ZEB1 expression is associated with prognosis of intrahepatic cholangiocarcinoma

2015 ◽  
Vol 69 (7) ◽  
pp. 593-599 ◽  
Author(s):  
Katsumi Terashita ◽  
Makoto Chuma ◽  
Yutaka Hatanaka ◽  
Kanako Hatanaka ◽  
Tomoko Mitsuhashi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Intrahepatic Cholangiocarcinoma ◽  
Poor Prognosis ◽  
Prognostic Indicators ◽  
Vimentin Expression ◽  
Altered Expression ◽  
Mesenchymal Transition ◽  
Related Proteins ◽  
Zeb1 Expression ◽  
E Cadherin

Background/AimIntrahepatic cholangiocarcinoma (ICC) is one of the most aggressive malignant tumours, so the identification of molecular targets for ICC is an important issue. Zinc finger E-box binding homeobox 1 (ZEB1) is a key inducer of epithelial–mesenchymal transition (EMT). The aim of the present study was to clarify the clinical significance of ZEB1 in ICC and the associations between ZEB1 expression and EMT-related proteins.MethodsWe immunohistochemically examined the expression of EMT-related proteins, namely ZEB1, vimentin and E-cadherin, in ICC specimens from 102 patients. The clinicopathological and prognostic values of these markers were evaluated.ResultsZEB1 and vimentin were expressed in 46.1% and 43.1% of tumours, respectively, and E-cadherin expression was lost in 44.1% of tumours. ZEB1 expression showed a significant inverse correlation with E-cadherin expression (p=0.004) and a positive correlation with vimentin expression (p=0.022). Altered expression of ZEB1 was associated with aggressive tumour characteristics, including advanced tumour stage (p=0.037), undifferentiated-type histology (p=0.017), lymph node metastasis (p=0.024) and portal vein invasion (p=0.037). Moreover, overall survival rates were significantly lower for patients with high ZEB1 expression than for patients with low ZEB1 expression (p=0.027). Kaplan–Meier analysis also identified E-cadherin expression (p=0.041) and vimentin expression (p=0.049) as prognostic indicators for overall survival.ConclusionsZEB1 expression is associated with tumour progression and poor prognosis in patients with ICC through positive correlations with vimentin and negative correlations with E-cadherin. ZEB1 expression is associated with a poor prognosis and might be an attractive target for the treatment of ICC.

scholarly journals 925 Utilizing multiplex immunofluorescence to explore the epithelial-mesenchymal transition in breast, ovarian cancers

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A970-A970
Author(s):  
Danielle Fails ◽  
Michael Spencer
Keyword(s):  
Breast Cancer ◽  
Invasive Ductal Carcinoma ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Ductal Carcinoma ◽  
Beta Catenin ◽  
Mesenchymal Transition ◽  
Cell Counts ◽  
Grade Ii ◽  
E Cadherin

BackgroundEpithelial-mesenchymal transition (EMT) is instrumental during embryonic development—assisting in extensive movement and differentiation of cells. However, during metastasis and tumorigenesis, this process is hijacked. The disruption of this developmental process, and subsequent acquisition of a mesenchymal phenotype, has been shown to increase therapeutic resistance and often leads to poor prognosis in breast cancer.1 Using bioinformatic resources and current clinical data, we designed a panel of biomarkers of value to specifically observe this epithelial/mesenchymal transition.MethodsHuman breast cancer FFPE tissue samples were stained with Bethyl Laboratories IHC-validated primary antibodies, followed by Bethyl HRP-conjugated secondary antibodies, and detected using Akoya Opal™ Polaris 7-color IHC kit fluorophores (Akoya Biosciences [NEL861001KT]). The panel consisted of beta-Catenin, E-Cadherin, Ki67, CD3e, PD-L1, and FOXP3. Antibody staining order was optimized using tissue microarray serial sections, three slides per target, and stained in either the first, third, or sixth position via heat-induced epitope retrieval (HIER) methods. Exposure time was maintained for all three slides/target and cell counts, signal intensity, background, and autofluorescence were analyzed. The final optimized order was then tested on the breast cancer microarray in seven-color mIF. Whole slide scans were generated using the Vectra Polaris® and analyses performed using InForm® and R® Studio.ResultsTwo integral EMT targets, E-Cadherin and beta-Catenin, were used to observe a key occurrence in this transition. Under tumorigenic circumstances, when released from the complex they form together (E-cadherin-B-catenin complex), Beta-catenin can induce EMT. This disjunction/activation of EMT can be seen in the invasive ductal carcinoma below (figure 1).The disorganized E-cadherin cells are in direct contrast to normal, non-cancerous cells in similar tissue. Total CD3e cell counts were down (2%), with 35% cells restricted to the stroma vs. the 1% seen intra-tumorally. Coupled with the elevated presence of Ki67 (10%), a level of rapid cancer growth and potential metastasis (Invasive Ductal Carcinoma Grade II) can be observed.Abstract 925 Figure 1Invasive ductal carcinoma, grade II stained with a 6-plex mIF panel designed to show the epithelial-mesenchymal transitionConclusionsThe presence of EMT in breast cancers is often indicative of a poor prognosis, so the need for reliable markers is imperative. E-Cadherin and beta-Catenin are both up-and-coming clinical targets that can serve to outline this transition within the tumor microenvironment. By utilizing these markers in mIF, closer spatial examination of proteins of interest can be achieved. The application of this mIF panel has the potential to provide invaluable insights into how tumor infiltrating lymphocytes behave in cancers exhibiting the hallmarks of EMT.AcknowledgementsWe would like to acknowledge Clemens Deurrschmid, PhD, Technical Applications Scientist Southeast/South Central, Akoya Biosciences for his assistance with image analysis.ReferencesHorne HN, Oh H, Sherman ME, et al. E-cadherin breast tumor expression, risk factors and survival: pooled analysis of 5,933 cases from 12 studies in the breast cancer association consortium. Sci Rep 2018;8:6574.

scholarly journals Peritumoral plasmacytoid dendritic cells predict a poor prognosis for intrahepatic cholangiocarcinoma after curative resection

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zhi-Qiang Hu ◽  
Zheng-Jun Zhou ◽  
Chu-Bin Luo ◽  
Hao-Yang Xin ◽  
Jia Li ◽  
...  
Keyword(s):  
Overall Survival ◽  
Dendritic Cells ◽  
Intrahepatic Cholangiocarcinoma ◽  
Poor Prognosis ◽  
Curative Resection ◽  
Carbohydrate Antigen ◽  
Plasmacytoid Dendritic Cells ◽  
Gamma Glutamyl Transferase ◽  
Advanced Tumor ◽  
Glutamyl Transferase

Abstract Background Plasmacytoid dendritic cells (pDCs) are present in various primary and metastatic human neoplasms; however, their clinical significance in intrahepatic cholangiocarcinoma is not clear. Methods To evaluate pDCs’ distributions in and around tumors as well as their potential function and predictive value for prognosis in patients undergoing curative resection, we performed immunohistochemistry to examine the expression of pDC marker BDCA2, and CD3, CD4, CD8 and Foxp3 in intratumoral and peritumoral tissues from 359 patients with intrahepatic cholangiocarcinoma and compared with prognostic and clinicopathologic factors. Results Results showed that patients with high numbers of BDCA2+ pDCs in peritumoral tissues were more likely to have elevated levels of carbohydrate antigen 19-9 and gamma-glutamyl transferase, larger and more tumors, advanced tumor-node-metastasis staging, more vascular/bile duct invasion, and lymphatic metastasis in association with greater chance of recurrence and shorter overall survival. Peritumoral tissues with larger numbers of pDCs also showed increased Foxp3+ regulatory T cell infiltration, both of which were found to be independent factors for predicting time to recurrence and overall survival. By contrast, patient outcomes were not associated with the presence of intratumoral pDCs. Conclusions Peritumoral pDC infiltration may indicate an immune tolerogenic peritumor microenvironment and can be used to predict a poor prognosis for patients undergoing curative resection for intrahepatic cholangiocarcinoma.

scholarly journals Disruption of Cancer Metabolic SREBP1/miR-142-5p Suppresses Epithelial–Mesenchymal Transition and Stemness in Esophageal Carcinoma

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 7 ◽  
Author(s):  
Chih-Ming Huang ◽  
Chin-Sheng Huang ◽  
Tung-Nien Hsu ◽  
Mao-Suan Huang ◽  
Iat-Hang Fong ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Survival Rate ◽  
Tumor Suppressor ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Regulatory Element ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
E Cadherin

Elevated activity of sterol regulatory element-binding protein 1 (SREBP1) has been implicated in the tumorigenesis of different cancer types. However, the functional roles of SREBP1 in esophageal cancer are not well appreciated. Here, we aimed to investigate the therapeutic potential of SREBP1 and associated signaling in esophageal cancer. Our initial bioinformatics analyses showed that SREBP1 expression was overexpressed in esophageal tumors and correlated with a significantly lower overall survival rate in patients. Additionally, tumor suppressor miR-142-5p was predicted to target SREBP1/ZEB1 and a lower miR-142-5p was correlated with poor prognosis. We then performed in vitro experiments and showed that overexpressing SREBP1 in OE33 cell line led to increased abilities of colony formation, migration, and invasion; the opposite was observed in SREBP1-silenced OE21cells and SREBP1-silencing was accompanied by the reduced mesenchymal markers, including vimentin (Vim) and ZEB1, while E-cadherin and tumor suppressor miR-142-5p were increased. Subsequently, we first demonstrated that both SREBP1 and ZEB1 were potential targets of miR-142-5p, followed by the examination of the regulatory circuit of miR-142-5p and SREBP1/ZEB1. We observed that increased miR-142-5p level led to the reduced tumorigenic properties, such as migration and tumor sphere formation, and both observations were accompanied by the reduction of ZEB1 and SREBP1, and increase of E-cadherin. We then explored the potential therapeutic agent targeting SREBP1-associated signaling by testing fatostatin (4-hydroxytamoxifen, an active metabolite of tamoxifen). We found that fatostatin suppressed the cell viability of OE21 and OE33 cells and tumor spheres. Interestingly, fatostatin treatment reduced CD133+ population in both OE21 and OE33 cells in concert of increased miR-142-5p level. Finally, we evaluated the efficacy of fatostatin using a xenograft mouse model. Mice treated with fatostatin showed a significantly lower tumor burden and better survival rate as compared to their control counterparts. The treatment of fatostatin resulted in the reduced staining of SREBP1, ZEB1, and Vim, while E-cadherin and miR-142-5p were increased. In summary, we showed that increased SREBP1 and reduced miR-142-5p were associated with increased tumorigenic properties of esophageal cancer cells and poor prognosis. Preclinical tests showed that suppression of SREBP1 using fatostatin led to the reduced malignant phenotype of esophageal cancer via the reduction of EMT markers and increased tumor suppressor, miR-142-5p. Further investigation is warranted for the clinical use of fatostatin for the treatment of esophageal malignancy.

scholarly journals Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin

2007 ◽  
Vol 204 (12) ◽  
pp. 2935-2948 ◽  
Author(s):  
Kevin G. Leong ◽  
Kyle Niessen ◽  
Iva Kulic ◽  
Afshin Raouf ◽  
Connie Eaves ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Poor Prognosis ◽  
Epithelial To Mesenchymal Transition ◽  
Breast Tumors ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
Slug Expression ◽  
Tumor Growth And Metastasis ◽  
Notch Activation ◽  
E Cadherin

Aberrant expression of Jagged1 and Notch1 are associated with poor outcome in breast cancer. However, the reason that Jagged1 and/or Notch overexpression portends a poor prognosis is unknown. We identify Slug, a transcriptional repressor, as a novel Notch target and show that elevated levels of Slug correlate with increased expression of Jagged1 in various human cancers. Slug was essential for Notch-mediated repression of E-cadherin, which resulted in β-catenin activation and resistance to anoikis. Inhibition of ligand-induced Notch signaling in xenografted Slug-positive/E-cadherin–negative breast tumors promoted apoptosis and inhibited tumor growth and metastasis. This response was associated with down-regulated Slug expression, reexpression of E-cadherin, and suppression of active β-catenin. Our findings suggest that ligand-induced Notch activation, through the induction of Slug, promotes tumor growth and metastasis characterized by epithelial-to-mesenchymal transition and inhibition of anoikis.

Immunohistochemical analysis of the epithelial to mesenchymal transition in uterine carcinosarcoma

2019 ◽  
Vol 29 (2) ◽  
pp. 277-281
Author(s):  
Mitsumasa Osakabe ◽  
Daisuke Fukagawa ◽  
Chie Sato ◽  
Ryo Sugimoto ◽  
Noriyuki Uesugi ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Immunohistochemical Analysis ◽  
Target Cells ◽  
Uterine Carcinosarcoma ◽  
Mesenchymal Transition ◽  
Significant Difference ◽  
Related Proteins ◽  
Expression Score ◽  
E Cadherin ◽  
Three Components

ObjectiveUterine carcinosarcoma (UCS) is a highly aggressive neoplasm that is composed of an intricate admixture of carcinomatous and sarcomatous elements. The relationship between UCS and the epithelial to mesenchymal transition (EMT) has been reported. In this study, we examined how expression of E-cadherin was associated with the expression of EMT-related proteins in UCS.MethodsUCS samples were histologically divided into three components: carcinomatous, transitional, and sarcomatous regions. Next, we examined the expression of E-cadherin and EMT-related proteins, including SNAI2, ZEB1, and TWIST1, in each component of the UCS using immunohistochemistry. The expression score was determined by combining the staining intensity and staining area of the target cells.ResultsThe expression score of E-cadherin was significantly lower in transitional and sarcomatous components than in the carcinomatous component. In addition, a significant difference in the low expression score of E-cadherin between transitional and sarcomatous components (transitional > sarcomatous components) was found. There were significant differences between the expression scores of ZEB1 in the three components (sarcomatous > transitional > carcinomatous components). However, no difference in the expression of TWIST1 between the components was found. Conversely, the expression level of SNAI2 was higher in sarcomatous or transitional components than in the carcinomatous component. However, a significant difference between the transitional and sarcomatous components was not detected.ConclusionThese results suggest that the EMT plays an essential role in the pathogenesis of UCS.

LncRNA CEACAMP8 Regulates the Proliferation, Invasion and Migration of Trophoblast Cells

2019 ◽  
Vol 9 (9) ◽  
pp. 1215-1221
Author(s):  
Li Jie ◽  
Zhangcai Zheng ◽  
Liping Liu ◽  
Yali Liu ◽  
Zhaoyan Meng ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Flow Cytometry Analysis ◽  
Trophoblast Cells ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Invasion And Migration ◽  
Qpcr Analysis ◽  
And Migration ◽  
E Cadherin

Preeclampsia (PE) is an idiopathic hypertension syndrome occurring after 20 weeks of gestation. Reports showed that lncRNAs expression was abnormal in preeclampsia. We aimed to investigate the role of lncRNA CEACAMP8 in the proliferation, invasion and migration of trophoblast cells to improve the preeclampsia. The cell transfection effects were determined by RT-qPCR analysis. The proliferation, invasion and migration of HTR-8/SVneo cells were detected by CCK-8 assay, transwell assay and wound healing assay. The flow cytometry analysis analyzed the cell cycle. Moreover, the expression of CDK2, cyclinD1, P21, MMP2, MMP9, E-cadherin, b-catenin and vimentin was determined by the western blot analysis. Consequently, CEACAMP8 inhibition promoted the proliferation, invasion and migration of HTR-8/SVneo cells and kept most of the cells in the S phase. The expression of proteins related to the proliferation, invasion and migration of HTR-8/SVneo cells were also changed in accordance with the increase of proliferation, invasion and migration of HTR-8/SVneo cells. In addition, lncRNA CEACAMP8 inhibition decreased the expression of E-cadherin and b-catenin, and increased the vimentin expression to promote the epithelial-mesenchymal transition. And, CEACAMP8 overexpression could reverse the above changes. This study indicated that CEACAMP8 inhibition promoted the proliferation, invasion and migration of HTR-8/SVneo cells and lncRNA CEACAMP8 overexpression reversed.

scholarly journals TAp63α Is Involved in Tobacco Smoke-Induced Lung Cancer EMT and the Anti-cancer Activity of Curcumin via miR-19 Transcriptional Suppression

2021 ◽  
Vol 9 ◽  
Author(s):  
Chunfeng Xie ◽  
Jianyun Zhu ◽  
Xue Yang ◽  
Cong Huang ◽  
Liping Zhou ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tobacco Smoke ◽  
Epithelial Mesenchymal Transition ◽  
Suppressor Gene ◽  
Inhibitory Effect ◽  
Vimentin Expression ◽  
Altered Expression ◽  
Mesenchymal Transition ◽  
Lung Cancer Patients ◽  
Anti Cancer

As a key risk factor for lung cancer, tobacco smoke (TS) influences several cellular processes, including epithelial-mesenchymal transition (EMT). TAp63α is a crucial transcription factor involved in tumor progression. The present study was designed to investigate the potential role and underlying mechanisms of TAp63α in TS-induced lung cancer EMT. We found that compared to normal tissues, the tumor tissues collected from lung cancer patients showed a lower level of TAp63α expression, along with downregulated E-cadherin expression and upregulated Vimentin expression. Results of treatment with TAp63α and TAp63α siRNA as well as with tumor growth factor-β (TGF-β) showed that TAp63α acted as a tumor suppressor gene, and its upregulated expression suppressed lung cancer EMT. Significantly, TS exposure altered expression of EMT-related markers, enhanced cell migratory and invasive capacities, and decreased the TAp63α expression level in lung cancer cells. Overexpression of TAp63α significantly alleviated TS-stimulated lung cancer EMT. Mechanistically, TAp63α expression transcriptionally reduced the miR-19 level, which resulted in the suppression of lung cancer EMT. Additionally, as a natural compound possessing anti-cancer effects, curcumin inhibited TS-induced lung cancer EMT by increasing TAp63α expression and reducing miR-19 expression. Collectively, our results indicate that TAp63α inhibits TS-induced lung cancer EMT via transcriptionally suppressing miR-19 and the inhibitory effect of TAp63α on miR-19 mediates the anti-cancer action of curcumin. These findings provide new insights into novel targets for lung cancer prevention.

scholarly journals Human Peripheral Blood-derived Mast Cells Contribute to Epithelial to Mesenchymal Transition in Bronchial Epithelial Cells in the Presence of IL-1β

2020 ◽  
Author(s):  
Xian-Song Wang ◽  
Li Xie ◽  
Kaiyu Zheng
Keyword(s):  
Mast Cells ◽  
Peripheral Blood ◽  
Epithelial To Mesenchymal Transition ◽  
Human Peripheral Blood ◽  
Cell Junctions ◽  
Vimentin Expression ◽  
Bronchial Epithelial ◽  
Mesenchymal Transition ◽  
Tgf Β1 ◽  
E Cadherin

Abstract Background: Bronchial epithelial to mesenchymal transition （EMT）is an important mechanism for the airway remodeling in asthmatics. Mast cell is one of the critical effector cells in pathogenesis of asthma. Although mast cells have been shown to release a plethora of pro-fibrotic factors with the potential to induce EMT, it is not clear whether mast cells also directly have an impact on the bronchial EMT. In this study, we investigated the contribution of human mast cells to EMT in human bronchial epithelial cell line 16-HBE. Methods: Human peripheral blood-derived mast cells were co-cultured with 16-HBE cells. The protein and mRNA expression of E-cadherin and vimentin in 16-HBE cells were analyzed by Western blot and quantitative real-time PCR. A scratch wound assay was performed to evaluate the migratory properties of the 16-HBE cells.Results: Mast cells alone failed to produce significant effects on the epithelial morphology, mobility, and expression of E-cadherin and vimentin. However, mast cells in combination of interleukin (IL)-1β significantly decreased E-cadherin expression but increased vimentin expression in the co-cultured 16-HBE cells, which exhibited a spindle-like appearance with reduced cell junctions and enhanced migration. The down-regulation of E-cadherin expression and up-regulation of vimentin expression were not abrogated by the transforming growth factor (TGF)-β1 neutralizing antibody.Conclusion: Mast cells combined with IL-1β, not mast cells alone, were able to induce EMT in 16-HBE cells through a TGF-β1-independent mechanism. The results of in vitro culture suggest the possibility that mast cells contribute to human bronchial epithelial EMT in the asthmatic airway tissues with high level of IL-1β.

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