Abstract
The protein 14-3-3δ interacts with Trp53 to maintain G2 arrest and thus regulates the cell cycle. Though dysfunction of 14-3-3δ caused by hyper-methylation of CpG islands was reported in several carcinomas, the exact role of this protein in the development of extrahepatic cholangiocarcinoma has not been fully elucidated. Here, we aim at investigating the clinical relevance between 14-3-3δ and human extrahepatic cholangiocarcinoma. We collected extrahepatic cholangiocarcinoma specimens of 65 patients in Beijing Chao Yang Hospital and evaluated their 14-3-3δ expression using immunohistochemistry. We categorized the patients into different subgroups according to clinic pathological factors, such as sex, age, tumor size, pathological classification, lymph node metastasis status, tumor stage, and serum markers including CEA, CA-242, or CA19-9, and further evaluated the correlation between 14-3-3δ expression and these potential prognostic factors. As a result, we detected 14-3-3δ expression in 53 out of 65 specimens (81.5%), and the expression was positively correlated with TNM stage, lymph node metastasis, and overall survival. Our results suggest that 14-3-3δ serves as an oncogenic driver in extrahepatic cholangiocarcinoma tumorigenesis rather than a cell cycle regulator; the overexpression of 14-3-3δ might be frequently acquired by tumor cells to escape appropriate cell cycle regulation. Thus, 14-3-3δ could be a potential target for extrahepatic cholangiocarcinoma diagnosis and therapy.
Highlights
Cholangiocarcinoma (CCA) is a rare malignant tumor that can initiate from anywhere in the biliary epithelium [1, 2]
Patients with extrahepatic CCA are usually asymptomatic in the early phases of the disease and diagnosed as late stages when the tumor cells have already metastasized [4]
The particular anatomic position can induce periductal extension and result in a very low radical excision rate; the prognosis for extrahepatic CCA patients is very poor as the overall survival for these patients is measured in months
Summary
Cholangiocarcinoma (CCA) is a rare malignant tumor that can initiate from anywhere in the biliary epithelium [1, 2]. Patients with extrahepatic CCA are usually asymptomatic in the early phases of the disease and diagnosed as late stages when the tumor cells have already metastasized [4]. The 14-3-3 proteins are important regulators of intracellular signaling pathways and play vital roles in diverse cellular events, which are in charge of the cell cycle, cell growth, differentiation, survival, apoptosis, and migration in different tissues [6]. We found the level of 14-3-3δ protein is elevated in cholangiocarcinoma, but the samples contained a large portion of intrahepatic CCA [14], the role and expression of 14-3-3δ in the development of extrahepatic CCA has not been well studied so far. We aim at investigating the expression level of 14-3-3δ and its clinical relevance in human extrahepatic CCA patients. By using 65 in-house human extrahepatic CCA patients’ specimens as well as their comprehensive follow up details, we seek to uncover the correlation of 14-3-3δ and various clinicopathological factors
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