CD146 Expression Correlates with Epithelial-Mesenchymal Transition Markers and a Poor Prognosis in Gastric Cancer
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CD146 has been regarded as a novel potential therapeutic target for multiple cancers. The aim of the study was to investigate the expression of CD146 in gastric cancer and evaluate its clinical-pathological and prognostic significance. The expression of CD146 and three epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, β-catenin and vimentin) was examined in 144 gastric cancers by immunohistochemistry. Fifty-nine cases (41.0%) were defined as positive for CD146 expression. We found that CD146 expression correlated positively with lymph node involvement and a poor prognosis, and retained an independent prognostic factor for gastric cancer patients. Furthermore, positive expression of CD146 was strongly associated with loss of the epithelial marker E-cadherin and acquisition of the expression of the mesenchymal markers nuclear β-catenin and vimentin. These findings suggest that CD146 might promote EMT and progression in gastric cancer, and thus may be a potential therapeutic target for patients with gastric cancers.Keywords:
CD146
Purpose: Epithelial mesenchymal transition (EMT) is a well characterized embryological process thought to play a vital role in tumor progression. The purpose of this study was to evaluate the expression of EMT-related factors and then use EMT status to identify high metastatic potential in commonly used human colorectal cancer cell lines. Methods: In 11 commonly used cell lines, total mRNA expression levels were checked for the cell markers E- cadherin, vimentin, N-cadherin, and fibronectin, and the transcription factors snail, slug, twist, and SIP1 using real time PCR. Results: E-cadherin expression was positive in COLO205, DLD1, and SW48 cell lines. Vimentin expression was positive in COLO205, DLD1, HCT15, KM20, and SW480. Three different EMT status groups were defined according to mRNA expression of the cell markers. The epithelial phenotype expressed E-cadherin without vimentin (SW48), incomplete EMT phenotypes either concurrently expressed or did not express both E-cadherin and vimentin (CACO2, COLO205, DLD1, KM12C, KM12SM, LoVo, and RKO), and complete EMT phenotypes expressed vimentin without E-cadherin (HCT15, KM20, and SW480). The mRNA expression of transcription factors had no correlation with expression of vimentin, N-cadherin, and fibronectin, but there was an inverse directional correlation between mRNA expression levels of transcription factors and E-cadherin. There were no statistically significant correlations, however. Conclusion: Ten cell lines among the 11 were included in the incomplete and complete EMT groups. These findings could provide evidence of the high tumorigenesis and metastatic properties. The levels of mRNA expression and EMT status of human colorectal cancer cell lines can be applied to further investigations into cancer progression. Keywords: Epithelial mesenchymal transition, Colorectal cancer, Cell line
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Objective: To investigate the role of TGF-β1 on Epithelial Mesenchymal Transition (EMT) and invasion ability in human bladder cancer cell line T24.
Methods: After pre-treatment with TGF-β1 of different concentrations for 24 h, we observed the morphological changes of T24 cells under phase-contrast microscopy. The mRNA and protein expression levels of EMT relative marker E-cadherin and Vimentin were detected by RT-PCR and Western blot. The effect of TGF-β1 on migration and invasion abilities of T2 cell line was detected with transwell migration and invasion assay.
Results: Results demonstrated that TGF-β1 could induce epithelial-mesenchymal transition in T24 cells. The mRNA and protein levels of epithelial marker E-cadherin were downregulated by TGF-β1, whereas those of mesenchymal maker protein Vimentin were upregulated. Furthermore, it is noted that TGF-β1 could significantly enhance the migration and invasion ability of T24 cells, which, however, could be effectively reversed by TGF-β1 inhibitor LY2109761.
Conclusion: TGF-β1 can enhance migration and invasion ability of T24 cells by inducing epithelial mesenchymal transition.
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Epithelial mesenchymal transition (EMT) is a biological process in which epithelial cells undergo extensive molecular reprogramming allowing these cells to undergo numerous biochemical changes and acquire a mesenchymal phenotype. This is accompanied by progressive loss of epithelial markers, gain in migratory potential and invasiveness, and enhanced capacity to produce extracellular matrix components. The digestion of underlying basement membrane facilitates the process of EMT and the fragmented anatomical appearance of the reticular basement membrane (Rbm) has been reported as a marker of completion of the process. EMT is considered critical during cancer metastasis and fibrosis. The intermediate filament protein vimentin is also an important marker of EMT and increases in abundance in epithelial cells undergoing EMT. It is also seen in tumour invasion, suggesting a particular role in cell migration. Vimentin has been most commonly used as marker to identify cells undergoing EMT in cancers; a positive correlation has been reported between vimentin and increased metastatic potential in breast cancer. This chapter reviews these issues, and highlights recent advances in understanding the role of vimentin in EMT as part of disease processes.
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Abstract The process of epithelial mesenchymal transition, whereby cells acquire molecular alterations and fibroblastic features, is a fundamental process of embryogenesis and cancer invasion/metastasis. The mechanisms responsible for epithelial mesenchymal transition remain elusive. Human tumors frequently establish constitutively activated RAS signaling, which contributes to the malignant phenotype. In an effort to dissect distinct RAS isoform specific functions, we previously established human colon cell lines stably overexpressing activated Harvey‐RAS (Ha‐RAS) and Kirsten‐RAS (Ki‐RAS). Using these, we observed that only oncogenic Ha‐RAS overexpression resulted in morphologic and molecular changes suggestive of epithelial to mesenchymal transition. We showed that vimentin, a key molecule of epithelial mesenchymal transition, was differentially regulated between Ha‐RAS and Ki‐RAS leading to a Ha‐RAS specific induction of a migrative phenotype and eventually epithelial to mesenchymal transition. We demonstrated that the AP‐1 sites in vimentin promoter could be involved in this regulation. A potential role of FRA‐1 was suggested in the regulation of vimentin during the Ha‐RAS‐induced epithelial to mesenchymal transition, in association with colon cell migration. Our results therefore propose that in colon cells, the induction of epithelial mesenchymal transition by oncogenic Ha‐RAS could occur through the overexpression of proteins like FRA‐1 and vimentin. © 2007 Wiley‐Liss, Inc.
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Objective To investigate the impact of migration inhibitory factor (MIF) over-expression on the epithelial to mesenchymal transition in human cervical cancer SiHa cells.Methods Recombinant plasmid pEGFP-N1-MIF was transfected into SiHa cells,and then of MIF mRNA relative quantitative expression was tested by RT-PCR.The mRNA and protein expression level of E-cadherin and vimentin were detected by RT-PCR and immunocytochemistry,respectively.Results RT-PCR results showed that MIF mRNA expression quantity in experimental group was higher than that in control group cells (F =2 950.278,P ＜ 0.01).In MIF-overexpressing SiHa cells,vimentin mRNA was increased and E-cadherin mRNA was decreased determined by RT-PCR (Fvalues were 2 135.048,1 893.563,P＜ 0.01).Immunocytochemistry results showed that vimentin expression quantity in experimental group cells were higher than that in control group cells,however,E-cadherin expression quantity was lower than that in control group cells (F values were 2 348.021,1 789.421,P ＜ 0.01).Conclusions The over-expression of MIF gene can significantly up-regulate the expression of vimentin,and down-regulate the expression of E-cadherin.Consequently,MIF over-expression induces epithelial to mesenchymal transition in human cervical cancer SiHa cells.
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Macrophage migration inhibitory factor; Epithelial-mesenchymal transition; Cervical cancer; E-cadherin; vimentin
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Mesenchymal stromal/stem cells (MSCs) constitute a promising tool in regenerative medicine and can be isolated from different human tissues. However, their biological properties are still not fully characterized. Whereas MSCs from different tissue exhibit many common characteristics, their biological activity and some markers are different and depend on their tissue of origin. Understanding the factors that underlie MSC biology should constitute important points for consideration for researchers interested in clinical MSC application.To characterize the biological activity of MSCs during longterm culture isolated from: bone marrow (BM-MSCs), adipose tissue (AT-MSCs), skeletal muscles (SM-MSCs), and skin (SK-MSCs).MSCs were isolated from the tissues, cultured for 10 passages, and assessed for: phenotype with immunofluorescence and flow cytometry, multipotency with differentiation capacity for osteo-, chondro-, and adipogenesis, stemness markers with qPCR for mRNA for Sox2 and Oct4, and genetic stability for p53 and c-Myc; 27 bioactive factors were screened using the multiplex ELISA array, and spontaneous fusion involving a co-culture of SM-MSCs with BM-MSCs or AT-MSCs stained with PKH26 (red) or PKH67 (green) was performed.All MSCs showed the basic MSC phenotype; however, their expression decreased during the follow-up period, as confirmed by fluorescence intensity. The examined MSCs express CD146 marker associated with proangiogenic properties; however their expression decreased in AT-MSCs and SM-MSCs, but was maintained in BM-MSCs. In contrast, in SK-MSCs CD146 expression increased in late passages. All MSCs, except BM-MSCs, expressed PW1, a marker associated with differentiation capacity and apoptosis. BM-MSCs and AT-MSCs expressed stemness markers Sox2 and Oct4 in long-term culture. All MSCs showed a stable p53 and c-Myc expression. BM-MSCs and AT-MSCs maintained their differentiation capacity during the follow-up period. In contrast, SK-MSCs and SM-MSCs had a limited ability to differentiate into adipocytes. BM-MSCs and AT-MSCs revealed similarities in phenotype maintenance, capacity for multilineage differentiation, and secretion of bioactive factors. Because AT-MSCs fused with SM-MSCs as effectively as BM-MSCs, AT-MSCs may constitute an alternative source for BM-MSCs.Long-term culture affects the biological activity of MSCs obtained from various tissues. The source of MSCs and number of passages are important considerations in regenerative medicine.
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Anaplastic thyroid cancer (ATC) remains a cancer with one of the worst prognoses, despite novel targeted therapies. The median survival rate has not improved for decades. Epithelial‑to‑mesenchymal transition (EMT) is a crucial step in physiological processes and in cancer progression, but the underlying mechanisms are not yet fully understood. The current study examined the role of microRNA (miR)‑200b in mesenchymal‑to‑epithelial transition in ATC. Total RNA and miR isolation were performed from ATC cell lines transfected with a miR‑200b mimic. After miR‑200b mimic transfection, expression levels of E‑cadherin, vimentin and zinc finger E‑box binding homeobox 1 (ZEB1) were confirmed by reverse transcription‑quantitative PCR and western blotting. Additionally, cell migration was evaluated using miR‑200b mimic and scrambled negative control‑transfected cells. A total of 14 human ATC and 15 non‑cancerous human thyroid tissues were immunohistochemically stained and scored as controls for E‑cadherin, vimentin and ZEB1. In ATC tissues and cell lines, the mesenchymal marker ZEB1 was significantly upregulated and the epithelial marker E‑cadherin was significantly downregulated. Additionally, the mesenchymal marker vimentin was significantly upregulated in ATC tissues and in one ATC cell line. MiR‑200b mimic transfection significantly increased vimentin and ZEB1 expression, but E‑cadherin expression remained below the measurement sensitivity. Furthermore, miR‑200b overexpression decreased cell migration. The current study suggested that miR‑200b may regulate the expression levels of mesenchymal markers such as vimentin and ZEB1 in ATC and may promote mesenchymal‑to‑epithelial transition.
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To summarize the expression and role of CD146 in mesenchymal stem cells (MSCs).The literature related to CD146 at home and abroad were extensively consulted, and the CD146 expression in MSCs and its function were summarized and analyzed.CD146 is a transmembrane protein that mediates the adhesion of cells to cells and extracellular matrix, and is expressed on the surface of various MSCs. More and more studies have shown that CD146 + MSCs have superior cell properties such as greater proliferation, differentiation, migration, and immune regulation abilities than CD146 - or unsorted MSCs, and the application of CD146 + MSCs in the treatment of specific diseases has also achieved better results. CD146 is also involved in mediating a variety of cellular signaling pathways, but whether it plays the same role in MSCs remains to be demonstrated by further experiments.The utilization of CD146 + MSCs for tissue regeneration will be conducive to improving the therapeutic effect of MSCs.总结 CD146 在 MSCs 中的表达情况及作用。.广泛查阅国内外 CD146 相关研究文献，对其在 MSCs 中的表达情况及作用进行总结分析。.CD146 是一种介导细胞间或细胞与细胞外基质间黏附的跨膜蛋白，表达于多种 MSCs 表面。越来越多研究表明，CD146 + MSCs 比 CD146 - MSCs 或未分选 MSCs 具有更加优良的细胞特性，如更强的增殖、分化、迁移和免疫调节等能力。应用 CD146 + MSCs 治疗特定疾病也获得了更佳效果。CD146 还参与介导多种细胞信号通路，但其在 MSCs 中是否发挥同样的作用还需进一步实验证明。.利用 CD146 + MSCs 进行组织和器官损伤修复将有利于提高 MSCs 的治疗效果。.
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Lysine-specific demethylase 1 (LSD1), which specifically demethylates histone H3 lysine 4 (H3K4) and lysine 9 (H3K9), is dysregulated in several cancers. We found that ectopic expression of LSD1 in cervical cancer cells promoted invasion and metastasis in vitro and in vivo, reduced the expression of the epithelial marker E-cadherin, and induced the expression of the mesenchymal marker, Vimentin. By contrast, LSD1 knockdown had the opposite effect and attenuated the HPV16 E7-induced epithelial-mesenchymal transition (EMT). We proposed a novel mechanism, whereby LSD1 is recruited to the Vimentin promoter and demethylates H3K4me1 and H3K4me2. Notably, HPV16 E7 enhanced the expression of LSD1, formed a complex with LSD1, and suppressed LSD1 demethylase activity by hindering the recruitment of LSD1 to the Vimentin promoter. Thus, LSD1 is a primary and positive regulator of the HPV16 E7-induced EMT and an attractive therapeutic target for alleviating HPV16 E7-induced EMT and tumor metastasis.
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