Expression of Phosphorylated Histone H2AX (γ-H2AX) in Normal and Neoplastic Squamous Epithelia of the Uterine Cervix: An Immunohistochemical Study With Epidermal Growth Factor Receptor
Expression of Phosphorylated Histone H2AX (γ-H2AX) in Normal and Neoplastic Squamous Epithelia of the Uterine Cervix: An Immunohistochemical Study With Epidermal Growth Factor Receptor
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DOI：
10.1097/pgp.0b013e3181eb2fcb
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发表时间：
2011-01-01
影响因子：
2.4
通讯作者：
Brunner, Andreas
中科院分区：
文献类型：
--
作者：
Brustmann, Hermann;Hinterholzer, Susanne;Brunner, Andreas
组蛋白γ-H_2AX是激活DNA损伤的标志，在不同的癌症及其前驱病变中过表达，提示在致癌转化中起作用。表皮生长因子受体(EGFR)在多种上皮性肿瘤中高表达。本研究旨在探讨从正常宫颈鳞状上皮(NE，n=33)到宫颈上皮内瘤变(CIN；CIN1，n=9；CIN2/3，n=33)和宫颈浸润性鳞状细胞癌(ISCC，n=33)的病理形态演变过程中，伽马-H_2AX的免疫组织化学表达是否参与其中，g-H_2AX的表达是否遵循EGFR免疫反应所显示的非典型鳞状细胞的增殖模式，以及它是否与ISCC的临床病理变量有关。对这两个因子的免疫染色进行半定量评分，分为中强度和强强度。从NE和CIN1到CIN2/3和ISCC，γ-H AX和EGFR的表达分别显著增加(P=0.0001)。在NE和CIN中，γ-H_2AX阳性反应见于上皮层细胞和基底型/旁基型细胞的胞核中，在ISCC的胞核包括角化细胞胞核中有不同程度的表达。EGFR染色主要见于NE的基底层/基底层细胞，在CIN和ISCC的非角化细胞中有不典型的角质形成细胞。此外，未成熟的鳞状化生组织被使用的抗体修饰。在国际妇产科联合会I期和II期、角化性和非角化性ISCC以及CIN2/3和ISCC之间，γ-H2AX和EGFR的免疫积分分别没有差异。然而，这两种因子的表达模式不同，这表明它们除了参与增殖外，还参与了不同的生物学机制。宫颈CIN2/3和ISCC中γ-H2AX的过表达反映了宫颈鳞状上皮细胞对DNA损伤增加的反应，并支持将不典型增生分为低度鳞状上皮内病变和高度鳞状上皮内病变。
The histone gamma-H2AX is a marker of activated DNA damage and is overexpressed in different cancers and their precursor lesions, indicating a role in oncogenic transformation. Epidermal growth factor receptor (EGFR) is overexpressed in many kinds of epithelial neoplasms. This study aimed to determine whether immunohistochemical expression of gamma-H2AX is involved in the progression of the morphological spectrum from normal squamous cervical epithelia (NE, n = 33) to cervical intraepithelial neoplasia (CIN; CIN1, n = 9; CIN2/3, n = 33) and cervical invasive squamous cell carcinoma (ISCC, n = 33), whether g-H2AX expression follows the pattern of proliferation of atypical squamous cells as shown by EGFR immunoreactivity, and whether it is correlated with clinicopathologic variables in ISCC. Immunostaining for both the factors was scored semiquantitatively for moderate and strong intensities. Gamma-H2AX and EGFR expression, respectively, increased from NE and CIN1 to CIN2/3 and ISCCs significantly (P = 0.0001, respectively). Gamma-H2AX reactivity was found in the nuclei of the cells of the upper epithelial levels and the cells of basal/parabasal type in variable quantities in NE and CIN; expression of gamma-H2AX was seen in the nuclei of ISCC including keratinizing cells in horn pearls. EGFR staining was mainly membranous and noted in basal/parabasal cells in NE and atypically proliferating keratinocytes in CIN and nonkeratinizing cells of ISCC. In addition, immature squamous metaplasias were decorated by the antibodies used. Immunoscores for gamma-H2AX and EGFR, respectively, did not differ between International Federation of Gynecology and Obstetrics stages I and II, keratinizing and nonkeratinizing ISCC, and CIN2/3 and ISCC. However, expression patterns were different for both the factors, suggesting their involvement in different biological mechanisms, with regard to gamma-H2AX apart from proliferation. Overexpression of gamma-H2AX in CIN2/3 and ISCC of the uterine cervix reflects the neoplastic transformation of cervical squamous epithelia in reaction to increased DNA-damage and supports the classification of dysplasia into low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions.