Cholangiocarcinoma (CCA) is a highly aggressive epithelial malignancy, representing 10–25% of primary hepatic malignancies worldwide[1–3]. It is defined anatomically as intrahepatic CCA (IHCC) and extrahepatic CCA (EHCC), the EHCC is further characterized as perihilar CCA, originating at the bifurcation of the common hepatic duct, or tumour of the distal bile duct. The diagnosis of EHCC is complex and is made with a combination of appropriate clinical suspicion, imaging techniques, endoscopic techniques, and cytopathological examination. Although there have been advances in the diagnosis and management of EHCC, these cancers remain challenging to treat because of their insensitivity to conventional therapies and inability to detect early tumor formation[4, 5]. In clinical practice, the most widely studied and used tumor marker is carbohydrate antigen 19 − 9 (CA19-9), however, CA19-9 has a wide variation in sensitivity (50%-90%) and specificity (54%-98%) and is often falsely elevated in benign biliary disease and/or cholangitis, with levels falling after relief of biliary obstruction and sepsis[6, 7]. Novel targets and biomarkers involved in the tumorogenesis and metastasis, diagnosis and prognosis of the EHCC are urgently needed.
Baculoviral IAP repeat-containing 7 (BIRC7), also known as Livin, encodes a member of the inhibitor of apoptosis protein (IAP) family, and contains a single copy of a baculovirus IAP repeat (BIR) as well as a RING-type zinc finger domain[8, 9]. The BIR domain has a well-characterized role in interacting with caspases and inhibiting apoptosis, while the RING finger domain sometimes enhances antiapoptotic activity but does not inhibit apoptosis alone[9, 10]. A series of previous studies have showed that aberrant BIRC7 expression is closely related to the occurrence, progress, clinical biological behaviors and prognosis of in various human cancer tissues, including melanoma, breast, colon, prostate cancer and hepatocellular carcinoma [11–13]. BIRC7 up-regulation is mainly a risk factor for cancer progression, poor prognosis and resistance to chemotherapy and radiotherapy [14, 15]. It might serve as a valuable biomarker of increased recurrence risk in prostate cancer . Moreover, it has been shown that down-regulation of BIRC7 expression resensitizes tumor cells to apoptosis and chemotherapy [15, 17] and leads to tumor volume reduction in a xenograft model of colorectal cancer . In short, BIRC7 might represent a new potential biomarker and target for future diagnosis and treatment of tumor.
Stanniocalcin 2 (STC2) encodes a secreted, homodimeric glycoprotein that is expressed in a wide variety of tissues and have autocrine or paracrine functions . STC2 and its homologues, STC1, may play a role in cellular calcium/phosphate homeostasis . Previous studies have revealed that STC2 plays an oncogenic role in many human cancers [21–27]. The differential expression levels of STC2 have certain guiding significance for the prediction, metastasis and prognosis of gastric cancer , colorectal cancer , prostate cancer , breast cancer, laryngeal squamous cell carcinomaand , head and neck squamous cell carcinoma, endometrial cancer , ect. Moreover, recent studies have found that STC2 protein expression may be a valuable biomarker for cancer progression, as well as a prognostic marker for poor outcome [24–27].
Little is currently known about the role of BIRC7 and STC2 in EHCC. The aim of this study was to investigate the clinicopathological significance and prognostic values of BIRC7 and STC in a large cohort of EHCC by immunohistochemistry.