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.