ORIGINAL ARTICLE
Evaluation of EZH2 and ERRα in colorectal carcinoma: an immunohistochemical study
1
Department of Pathology, Faculty of Medicine, Ain Shams University, Egypt
2
Department of Clinical Oncology, Faculty of Medicine, Ain Shams University, Egypt
Submission date: 2021-03-29
Final revision date: 2021-09-09
Acceptance date: 2021-09-10
Publication date: 2022-01-20
Pol J Pathol 2021;72(3):200-210
KEYWORDS
TOPICS
ABSTRACT
The combined immunohistochemical evaluation of EZH2 (enhancer of zeste homolog 2) and ERRα (estrogen-related receptor α), in relation to clinicopathological prognostic factors and patients’ outcome, has not been performed yet in colorectal carcinoma (CRC). In order to achieve this aim, 120 samples were extracted;
60 cases of CRC; and 60 samples from normal colonic tissue.
Our study showed that 63.3% and 38.3% of CRC cases reveal high EZH2 and high ERRα nuclear expression, respectively. 6.6% and 8.3% of normal colonic mucosa samples express low EZH2 and low ERRα nuclear expression, respectively. High EZH2 and high ERRα expression correlate with late tumor stages (p = 0.001 each), high grade (p = 0.001, p = 0.009 respectively), positive lymph node involvement (p = 0.001, p = 0.002 respectively) and larger tumor size (p = 0.001 each). There is a moderate highly statistically significant agreement (κ = 0.467, p = 0.001) between EZH2 and ERRα immunohistochemical expression. By Kaplan Meier analysis, high EZH2 and high ERRα show statistically significant shorter overall survival, and progression free survival than cases with low EZH2 and low ERRα immunohistochemical expression, respectively. Thus, EZH2 and ERRα might serve as potential promising prognostic markers in CRC.
60 cases of CRC; and 60 samples from normal colonic tissue.
Our study showed that 63.3% and 38.3% of CRC cases reveal high EZH2 and high ERRα nuclear expression, respectively. 6.6% and 8.3% of normal colonic mucosa samples express low EZH2 and low ERRα nuclear expression, respectively. High EZH2 and high ERRα expression correlate with late tumor stages (p = 0.001 each), high grade (p = 0.001, p = 0.009 respectively), positive lymph node involvement (p = 0.001, p = 0.002 respectively) and larger tumor size (p = 0.001 each). There is a moderate highly statistically significant agreement (κ = 0.467, p = 0.001) between EZH2 and ERRα immunohistochemical expression. By Kaplan Meier analysis, high EZH2 and high ERRα show statistically significant shorter overall survival, and progression free survival than cases with low EZH2 and low ERRα immunohistochemical expression, respectively. Thus, EZH2 and ERRα might serve as potential promising prognostic markers in CRC.
REFERENCES (44)
1.
Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin 2017; 67: 177-193.
2.
Duan R, Du W, Guo W. EZH2: a novel target for cancer treatment. J Hematol Oncol 2020; 13: 104.
3.
Kleer CG, Cao Q, Varambally S, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A 2003; 100: 11606-11611.
4.
Bachmann IM, Halvorsen OJ, Collett K, et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol 2006; 24: 268-273.
5.
Hinz S, Weikert S, Magheli A, et al. Expression profile of the polycomb group protein enhancer of Zeste homologue 2 and its prognostic relevance in renal cell carcinoma. J Urol 2009; 182: 2920-2925.
6.
Liu X, Liu H, Gu L, et al. EZH2 expression and its correlation with clinicopathological features in patients with colorectal carcinoma. Open Life Sci 2016; 11: 287-292.
7.
Chen Z, Yang P, Li W, et al. Expression of EZH2 is associated with poor outcome in colorectal cancer. Oncol Lett 2018; 15: 2953-2961.
8.
Kurihara H, Maruyama R, Ishiguro K, et al. The relationship between EZH2 expression and microRNA-31 in colorectal cancer and the role in evolution of the serrated pathway. Onco-target. 2016; 7: 12704-12717.
9.
Takawa M, Masuda K, Kunizaki M, et al. Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker. Cancer Sci 2011; 102: 1298-1305.
10.
Lin YW, Ren LL, Xiong H, et al. Role of STAT3 and vitamin D receptor in EZH2-mediated invasion of human colorectal cancer. J Pathol 2013; 230: 277-290.
11.
Cavallini A, Notarnicola M, Giannini R, et al. Oestrogen receptor-related receptor alpha (ERRalpha) and oestrogen receptors (Eralpha and Erbeta) exhibit different gene expression in human colorectal tumour progression. Eur J Cancer 2005; 41: 1487-1494.
12.
Bernatchez G, Giroux V, Lassalle T, et al. ERRα metabolic nuclear receptor controls growth of colon cancer cells. Carcinogenesis 2013; 34: 2253-2261.
13.
Liang R, Lin Y, Yuan CL, et al. High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer. Oncol Lett 2018; 15: 5933-5939.
14.
Shi B, Liang J, Yang X, et al. Integration of estrogen and Wnt signaling circuits by the polycomb group protein EZH2 in breast cancer cells. Mol Cell Biol 2007; 27: 5105-5119.
15.
Wang X, Belguise K, O’Neill CF, et al. RelB NF-kappaB represses estrogen receptor alpha expression via induction of the zinc finger protein Blimp1. Mol Cell Biol 2009; 29: 3832-3844.
16.
Sas L, Lardon F, Vermeulen PB, et al. The interaction between ER and NFκB in resistance to endocrine therapy. Breast Cancer Res 2012; 14: 212.
17.
Hua H, Zhang H, Kong Q, Jiang Y. Mechanisms for estrogen receptor expression in human cancer. Exp Hematol Oncol 2018; 7: 24.
18.
Maingi JW, Tang S, Liu S, Ng et al. Targeting estrogen receptors in colorectal cancer. Mol Biol Rep 2020; 47: 4087-4091.
19.
Abdel Raouf SM, Ibrahim TR, Abdelaziz LA, et al. Prognostic Value of TWIST1 and EZH2 Expression in Colon Cancer. J Gastrointest Cancer 2021; 52: 90-98.
20.
Harvey JM, Clark GM, Osborne CK, et al. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999; 17: 1474-1481.
21.
Hsu SM, Raine L, Fanger H. Use of avidin -biotin – peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabelled antibody (PAP) procedures. J Histochem Cytochem 1981; 29: 577–580.
22.
Shinozaki-Ushiku A, Ushiku T, Morita S, et al. Diagnostic utility of BAP1 and EZH2 expression in malignant mesothelioma. Histopathology 2017; 70: 722-733.
23.
Yoshimura M, Kinoshita Y, Hamasaki M, et al. Highly expressed EZH2 in combination with BAP1 and MTAP loss, as detected by immunohistochemistry, is useful for differentiating malignant pleural mesothelioma from reactive mesothelial hyperplasia. Lung Cancer 2019; 130: 187-193.
24.
Fluge Ø, Gravdal K, Carlsen E, et al.; Norwegian Gastrointestinal Cancer Group. Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis. Br J Cancer 2009; 101: 1282-1289.
25.
Ye SB, Cheng YK, Zhang L, et al. Prognostic value of estrogen receptor-α and progesterone receptor in curatively resected colorectal cancer: a retrospective analysis with independent validations. BMC Cancer 2019; 19: 933.
26.
Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87-108.
27.
Ohuchi M, Sakamoto Y, Tokunaga R, et al. Increased EZH2 expression during the adenoma-carcinoma sequence in colorectal cancer. Oncol Lett 2018; 16: 5275-5281.
28.
Wang CG, Ye YJ, Yuan J, et al. EZH2 and STAT6 expression profiles are correlated with colorectal cancer stage and prognosis. World J Gastroenterol 2010; 16: 2421-2427.
29.
Fussbroich B, Wagener N, Macher-Goeppinger S, et al. EZH2 depletion blocks the proliferation of colon cancer cells. PloS One 2011; 6: e21651.
30.
Meng X, Huang Z, Wang R, et al. The prognostic role of EZH2 expression in rectal cancer patients treated with neoadjuvant chemoradiotherapy. Radiat Oncol 2014; 9: 188.
31.
Song-Bing H, Hao Z, Jian Z, et al. Inhibition of EZH2 expression is associated with the proliferation, apoptosis and migration of SW620 colorectal cancer cells in vitro. Exp Biol Med (Maywood) 2015; 240: 546-555.
32.
Zhang Y, Lin C, Liao G, et al. MicroRNA-506 suppresses tumor proliferation and metastasis in colon cancer by directly targeting the oncogene EZH2. Oncotarget 2015; 6: 32586-32601.
33.
Nagarsheth N, Peng D, Kryczek I, et al. PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer. Cancer Res 2016; 76: 275-282.
34.
Liu Z, Yang L, Zhong C, Zhou L. EZH2 regulates H2B phosphorylation and elevates colon cancer cell autophagy. J Cell Physiol 2020; 235: 1494-1503.
35.
Wang W, Wang F, Zong G, et al. Prognostic significance of EZH2 expression in patients with digestive cancers: a meta-analysis. Int J Clin Exp Med 2015; 8: 16043-16049.
36.
Vilorio-Marqués L, Martín V, Diez-Tascón C, et al. The role of EZH2 in overall survival of colorectal cancer: a meta-analysis. Sci Rep 2017; 7: 13806.
37.
Yamamoto I, Nosho K, Kanno S, et al. EZH2 expression is a prognostic biomarker in patients with colorectal cancer treated with anti-EGFR therapeutics. Oncotarget 2017; 8: 17810-17818.
38.
Crea F, Fornaro L, Paolicchi E, et al. An EZH2 polymorphism is associated with clinical outcome in metastatic colorectal cancer patients. Ann Oncol 2012; 23: 1207-1213.
39.
Wang J, Ma ZB, Li K, Guo GH. Association between EZH2 polymorphisms and colorectal cancer risk in Han Chinese population. Med Oncol 2014; 31: 874.
40.
Chen JF, Luo X, Xiang LS, et al. EZH2 promotes colorectal cancer stem-like cell expansion by activating p21cip1-Wnt/β-catenin signalling. Oncotarget 2016; 7: 41540-41558.
41.
Bremer SCB, Conradi LC, Mechie NC, et al. Enhancer of Zeste Homolog 2 in Colorectal Cancer Development and Progression. Digestion 2021; 102: 227-235.
42.
Böhm J, Muenzner JK, Caliskan A, et al. Loss of enhancer of zeste homologue 2 (EZH2) at tumor invasion front is correlated with higher aggressiveness in colorectal cancer cells. J Cancer Res Clin Oncol 2019; 145: 2227-2240.
43.
Nüssler NC, Reinbacher K, Shanny N, et al. Sex-specific differences in the expression levels of estrogen receptor subtypes in colorectal cancer. Gend Med 2008; 5: 209-217.
44.
Caiazza F, Ryan EJ, Doherty G, et al. Estrogen receptors and their implications in colorectal carcinogenesis. Front Oncol 2015; 5: 19.
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