TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer

Masami Kuramochi, Hiroshi Fukuhara, Takahiro Nobukuni, Takamasa Kanbe, Tomoko Maruyama, Hara P. Ghosh, Mathew Pletcher, Minoru Isomura, Masataka Onizuka, Tadaichi Kitamura, Takao Sekiya, Roger H Reeves, Yoshinori Murakami

Research output: Contribution to journalArticle

Abstract

The existence of tumor-suppressor genes was originally demonstrated by functional complementation through whole-cell and microcell fusion1,2. Transfer of chromosome 11 into a human non-small-cell lung cancer (NSCLC) cell line, A549, suppresses tumorigenicity3. Loss of heterozygosity (LOH) on the long arm of chromosome 11 has been reported in NSCLC and other cancers4-6. Several independent studies indicate that multiple tumor-suppressor genes are found in this region, including the gene PPP2R1B at 11q23-24 (ref. 7). Linkage studies of NSCLC are precluded because no hereditary forms are known8,9. We previously identified a region of 700 kb on 11q23.2 that completely suppresses tumorigenicity of A549 human NSCLC cells10. Most of this tumor-suppressor activity localizes to a 100-kb segment by functional complementation. Here we report that this region contains a single confirmed gene, TSLC1, whose expression is reduced or absent in A549 and several other NSCLC, hepatocellular carcinoma (HCC) and pancreatic cancer (PaC) cell lines. TSLC1 expression or suppression is correlated with promoter methylation state in these cell lines. Restoration of TSLC1 expression to normal or higher levels suppresses tumor formation by A549 cells in nude mice. Only 2 inactivating mutations of TSLC1 were discovered in 161 tumors and tumor cell lines, both among the 20 primary tumors with LOH for 11q23.2. Promoter methylation was observed in 15 of the other 18 primary NSCLC, HCC and PaC tumors with LOH for 11q23.2. Thus, attenuation of TSLC1 expression occurred in 85% of primary tumors with LOH. Hypermethylation of the TSLC1 promoter would seem to represent the 'second hit' in NSCLC with LOH.

Original languageEnglish (US)
Pages (from-to)427-430
Number of pages4
JournalNature Genetics
Volume27
Issue number4
DOIs
StatePublished - 2001

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Tumor Suppressor Genes
Non-Small Cell Lung Carcinoma
Loss of Heterozygosity
Neoplasms
Chromosomes, Human, Pair 11
Liver Neoplasms
Pancreatic Neoplasms
Methylation
Hepatocellular Carcinoma
Cell Line
Tumor Cell Line
Nude Mice
Genes
Mutation

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Kuramochi, M., Fukuhara, H., Nobukuni, T., Kanbe, T., Maruyama, T., Ghosh, H. P., ... Murakami, Y. (2001). TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer. Nature Genetics, 27(4), 427-430. https://doi.org/10.1038/86934

TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer. / Kuramochi, Masami; Fukuhara, Hiroshi; Nobukuni, Takahiro; Kanbe, Takamasa; Maruyama, Tomoko; Ghosh, Hara P.; Pletcher, Mathew; Isomura, Minoru; Onizuka, Masataka; Kitamura, Tadaichi; Sekiya, Takao; Reeves, Roger H; Murakami, Yoshinori.

In: Nature Genetics, Vol. 27, No. 4, 2001, p. 427-430.

Research output: Contribution to journalArticle

Kuramochi, M, Fukuhara, H, Nobukuni, T, Kanbe, T, Maruyama, T, Ghosh, HP, Pletcher, M, Isomura, M, Onizuka, M, Kitamura, T, Sekiya, T, Reeves, RH & Murakami, Y 2001, 'TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer', Nature Genetics, vol. 27, no. 4, pp. 427-430. https://doi.org/10.1038/86934
Kuramochi M, Fukuhara H, Nobukuni T, Kanbe T, Maruyama T, Ghosh HP et al. TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer. Nature Genetics. 2001;27(4):427-430. https://doi.org/10.1038/86934
Kuramochi, Masami ; Fukuhara, Hiroshi ; Nobukuni, Takahiro ; Kanbe, Takamasa ; Maruyama, Tomoko ; Ghosh, Hara P. ; Pletcher, Mathew ; Isomura, Minoru ; Onizuka, Masataka ; Kitamura, Tadaichi ; Sekiya, Takao ; Reeves, Roger H ; Murakami, Yoshinori. / TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer. In: Nature Genetics. 2001 ; Vol. 27, No. 4. pp. 427-430.
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abstract = "The existence of tumor-suppressor genes was originally demonstrated by functional complementation through whole-cell and microcell fusion1,2. Transfer of chromosome 11 into a human non-small-cell lung cancer (NSCLC) cell line, A549, suppresses tumorigenicity3. Loss of heterozygosity (LOH) on the long arm of chromosome 11 has been reported in NSCLC and other cancers4-6. Several independent studies indicate that multiple tumor-suppressor genes are found in this region, including the gene PPP2R1B at 11q23-24 (ref. 7). Linkage studies of NSCLC are precluded because no hereditary forms are known8,9. We previously identified a region of 700 kb on 11q23.2 that completely suppresses tumorigenicity of A549 human NSCLC cells10. Most of this tumor-suppressor activity localizes to a 100-kb segment by functional complementation. Here we report that this region contains a single confirmed gene, TSLC1, whose expression is reduced or absent in A549 and several other NSCLC, hepatocellular carcinoma (HCC) and pancreatic cancer (PaC) cell lines. TSLC1 expression or suppression is correlated with promoter methylation state in these cell lines. Restoration of TSLC1 expression to normal or higher levels suppresses tumor formation by A549 cells in nude mice. Only 2 inactivating mutations of TSLC1 were discovered in 161 tumors and tumor cell lines, both among the 20 primary tumors with LOH for 11q23.2. Promoter methylation was observed in 15 of the other 18 primary NSCLC, HCC and PaC tumors with LOH for 11q23.2. Thus, attenuation of TSLC1 expression occurred in 85{\%} of primary tumors with LOH. Hypermethylation of the TSLC1 promoter would seem to represent the 'second hit' in NSCLC with LOH.",
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