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. 2013;8(2):e56366.
doi: 10.1371/journal.pone.0056366. Epub 2013 Feb 15.

Reduced expression of ZDHHC2 is associated with lymph node metastasis and poor prognosis in gastric adenocarcinoma

Shu-Mei Yan  1 , Jian-Jun Tang, Chun-Yu Huang, Shao-Yan Xi, Ma-Yan Huang, Jian-Zhong Liang, Yuan-Xue Jiang, Yu-Hong Li, Zhi-Wei Zhou, Ingemar Ernberg, Qiu-Liang Wu, Zi-Ming Du
Affiliations

Reduced expression of ZDHHC2 is associated with lymph node metastasis and poor prognosis in gastric adenocarcinoma

Shu-Mei Yan et al. PLoS One. 2013.

Abstract

Background: Zinc finger, DHHC-type containing 2 (ZDHHC2), originally named as reduced expression associated with metastasis protein (REAM), has been proposed as a putative tumor/metastasis suppressor gene and is often aberrantly decreased in human cancers. However ZDHHC2 expression pattern and its clinical significance have not yet been investigated in gastric adenocarcinoma.

Methodology/principal findings: Quantitative Real-Time PCR (qRT-PCR) and immunostaining were performed to detect ZDHHC2 expression in gastric adenocarcinoma, and then the correlation between ZDHHC2 expression and clinicpathologic parameters, and patient survival was analyzed. Compared to the adjacent normal tissues, ZDHHC2 expression was significantly reduced in gastric tumor tissues as shown by qRT-PCR and immunostaining. Low expression of ZDHHC2 was observed in 44.7% (211/472) of gastric adenocarcinoma patients, and was associated significantly with lymph node metastasis (p<0.001) and histological grade (p<0.001). Multivariate Cox regression analysis indicated that ZDHHC2 expression had a significant, independent predictive value for survival of gastric cancer patients (HR = 0.627, p = 0.001).

Conclusions/significance: Our data suggest that reduced ZDHHC2 expression is associated with lymph node metastasis and independently predicts an unfavorable prognosis in gastric adenocarcinoma patients.

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Conflict of interest statement

Competing Interests: One of the co-authors, Ingemar Ernberg, is a PLOS ONE Editorial Board member. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. ZDHHC2 expression in gastric cancer and normal tissues.
(A) The fold change of ZDHHC2 expression in gastric cancer tumor tissues compared to paired adjacent normal tissues (n = 45) assessed by qRT-PCR. (B)The average relative expression of mRNA level of ZDHHC2 in gastric cancer tumor tissues compared to paired adjacent normal tissues (n = 45). (C)The mean staining score of ZDHHC2 in gastric cancer tumor tissues compared to paired adjacent normal tissues (n = 45) assessed by immunohistochemistry.
Figure 2
Figure 2. Immunohistochemistry analysis of ZDHHC2 expression in gastric cancer and adjacent normal tissues.
Immunohistochemistry was performed to ZDHHC2 expression in gastric cancer tissues as well as adjacent normal tissues (A). Weak ZDHHC2 expression was observed in the cytoplasm of gastric cancer tissues (B). Strong ZDHHC2 expression was observed predominantly in the cytoplasm of adjacent normal tissues (C).
Figure 3
Figure 3. Immunohistochemistry analysis of ZDHHC2 expression in different differentiated gastric cancer.
Compared to the normal tissues (A), ZDHHC2 expression was almost negative in patients with poorly differentiated carcinoma (G3) (B), while weak ZDHHC2 expression (G2) and strong ZDHHC2 expression (G1) were found in moderately differentiated gastric cancer and well-differentiated gastric cancer respectively (C and D).
Figure 4
Figure 4. Kaplan-Meier curves for overall survival of the 472 gastric cancer patients.
(A), Kaplan-Meier curves for overall survival (OS) of the 472 gastric cancer patients; (B), Kaplan-Meier curves for OS in gastric cancer patients with low level and high level ZDHHC2 expression; (C), Kaplan-Meier curves for OS in early stage (stage I and II) gastric cancer patients with low level and high level ZDHHC2 expression; (D), Kaplan-Meier curves for OS in advanced stage (stage III and IV) gastric cancer patients with low level and high level ZDHHC2 expression.
Figure 5
Figure 5. Kaplan-Meier curves for overall survival of 202 gastric cancer patients with highest ZDHHC2 expression and with lowest ZDHHC2 expression.
(A), Kaplan-Meier curves for overall survival (OS) of the 202 gastric cancer patients; (B), Kaplan-Meier curves for OS in gastric cancer patients with highest ZDHHC2 expression (composite score more than 8, n = 128) and with lowest ZDHHC2 expression (composite score less than 4, n = 74).
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Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 81172565 and No. 81202135). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.