Brief Article
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World J Gastroenterol. Nov 28, 2013; 19(44): 8099-8107
Published online Nov 28, 2013. doi: 10.3748/wjg.v19.i44.8099
Decreased histone H2B monoubiquitination in malignant gastric carcinoma
Zi-Jing Wang, Jing-Lin Yang, Yi-Ping Wang, Jiang-Yan Lou, Jie Chen, Cong Liu, Lian-Di Guo
Zi-Jing Wang, Jiang-Yan Lou, Jie Chen, Cong Liu, Lian-Di Guo, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of the Ministry of Education, Department of Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Zi-Jing Wang, Jing-Lin Yang, Yi-Ping Wang, Department of Digestive Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Author contributions: Wang ZJ, Liu C designed the study and wrote the manuscript; Wang ZJ performed the experiments; Yang JL, Wang YP summarized the immunostaining results and analyzed the data; Lou JY, Chen J provided vital reagents and clinical samples; Guo LD wrote the discussion and revised the entire article for intellectual content; all authors have read and approved the final version of the manuscript.
Supported by The Ministry of Science and Technology of China, No. 2011CB966200 and 2013CB911000; the National Natural Science Foundation of China, No. 30970950, 81071362, and 31171319; the Program for Changjiang Scholars and Innovative Research Team in University of Ministry of Education of China, the Department of Science and Technology of Sichuan Province, No. 2011SZ0002 and 2012JQ0005; and the Bureau of Science and Technology of Chengdu, No. 11PPYB072SF
Correspondence to: Cong Liu, PhD, Professor, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of the Ministry of Education, Department of Gynecology, West China Second University Hospital, Sichuan University, No.20, Section 3, Ren Min Nan Lu Road, Chengdu 610041, Sichuan Province, China. congliu@scu.edu.cn
Telephone: +86-28-85501727 Fax: +86-28-85501727
Received: August 5, 2013
Revised: September 23, 2013
Accepted: October 19, 2013
Published online: November 28, 2013
Processing time: 128 Days and 19.2 Hours
Abstract

AIM: To investigate H2B monoubiquitination (uH2B) and H3K4 di- and tri-methylation (H3K4-2me, H3K4-3me) levels and their clinical significance in gastric cancer (GC).

METHODS: Immunohistochemistry (IGC) was used to detect the differential levels of uH2B, H3K4-2me and H3K4-3me modifications in GC specimens from chemo/radiotherapy-naïve patients who underwent potentially curative surgical resection (n = 159) and in a random sampling of non-tumor gastric epithelium specimens (normal controls, n = 20). The immunohistochemistry (IHC)-detected modifications were classified as negative, low-level, or high-level using a dual-rated (staining intensity and percentage of positively-stained cells) semi-quantitative method. The relationships between uH2B modification levels and clinicopathological parameters of GC were assessed by a Wilcoxon rank sum test (pairwise comparisons) and the Kruskal-Wallis H test (multiple comparisons). The correlation between uH2B modification and survival was estimated by Kaplan-Meier analysis, and the role of uH2B as an independent prognostic factor for survival was assessed by multivariate Cox regression analysis.

RESULTS: The presence and level of H3K4-2me and H3K4-3me IHC staining was similar between the normal controls and GC specimens. In contrast, the level of uH2B was significantly lower in the malignant gastric tissues (vs normal control tissues) and decreased along with increases in dedifferentiation (well differentiated > moderately differentiated > poorly differentiated). The level of uH2B correlated with tumor differentiation (P < 0.001), Lauren’s diffuse- and intestinal-type classification (P < 0.001), lymph node metastasis (P = 0.049) and tumor-node-metastasis stage (P = 0.005). Patients with uH2B+ staining had higher 5-year survival rates than patients with uH2B-staining (52.692 ± 2.452 vs 23.739 ± 5.207, P < 0.001). The uH2B level was an independent prognostic factor for cancer-specific survival (95%CI: 0.237-0.677, P = 0.001).

CONCLUSION: uH2B displays differential IHC staining patterns corresponding to progressive stages of GC. uH2B may contribute to tumorigenesis and could be a potential therapeutic target.

Keywords: Gastric cancer, Epigenetics, Histone modification, H2B monoubiquination, Nuclear immunostaining

Core tip: The abundant H2B monoubiquination (uH2B) modification detected by immunohistochemistry (IHC) in normal human gastric epithelium is decreased in malignant gastric cancer specimens, and the decreasing trend is correlated with decreased tumor differentiation, Lauren’s classification intestinal-type, presence of lymph node metastasis, and TNM stage. Positive uH2B staining is associated with higher 5-year survival. Multivariate analysis identified uH2B modification level as an independent prognostic factor for gastric cancer-specific survival. Collectively, these findings indicate the clinical significance of IHC-detected uH2B differential staining patterns as a potential prognostic biomarker in early stage gastric cancer.