Bone morphogenetic protein-6 suppresses TGF-β_(2)-induced epithelial-mesenchymal transition in retinal pigment epithelium

AIM:To evaluate the effect of bone morphogenetic protein-6(BMP-6)on transforming growth factor(TGF)-β_(2)-induced epithelial-mesenchymal transition(EMT)in retinal pigment epithelium(RPE).METHODS:Adult retinal pigment epithelial cell line(ARPE-19)were randomly divided into control,TGF-β_(2)(5μg/L),and BMP-6 small interfering RNA(siRNA)group.The cell morphology was observed by microscopy,and the cell migration ability were detected by Transwell chamber.The EMT-related indexes and BMP-6 protein levels were detected by Western blotting.Furthermore,a BMP-6 overexpression plasmid was constructed and RPE cells were divided into the control group,TGF-β_(2)+empty plasmid group,BMP-6 overexpression group,and TGF-β_(2)+BMP-6 overexpression group.The EMT-related indexes and extracellular regulated protein kinases(ERK)protein levels were detected.RESULTS:Compared with the control group,the migration of RPE cells in the TGF-β_(2) group was significantly enhanced.TGF-β_(2) increased the protein expression levels ofα-smooth muscle actin(α-SMA),fibronectin and vimentin but significantly decreased the protein levels of E-cadherin and BMP-6(P<0.05)in RPE.Similarly,the migration of RPE cells in the BMP-6 siRNA group was also significantly enhanced.BMP-6 siRNA increased the protein expression levels ofα-SMA,fibronectin and vimentin but significantly decreased the protein expression levels of E-cadherin(P<0.05).Overexpression of BMP-6 inhibited the migration of RPE cells induced by TGF-β_(2) and prevented TGF-β_(2) from affecting EMT-related biomarkers(P<0.05).CONCLUSION:BMP-6 prevents the EMT in RPE cells induced by TGF-β_(2),which may provide a theoretical basis for the prevention and treatment of proliferative vitreoretinopathy.

Role of reactive oxygen species in epithelial-mesenchymal transition and apoptosis of human lens epithelial cells

AIM:To investigate the role of reactive oxygen species(ROS)in epithelial–mesenchymal transition(EMT)and apoptosis of human lens epithelial cells(HLECs).METHODS:Flow cytometry was used to assess ROS production after transforming growth factorβ2(TGF-β2)induction.Apoptosis of HLECs after H_(2)O_(2) and TGF-β2 interference with or without ROS scavenger N-acetylcysteine(NAC)were assessed by flow cytometry.The corresponding protein expression levels of the EMT markerα-smooth muscle actin(α-SMA),the extracellular matrix(ECM),marker fibronectin(Fn),and apoptosis-associated proteins were detected by using Western blotting in the presence of an ROS scavenger(NAC).Wound-healing and Transwell assays were used to assess the migration capability of HLECs.RESULTS:TGF-β2 stimulates ROS production within 8h in HLECs.Additionally,TGF-β2 induced HLECs cell apoptosis,EMT/ECM synthesis protein markers expression,and pro-apoptotic proteins production;nonetheless,NAC treatment prevented these responses.Similarly,TGF-β2 promoted HLECs cell migration,whereas NAC inhibited cell migration.We further determined that although ROS initiated apoptosis,it only induced the accumulation of the EMT markerα-SMA protein,but not COL-1 or Fn.CONCLUSION:ROS contribute to TGF-β2-induced EMT/ECM synthesis and cell apoptosis of HLECs;however,ROS alone are not sufficient for EMT/ECM synthesis.

Cross-talk between microRNA-let7c and transforming growth factor-β2 during epithelial-to-mesenchymal transition of retinal pigment epithelial cells

AIM: To explore the roles of microRNA-let7 c(miR-let7 c) and transforming growth factor-β2(TGF-β2) and cellular signaling during epithelial-to-mesenchymal transition(EMT) of retinal pigment epithelial cells. METHODS: Retinal pigment epithelial(ARPE-19) cells were cultured with no serum for 12 h, and then with recombinant human TGF-β2 for different lengths of time. ARPE-19 cells were transfected with 1×106 TU/mL miR-let7 c mimcs(miR-let7 cM), miR-let7 c mimcs negative control(miR-let7cMNC) and miR-let7 c inhibitor(miR-let7 cI) using the transfection reagent. The expression of keratin-18, vimentin, N-cadherin, IKB alpha, p65 were detected by Western blot, quantitative polymerase chain reaction and immunofluorescence. RESULTS: The expression of miR-let7c was dramatically reduced and the nuclear factor-kappa B(NF-κB) signaling pathway was activated after induction by TGF-β2(P<0.05). In turn, overexpressed miR-let7 c significantly inhibited TGF-β2-induced EMT(P<0.05). However, miR-let7 c was unable to inhibit TGF-β2-induced EMT when the NF-κB signaling pathway was inhibited by BAY11-7082(P<0.01). CONCLUSION: The miR-let7 c regulates TGF-β2-induced EMT through the NF-κB signaling pathway in ARPE-19 cells.

Erbin Interacts with Sema4C and Inhibits Sema4C-induced Epithelial-mesenchymal Transition in HK2 Cells

Erbin, a member of Leucine-rich repeat and PDZ-containing protein family, was found to inhibit TGF-β-induced epithelial-mesenchymal transition （EMT） in our previous study. However, the mechanism of Erbin in regulating EMT is unclear. Semaphorin protein Sema4C, with PDZ binding site at C-terminal has been recognized as a positive regulator of EMT. Here, we aimed to examine the inter- action between Erbin and Sema4C. HK2 cells were treated with TGF-β1, or transfected with Erbin and （or） Sema4C. Interaction of Erbin and Sema4C was identified by immunoprecipitation. RT-PCR was used to detect the expression of Erbin and Sema4C at mRNA level after transfection. The expression levels of Erbin, Sema4C, and markers of EMT were measured by using Western blotting or ELISA. Af- ter HK2 cells were stimulated with 10 ng/mL TGF-β1 for 72 h, the protein expression levels of Erbin and Sema4C were both up-regulated, and immunoprecipitation results showed Erbin interacted with Sema4C in HK2 cells both at endogenous and exogenous levels. Furthermore, overexpression of Sema4C suppressed E-cadherin, induced vimentin and promoted fibronectin secretion, indicating Sema4C promotes the process of EMT. However, HK2 cells overexpressing Erbin were resistant to Sema4C-induced EMT. In contrast, Erbin specific siRNA promoted EMT induced by Sema4C. Taken together, these results suggest that Erbin can interact with Sema4C, and co-expression of Erbin blocks the process of Sema4C-induced EMT.

In vitro inhibition of proliferation,migration and epithelial-mesenchymal transition of human lens epithelial cells by fasudil

AIM： To study the potential role of fasudil as a treatment for posterior capsular opacification（PCO） of the human crystalline lens.METHODS： Human lens epithelial cells（HLECs; line SRA01/04） was exposed to transforming growth factor-β2（TGF-β2） to induce the process of epithelial-mesenchymal transition（EMT）. Fasudil was applied to the cell samples. Its effect on overall HLECs proliferation and migration was studied, as was its influence on EMT induction by TGF-β2 using cell migration assay, MTT colorimetric assay and Western blot assay.RESULTS： Fasudil inhibited the proliferation of SRA01/04. Its effect was time-and concentration-dependent. The migration of SRA01/04 cells was significantly reduced 24-72 h after fasudil treatment, and the half maximal inhibitory concentration（IC50） was 22.37 μmol/mL at 72 h. Reversal of the elongated, fibroblast-like shape changes induced by TGF-β2 in SRA01/04 cells was observed. Fasudil up-regulated the expression of Connexin43 protein and down-regulated the expression of α-SMA protein compared with the cells treated with TGF-β2. Furthermore, when exposed to fasudil, the phosphorylation of Rhoassociated protein kinase（Rock） and myosin light chain（MLC） could not be activated in the cell preparations.CONCLUSION： Fasudil suppresses the proliferation and migration of SRA01/04 cells, and inhibits the process of EMT induced by TGF-β2. These results suggest that fasudil may serve as a therapeutic agent for PCO.

Dexmedetomidine Attenuates High Glucose-induced HK-2 Epithelial-mesenchymal Transition by Inhibiting AKT and ERK

Objective To explore the protective effects of dexmedetomidine(Dex)against high glucose-induced epithelial-mesenchymal transition in HK-2 cells and relevant mechanisms.Methods HK-2 cells were exposed to either glucose or glucose+Dex for 6 h.The production of ROS,morphology of HK-2 cells,and cell cycle were detected.Moreover,the expression of AKT,p-AKT,ERK,pERK,PI3 K,E-Cadherin,Claudin-1,andα-SMA were determined and compared between HK-2 cells exposed to glucose and those exposed to both glucose and Dex with or without PI3 K/AKT pathway inhibitor LY294002 and ERK pathway inhibitor U0126.Results Compared with HK-2 cells exposed to high level of glucose,the HK-2 cells exposed to both high level of glucose and Dex showed:(1)lower level of ROS production;(2)cell morphology was complete;(3)more cells in G1 phase;(4)lower expression of p-AKT,p-ERK andα-SMA,higher expression of ECadherin and Claudin-1.PI3 K/AKT inhibitor LY294002 and ERK inhibitor U0126 decreased the expression of p-AKT,p-ERK andα-SMA,and increased the expression of E-Cadherin and Claudin-1.Conclusion Dex can attenuate high glucose-induced HK-2 epithelial-mesenchymal transition by inhibiting AKT and ERK.

Evaluation of epithelial-mesenchymal transitioned circulating tumor cells in patients with resectable gastric cancer: Relevance to therapy response

AIM: To evaluate the epithelial-to-mesenchymal transition(EMT) of circulating tumor cells(CTCs) in gastric cancer patients.METHODS: We detected tumor cells for expression of four epithelial(E^+) transcripts(keratins 8, 18, and 19 and epithelial cell adhesion molecule) and two mesenchymal(M^+) transcripts(Vimentin and Twist) by a quantifiable, dual-colorimetric RNA-in situ hybridization assay. Between July 2014 and October 2014, 44 patients with gastric cancer were recruited for CTC evaluation. Blood samples were obtained from selected patients during the treatment course [before surgery, after surgery and at the 6^(th) cycle of XELOX based chemotherapy(about 6 mo postoperatively)].RESULTS: We found the EMT phenomenon in which there were a few biphenotypic E^+/M^+ cells in primary human gastric cancer specimens. Of the 44 patients, the presence of CTCs was reported in 35(79.5%) patients at baseline. Five types of cells including from exclusively E^+ CTCs to intermediate CTCs and exclusively M^+ CTCs were identified(4 patients with M^+ CTCs and 10 patients with M^+ or M^+ > E^+ CTCs). Further, a chemotherapy patient having progressive disease showed a proportional increase of mesenchymal CTCs in the post-treatment blood specimens. We used NCI-N87 cells to analyze the linearity and sensitivity of Can Patrol^(TM) system and the correlation coefficient(R^2) was 0.999.CONCLUSION: The findings suggest that the EMT phenomenon was both in a few cells of primary tumors and abundantly in CTCs from the blood of gastric cancer patients, which might be used to monitor therapy response.

Proteinase-activated receptor 2 promotes tumor cell proliferation and metastasis by inducing epithelialmesenchymal transition and predicts poor prognosis in hepatocellular carcinoma

AIM To clarify the role of proteinase-activated receptor 2(PAR2) in hepatocellular carcinoma, especially in the process of metastasis.METHODS PAR2 expression levels were assessed by qRT-PCR and immunohistochemistry(IHC) in patient tissues and in hepatocellular carcinoma cell lines SMMC-7721 and Hep G2. Cell proliferation and metastasis were assessed both in vitro and in vitro. Immunoblotting was carried out to monitor the levels of mitogen-activated protein kinase(MAPK) and epithelial-mesenchymal transition markers.RESULTS The prognosis was significantly poorer in patients with high PAR2 levels than in those with low PAR2 levels. Patients with high PAR2 levels had advanced tumor stage(P = 0.001, chi-square test), larger tumor size(P = 0.032, chi-square test), and high microvascular invasion rate(P = 0.037, chi-square test). The proliferation and metastasis ability of SMMC-7721 and Hep G2 cells was increased after PAR2 overexpression, while knockdown of PAR2 decreased the proliferation and metastasis ability of SMMC-7721 and Hep G2 cells. Knockdown of PAR2 also inhibited hepatocellular carcinoma tumor cell growth and liver metastasis in nude mice. Mechanistically, PAR2 increased the proliferation ability of SMMC-7721 and Hep G2 cells via ERK activation. Activated ERK further promoted the epithelial-mesenchymal transition of these cells, which endowed them with enhanced migration and invasion ability. CONCLUSION These data suggest that PAR2 plays an important role in the proliferation and metastasis of hepatocellular carcinoma. Therefore, targeting PAR2 may present a favorable target for treatment of this malignancy.

Roles of Rho/Rock Signaling Pathway in Silica-induced Epithelial-mesenchymal Transition in Human Bronchial Epithelial Cells

Objective To investigate the roles of Rho/Rock signaling pathway in silica-induced Epithelial-mesenchymal transition （EMT） in human bronchial epithelial cells （BEC） in vitro. Methods Human BEC were incubated with silica with various concentrations for indicated times. Cell viability was assayed by MTT test. Morphologic Changes were observed by microscope. Mesenchymal marker a-smooth muscle actin （a-SMA）, vimentin （Vim）, and epithelial marker E-cadherin （E-cad） were analyzed by Western Blot. The pull-down assay was used to measure Rho activity. In the prevention experiments, the specific inhibitor for Rho effector ROCK （Y27632） was used to inhibit the activity of Rho. Results Human BEC stimulated with silica were converted from a ＂cobblestone＂ epithelial structure into an elongated fibroblast-like shape structure. Incubation of human BEC with silica induced de novo expression of a-SMA and Vim, and loss of E-cad. Also, silica treatment resulted in Rho activation in human BEC. Y27632 up-regulated the E-cad expression but attenuated a-SMA and Vim expression in silica-stimulated cells. Conclusion The activation of Rho/ROCK signaling pathways is most likely involved in Silica-induced EMT in human bronchial epithelial cells.

Side Population Cells in Human Gallbladder Cancer Cell Line GBC-SD Regulated by TGF-β-induced Epithelial-mesenchymal Transition

Mounting evidence has shown that side population （SP） cells are enriched for cancer stem cells （CSCs） responsible for cancer malignancy. In this study, SP technology was used to isolate a small subpopulation of SP cells in human gallbladder cancer cell line GBC-SD, and SP cells which had superior potential for proliferation in vitro and tumorigenesis in vivo were identified. Importantly, the abundance of GBC-SD SP cells was increased by a transforming growth factor-β （TGF-β）-induced epithelial-mesenchymal transition （EMT）, and this effect was accompanied with a strong up-regulation of ABCG2 mRNA expression, and a decreased sensitivity to mitoxantrone. SP cells were restored upon the removal of TGF-β and the reversion of the cells to an epithelial phenotype, and smad3-specific siRNA reduced SP abundance in response to TGF-β. In conclusion, TGF-β-induced EMT by smad-dependent signaling pathway promotes cancer development and anti-cancer drug resistant phenotype by augmenting the abundance of GBC-SD SP cells, and a better understanding of mechanisms involved in TGF-β-induced EMT may provide a novel strategy for preventing cancer progression.

Expression of transcription factors Slug in the lens epithelial cells undergoing epithelial-mesenchymal transition induced by connective tissue growth factor

AIMTo investigate the expression of transcription factors Slug in human lens epithelial cells (HLECs) undergoing epithelial-mesenchymal transition (EMT) induced by connective tissue growth factor (CTGF).METHODSHLECs were treated with CTGF of different concentrations (20, 50 and 100 ng/mL) or without CTGF (control) for 24h. The morphological changes of HLECs were analysed by microscopy. The expression and cellular localization of Slug was evaluated by immumo-fluorescence. Expressions of Slug, E-cadherin and alpha smooth muscle actin (&#x003b1;-SMA) were further determined by Western blot analysis.RESULTSHLECs showed spidle fibrolasts-like characteristics and loosely connected each other after CTGF treatment. The immuno-fluorescence staining indicated that Slug was localized in the nuclei and its expression was induced by CTGF. The relative expressions of Slug protein were 1.64&#x000b1;0.11, 1.96 &#x000b1;0.03, 3.12 &#x000b1;0.10, and 4.08&#x000b1;0.14, respectively, in response to control group and treatment with CTGF of 20, 50 and 100 ng/mL (F=443.86, P&#x0003c;0.01). The increased Slug protein levels were correlated well with up-expression of &#x003b1;-SMA (0.78&#x000b1;0.05, 0.85&#x000b1;0.06, 2.17&#x000b1;0.15, 2.86&#x000b1;0.10; F=449.85, P&#x0003c;0.01) and down-expression of E-cadherin (2.50&#x000b1;0.11, 1.79&#x000b1;0.26, 1.05&#x000b1;0.14, 0.63&#x000b1;0.08; F=101.55, P&#x0003c;0.01).CONCLUSIONTranscription factor Slug may be involved in EMT of HLECs induced by CTGF in vitro.

EDIL3 depletion suppress epithelial-mesenchymal transition of lens epithelial cells via transforming growth factor β pathway

AIM： To study the effect of discoidin I-like domaincontaining protein 3（EDIL3） depletion on the proliferation and epithelial-mesenchymal transition（EMT） in human lens epithelial cells（LECs）. METHODS： RNA interference was used to inhibit the expression of EDIL3 in human LECs in vitro. The morphology of cells was observed using an inverted microscope. Cell proliferation was assessed using Ed U kit. Cell migration was investigated using Transwell chamber and EMT of LECs was assessed using confocal microscope and Western blotting. The transforming growth factor β（TGFβ） pathway was investigated using Western blotting. RESULTS： The data showed that silencing EDIL3 expression changed LECs morphology and suppressed LECs proliferation（P〈0.05） and migration（P〈0.01）. Furthermore, the result of Western blotting showed that EDIL3 depletion reduced the expression of α-smooth muscle actin（α-SMA）（P〈0.001） and vimentin（P〈0.01）, while increased the expression of E-cadherin（P〈0.001）. EDIL3 depletion could suppress the phosphorylation of Smad2（P〈0.01） and Smad3（P〈0.01） and the activation of exracellular signal regulated kinase（ERK）（P〈0.05）. CONCLUSION： The findings indicate that EDIL3 might participate in the proliferation and EMT in LECs via TGFβ pathway and may be a potential therapeutic target for the treatment of posterior capsule opacification.

Effects of bisphenol compounds on the growth and epithelial mesenchymal transition of MCF-7 CV human breast cancer cells

Bisphenol-A（BPA） has been considered as an endocrine disrupting chemical（EDC） because it can exert estrogenic properties.For bisphenol-S（BPS） and bisphenol-F（BPF） that are BPA analogs and substitutes,their risk to estrogendependent cancer has been reported rarely compared with the numerous cases of BPA.In this study,we examined whether BPA,BPS,and BPF can lead to the proliferation,migration,and epithelial mesenchymal transition（EMT） of MCF-7 clonal variant（MCF-7 CV） breast cancer cells expressing estrogen receptors（ERs）.In a cell viability assay,BPA,BPS,and BPF significantly increased proliferation of MCF-7 CV cells compared to control（DMSO） as did17β-estradiol（E2）.In Western blotting assay,BPA,BPS,and BPF enhanced the protein expression of cell cycle progression genes such as cyclin D1 and E1.In addition,MCF-7 CV cells lost cell to cell contacts and acquired fibroblast-like morphology by the treatment of BPA,BPS,or BPF for 24 hours.In cell migration assay,BPA,BPS,and BPF accelerated the migration capability of MCF-7 CV cells as did E2.In relation with the EMT process,BPA,BPS,and BPF increased the protein expression of N-cadherin,while they decreased the protein expression of Ecadherin.When BPA,BPS,and BPF were co-treated with ICI 182,780,an ER antagonist,proliferation effects were reversed,the expression of cyclin D1 and cyclin E1 was downregulated,and the altered cell migration and expression of N-cadherin and E-cadherin by BPA,BPS,and BPF were restored to the control level.Thus,these results imply that BPS and BPF also have the risk of breast cancer progression as much as BPA in the induction of proliferation and migration of MCF-7 CV cells by regulating the protein expression of cell cycle-related genes and EMT markers via the ER-dependent pathway.

Epithelial-Mesenchymal Transition and Breast Cancer Stem Cells in Breast Cancer Progression

Breast cancer stem cells (BCSCs) are a small subpopulation of cancer cells having the ability of self-renewing and multi-lineage differentiation, which have also been termed as “tumor-initiating cells”. And in recent years, the role of epithelial mesenchymal transition (EMT) in malignant tumors has been valued. This paper will briefly review and discuss the relationship between BCSCs and EMT.

Human lens epithelial cell apoptosis and epithelial to mesenchymal transition in femtosecond laser-assisted cataract surgery

AIM： To evaluate human lens epithelium cell apoptosis and epithelial to mesenchymal transition （EMT） induced by femtosecond laser in femtosecond laser assisted cataract surgery （FLACS）. METHODS： Sixty cataract patients with N2 to N3 stage according to the LOCS III were enrolled in this study and divided into three groups randomly： FLACSl group （cataract surgery by FLACS with LenSx）, FLACS2 group （cataract surgery by FLACS with LensAR） and manual group （cataract surgery by phacoemulsification）. Patients in two FLACS groups performed anterior capsulotomy by LenSx or LensAR laser system. Patients in the manual group were performed continuous curvilinear capsulorrhexis （CCC） manually. The anterior capsules were fixed right after moved out of eye. Hematoxylin-eosine staining, immunofluorescence staining and real-time PCR were performed in order to observe human lens epithelium cells changes after cataract surgery. RESULTS： The capsule cutting edge was shown irregularity and roughness in two FLACS groups and smooth edge in manual capsulotomy by pathologic staining. Irregularities of the cell configuration with partly swollen and destroyed nuclei were observed in two FLACS groups. Femtosecond laser could induce a significantly higher cell apoptosis in human lens epithelium cell than manually performed CCC （P〈0.05）. Lens epithelium cells apoptosis were correlated with femtosecond laser duration according to Pearson correlation analysis. Decreased N-cadherin expression, alpha-SMA and FSP-1 level in two FLACS groups showed the inhibition of cell EMT. CONCLUSION： Femtosecond laser may affect the apoptosis and EMT of lens epithelium cells which are under the peeled central lens capsule.

Effect of h GC-MSCs from human gastric cancer tissue on cell proliferation, invasion and epithelial-mesenchymal transition in tumor tissue of gastric cancer tumor-bearing mice

Objective: To study the effect of h GC-MSCs from human gastric cancer tissue on cell proliferation, invasion and epithelial-mesenchymal transition in tumor tissue of gastric cancer tumor-bearing mice. Methods: BABL/c nude mice were selected as experimental animals and gastric cancer tumor-bearing mice model were established by subcutaneous injection of gastric cancer cells, randomly divided into different intervention groups. h GC-MSCs group was given different amounts of gastric cancer cells for subcutaneous injection, PBS group was given equal volume of PBS for subcutaneous injection. Then tumor tissue volume were determined, tumor-bearing mice were killed and tumor tissues were collected, m RNA expression of proliferation, invasion, EMT related molecules were determined. Results: 4, 8, 12, 16, 20 d after intervention, tumor tissue volume of h GC-MSCs group were significantly higher than those of PBS group and the more the number of h GC-MSCs, the higher the tumor tissue volume; m RNA contents of Ki-67, PCNA, Bcl-2, MMP-2, MMP-7, MMP-9, MMP-14, N-cadherin, vimentin, Snail and Twist in tumor tissue of h GC-MSCs group were higher than those of PBS group, and m RNA contents of Bax, TIMP1, TIMP2 and E-cadherin were lower than those of PBS group. Conclusions: h GC-MSCs from human gastric cancer tissue can promote the tumor growth in gastric cancer tumor-bearing mice, and the molecular mechanism includes promoting cell proliferation, invasion and epithelial-mesenchymal transition.

Hepatic regeneration and the epithelial to mesenchymal transition

Liver injuries are repaired by fibrosis and regeneration. The core stage is the repair response and fibrosis formation as a scar. The cause of overly-responsive scar formation and diminished regeneration, especially in liver fibrosis and cirrhosis, is still unknown. The epithelial to mesenchymal transition (EMT), a previously discovered mechanism, plays an important role in liver fibrosis and tumor metastasis. Recently, EMT has been found to be associated with liver and bile duct cell fibrosis. Analyzing the established models and chronic disease processes, we propose that EMT liver cells may also lose their regenerative capability due to phenotype changes and that the remaining liver cells may quickly lose their regenerative capability in liver fibrosis or cirrhosis. Recognizing these phenotype changes or transition cells may play an important role in targeting therapy to reverse fibrosis not only by disrupting the transition that is necessary to produce the extracellular matrix but also by restoring the regenerative capacity of EMT-like cells.

Epithelial Mesenchymal Transition and its Roles on Chemoresistance in Non-small Cell Lung Cancer

Objective:Previous reported have demonstrated that an intricate link between epithelial-mesenchymal transition(EMT) and anticancer drug resistance in cell culture and animal model. The aim of this study is to further investigate the relationship between chemoresistance and EMT in non-small cell lung cancer(NSCLC) through observing the expression status of EMT markers and resistance protein in histological level. Methods: The resistance protein, excision repair cross-complementing 1(ERCCl) and EMT markers, including E-cadherin and vimentin, were detected by immunohistochemistry in 100 cases of NSCLC, half of that were treated with pre-operative neoadjuvant chemotherapy(neoadjuvant chemotherapy group), and the other underwent surgery alone(simple surgery group). Results: There were significant positive correlations between the expression of ERCCl and vimentin in neoadjuvant chemotherapy group(r =0.471,P = 0.01) and simple surgery group( r = 0.380,P = 0.01), and significant negative correlations between the ERCCl and E-cadherin in neoadjuvant chemotherapy group(r =-0.401,P = 0.01) and simple surgery group(r =-0.295,P = 0.03.In neoadjuvant chemotherapy group, EMT status(p = 0.04) and drug resistance(p = 0.03) were more apparent than simple surgery group. The expression levels of ERCCl, vimentin and E-cadherin were all related to differentiated degree and lymph node metastasis in both groups(P < 0.05). Conclusion: This study indicated that chemoresistance is correlated with the occurrence of EMT in NSCLC at tissue level, suggesting that selective targeting of EMT-phenotypic cells for declining chemoresistance may be a plausible therapeutic strategy.

Role of epithelial-mesenchymal transition in gastric cancer initiation and progression

Gastric cancer is one of the most common malignant tumors worldwide.Due to its intricate initiation and progression mechanisms,early detection and effective treatment of gastric cancer are difficult to achieve.The epithelial-mesenchymal transition(EMT)is characterized as a fundamental process that is critical for embryonic development,wound healing and fibrotic disease.Recent evidence has established that aberrant EMT activation in the human stomach is closely associated with gastric carcinogenesis and tumor progression.EMT activation endows gastric epithelial cells with increased characteristics of mesenchymal cells and reduces their epithelial features.Moreover,mesenchymal cells tend to dedifferentiate and acquire stem cell or tumorigenic phenotypes such as invasion,metastasis and apoptosis resistance as well as drug resistance during EMT progression.There are a number of molecules that indicate the stage of EMT(e.g.,E-cadherin,an epithelial cell biomarker);therefore,certain transcriptional proteins,especially E-cadherin transcriptional repressors,may participate in the regulation of EMT.In addition,EMT regulation may be associated with certain epigenetic mechanisms.The aforementioned molecules can be used as early diagnostic markers for gastric cancer,and EMT regulation can provide potential targets for gastric cancer therapy.Here,we review the role of these aspects of EMT in gastric cancer initiation and development.

Inflammatory microenvironment contributes to epithelial-mesenchymal transition in gastric cancer

Gastric cancer(GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori(H. pylori). Infection with H. pylori leads to an active inflammatory microenvironment that is maintained by immune cells such as T cells, macrophages, natural killer cells, among other cells. Immune cell dysfunction allows the initiation and accumulation of mutations in GC cells, inducing aberrant proliferation and protection from apoptosis. Meanwhile, immune cells can secrete certain signals, including cytokines, and chemokines, to alter intracellular signaling pathways in GC cells. Thus, GC cells obtain the ability to metastasize to lymph nodes by undergoing the epithelial-mesenchymal transition(EMT), whereby epithelial cells lose their epithelial attributes and acquire a mesenchymal cell phenotype. Metastasis is a leading cause of death for GC patients, and the involved mechanisms are still under investigation. In this review, we summarize the current research on how the inflammatory environment affects GC initiation and metastasis via EMT.