Up-regulation of annexin A2 in cholangiocarcinoma caused by Opisthorchis viverrini and its implication as a prognostic marker

Abstract

Cholangiocarcinoma (CCA), or cancer of the bile ducts, is primarily associated with infection with the liver fluke Opisthorchis viverrini in northeast Thailand. The disease . is associated with late presentation, poses challenges for diagnosis and has a high mortality rate – features that highlight the need for tumor markers. At present, there are no specific tumor markers that can indicate the early stages and status of CCA. Proteomic analysis of the proteins expressed on the surface of tumor cells is particularly difficult since proteome-wide analysis of surface membrane proteins has thus far been hampered by the lack of effective strategies to profile hydrophobic membrane proteins. In this study, a sequential protein extraction was utilized to overcome this problem. Membrane protein was extracted from four CCA cell lines with different tumor forming capabilities. The non-tumor H69 biliary cell line was used as a control. Two-dimensional-PAGE followed by MALDI-TOF-MS was used to identify differentially expressed proteins. Among 20 up-regulated membrane proteins identified in the CCA cell lines was ANXA2, a participant in tumor invasion and metastasis in other cancers. Accordingly, ANXA2 was verified in human subjects by probing, using a commercial anti-mouse monoclonal antibody and a tissue microarray of CCA (301 diagnosed cases), where it was found to associate with one of several tumor progression stages as reflected by lymphatic invasion (P = 0.014) and metastasis (P = 0.026). Patients with high expression of ANXA2 had a significantly shorter survival time (P = 0.011). ANXA2 expression in tumors may be useful for predicting the poor outcome of CCA patients.

Candidate genes involving in tumorigenesis of cholangiocarcinoma induced by Opisthorchis viverrini infection

“…Compelling evidence from the literature suggests that annexin II may be a potential target for the development of effective therapeutic strategies for the treatment of cancer and its metastasis (Sharma and Sharma 2007). It was reported that Anxa2 protein was up-regulated in the tissues of OV-associated CCA patients and the up-regulation was correlated with the tumor progression stages and survivals (Yonglitthipagon et al 2010). Our results further confirmed the up-regulated expression in CCA, suggesting that Anxa2 can be a promising biomarker.…”

“…Some genes or signaling pathway have been found to be likely involved in the tumorigenesis or potential as biomarkers, for example, KRAS and TP53 (Tangkawattana et al 2008), RB1 signaling pathway genes (Boonmars et al 2009b), annexin A2, MMP-9 (Yonglitthipagon et al 2010), and IL-6 (Sripa et al 2009). However, most of these approaches used patient tissues that are usually in late stage of CCA.…”

Expression of Annexin A2 and Its Correlation With Drug Resistance and Recurrence of Bladder Cancer

“…In the cholangiocarcinoma cells, ANXA2 was upregulated. 21 Maxwell et al also studied ANXA2 associated with oxidative processes and inflammation in stage 1 endometrial cancer tissues based on proteomic analysis. 22 The expressions of ANXA2 also correlated with cervical cancer 23 and pancreatic cancer.…”

Novel Potential Biomarkers for Opisthorchis viverrini Infection and Associated Cholangiocarcinoma

“…Proteomics offers an unprecedented opportunity for identifying new biomarkers and therapeutic targets and providing an understanding of the biochemical pathways involved in pathogenesis (20). Using a shotgun proteomic approach, Kristiansen et al (25). In addition, these authors extended their analyses to include a computational analysis of the promoter regions of the proliferation-associated genes.…”