encoded on chromosome 6 or is regulated by genes on chromosome 6. Purpose: Our objective was to identify the gene(s) responsible for the suppression of metastasis in chromosome 6/melanoma cell hybrids. Methods: A modified subtractive hybridization technique was used to compare the expression of messenger RNAs (mRNAs), via an analysis of complementary DNAs (cDNAs), in metastatic cells (C8161 or MelJuSo) and nonmetastatic hybrid clones (neo6/C8161 or neo6/MelJuSo). Results: A novel cDNA, designated KiSS-1, was isolated from malignant melanoma cells that had been suppressed for metastatic potential by the introduction of human chromosome 6. Northern blot analyses comparing mRNAs from a panel of human melanoma cells revealed that KiSS-1 mRNA expression occurred only in nonmetastatic melanoma cells. Expression of this mRNA in normal heart, brain, liver, lung, and skeletal muscle was undetectable by northern blot analysis. Weak expression was found in the kidney and pancreas, but the highest expression was observed in the placenta. The KiSS-1 cDNA encodes a predominantly hydrophilic, 164 amino acid protein with a polyproline-rich domain indicative of an SH3 ligand (binds to the homology 3 domain of the oncoprotein Src) and a putative protein kinase C-α phosphorylation site. Transfection of a full-length KiSS-1 cDNA into C8161 melanoma cells suppressed metastasis in an expression-dependent manner. Conclusions: These data strongly suggest that KiSS-1 expression may suppress the metastatic potential of malignant melanoma cells. Implications: KISS-1 may be a useful marker for distinguishing metastatic melanomas from nonmetastatic melanomas.

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