Abstract
BackgroundCancer recurrence is one of the most concerning clinical problems of cholangiocarcinoma (CCA) patients after treatment. However, an identification of predictive factor on Opisthorchis viverrini (OV)-associated CCA recurrence is not well elucidated. In the present study, we aimed to investigate the correlation of twelve targeted protein kinases with CCA recurrence.MethodsTwelve protein kinases, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, 3, 4 (HER2, HER3, HER4), vascular endothelial growth factor receptor 3 (VEGFR3), vascular endothelial growth factor-C (VEGF-C), erythropoietin-producing hepatocellular carcinoma receptor type-A3 (EphA3), EphrinA1, phosphor-serine/threonine kinase 1 (p-Akt1), serine/threonine kinase 1 (Akt1), beta-catenin and protein Wnt5a (Wnt5a) were examined using immunohistochemistry. Pre-operative serum tumor markers, CA19–9 and CEA were also investigated.ResultsAmong twelve protein kinases, EGFR, HER4, and EphA3 were associated with tumor recurrence status, recurrence-free survival (RFS) and overall survival (OS). Multivariate cox regression demonstrated that EGFR, HER4, EphA3 or the panel of high expression of these proteins was an independent prognostic factor for tumor recurrence. The combination of high expression of these proteins with a high level of CA19–9 could improve the predictive ability on tumor recurrence. Moreover, the patients were stratified more accurately when analyzed using the combination of high expression of these proteins with primary tumor (T) or lymph node metastasis (N) status.ConclusionEGFR, HER4, EphA3 or the panel of high expression of these proteins is an independent prognostic factor for post-operative CCA recurrence.
Highlights
Cancer recurrence is one of the most concerning clinical problems of cholangiocarcinoma (CCA) patients after treatment
We found that many protein kinases were upregulated in CCA tissue and cell lines, including receptor tyrosine kinase, the epidermal growth factor receptor (EGFR) family, vascular endothelial growth factor (VEGFR) receptor, erythropoietinproducing hepatocellular carcinoma (Eph) receptor, and many down-steam kinases such as serine/threonine kinase or protein kinase B (Akt), and Wnt/beta-catenin signaling pathways [8]
Our group reported that high expressions of vascular endothelial growth factor receptor 3 (VEGFR3), erythropoietin-producing hepatocellular carcinoma receptor type-A3 (EphA3) and their ligands were correlated with CCA metastasis [10]
Summary
Cancer recurrence is one of the most concerning clinical problems of cholangiocarcinoma (CCA) patients after treatment. Molecular biomarkers are widely studied because it is used for the predicting of tumor progression or recurrence, but can be employed as drug target for cancer treatment. The results showed that high expression of protein in this pathway was mostly involved in the worse clinical outcome of CCA patients. Targeting of this pathway using NVP-BEZ235 could inhibit tumor growth and metastasis through reduced protein kinase activation [11]. The result showed the alteration of Wnt proteins was associated with poor prognosis of CCA patients, and inhibition of betacatenin expression could inhibit CCA cell growth [12]
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