Zi-Jing Wang1, Jing-Lin Yang, Yi-Ping Wang, Jiang-Yan Lou, Jie Chen, Cong Liu, Lian-Di Guo. 1. 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.
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.
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.
Authors: Yue Zhao; Guillaume Lang; Saya Ito; Jacques Bonnet; Eric Metzger; Shun Sawatsubashi; Eriko Suzuki; Xavier Le Guezennec; Hendrik G Stunnenberg; Aleksey Krasnov; Sofia G Georgieva; Roland Schüle; Ken-Ichi Takeyama; Shigeaki Kato; László Tora; Didier Devys Journal: Mol Cell Date: 2008-01-18 Impact factor: 17.970
Authors: Zhuo Zhang; Amanda Jones; Heui-Yun Joo; Dewang Zhou; Ying Cao; Shaoxia Chen; Hediye Erdjument-Bromage; Matthew Renfrow; Hang He; Paul Tempst; Tim M Townes; Keith E Giles; Ligeng Ma; Hengbin Wang Journal: Genes Dev Date: 2013-07-03 Impact factor: 11.361
Authors: M H Koken; P Reynolds; I Jaspers-Dekker; L Prakash; S Prakash; D Bootsma; J H Hoeijmakers Journal: Proc Natl Acad Sci U S A Date: 1991-10-15 Impact factor: 11.205
Authors: William W Hwang; Shivkumar Venkatasubrahmanyam; Alexandra G Ianculescu; Amy Tong; Charles Boone; Hiten D Madhani Journal: Mol Cell Date: 2003-01 Impact factor: 17.970
Authors: Karl W Henry; Anastasia Wyce; Wan-Sheng Lo; Laura J Duggan; N C Tolga Emre; Cheng-Fu Kao; Lorraine Pillus; Ali Shilatifard; Mary Ann Osley; Shelley L Berger Journal: Genes Dev Date: 2003-10-16 Impact factor: 11.361
Authors: Keqiang Zhang; Jinhui Wang; Tommy R Tong; Xiwei Wu; Rebecca Nelson; Yate-Ching Yuan; Theresa Reno; Zheng Liu; Xinwei Yun; Jae Y Kim; Ravi Salgia; Dan J Raz Journal: Int J Cancer Date: 2017-05-31 Impact factor: 7.396
Authors: Ohad Tarcic; Ioannis S Pateras; Tomer Cooks; Efrat Shema; Julia Kanterman; Hadas Ashkenazi; Hana Boocholez; Ayala Hubert; Ron Rotkopf; Michal Baniyash; Eli Pikarsky; Vassilis G Gorgoulis; Moshe Oren Journal: Cell Rep Date: 2016-02-04 Impact factor: 9.423
Authors: Chang S Chan; Saurabh V Laddha; Peter W Lewis; Matthew S Koletsky; Kenneth Robzyk; Edaise Da Silva; Paula J Torres; Brian R Untch; Janet Li; Promita Bose; Timothy A Chan; David S Klimstra; C David Allis; Laura H Tang Journal: Nat Commun Date: 2018-10-12 Impact factor: 14.919
Authors: Ohad Tarcic; Roy Z Granit; Ioannis S Pateras; Hadas Masury; Bella Maly; Yaara Zwang; Yosef Yarden; Vassilis G Gorgoulis; Eli Pikarsky; Ittai Ben-Porath; Moshe Oren Journal: Cell Death Differ Date: 2017-02-03 Impact factor: 15.828