Keratin 17 in premalignant and malignant squamous lesions of the cervix: proteomic discovery and immunohistochemical validation as a diagnostic and prognostic biomarker.
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.
1] Department of Pharmacological Sciences, Stony Brook School of Medicine, Stony Brook, NY, USA [2] Department of Pathology, Stony Brook School of Medicine, Stony Brook, NY, USA [3] Department of Biology, Research Group Genetic Toxicology and Cytogenetics, Faculty of Natural Sciences and Education, Universidad del Cauca, Popayán, Colombia.
Luisa F
LF
Escobar-Hoyos
1] Department of Applied Mathematics and Statistics, Stony Brook School of Medicine, Stony Brook, NY, USA [2] Department of Preventive Medicine, Stony Brook School of Medicine, Stony Brook, NY, USA.
Jie
J
Yang
Department of Applied Mathematics and Statistics, Stony Brook School of Medicine, Stony Brook, NY, USA.
Jiawen
J
Zhu
Department of Pharmacological Sciences, Stony Brook School of Medicine, Stony Brook, NY, USA.
Julie-Ann
JA
Cavallo
Department of Pathology, Stony Brook School of Medicine, Stony Brook, NY, USA.
Haiyan
H
Zhai
Department of Pathology, Stony Brook School of Medicine, Stony Brook, NY, USA.
Stephanie
S
Burke
Proteomics Center, Stony Brook School of Medicine, Stony Brook, NY, USA.
Antonius
A
Koller
1] Department of Pharmacological Sciences, Stony Brook School of Medicine, Stony Brook, NY, USA [2] Department of Pathology, Stony Brook School of Medicine, Stony Brook, NY, USA [3] Proteomics Center, Stony Brook School of Medicine, Stony Brook, NY, USA.
Emily I
EI
Chen
Department of Pathology, Stony Brook School of Medicine, Stony Brook, NY, USA.
Kenneth R
KR
Shroyer
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D053537:Keratin-17 / Q000032:analysis*; D053527:Keratin-4 / Q000032:analysis; D008679:Metaplasia; D008875:Middle Aged; D011230:Precancerous Conditions / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D011237:Predictive Value of Tests; D011379:Prognosis; D040901:Proteomics / Q000379:methods; D015203:Reproducibility of Results; D065310:Squamous Intraepithelial Lesions of the Cervix / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D053719:Tandem Mass Spectrometry; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D055815:Young Adult
D014408:Biomarkers, Tumor; D053537:Keratin-17; D053527:Keratin-4