Epithelial-mesenchymal transition (EMT) is characterized by the loss of epithelial markers and the gain of mesenchymal markers. EMT is believed to be a major mechanism supporting cancer cell metastasis. The activation of EMT can be induced by various types of inflammatory cytokines including transforming growth factor β (TGF-β) whereas bone morphogenetic protein-7 (BMP-7) can inhibit this process. In this study, the up-regulation of Twist transcription factor and N-cadherin, mesenchymal marker in CCA tissues, has been demonstrated and it has been found that the high expression of Twist was significantly associated with poor prognosis of CCA patients (P = 0.010). Moreover, CCA samples showing Twist nuclear expression were significantly correlated with the up-regulation of N-cadherin (P = 0.024). These results also showed that the inflammatory mediator TGF-β induces CCA cell migration, one of the metastatic processes possibly via stimulation of Twist, N-cadherin and vimentin expression. Additionally, it has been shown that BMP-7 inhibits TGF-β-induced CCA cell migration, through inhibition of TGF-β-mediated Twist and N-cadherin expressions. These data reinforce the rationale to use BMP-7 as an EMT inhibitor to suppress the progression of CCA and might be a therapeutic approach to improve efficiency for CCA treatment.
These studies demonstrate that TNF-α plays crucial role in the progression of CCA by activating TGF-β signaling and the induction of ZEB2 and S100A4, EMT-related proteins expression.
Cholangiocarcinoma (CCA) is a major
health problem in northeastern
Thailand. The majority of CCA cases are clinically silent and difficult
to detect at an early stage. Although abdominal ultrasonography (US)
can detect premalignant periductal fibrosis (PDF), this method is
not suitable for screening populations in remote areas. With the goal
of developing a blood test for detecting CCA in the at-risk population,
we carried out serum protein biomarker discovery and qualification.
Label-free shotgun proteomics was performed on depleted serum samples
from 30 participants (n = 10 for US-normal, US-PDF,
and CCA groups). Of 40 protein candidates selected using multiple
reaction monitoring on 90 additional serum samples (n = 30 per group), 11 discriminatory proteins were obtained using
supervised multivariate statistical analysis. We further evaluated
3 candidates using ELISA and immunohistochemistry (IHC). S100A9, thioredoxin
(TRX), and cadherin-related family member 2 (CDHR2) were significantly
different between CCA and normal, and CCA and PDF groups when measured
in an additional 247 serum samples (P < 0.0001).
By IHC, TRX and CDHR2 were detected in the cytoplasm and nucleus of
CCA and inflammatory cells. S100A9 was detected in the infiltrating
tumor stroma immune cells. Proteomics discovery and qualification
in depleted sera revealed promising biomarker candidates for CCA diagnosis.
Cholangiocarcinoma (CCA) is a primary malignant tumor of the epithelial lining of biliary track associated with endemic
Opisthorchis viverrini
(Ov) infection in northeastern Thailand. Ov-associated periductal fibrosis (PDF) is the precancerous lesion for CCA, and can be detected by ultrasonography (US) to facilitate early detection. However, US cannot be used to distinguish PDF from cancer. Therefore, the objective of this study was to discover and qualify potential urine biomarkers for CCA detection in at-risk population. Biomarker discovery was conducted on pooled urine samples, 42 patients per group, with PDF or normal bile duct confirmed by ultrasound. After depletion of high abundance proteins, 338 urinary proteins were identified from the 3 samples (normal-US, PDF-US, CCA). Based on fold change and literature review, 70 candidate proteins were selected for qualification by multiple reaction monitoring mass spectrometry (MRM-MS) in 90 individual urine samples, 30 per group. An orthogonal signal correction projection to latent structures discriminant analysis (O-PLS-DA) multivariate model constructed from the 70 candidate biomarkers significantly discriminated CCA from normal and PDF groups (P = 0.003). As an independent validation, the expression of 3 candidate proteins was confirmed by immunohistochemistry in CCA tissues: Lysosome associated membrane glycoprotein 1 (LAMP1), lysosome associated membrane glycoprotein 2 (LAMP2) and cadherin-related family member 2 (CDHR2). Further evaluation of these candidate biomarkers in a larger cohort is needed to support their applicability in a clinical setting for screening and monitoring early CCA and for CCA surveillance.
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