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Nuclear factor-kappaB-dependent expression of metastasis suppressor KAI1/CD82 gene in lung cancer cell lines
T Shinohara1, T Miki, N Nishimura
1Third Department of Internal Medicine, The University of Tokushima School of Medicine, Japan.
Abstract:
KAI1/CD82 has been shown to be a metastasis suppressor for several human cancers, and a recent study revealed that wild-type tumor suppressor p53 can directly activate KAI1/CD82 gene expression. However, the response of KAI1/CD82 expression in cancer cells to exogenous stimulants has not been investigated. The present study examined whether tumor necrosis factor (TNF), which mediates many of the cellular responses associated with inflammatory reactions or cancer progression, can affect the KAI1/CD82 expression in lung cancer cells and, if so, whether nuclear factor (NF)-kappaB, a key molecule in TNF-mediated gene expression, is involved in the mechanism of KAI1/CD82 induction. Our results demonstrated that expression of KAI1/CD82 in PC-14 cells expressing mutant p53 could be augmented by TNF-alpha, and that transfer of the gene for a specific inhibitor of NF-kappaB, IkappaB alphaSR (mutant IkappaB alpha; NF-kappaB super-repressor), into PC-14 cells could inhibit this augmentation. The amount of NF-kappaB in the nucleus of PC-14/IkappaB alphaSR cells correlated well with KAI1/CD82 mRNA and protein expression. In addition, IkappaB alphaSR gene transfer inhibited the spontaneous expression of KAI1/CD82 protein in KAI1/CD82-high-expressing RERF-LC-OK cells, which contain a mutant-type p53. These observations indicate that NF-kappaB activation may play a role in the regulation of KAI1/CD82 expression in lung cancer cells independently of wild-type p53, and suggest that KAI1/CD82 expression may be regulated by interaction with the host microenvironment.
Insights
Tumor necrosis factor (TNF) can increase KAI1/CD82 expression in lung cancer cells. Nuclear factor-kappaB (NF-kappaB) activation regulates KAI1/CD82, independent of wild-type p53, suggesting microenvironment interactions influence cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- KAI1/CD82 acts as a metastasis suppressor in various human cancers.
- Wild-type tumor suppressor p53 directly activates KAI1/CD82 gene expression.
- The effect of external stimuli on KAI1/CD82 expression in cancer cells remains largely unexplored.
Purpose of the Study:
- To investigate if tumor necrosis factor (TNF) affects KAI1/CD82 expression in lung cancer cells.
- To determine the involvement of nuclear factor-kappaB (NF-kappaB) in TNF-induced KAI1/CD82 expression.
- To explore the role of NF-kappaB in KAI1/CD82 regulation independently of p53 status.
Main Methods:
- Utilized PC-14 lung cancer cells with mutant p53.
- Administered TNF-alpha to assess its impact on KAI1/CD82 expression.
- Introduced IkappaB alphaSR (NF-kappaB super-repressor) gene into cancer cells.
- Quantified KAI1/CD82 mRNA and protein levels.
- Examined KAI1/CD82 expression in RERF-LC-OK cells with mutant p53.
Main Results:
- TNF-alpha significantly augmented KAI1/CD82 expression in PC-14 cells (mutant p53).
- Inhibition of NF-kappaB by IkappaB alphaSR blocked TNF-alpha-induced KAI1/CD82 augmentation.
- Nuclear NF-kappaB levels correlated with KAI1/CD82 mRNA and protein expression.
- IkappaB alphaSR gene transfer suppressed spontaneous KAI1/CD82 expression in RERF-LC-OK cells (mutant p53).
Conclusions:
- NF-kappaB activation regulates KAI1/CD82 expression in lung cancer cells.
- This regulation occurs independently of wild-type p53.
- KAI1/CD82 expression may be modulated by interactions with the host tumor microenvironment.