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DLC-1 operates as a tumor suppressor gene in human non-small cell lung carcinomas

Bao-Zhu Yuan1, Amy M Jefferson, Kimberly T Baldwin

  • 1Laboratory of Genetic Susceptibility, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA. bby1@cdc.gov

Oncogene
|December 9, 2003
PubMed

Insights

The Deleted in Liver Cancer (DLC-1) gene is frequently silenced in non-small cell lung carcinoma (NSCLC) primarily through DNA methylation. Restoring DLC-1 expression inhibits NSCLC cell growth and tumorigenicity, identifying it as a tumor suppressor.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The Deleted in Liver Cancer (DLC-1) gene, located at chromosome 8p21-22, is known to suppress tumor growth in breast and liver cancers.
  • Genomic alterations, including deletion and promoter methylation, frequently affect DLC-1 in various human cancers.
  • The 8p21-22 region is often deleted in non-small cell lung carcinoma (NSCLC), suggesting a potential role for DLC-1 in lung tumorigenesis.

Purpose of the Study:

  • To investigate alterations of the DLC-1 gene in non-small cell lung carcinoma (NSCLC).
  • To determine the mechanism of DLC-1 downregulation in NSCLC.
  • To evaluate the functional role of DLC-1 as a tumor suppressor in NSCLC.

Main Methods:

  • Analysis of DLC-1 mRNA expression in primary NSCLC tumors and cell lines.
  • Assessment of genomic deletion and promoter methylation as mechanisms for DLC-1 silencing.
  • Treatment of NSCLC cell lines with 5-aza-2'-deoxycytidine to induce DLC-1 reactivation.
  • Southern blotting to detect aberrant DLC-1 promoter methylation.
  • Gene transfer experiments to restore DLC-1 expression in NSCLC cells.
  • In vivo tumorigenicity assays in nude mice.

Main Results:

  • A significant decrease or absence of DLC-1 mRNA expression was observed in 95% of primary NSCLC and 58% of NSCLC cell lines.
  • Aberrant DNA methylation was identified as the primary mechanism for DLC-1 transcriptional silencing in NSCLC, with reactivation observed in 82% of cell lines after 5-aza-2'-deoxycytidine treatment.
  • Aberrant DLC-1 promoter methylation was detected in 73% of NSCLC cell lines with downregulated DLC-1.
  • Restoration of DLC-1 expression in DLC-1-negative NSCLC cell lines significantly inhibited cell proliferation and colony formation.
  • Stable transfer of DLC-1 abolished tumorigenicity in nude mice for two tested cell lines.

Conclusions:

  • DLC-1 is frequently downregulated in non-small cell lung carcinoma (NSCLC), primarily due to aberrant promoter methylation.
  • DLC-1 functions as a bona fide tumor suppressor gene in NSCLC, inhibiting cell proliferation, colony formation, and tumorigenicity.
  • Restoring DLC-1 expression represents a potential therapeutic strategy for NSCLC.

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