Expression of p14ARF, p15INK4b, p16INK4a and skp2 increases during esophageal squamous cell cancer progression

Bai,Peng; Xiao,Xue; Zou,Juan; Cui,Lin; Bui Nguyen,Tri  M.; Liu,Jinsong; Xiao,Jianguo; Chang,Bin; Wu,Jin; Wang,He

doi:10.3892/etm.2012.523

Expression of p14ARF, p15INK4b, p16INK4a and skp2 increases during esophageal squamous cell cancer progression

Authors:
- Peng Bai
- Xue Xiao
- Juan Zou
- Lin Cui
- Tri M. Bui Nguyen
- Jinsong Liu
- Jianguo Xiao
- Bin Chang
- Jin Wu
- He Wang
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Affiliations: West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Department of Biochemistry and Molecular Biology, George Washington University, Washington, D.C., USA, Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA, Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA, Department of Pathology, Shihezi University School of Medicine, Xinjiang 82002, P.R. China, Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
Published online on: March 22, 2012 https://doi.org/10.3892/etm.2012.523
Pages: 1026-1032

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Abstract

Esophageal carcinoma is the sixth most common cause of cancer-related mortality in the world. Senescence and apoptosis are assumed to be two main mechanisms that inhibit age-related carcinogenesis. p14ARF, p15INK4b and p16INK4a, which are known to induce senescence by regulating G1 cell cycle arrest, have been identified as senescence markers. However, the mechanism by which senescence and apoptosis causes neoplasia in esophageal squamous cell carcinoma (ESCC) has not been identified. In this study, 20 cases of normal esophageal tissues, 11 cases of esophageal intraepithelial dysplasia (EID) and 60 cases of ESCC were obtained and pathologically diagnosed. Immunohistochemical staining was performed to assess the expression of p14ARF, p15INK4b, p16INK4a, skp2, bcl-2 and ki-67. The senescence markers p14ARF and p16INK4a were found to be expressed in 15 and 10% of the normal tissues, 82 and 73% of the EID cases and 100 and 88% of the ESCC cases, respectively. The expression of p15INK4b was low in normal tissues, while 92% of the ESCC specimens were diffusely and markedly stained, involving the basal, middle and upper portion of the epithelium. The nuclear expression markers ki-67 and skp2 were highly expressed in ESCC tissues (100 and 72%, respectively). bcl-2 was expressed weakly in normal tissues (10%) and demonstrated various staining patterns in carcinoma specimens (strong in 60%, negative in 40%). MI was 0.09% in normal tissues and 0.95% in the ESCC specimens. Apart from the increased proliferation in esophageal carcinogenesis, as indicated in the ki-67 and skp2 indices, there was an increased expression of senescence‑associated molecular markers in the ESCC specimens, which indicates that the senescence pathway may be activated and become a part of cancer development. Of greatest interest to us was that, when compared with clinical information, the expression of the senescence markers was markedly high in the poorly differentiated specimens with lymph node metastasis, indicating that senescence markers may have diagnostic potential in clinical settings.

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