The cell-biological program termed the epithelial-to-mesenchymal transition （EMT） plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circui...The cell-biological program termed the epithelial-to-mesenchymal transition （EMT） plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circuits of a particular cell, this program can drive fully epithelial cells to enter into a series of phenotypic states arrayed along the epithelial-mesenehymal phenotypic axis. These cell states display distinctive cellular characteristics, including stemness, invasiveness, drug-resistance and the ability to form metastases at distant organs, and thereby contribute to cancer metastasis and relapse. Currently we still lack a coherent overview of the molecular and biochemical mechanisms inducing cells to enter various states along the epithelial-mesenchymal phenotypic spectrum. An improved understanding of the dynamic and plastic nature of the EMT program has the potential to yield novel therapies targeting this cellular program that may aid in the management of high-grade malignancies.展开更多
Epithelial-to-mesenchymal transition(EMT)is implicated in a wide array of malignant behaviors of cancers,including proliferation,invasion,and metastasis.Most notably,previou studies have indicated that both cancer ste...Epithelial-to-mesenchymal transition(EMT)is implicated in a wide array of malignant behaviors of cancers,including proliferation,invasion,and metastasis.Most notably,previou studies have indicated that both cancer stem-like properties and drug resistance were associated with EMT.Furthermore,microRNAs(miRNAs)play a pivotal role in the regulation of EMT phenotype,as a result,some miRNAs impact cancer stemness and drug resistance.Therefore,understanding the relationship between EMT-associated miRNAs and cancer stemness/drug resistance is beneficial to both basic research and clinical treatment.In this review,we preliminarily looked into the various roles that the EMT-associated miRNAs play in the stem-like nature of malignant cells.Then,we reviewed the interaction between EMT-associated miRNAs and the drugresistant complex signaling pathways of multiple cancers including lung cancer,gastric cancer,gynecologic cancer,breast cancer,liver cancer,colorectal cancer,pancreatic cancer,esophageal cancer,and nasopharyngeal cancer.We finally discussed the relationship between EMT,cancer stemness,and drug resistance,as well as looked forward to the potential applications of miRNA therapy for malignant tumors.展开更多
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...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.展开更多
Hepatocellular carcinoma （HCC） is a major health prob- lem, being the sixth most common cancer world-wide. Dysregulation of the balance between proliferation and cell death represents a pro-tumorigenic principle in ...Hepatocellular carcinoma （HCC） is a major health prob- lem, being the sixth most common cancer world-wide. Dysregulation of the balance between proliferation and cell death represents a pro-tumorigenic principle in hu- man hepatocarcinogenesis. This review updates the recent relevant contributions reporting molecular altera- tions for HCC that induce an imbalance in the regulation of apoptosis. Alterations in the expression and/or activation of p53 are frequent in HCC cells, which confer on them resistance to chemotherapeutic drugs. Many HCCs are also insensitive to apoptosis induced either by death receptor ligands, such as FasL or TRAIL, or by transforming growth factor-beta （TGF-β）. Although the expression of some pro-apoptotic genes is decreased, the balance between death and survival is dysregulated in HCC mainly due to overactivation of anti-apoptotic pathways. Indeed, some molecules involved in counter- acting apoptosis, such as Bcl-X1, Mcl-1, c-IAP1, XIAP or survivin are over-expressed in HCC cells. Furthermore, some growth factors that mediate cell survival are upregulated in HCC, as well as the molecules involved in the machinery responsible for cleavage of their pro- forms to an active peptide. The expression and/or activation of the JAK/STAT, PI3K/AKT and RAS/ERKs path- ways are enhanced in many HCC cells, conferring on them resistance to apoptotic stimuli. Finally, recent evi- dence indicates that inflammatory processes, as well as the epithelial-mesenchymal transitions that occur in HCC cells to facilitate their dissemination, are related to cell survival. Therefore, therapeutic strategies to selectively inhibit anti-apoptotic signals in liver tumor cells have the potential to provide powerful tools to treat HCC.展开更多
The process of epithelial to mesenchymal transition(EMT), first noted during embryogenesis, has also been reported in tumor formation and leads to the development of metastatic growth. It is a naturally occurring proc...The process of epithelial to mesenchymal transition(EMT), first noted during embryogenesis, has also been reported in tumor formation and leads to the development of metastatic growth. It is a naturally occurring process that drives the transformation of adhesive,non-mobile epithelial like cells into mobile cells with a mesenchymal phenotype that have ability to migrate to distant anatomical sites. Activating complex network of embryonic signaling pathways, including Wnt, Notch,hedgehog and transforming growth factor-β pathways,lead to the upregulation of EMT activating transcription factors, crucial for normal tissue development and maintenance. However, deregulation of tightly regulated pathways affecting the process of EMT has been recently investigated in various human cancers. Given the critical role of EMT in metastatic tumor formation,better understanding of the mechanistic regulation provides new opportunities for the development of potential therapeutic targets of clinical importance.展开更多
Background:The chemoresistance of prostate cancer(PCa)is invariably associated with the aggressiveness and metastasis of this disease.New emerging evidence indicates that the epithelial-to-mesenchymal transition(EMT)m...Background:The chemoresistance of prostate cancer(PCa)is invariably associated with the aggressiveness and metastasis of this disease.New emerging evidence indicates that the epithelial-to-mesenchymal transition(EMT)may play pivotal roles in the development of chemoresistance and metastasis.As a hallmark of EMT,E-cadherin is suggested to be a key marker in the development of chemoresistance.However,the molecular mechanisms underlying PCa chemoresistance remain unclear.The current study aimed to explore the association between EMT and chemoresistance in PCa as well as whether changing the expression of E-cadherin would affect PCa chemoresistance.Methods:Parental PC3 and DU145 cells and their chemoresistant PC3-Tx R and DU145-Tx R cells were analyzed.PC3-Tx R and DU145-Tx R cells were transfected with E-cadherin-expressing lentivirus to overexpress E-cadherin;PC3 and DU145 cells were transfected with small interfering RNA to silence E-cadherin.Changes of EMT phenotype-related markers and signaling pathways were assessed by Western blotting and quantitative real-time polymerase chain reaction.Tumor cell migration,invasion,and colony formation were then evaluated by wound healing,transwell,and colony formation assays,respectively.The drug sensitivity was evaluated using MTS assay.Results:Chemoresistant PC3-Tx R and DU145-Tx R cells exhibited an invasive and metastatic phenotype that associated with EMT,including the down-regulation of E-cadherin and up-regulation of Vimentin,Snail,and N-cadherin,comparing with that of parental PC3 and DU145 cells.When E-cadherin was overexpressed in PC3-Tx R and DU145-Tx R cells,the expression of Vimentin and Claudin-1 was down-regulated,and tumor cell migration and invasion were inhibited.In particular,the sensitivity to paclitaxel was reactivated in E-cadherin-overexpressing PC3-Tx R and DU145-Tx R cells.When E-cadherin expression was silenced in parental PC3 and DU145 cells,the expression of Vimentin and Snail was up-regulated,and,particularly,the sensitivity to paclitaxel was dec展开更多
Epithelial-to-mesenchymal and mesenchymal-to-epi- thelial transitions are well established biological events which have an important role in not just normal tissue and organ development, but in the pathogenesis of dis...Epithelial-to-mesenchymal and mesenchymal-to-epi- thelial transitions are well established biological events which have an important role in not just normal tissue and organ development, but in the pathogenesis of diseases. Increasing evidence has established their presence in the human colon during colorectal carcinogenesis and cancer invasion, chronic inflammation-related fibrosis and in the course of mucosal healing. A large body of evidence supports the role for transforming growth factor-13 and its downstream Smad signaling, the phosphatidylinositol 3＇-kinase/Akt/mTOR axis, the Ras-mitogen-activated protein kinase/Snail/Slug and FOXC2 pathway, and Hedgehog signaling and microR- NAs in the development of colorectal cancers via epi- thelial-to-mesenchymal transition. C-met and Frizzled-7, among others, seem to be the principle effectors of mesenchymal-to-epithelial transition, hence have a role not just in mucosal regeneration but in the progression of colonic wall fibrosis. Here we discuss a role for these pathways in the initiation and development of the transition events. A better understanding of their induction and regulation may lead to the identification of pathways and factors that could be potent therapeu- tic targets. The inhibition of epithelial-to-mesenchymal transition using mTOR kinase inhibitors targeting theATP binding pocket and which inhibit both mTORC1 and mTORC2, RNA aptamers or peptide mimetics, such as a Wnt5A-mimetic, may all be useful in both cancer treatment and delaying fibrosis, while the induction of mesenchymal-to-epithelial transition in induced pluripotent stem cells may enhance epithelial healing in the case of severe mucosal damage. The preliminary results of the current studies are promising, but more clinical investigations are needed to develop new and safe therapeutic strategies for diseases of the colon.展开更多
Objective： To investigate the effect of the Uremic Clearance Granule （UCG, 尿毒清颗粒）, a Chinese patent medicine, on tubular epithelial-to-mesenchymal transition （EMT） in a unilateral ureteral obstruction （UUO...Objective： To investigate the effect of the Uremic Clearance Granule （UCG, 尿毒清颗粒）, a Chinese patent medicine, on tubular epithelial-to-mesenchymal transition （EMT） in a unilateral ureteral obstruction （UUO） model in vivo and transforming growth factor （TGF）- 131 induced EMT of HK-2 cells in vitro. Methods： In vivo study, 50 Sprague Dawley rats were divided into three groups： a sham operation group （n=10）, a UUO group （n=20）, and a UUO with UCG treatment group （n=20）. The UCG was given at a dose of 4.5 g/kg body weight per day by gavage after surgery. In vitro study, HK-2 cells were cultured in 10% fetal bovine serum （FBS）, 10% healthy rat serum, 10% FBS and TGF-13 1 （10 ng/mL）, 10% healthy rat serum and TGF-13 1, or 10% rat serum containing the uremic clearance granule and TGF-13 1. The expression of the epithelial marker E-cadherin and the mesenchymal markers vimentin and e^-smooth muscle actin （ot-SMA） in kidney tissues and HK-2 cells were investigated by Western blot analysis and immunofluorescence staining. Results： The rats of the UUO group showed obvious tubulointerstitial fibrosis, compared with the sham operation group rats. Tubulointerstitial fibrosis score was reduced by 17.5%± 1.1% at day 7 and by 20.0%_＋ 1.2% at day 14 in the UCG-treated group, compared with the UUO group. The UCG could maintained expression of E-cadherin and suppressed expression of vimentin and α-SMA in kidney tissues of UUO rats at days 7 and 14, as determined by Western blot analysis and immunofluorescence staining. Rat serum containing the UCG partially inhibited TGF- β 1-induced fibroblast phenotype of HK-2 cells and maintained the epithelial morphology of HK-2 cells in vitro. This occurred partially through a reduction of vimentin expression and an increase of E-cadherin expression. Conclusion： These results suggest that the UCG prevents tubular EMT and may be a promising agent for treating tubulointerstitial fibrosis.展开更多
目的:探讨加味六君子汤对腹膜纤维化大鼠TGF-β/Smad信号通路的影响。方法:用5/6肾切除联合腹腔注射4.25%腹透液+脂多糖(LPS)建立腹膜纤维化大鼠模型,实验分空白组(A组)、模型组(B组)、西药组(C组)、中药高剂量组(D组)、中药低剂量组(E...目的:探讨加味六君子汤对腹膜纤维化大鼠TGF-β/Smad信号通路的影响。方法:用5/6肾切除联合腹腔注射4.25%腹透液+脂多糖(LPS)建立腹膜纤维化大鼠模型,实验分空白组(A组)、模型组(B组)、西药组(C组)、中药高剂量组(D组)、中药低剂量组(E组),Western印迹法检测TGF-β1、p-Smad2/3、Smad7和α-SMA、E-cadherin蛋白的表达:RT-PCR法测定TGF-β1、α-SMA、E-cadherin m RNA水平。结果:与A组相比,B组、C组、D组、E组TGF-β1、p-Smad2/3、α-SMA蛋白和α-SMAm RNA表达水平升高,有显著性差异(P<0.05);与B组相比,C组、D组、E组TGF-β1、p-Smad2/3、α-SMA蛋白和α-SMAm RNA表达水平降低,Smad7和E-cadherin蛋白和E-cadherin m RNA表达水平增高,有显著性差异(P<0.05)。结论:加味六君子汤可能通过TGF-β/Smad信号通路,抑制腹膜间皮细胞EMT进程,进而起到一定拮抗腹膜纤维化作用。展开更多
Interleukin-10(IL-10), a cytokine with anti-inflammatory and immunomodulatory functions, regulates the biology of B and T cells. The present review describes the role of IL-10 in normal renal physiology, during acute ...Interleukin-10(IL-10), a cytokine with anti-inflammatory and immunomodulatory functions, regulates the biology of B and T cells. The present review describes the role of IL-10 in normal renal physiology, during acute kidney injury and in the development of chronic renal failure. We further discuss IL-10-induced cellular and molecular pathways and their link to the progression of kidney injury.展开更多
AIM: To investigate the mechanism by which Qinggan Huoxue Recipe (QGHXR) inhibits epithelial-to-mesenchymal transition (EMT) in rats with alcoholic liver fibrosis (ALF).METHODS: A total of 75 male SD rats were used to...AIM: To investigate the mechanism by which Qinggan Huoxue Recipe (QGHXR) inhibits epithelial-to-mesenchymal transition (EMT) in rats with alcoholic liver fibrosis (ALF).METHODS: A total of 75 male SD rats were used to induce ALF. Serum biochemical indicators, including alanine aminotransferase, aspartate aminotransferase, laminin and hyaluronidase, were measured. Liver histopathological changes were evaluated using hematoxylin-eosin and Sirius red staining. EMT was examined by analyzing the expression of the epithelial marker E-cadherin and the mesenchymal markers vimentin and fibronectin using RT-PCR and Western blot. The inhibitory effect of QGHXR on EMT markers, as well as its effect on molecules associated with the transforming growth factor (TGF)-β1/Smad signaling pathway, including TGF-β1, Smad3, snail, occludin, ZO-1 and claudin, was also examined.RESULTS: Compared with normal control rats, ALF rats exhibited a decrease in E-cadherin levels (mRNA: ALF 0.16 ± 0.05 vs control 1.00 ± 0.08; protein: ALF 0.09 ± 0.05 vs control 0.70 ± 0.17, P < 0.01) and an increase in vimentin and fibronectin levels (mRNA: 11.43 ± 0.39 vs 1.00 ± 0.19 and 9.91 ± 0.34 vs 1.00 ± 0.44, respectively, P < 0.01; protein: 1.13 ± 0.42 vs 0.09 ± 0.03 and 1.16 ± 0.43 vs 0.09 ± 0.00, respectively, P < 0.01). This indicates that EMT occurred in ALF rats. In addition, the TGF-β1/Smad signaling pathway was activated in ALF rats, as evidenced by the increase in TGF-β1 and snail levels (mRNA: 1.76 ± 0.12 vs 1.00 ± 0.05 and 6.98 ± 0.41 vs 1.00 ± 0.10, respectively, P < 0.01; protein: 1.43 ± 0.05 vs 0.12 ± 0.03 and 1.07 ± 0.29 vs 0.07 ± 0.02, respectively, P < 0.01) and the decrease in Smad3 levels (mRNA: 0.05 ± 0.01 vs 1.00 ± 0.12, P < 0.01; protein: 0.06 ± 0.05 vs 0.89 ± 0.12, 展开更多
Background:Cancer-associated fibroblasts(CAFs)play an important role in the induction of chemo-resistance.This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors(...Background:Cancer-associated fibroblasts(CAFs)play an important role in the induction of chemo-resistance.This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors(TKIs),sorafenib and lenvatinib,and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma(HCC).Methods:We performed a systematic integrative analysis of publicly available gene expression datasets and whole-transcriptome sequencing data from 9 pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues,respectively,to identify key molecules that might induce resistance to TKIs.We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms.The associations of plasma secreted phosphoprotein 1(SPP1)expression levels before sorafenib/lenvatinib treatment with progression-free survival(PFS)and overall survival(OS)of 54 patients with advanced HCC were evaluated using Kaplan-Meier and Cox regression analysis.Results:Bioinformatic analysis identified CAF-derived SPP1 as a candidate molecule driving TKI resistance.SPP1 inhibitors reversed CAF-induced TKI resistance in vitro and in vivo.CAF-derived SPP1 activated rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)through the integrin-protein kinase C-alpha(PKCα)signaling pathway and promoted epithelial-to-mesenchymal transition(EMT).A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS(P=0.026)and OS(P=0.047)in patients with advanced HCC after TKI treatment.Conclusions:CAF-derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion.Its inhibition represents a promising therapeutic strategy against TKI resistance inHCC.Moreover,plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction.展开更多
The origins of the complex process of intratumoral heterogeneity have been highly debated and different cellular mechanisms have been hypothesized to account for the diversity within a tumor. The clonal evolution and ...The origins of the complex process of intratumoral heterogeneity have been highly debated and different cellular mechanisms have been hypothesized to account for the diversity within a tumor. The clonal evolution and cancer stem cell(CSC) models have been proposed as drivers of this heterogeneity. However, the concept of cancer stem cell plasticity and bidirectional conversion between stem and non-stem cells has added additional complexity to these highly studied paradigms and may help explain the tumor heterogeneity observed in solid tumors. The process of cancer stem cell plasticity in which cancer cel s harbor the dynamic ability of shifting from a non-CSC state to a CSC state and vice versa may be modulated by specific microenvironmental signals and cellular interactions arising in the tumor niche. In addition to promoting CSC plasticity, these interactions may contribute to the cellular transformation of tumor cells and affect response to chemotherapeutic and radiation treatments by providing CSCs protection from these agents. Herein, we review the literature in support of this dynamic CSC state, discuss the effectors of plasticity, and examine their role in the development and treatment of cancer.展开更多
文摘The cell-biological program termed the epithelial-to-mesenchymal transition （EMT） plays an important role in both development and cancer progression. Depending on the contextual signals and intracellular gene circuits of a particular cell, this program can drive fully epithelial cells to enter into a series of phenotypic states arrayed along the epithelial-mesenehymal phenotypic axis. These cell states display distinctive cellular characteristics, including stemness, invasiveness, drug-resistance and the ability to form metastases at distant organs, and thereby contribute to cancer metastasis and relapse. Currently we still lack a coherent overview of the molecular and biochemical mechanisms inducing cells to enter various states along the epithelial-mesenchymal phenotypic spectrum. An improved understanding of the dynamic and plastic nature of the EMT program has the potential to yield novel therapies targeting this cellular program that may aid in the management of high-grade malignancies.
基金supported by grants from the National Natural Science Foundation of China(81673760 and 81874397).
文摘Epithelial-to-mesenchymal transition(EMT)is implicated in a wide array of malignant behaviors of cancers,including proliferation,invasion,and metastasis.Most notably,previou studies have indicated that both cancer stem-like properties and drug resistance were associated with EMT.Furthermore,microRNAs(miRNAs)play a pivotal role in the regulation of EMT phenotype,as a result,some miRNAs impact cancer stemness and drug resistance.Therefore,understanding the relationship between EMT-associated miRNAs and cancer stemness/drug resistance is beneficial to both basic research and clinical treatment.In this review,we preliminarily looked into the various roles that the EMT-associated miRNAs play in the stem-like nature of malignant cells.Then,we reviewed the interaction between EMT-associated miRNAs and the drugresistant complex signaling pathways of multiple cancers including lung cancer,gastric cancer,gynecologic cancer,breast cancer,liver cancer,colorectal cancer,pancreatic cancer,esophageal cancer,and nasopharyngeal cancer.We finally discussed the relationship between EMT,cancer stemness,and drug resistance,as well as looked forward to the potential applications of miRNA therapy for malignant tumors.
基金Supported by Major Program of Science and Technology Program of Guangzhou,No.201300000087Research Fund of Public Welfare in Health Industry of National Health and Family Planning Commission of China,No.201402015 and No.201502039+1 种基金National Key Technology R&D Program,No.2013BAI05B05Key Clinical Specialty Discipline Construction Program
文摘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.
文摘Hepatocellular carcinoma （HCC） is a major health prob- lem, being the sixth most common cancer world-wide. Dysregulation of the balance between proliferation and cell death represents a pro-tumorigenic principle in hu- man hepatocarcinogenesis. This review updates the recent relevant contributions reporting molecular altera- tions for HCC that induce an imbalance in the regulation of apoptosis. Alterations in the expression and/or activation of p53 are frequent in HCC cells, which confer on them resistance to chemotherapeutic drugs. Many HCCs are also insensitive to apoptosis induced either by death receptor ligands, such as FasL or TRAIL, or by transforming growth factor-beta （TGF-β）. Although the expression of some pro-apoptotic genes is decreased, the balance between death and survival is dysregulated in HCC mainly due to overactivation of anti-apoptotic pathways. Indeed, some molecules involved in counter- acting apoptosis, such as Bcl-X1, Mcl-1, c-IAP1, XIAP or survivin are over-expressed in HCC cells. Furthermore, some growth factors that mediate cell survival are upregulated in HCC, as well as the molecules involved in the machinery responsible for cleavage of their pro- forms to an active peptide. The expression and/or activation of the JAK/STAT, PI3K/AKT and RAS/ERKs path- ways are enhanced in many HCC cells, conferring on them resistance to apoptotic stimuli. Finally, recent evi- dence indicates that inflammatory processes, as well as the epithelial-mesenchymal transitions that occur in HCC cells to facilitate their dissemination, are related to cell survival. Therefore, therapeutic strategies to selectively inhibit anti-apoptotic signals in liver tumor cells have the potential to provide powerful tools to treat HCC.
文摘The process of epithelial to mesenchymal transition(EMT), first noted during embryogenesis, has also been reported in tumor formation and leads to the development of metastatic growth. It is a naturally occurring process that drives the transformation of adhesive,non-mobile epithelial like cells into mobile cells with a mesenchymal phenotype that have ability to migrate to distant anatomical sites. Activating complex network of embryonic signaling pathways, including Wnt, Notch,hedgehog and transforming growth factor-β pathways,lead to the upregulation of EMT activating transcription factors, crucial for normal tissue development and maintenance. However, deregulation of tightly regulated pathways affecting the process of EMT has been recently investigated in various human cancers. Given the critical role of EMT in metastatic tumor formation,better understanding of the mechanistic regulation provides new opportunities for the development of potential therapeutic targets of clinical importance.
基金supported by National Natural Science Foundation of China(NSFC)Key Project(No.81130046)NSFC(Nos.81272415 and 81171993)+1 种基金Guangxi Key Projects(No.2013GXNSFEA053004)Youth Science Foundation of Guangxi Medical University(No.GXMUYSF201539)
文摘Background:The chemoresistance of prostate cancer(PCa)is invariably associated with the aggressiveness and metastasis of this disease.New emerging evidence indicates that the epithelial-to-mesenchymal transition(EMT)may play pivotal roles in the development of chemoresistance and metastasis.As a hallmark of EMT,E-cadherin is suggested to be a key marker in the development of chemoresistance.However,the molecular mechanisms underlying PCa chemoresistance remain unclear.The current study aimed to explore the association between EMT and chemoresistance in PCa as well as whether changing the expression of E-cadherin would affect PCa chemoresistance.Methods:Parental PC3 and DU145 cells and their chemoresistant PC3-Tx R and DU145-Tx R cells were analyzed.PC3-Tx R and DU145-Tx R cells were transfected with E-cadherin-expressing lentivirus to overexpress E-cadherin;PC3 and DU145 cells were transfected with small interfering RNA to silence E-cadherin.Changes of EMT phenotype-related markers and signaling pathways were assessed by Western blotting and quantitative real-time polymerase chain reaction.Tumor cell migration,invasion,and colony formation were then evaluated by wound healing,transwell,and colony formation assays,respectively.The drug sensitivity was evaluated using MTS assay.Results:Chemoresistant PC3-Tx R and DU145-Tx R cells exhibited an invasive and metastatic phenotype that associated with EMT,including the down-regulation of E-cadherin and up-regulation of Vimentin,Snail,and N-cadherin,comparing with that of parental PC3 and DU145 cells.When E-cadherin was overexpressed in PC3-Tx R and DU145-Tx R cells,the expression of Vimentin and Claudin-1 was down-regulated,and tumor cell migration and invasion were inhibited.In particular,the sensitivity to paclitaxel was reactivated in E-cadherin-overexpressing PC3-Tx R and DU145-Tx R cells.When E-cadherin expression was silenced in parental PC3 and DU145 cells,the expression of Vimentin and Snail was up-regulated,and,particularly,the sensitivity to paclitaxel was dec
文摘Epithelial-to-mesenchymal and mesenchymal-to-epi- thelial transitions are well established biological events which have an important role in not just normal tissue and organ development, but in the pathogenesis of diseases. Increasing evidence has established their presence in the human colon during colorectal carcinogenesis and cancer invasion, chronic inflammation-related fibrosis and in the course of mucosal healing. A large body of evidence supports the role for transforming growth factor-13 and its downstream Smad signaling, the phosphatidylinositol 3＇-kinase/Akt/mTOR axis, the Ras-mitogen-activated protein kinase/Snail/Slug and FOXC2 pathway, and Hedgehog signaling and microR- NAs in the development of colorectal cancers via epi- thelial-to-mesenchymal transition. C-met and Frizzled-7, among others, seem to be the principle effectors of mesenchymal-to-epithelial transition, hence have a role not just in mucosal regeneration but in the progression of colonic wall fibrosis. Here we discuss a role for these pathways in the initiation and development of the transition events. A better understanding of their induction and regulation may lead to the identification of pathways and factors that could be potent therapeu- tic targets. The inhibition of epithelial-to-mesenchymal transition using mTOR kinase inhibitors targeting theATP binding pocket and which inhibit both mTORC1 and mTORC2, RNA aptamers or peptide mimetics, such as a Wnt5A-mimetic, may all be useful in both cancer treatment and delaying fibrosis, while the induction of mesenchymal-to-epithelial transition in induced pluripotent stem cells may enhance epithelial healing in the case of severe mucosal damage. The preliminary results of the current studies are promising, but more clinical investigations are needed to develop new and safe therapeutic strategies for diseases of the colon.
基金Supported by the National Basic Research Program of China(No.2011CB944004)the Program of the National Natural Science Foundation of China(No.30971377)the Science and Technology Project of Beijing,China(No.D09050704310904)
文摘Objective： To investigate the effect of the Uremic Clearance Granule （UCG, 尿毒清颗粒）, a Chinese patent medicine, on tubular epithelial-to-mesenchymal transition （EMT） in a unilateral ureteral obstruction （UUO） model in vivo and transforming growth factor （TGF）- 131 induced EMT of HK-2 cells in vitro. Methods： In vivo study, 50 Sprague Dawley rats were divided into three groups： a sham operation group （n=10）, a UUO group （n=20）, and a UUO with UCG treatment group （n=20）. The UCG was given at a dose of 4.5 g/kg body weight per day by gavage after surgery. In vitro study, HK-2 cells were cultured in 10% fetal bovine serum （FBS）, 10% healthy rat serum, 10% FBS and TGF-13 1 （10 ng/mL）, 10% healthy rat serum and TGF-13 1, or 10% rat serum containing the uremic clearance granule and TGF-13 1. The expression of the epithelial marker E-cadherin and the mesenchymal markers vimentin and e^-smooth muscle actin （ot-SMA） in kidney tissues and HK-2 cells were investigated by Western blot analysis and immunofluorescence staining. Results： The rats of the UUO group showed obvious tubulointerstitial fibrosis, compared with the sham operation group rats. Tubulointerstitial fibrosis score was reduced by 17.5%± 1.1% at day 7 and by 20.0%_＋ 1.2% at day 14 in the UCG-treated group, compared with the UUO group. The UCG could maintained expression of E-cadherin and suppressed expression of vimentin and α-SMA in kidney tissues of UUO rats at days 7 and 14, as determined by Western blot analysis and immunofluorescence staining. Rat serum containing the UCG partially inhibited TGF- β 1-induced fibroblast phenotype of HK-2 cells and maintained the epithelial morphology of HK-2 cells in vitro. This occurred partially through a reduction of vimentin expression and an increase of E-cadherin expression. Conclusion： These results suggest that the UCG prevents tubular EMT and may be a promising agent for treating tubulointerstitial fibrosis.
文摘目的:探讨加味六君子汤对腹膜纤维化大鼠TGF-β/Smad信号通路的影响。方法:用5/6肾切除联合腹腔注射4.25%腹透液+脂多糖(LPS)建立腹膜纤维化大鼠模型,实验分空白组(A组)、模型组(B组)、西药组(C组)、中药高剂量组(D组)、中药低剂量组(E组),Western印迹法检测TGF-β1、p-Smad2/3、Smad7和α-SMA、E-cadherin蛋白的表达:RT-PCR法测定TGF-β1、α-SMA、E-cadherin m RNA水平。结果:与A组相比,B组、C组、D组、E组TGF-β1、p-Smad2/3、α-SMA蛋白和α-SMAm RNA表达水平升高,有显著性差异(P<0.05);与B组相比,C组、D组、E组TGF-β1、p-Smad2/3、α-SMA蛋白和α-SMAm RNA表达水平降低,Smad7和E-cadherin蛋白和E-cadherin m RNA表达水平增高,有显著性差异(P<0.05)。结论:加味六君子汤可能通过TGF-β/Smad信号通路,抑制腹膜间皮细胞EMT进程,进而起到一定拮抗腹膜纤维化作用。
文摘Interleukin-10(IL-10), a cytokine with anti-inflammatory and immunomodulatory functions, regulates the biology of B and T cells. The present review describes the role of IL-10 in normal renal physiology, during acute kidney injury and in the development of chronic renal failure. We further discuss IL-10-induced cellular and molecular pathways and their link to the progression of kidney injury.
基金Supported by National Natural Science Foundation of China,No.81202979Shanghai Rising-Star Program,No.15QA1403500
文摘AIM: To investigate the mechanism by which Qinggan Huoxue Recipe (QGHXR) inhibits epithelial-to-mesenchymal transition (EMT) in rats with alcoholic liver fibrosis (ALF).METHODS: A total of 75 male SD rats were used to induce ALF. Serum biochemical indicators, including alanine aminotransferase, aspartate aminotransferase, laminin and hyaluronidase, were measured. Liver histopathological changes were evaluated using hematoxylin-eosin and Sirius red staining. EMT was examined by analyzing the expression of the epithelial marker E-cadherin and the mesenchymal markers vimentin and fibronectin using RT-PCR and Western blot. The inhibitory effect of QGHXR on EMT markers, as well as its effect on molecules associated with the transforming growth factor (TGF)-β1/Smad signaling pathway, including TGF-β1, Smad3, snail, occludin, ZO-1 and claudin, was also examined.RESULTS: Compared with normal control rats, ALF rats exhibited a decrease in E-cadherin levels (mRNA: ALF 0.16 ± 0.05 vs control 1.00 ± 0.08; protein: ALF 0.09 ± 0.05 vs control 0.70 ± 0.17, P < 0.01) and an increase in vimentin and fibronectin levels (mRNA: 11.43 ± 0.39 vs 1.00 ± 0.19 and 9.91 ± 0.34 vs 1.00 ± 0.44, respectively, P < 0.01; protein: 1.13 ± 0.42 vs 0.09 ± 0.03 and 1.16 ± 0.43 vs 0.09 ± 0.00, respectively, P < 0.01). This indicates that EMT occurred in ALF rats. In addition, the TGF-β1/Smad signaling pathway was activated in ALF rats, as evidenced by the increase in TGF-β1 and snail levels (mRNA: 1.76 ± 0.12 vs 1.00 ± 0.05 and 6.98 ± 0.41 vs 1.00 ± 0.10, respectively, P < 0.01; protein: 1.43 ± 0.05 vs 0.12 ± 0.03 and 1.07 ± 0.29 vs 0.07 ± 0.02, respectively, P < 0.01) and the decrease in Smad3 levels (mRNA: 0.05 ± 0.01 vs 1.00 ± 0.12, P < 0.01; protein: 0.06 ± 0.05 vs 0.89 ± 0.12,
文摘Background:Cancer-associated fibroblasts(CAFs)play an important role in the induction of chemo-resistance.This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors(TKIs),sorafenib and lenvatinib,and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma(HCC).Methods:We performed a systematic integrative analysis of publicly available gene expression datasets and whole-transcriptome sequencing data from 9 pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues,respectively,to identify key molecules that might induce resistance to TKIs.We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms.The associations of plasma secreted phosphoprotein 1(SPP1)expression levels before sorafenib/lenvatinib treatment with progression-free survival(PFS)and overall survival(OS)of 54 patients with advanced HCC were evaluated using Kaplan-Meier and Cox regression analysis.Results:Bioinformatic analysis identified CAF-derived SPP1 as a candidate molecule driving TKI resistance.SPP1 inhibitors reversed CAF-induced TKI resistance in vitro and in vivo.CAF-derived SPP1 activated rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)through the integrin-protein kinase C-alpha(PKCα)signaling pathway and promoted epithelial-to-mesenchymal transition(EMT).A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS(P=0.026)and OS(P=0.047)in patients with advanced HCC after TKI treatment.Conclusions:CAF-derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion.Its inhibition represents a promising therapeutic strategy against TKI resistance inHCC.Moreover,plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction.
文摘The origins of the complex process of intratumoral heterogeneity have been highly debated and different cellular mechanisms have been hypothesized to account for the diversity within a tumor. The clonal evolution and cancer stem cell(CSC) models have been proposed as drivers of this heterogeneity. However, the concept of cancer stem cell plasticity and bidirectional conversion between stem and non-stem cells has added additional complexity to these highly studied paradigms and may help explain the tumor heterogeneity observed in solid tumors. The process of cancer stem cell plasticity in which cancer cel s harbor the dynamic ability of shifting from a non-CSC state to a CSC state and vice versa may be modulated by specific microenvironmental signals and cellular interactions arising in the tumor niche. In addition to promoting CSC plasticity, these interactions may contribute to the cellular transformation of tumor cells and affect response to chemotherapeutic and radiation treatments by providing CSCs protection from these agents. Herein, we review the literature in support of this dynamic CSC state, discuss the effectors of plasticity, and examine their role in the development and treatment of cancer.
