EZH2 is associated with malignant behavior in pancreatic IPMN via p27Kip1 downregulation.
EZH2 is associated with malignant behavior in pancreatic IPMN via p27Kip1 downregulation.
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DOI：
10.1371/journal.pone.0100904
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Baba H
中科院分区：
文献类型：
--
作者：
Kuroki H;Hayashi H;Okabe H;Hashimoto D;Takamori H;Nakahara O;Nakagawa S;Fukushima Y;Chikamoto A;Beppu T;Hirota M;Iyama K;Baba H
胰腺导管内乳头状黏液性肿瘤(IPMN)发生的表观遗传学机制尚不清楚。本研究的目的是研究ZAST同源增强子2(EZH2)的改变在胰腺IPMN进展中的作用。对54例手术切除的胰腺IPMN标本共181个病变(正常导管48个，腺瘤50个，交界性不典型53个，原位癌19个，浸润性癌11个)进行免疫组织化学染色(EZH2、Ki-67、p27Kip1)。采用石蜡包埋切片方法，成功地从20例IPMN病变(交界性IPMN 9例，CIS 6例，浸润性癌5例)和7例正常胰腺导管组织中提取总RNA，用实时荧光定量聚合酶链式反应(Real-time PCR)检测EZH2和p27Kip1基因的表达水平。免疫组织化学分析显示，Ki-67阳性细胞核显示的细胞增殖活性在IPMN进展过程中增强(正常导管和腺瘤；交界性非典型性和顺≈浸润性癌)。EZH2的表达与细胞增殖活性相似(正常导管、腺瘤、交界性非典型性癌、顺≈浸润性癌)。EZH2在恶性(CIS和浸润癌)IPMN中的表达明显高于腺瘤和交界性非典型性IPMN。EZH2在IPMN皮损中的表达水平与Ki-67阳性核比率呈正相关(p<；0.0001)。恶性IPMN中EZH2阳性细胞不表达p27Kip1。恶性病变中EZH2mRNA的表达显著高于良性病变(p<；0.0001)。而恶性病变组织中p27Kip1mRNA的表达水平显著低于良性病变组织(p<；0.0109)，且二者表达水平呈负相关(p = 0.0109)。EZH2通过下调p27Kip1的表达与胰腺IPMN的细胞增殖加速和恶性进展有关。
The epigenetic mechanism of tumorigenesis in pancreatic intraductal papillary mucinous neoplasm (IPMN) remains largely unknown. The aim of this study is to examine the role of enhancer of zeste homologue 2 (EZH2) alteration in pancreatic IPMN progression. Fifty-four surgically resected pancreatic IPMN specimens, including a total of 181 lesions (normal duct in 48, adenoma in 50, borderline atypia in 53, carcinoma in situ (CIS) in 19, and invasive carcinoma in 11) were analyzed by immunohistochemical staining (EZH2, Ki-67, p27Kip1). Using paraffin embedded sections, total RNA was successfully extracted from 20 IPMN lesions (borderline IPMN in 9, CIS in 6, invasive carcinoma in 5) and 7 pancreatic normal ducts, and then levels of EZH2 and p27Kip1 mRNA were analyzed by real time PCR. In immunohistochemical analysis, cell proliferative activity revealed by Ki-67 positive nuclei was increased during IPMN progression (normal duct<adenoma<borderline atypia<CIS ≈ invasive carcinoma). EZH2 expression displayed a similar pattern (normal duct<adenoma<borderline atypia<CIS ≈ invasive carcinoma) with cell proliferative activity. EZH2 expression in malignant (CIS and invasive carcinoma) IPMNs was significantly higher than that in adenoma and borderline-atypia IPMNs. EZH2 expression level in IPMN lesions was positively correlated with the Ki-67 positive nuclear ratio (p<0.0001). EZH2-positive cells in malignant IPMN did not express p27Kip1. EZH2 mRNA expressions in malignant lesions were significantly higher than those in benign lesions (p<0.0001). In contrast, p27Kip1 mRNA in malignant lesions was significantly decreased compared to those in benign lesion (p<0.05), and there was an inverse correlation between EZH2 and p27Kip1 mRNA levels (p = 0.0109). EZH2 is associated with the accelerated cell proliferation and malignant step in pancreatic IPMN via the downregulation of p27Kip1.
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DOI：
10.1158/1078-0432.ccr-08-1013
发表时间：
2008-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Ougolkov AV;Bilim VN;Billadeau DD
通讯作者：
Billadeau DD
影响因子：
9
作者：
Sohn, TA;Yeo, CJ;Lillemoe, KD
通讯作者：
Lillemoe, KD
影响因子：
64.8
作者：
Varambally, S;Dhanasekaran, SM;Chinnaiyan, AM
通讯作者：
Chinnaiyan, AM
影响因子：
10.5
作者：
Mallen-St Clair, Jon;Soydaner-Azeloglu, Rengin;Bar-Sagi, Dafna
通讯作者：
Bar-Sagi, Dafna
影响因子：
56.9
作者：
Cao, R;Wang, LJ;Zhang, Y
通讯作者：
Zhang, Y