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Aberrant Methylation of IL-12Rβ2 Gene in Lung Adenocarcinoma Cells Is Associated with Unfavorable Prognosis

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Abstract

Background

Interleukin-12 receptor β2 (IL-12Rβ2) knock-out mice develop lung adenocarcinoma, and epigenetic silencing by CpG methylation leads to loss of this gene in B-cell malignancies. The aim of this study was to determine whether IL-12Rβ2 methylation is a common feature in human lung cancer.

Methods

We examined mRNA expression of IL-12Rβ2 in lung cancer cell lines, and normal bronchial, and tracheal epithelial cells using RT-PCR, and we examined the methylation status of IL-12Rβ2 in primary lung cancers.

Results

Loss of expression was found in 10 of 13 (77%) NSCLC cell lines, and 2 of 5 (40%) SCLC cell lines compared with normal bronchial or tracheal cells. Treatment of 11 expression-negative cell lines with a demethylating agent restored expression in all cases. Aberrant methylation status of IL-12Rβ2 gene was reversely concordant with its mRNA expression. IL-12Rβ2 methylation was detected in 96 of 230 primary NSCLCs (42%) and 3 of 6 primary SCLCs (50%). IL-12Rβ2 methylation correlated with poorer prognosis in lung adenocarcinomas (hazard ratio = 2.33, P = 0.0059).

Conclusions

We conclude that epigenetic silencing of IL-12Rβ2 is a frequent event in lung cancers. Aberrant methylation of this gene seems to be a useful predictor of long-term outcome for adenocarcinoma of the lung.

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Acknowledgments

This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (7303, 18591540, 2006), a grant from the Smoking Research Foundation (2006), and by the Emphasis Research Project by expenditure at the discretion of the president of Chiba University in 2005.

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Authors and Affiliations

  1. Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan

    Makoto Suzuki MD, Toshihiko Iizasa MD, Takahiro Nakajima MD, Rieko Kubo PhD, Akira Iyoda MD & Takehiko Fujisawa MD

  2. Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan

    Kenzo Hiroshima MD & Yukio Nakatani MD

Authors
  1. Makoto Suzuki MD
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  2. Toshihiko Iizasa MD
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  3. Takahiro Nakajima MD
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  4. Rieko Kubo PhD
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  5. Akira Iyoda MD
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  6. Kenzo Hiroshima MD
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  7. Yukio Nakatani MD
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  8. Takehiko Fujisawa MD
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Corresponding author

Correspondence to Takehiko Fujisawa MD.

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Suzuki, M., Iizasa, T., Nakajima, T. et al. Aberrant Methylation of IL-12Rβ2 Gene in Lung Adenocarcinoma Cells Is Associated with Unfavorable Prognosis. Ann Surg Oncol 14, 2636–2642 (2007). https://doi.org/10.1245/s10434-006-9310-7

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  • DOI: https://doi.org/10.1245/s10434-006-9310-7

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