Background/Aim: Bcl-2-like protein 11 (BIM) is a pro-apoptotic member of the Bcl-2 protein family. BIM elicits cell death by binding to pro-survival Bcl-2 proteins. Even though the association of BIM expression with cell death has been investigated, its clinical survival significance in cervical cancer has not. In the current study, the prognostic significance of BIM in cervical cancer was investigated. Patients and Methods: The study included normal cervical tissues (n=254), cervical intraepithelial neoplasia (CIN) tissues (n=275), and invasive cervical cancer (n=164). In order to identify BIM expression, immunohistochemistry (IHC) was performed, and IHC scoring by quantitative digital image analysis was determined. Then, the association of BIM with prognostic factors was investigated. Results: BIM expression was higher in cervical cancer than normal cervical tissues (p<0.001). Well and moderate differentiation indicated higher BIM expression than did poor differentiation (p=0.001). Also, BIM expression was high in radiation-sensitive cervical cancer relative to radiation-resistant cancer (p=0.049). High BIM expression showed better 5-year disease-free survival (DFS) and overall survival (OS) rates (p=0.049 and π=0.030, respectively) than did low expression. In a multivariate analysis, BIM was shown to be an independent risk factor for DFS and OS in cervical cancer, with hazard ratios of 0.22 (p=0.006) and 0.46 (p=0.046), respectively. Conclusion: BIM is associated with favorable prognostic markers for prediction of DFS and OS in cervical cancer. High BIM expression is a potential prognostic marker as well as a chemotherapeutic target for cervical cancer.
Bibliographical noteFunding Information:
Patient selection. The study included 439 patients who had been diagnosed as cervical intraepithelial neoplasia (CIN, n=275) and cervical cancer (n=164) as well as 254 matched non-adjacent normal cervices between 1996 and 2010 at Gangnam Severance Hospital, Yonsei University College of Medicine in Seoul, Republic of Korea. Some of the 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 (NRF-2012M3A9B8021800). The patients’ data including age, cancer stage, tumor differentiation, cell type, tumor size, lymphovascular invasion, lymph node (LN) metastasis and radiation therapy were collected. The tumor stage was determined based on the International Federation of Gynecology and Obstetrics (FIGO) scale and was histologically classified and graded according on the World Health Organization (WHO) grade. Patients with operability indications underwent radical hysterectomy with pelvic and aortic LN dissection; in certain cases, concurrent chemo-radiation therapy was added depending on risk factors such as LN metastasis, parametrial invasion and positive resection margin. Patients with inoperability indications received either radiation or chemo-radiation therapy. Radiation resistance was designated as “recurrence” within 3 years after radiation or chemo-radiation therapy, while radiation sensitivity was designated as “no recurrence” within 3 years after radiation or chemo-radiation therapy (12, 13). This study was approved by the Institutional Review Board (IRB #3-2010-0030; Seoul, Korea) of Gangnam Severance Hospital. It was additionally approved by the Office of Human Subjects Research at the National Institutes of Health (Bethesda, MD, USA).
This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), the National Cancer Institute, the Center for Cancer Research, and grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0005230, 2011-0010286 and 2011-0007146).
All Science Journal Classification (ASJC) codes
- Cancer Research