Circulating TGF-β1 as the potential epithelial mesenchymal transition-biomarker for diagnosis of cholangiocarcinoma

Phongsaran Kimawaha, Apinya Jusakul, Prem Junsawang, Watcharin Loilome, Narong Khuntikeo, Anchalee Techasen


Background: Cholangiocarcinoma (CCA) is a malignant tumor arising from bile duct epithelium. The oncogenic risk factor is infection by the liver fluke, Opisthorchis viverrini (Ov). One of key mechanism in the development of CCA is epithelial mesenchymal transition (EMT). We aimed to investigate the expression of EMT-related proteins namely, E-cadherin, TGF-β1 and BMP-7 in CCA tissues, to determine the level of candidate EMT-related protein, and to examine whether there were significant correlations with clinicopathological data in sera of CCA patients compared with normal groups.
Methods: The expression of E-cadherin, TGF-β1 and BMP-7 was analyzed in human CCA tissues by immunohistochemistry and altered expressions compared to clinicopathological data were analyzed to identify the potential candidate EMT-biomarker. Subsequently, the level of candidate marker was determined in sera of CCA patients compared with normal and inflammatory-related diseases groups by enzyme-linked immunosorbent assay (ELISA).
Results: Immunohistochemical analysis showed that E-cadherin was expressed at a low level whereas TGF-β1 and BMP-7 showed high expression in CCA tissues when compared with liver from cadaveric donor. Interestingly, only high TGF-β1 expression in CCA tissues was significantly correlated with lymph node metastasis, severe cancer stage, intrahepatic CCA type and shorter survival time of CCA patients (P<0.05). Consequently, TGF-β1 was selected to determine the level in serum of CCA patients using ELISA. The results showed that serum TGF-β1 level was elevated in CCA patients compared to the normal group. Patients with high TGF-β1 levels were significantly correlated with metastasis status (P=0.03). Furthermore, receiver operating characteristic (ROC) analysis showed that serum TGF-β1 level is effective in distinguishing CCA patients from normal at the cut-off of 38.54 ng/mL with high sensitivity (71.1%) and specificity (68.9%) and from inflammatory-related diseases group at the cut-off of 38.67 ng/mL with effective sensitivity (68.0%) and specificity (71.1%). Furthermore, TGF-β1 could serve as a novel metastatic biomarker in CCA to diagnose the disease with 48.95 ng/mL as the cut-off along with the desired sensitivity and specificity (48.2% and 88.9% respectively).
Conclusions: The results of this study show that TGF-β1 could be a potential EMT-biomarker for diagnosis and prognosis of CCA.

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