Keratin 17 in premalignant and malignant squamous lesions of the cervix: proteomic discovery and immunohistochemical validation as a diagnostic and prognostic biomarker.
Keratin 17 in premalignant and malignant squamous lesions of the cervix: proteomic discovery and immunohistochemical validation as a diagnostic and prognostic biomarker.
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DOI：
10.1038/modpathol.2013.166
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发表时间：
2014-04
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影响因子：
--
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中科院分区：
文献类型：
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大多数先前描述的宫颈高级别鳞状上皮内病变（HSIL）和鳞状细胞癌的免疫组织化学标志物可能有助于提高诊断准确性，但具有最小的预后价值。本研究的目的是鉴定和验证新的候选生物标志物，这些生物标志物有可能提高宫颈HSIL和鳞状细胞癌的诊断和预后准确性。采用基于质谱法的散弹枪蛋白质组学方法对正常宫颈外鳞、低级别鳞状上皮内病变（LSIL）、HSIL和鳞状细胞癌切片的显微解剖组织切片进行分析，以发现生物标志物。候选生物标志物的诊断特异性随后通过组织微阵列的免疫组织化学分析进行评估。在蛋白组学分析鉴定的1750个蛋白中，角蛋白4 （KRT4）和角蛋白17 （KRT17）在从正常宫颈外鳞黏膜到鳞状细胞癌的病例谱中表现出相互的表达模式。免疫组织化学研究证实，与其他诊断类型相比，KRT4在鳞状细胞癌中的表达明显降低。KRT17在HSIL和鳞状细胞癌中的表达明显高于正常宫颈外鳞粘膜和LSIL。KRT17在未成熟鳞状皮化生和宫颈内膜储备细胞中也有高表达，但在成熟鳞状皮化生中一般未检测到。此外，KRT17的高表达水平与鳞状细胞癌患者的低生存率显著相关（风险比= 14.76,P = 0.01）。综上所述，KRT4和KRT17的表达均与宫颈鳞状黏膜的组织病理学有关；KRT17在未成熟鳞状皮化生、HSIL和鳞状细胞癌中高度过表达，KRT17在鳞状细胞癌中的水平可能有助于识别宫颈癌死亡风险最高的患者。
Most previously described immunohistochemical markers of cervical high-grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma may help to improve diagnostic accuracy but have a minimal prognostic value. The goals of the current study were to identify and validate novel candidate biomarkers that could potentially improve diagnostic and prognostic accuracy for cervical HSIL and squamous cell carcinoma. Microdissected tissue sections from formalin-fixed paraffin-embedded normal ectocervical squamous mucosa, low-grade squamous intraepithelial lesion (LSIL), HSIL and squamous cell carcinoma sections were analyzed by mass spectrometry-based shotgun proteomics for biomarker discovery. The diagnostic specificity of candidate biomarkers was subsequently evaluated by immunohistochemical analysis of tissue microarrays. Among 1750 proteins identified by proteomic analyses, keratin 4 (KRT4) and keratin 17 (KRT17) showed reciprocal patterns of expression in the spectrum of cases ranging from normal ectocervical squamous mucosa to squamous cell carcinoma. Immunohistochemical studies confirmed that KRT4 expression was significantly decreased in squamous cell carcinoma compared with the other diagnostic categories. By contrast, KRT17 expression was significantly increased in HSIL and squamous cell carcinoma compared with normal ectocervical squamous mucosa and LSIL. KRT17 was also highly expressed in immature squamous metaplasia and in endocervical reserve cells but was generally not detected in mature squamous metaplasia. Furthermore, high levels of KRT17 expression were significantly associated with poor survival of squamous cell carcinoma patients (Hazard ratio = 14.76, P = 0.01). In summary, both KRT4 and KRT17 expressions are related to the histopathology of the cervical squamous mucosa; KRT17 is highly overexpressed in immature squamous metaplasia, in HSIL, and in squamous cell carcinoma and the level of KRT17 in squamous cell carcinoma may help to identify patients who are at greatest risk for cervical cancer mortality.
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