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Suppressor of Cytokine Signaling 4 Detected as a Novel Gastric Cancer Suppressor Gene using Double Combination Array Analysis

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Abstract

Background

Molecular mechanisms behind the oncogenesis of gastric cancer (GC) have yet to be identified.

Methods

A novel candidate tumor-suppressor gene, which is also associated with inhibition of epidermal growth factor (EGF), was sought by means of double combination array analysis for use as a prognostic marker of GC. This consisted of expression array and single nucleotide polymorphism array analysis, along with a literature search. Cancerous and noncancerous tissues from an 82-year-old man with GC were analyzed simultaneously.

Results

The expression array and literature search identified that the suppressor of cytokine signaling 4 (SOCS4), a negative feedback regulator of EGF signaling, had significantly attenuated expression in tumor tissue. Although chromosomal deletion was not found at 14q22 where SOCS4 is located, numerous CpG sites were observed in the promoter region of the SOCS4 gene. Several GC cell lines showed reactivation of SOCS4 mRNA expression after treatment with 5-aza-2′-deoxycytidine. Using surgically resected specimens, we found that 40 of 50 (80%) tumor tissues exhibited promoter hypermethylation of the SOCS4 gene. Consequently, SOCS4 expression in tumor tissues was significantly weaker than in noncancerous counterparts (P < 0.0001). In the survival analysis, SOCS4 hypermethylation was associated with a poor prognosis of GC patients (P = 0.0320).

Conclusions

Double combination array analysis suggested that SOCS4 could be a novel candidate for further exploration as a tumor-suppressor gene in GC. Hypermethylation was the mechanism by which SOCS4 was silenced and was implicated in the development of GC. SOCS4 methylation might be an informative marker in predicting the prognosis.

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Conflict of interest

We do not have any commercial interest or sources of financial or material support to report.

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Authors and Affiliations

  1. Department of Surgery II, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Daisuke Kobayashi, Shuji Nomoto, Yasuhiro Kodera, Michitaka Fujiwara, Masahiko Koike, Goro Nakayama & Norifumi Ohashi

  2. Nagoya Central Hospital, 3-7-7 Taiko, Nakamura-ku, Nagoya, 453-0801, Japan

    Akimasa Nakao

Authors
  1. Daisuke Kobayashi
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  2. Shuji Nomoto
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  3. Yasuhiro Kodera
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  4. Michitaka Fujiwara
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  5. Masahiko Koike
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  6. Goro Nakayama
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  7. Norifumi Ohashi
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  8. Akimasa Nakao
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Correspondence to Shuji Nomoto.

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Kobayashi, D., Nomoto, S., Kodera, Y. et al. Suppressor of Cytokine Signaling 4 Detected as a Novel Gastric Cancer Suppressor Gene using Double Combination Array Analysis. World J Surg 36, 362–372 (2012). https://doi.org/10.1007/s00268-011-1358-2

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  • DOI: https://doi.org/10.1007/s00268-011-1358-2

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