Kim MA, Lee HS, Lee HE, Kim JH, Yang HK, Kim WHPrognostic importance of epithelial-mesenchymal transition-related protein expression in gastric carcinoma. Histopathology 54(4): 442-451

Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
Histopathology (Impact Factor: 3.45). 04/2009; 54(4):442-51. DOI: 10.1111/j.1365-2559.2009.03247.x
Source: PubMed


Epithelial-mesenchymal transition (EMT) is defined as switching of polarized epithelial cells to a migratory fibroblastoid phenotype. EMT is known to be involved in the progression and metastasis of various cancers. The aim was to evaluate the expression of EMT-related proteins in gastric carcinoma (GC).
The expression of nine EMT-related proteins in the GC tissues of 598 patients was evaluated by immunohistochemistry using a tissue array method. In addition, clinicopathological characteristics and survival were compared with the expression of EMT-related proteins. Loss of epithelial protein and/or acquisition of the expression of mesenchymal proteins were observed in GC. These protein alterations were associated with diffuse type histology, advanced stage and poor patient outcome, respectively. Subjects were divided into three groups according to degree of EMT-related protein alteration. Increases in alteration of EMT-related protein were found to be significantly associated with poorly differentiated histology, higher pTNM stage and unfavourable outcome. Multivariate analysis showed that alterations in the expression of EMT-related proteins were independently associated with poor prognosis.
Loss of epithelial proteins and/or the acquisition of mesenchymal proteins are associated with poorly differentiated histology, advanced stage and poor outcome in GC. The awareness and inhibition of EMT offer a promising target for prevention of metastatic progression and invasion.

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    • "Our study suggested EMT-related genes are associated with the process of gastric cancer, consistent with previous researches observing loss of epithelial protein and/or acquisition of the expression of mesenchymal proteins occurred in gastric carcinoma. Furthermore, they were respectively correlated to poorly differentiated histology, advanced stage and poor patient outcome [38]. In addition, PDCD4 is a newly found molecule that plays a vital role on many biological processes that may cause disease or occurrence and development of tumor. "
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    ABSTRACT: Helicobacter pylori, a Gram-negative, microaerophilic bacterium found in the stomach, is assumed to be associated with carcinogenesis, invasion and metastasis in digestive diseases. Cytotoxin-associated gene A (CagA) is an oncogenic protein of H. pylori that is encoded by a Cag pathogenicity island related to the development of gastric cancer. The epithelial-mesenchymal transition (EMT) is the main biological event in invasion or metastasis of epithelial cells. H. pylori may promote EMT in human gastric cancer cell lines, but the specific mechanisms are still obscure. We explored the underlying molecular mechanism of EMT induced by H. pylori CagA in gastric cancer. In our article, we detected gastric cancer specimens and adjacent non-cancerous specimens by immunohistochemistry and found increased expression of the EMT-related regulatory protein TWIST1 and the mesenchymal marker vimentin in cancer tissues, while programmed cell death factor 4 (PDCD4) and the epithelial marker E-cadherin expression decreased in cancer specimens. These changes were associated with degree of tissue malignancy. In addition, PDCD4 and TWIST1 levels were related. In gastric cancer cells cocultured with CagA expression plasmid, CagA activated TWIST1 and vimentin expression, and inhibited E-cadherin expression by downregulating PDCD4. CagA also promoted mobility of gastric cancer cells by regulating PDCD4. Thus, H. pylori CagA induced EMT in gastric cancer cells, which reveals a new signaling pathway of EMT in gastric cancer cell lines.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "The repression of E-cadherin by snail, or other repressors leads indirectly to increase in expression of N-cadherin, vimentin and other mesenchymal gene products. The cells then acquired a more invasive and metastatic phenotype and numerous studies have demonstrated the correlation of EMT activation with poor prognosis including tumor relapse and metastasis [30]–[32]. The findings of this study is consistent with the results obtained in a very recent study by Malenstein et al stating that long-term exposure of HepG2 cells to sorafenib induces sorafenib resistance with enhanced EMT and increased invasive ability [33]. "
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    ABSTRACT: Acquired resistance towards sorafenib treatment was found in HCC patients, which results in poor prognosis. To investigate the enhanced metastatic potential of sorafenib resistance cells, sorafenib-resistant (SorR) cell lines were established by long-term exposure of the HCC cells to the maximum tolerated dose of sorafenib. Cell proliferation assay and qPCR of ABC transporter genes (ABCC1-3) were first performed to confirm the resistance of cells. Migration and invasion assays, and immunoblotting analysis on the expression of epithelial to mesenchymal transition (EMT) regulatory proteins were performed to study the metastatic potential of SorR cells. The expression of CD44 and CD133 were studied by flow cytometry and the gene expressions of pluripotency factors were studied by qPCR to demonstrate the enrichment of cancer stem cells (CSCs) in SorR cells. Control (CTL) and SorR cells were also injected orthotopically to the livers of NOD-SCID mice to investigate the development of lung metastasis. Increased expressions of ABCC1-3 were found in SorR cells. Enhanced migratory and invasive abilities of SorR cells were observed. The changes in expression of EMT regulatory proteins demonstrated an activation of the EMT process in SorR cells. Enriched proportion of CD44(+) and CD44(+)CD133(+) cells were also observed in SorR cells. All (8/8) mice injected with SorR cells demonstrated lung metastasis whereas only 1/8 mouse injected with CTL cells showed lung metastasis. HCC cells with sorafenib resistance demonstrated a higher metastatic potential, which may be due to the activated EMT process. Enriched CSCs were also demonstrated in the sorafenib resistant cells. This study suggests that advanced HCC patients with acquired sorafenib resistance may have enhanced tumor growth or distant metastasis, which raises the concern of long-term sorafenib treatment in advanced HCC patients who have developed resistance of sorafenib.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "EMT was characterized by different regulations of epithelial and mesenchymal genes. The increase of mesenchymal markers vimentin and N-cadherin and the loss of epithelial marker E-cadherin were associated with EMT [2, 3]. Transforming growth factor-β1 (TGF-β1) had been suggested to be an important inducer of EMT in various cancers [4]. "
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    ABSTRACT: MicroRNAs (miRNAs) have been implied to play crucial roles for epithelial-to-mesenchymal transition (EMT) of non-small-cell lung cancer cells (NSCLC cells). Here we found that the expression of miR-149, downregulated in lung cancer, was inversely correlated with invasive capability and the EMT phenotype of NSCLC cells. miR-149 inhibited EMT in NSCLC cells. Furthermore, we demonstrated that miR-149 directly targeted Forkhead box M1 (FOXM1), and FOXM1 was involved in the EMT induced by TGF- β 1 in A549 cells. Overexpression of FOXM1 restored EMT process inhibited by miR-149. Our work suggested that miR-149 might be an EMT suppressor in NSCLC cells.
    Full-text · Article · May 2013 · Biochemistry Research International
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