Background: NKG2D (natural killer group 2, member D) is thought to play an important role in mediating the activation of anticancer immune response. Expression of NKG2D ligands (NKG2DLs) is pronounced in malignancies and the heterogeneity of NKG2DL expression remains unclear. Here, we investigate the expression and clinical significance of NKG2DLs in cervical cancer. Methods: Immunohistochemical analyses of MICA/B, ULBP1, ULBP2, ULBP3, RAET1E, and RAET1G were performed using tissue microarray analysis of 200 cervical cancers, 327 high-grade cervical intraepithelial neoplasias (CINs), 99 low-grade CINs, and 541 matched nonadjacent normal cervical epithelial tissues and compared the data with clinicopathologic variables, including the survival of cervical cancer patients. Results: MICA/B, ULBP1, and RAET1E expression was higher in cervical cancer than in low-grade CIN (p<0.001, p=0.012, p=0.013, respectively) and normal cervix (all p<0.001). Among these markers, expression of ULBP1 was significantly different depending on patient tumor stage (p=0.010) and tumor size (p=0.045). ULBP1 expression was correlated with MICA/B (p<0.001) and ULBP2 (p=0.002) expression in cervical cancer. While MICA/B+ or ULBP1+ patients had improved disease-free survival time (p=0.027 and p=0.009, respectively) relative to that of the low expression group, RAET1E+ or RAET1G+ was correlated with shorter survival time (p=0.018 and p=0.029, respectively). However, in terms of overall survival, the ULBP1+ group had significantly longer survival time than the low expression group (p=0.009). Multivariate analysis indicated that MICA/B+/ULBP1+ (HR=0.16, p=0.015) and ULBP1+ (HR=0.31, p=0.024) are independent prognostic factors of disease-free survival in cervical cancer. Conclusions: High expression of either ULBP1 or MICA/B and ULBP1 combined is an indicator of good prognosis in cervical cancer, suggesting their potential utility as prognostic tests in clinical assessment.
Bibliographical noteFunding Information:
The study subjects were comprised of 200 cervical cancer and 426 cervical intraepithelial neoplasias (CINs) patients who underwent surgical resection at Gangnam Severance Hospital, Yonsei University College of Medicine between March 1996 and March 2010. Additional paraffin blocks were provided by the Korea Gynecologic Cancer Bank through the Bio & Medical Technology Development Program of the Ministry of Education, Science and Technology, Korea. All patients had a histological diagnosis of cervical carcinoma or CIN, and the cervical cancer patients were clinically staged according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. Patients with cervical cancer underwent type 3 radical hysterectomy with pelvic lymph node dissection, and, in cases of increased risk of relapse (assessed from spread to lymph node, parametrial invasion, and cancer close to resection margins), platinum-based concurrent chemoradiation was added. Medical records were reviewed to obtain data including age, Hybrid Capture® 2 results, surgical procedure, survival time, and survival status. Response to therapy was assessed by either computed tomography or magnetic resonance imaging in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.0) . Data on tumor size, cell type, tumor grade, and lymph node metastases were obtained from pathology reports. Tissue samples were collected from patients who had signed informed consent forms, which was approved by the Institutional Review Boards of Gangnam Severance Hospital. This study was additionally approved by the Office of Human Subjects Research at the National Institute of Health.
This work was supported in part by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (2011–0007146) and faculty research grants from Yonsei University College of Medicine for 2014 (6-2014-0072) and Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research.
© 2014 Cho et al.
All Science Journal Classification (ASJC) codes
- Cancer Research