scholarly journals JianPi JieDu Recipe Inhibits Epithelial-to-Mesenchymal Transition in Colorectal Cancer through TGF-β/Smad Mediated Snail/E-Cadherin Expression

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Xuan Liu ◽  
Qing Ji ◽  
Wanli Deng ◽  
Ni Chai ◽  
Yuanyuan Feng ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Mesenchymal Transition ◽  
New Findings ◽  
Smad Signaling Pathway ◽  
Underlying Mechanisms ◽  
E Cadherin

JPJD was an ideal alternative traditional Chinese medicine compound in the prevention and treatment of CRC, but its underlying mechanisms has not been fully elucidated. In this study, we demonstrated in vitro that TGF-β-induced EMT promoted the invasion and metastasis of CRC cells, reduced the expression of E-cadherin, and elevated the expression of Vimentin. However, JPJD could inhibit the invasive and migratory ability of TGF-β-stimulated CRC cells in a concentration-dependent manner through increasing the expression of E-cadherin and repressing the expression of Vimentin, as well as the inhibition of TGF-β/Smad signaling pathway. Meanwhile, JPJD reduced the transcriptional activities of EMT-associated factors Snail and E-cadherin during the initiation of TGF-β-induced EMT. In vivo, the results demonstrated that JPJD can significantly inhibit the liver and lung metastasis of orthotopic CRC tumor in nude mice, as well as significantly prolonging the survival time of tumor-bearing in a dose-dependent manner. Additionally, JPJD can upregulate the expression of E-cadherin and Smad2/3 in the cytoplasm and downregulate the expression of Vimentin, p-Smad2/3, and Snail in the orthotopic CRC tumor tissues. In conclusions, our new findings provided evidence that JPJD could inhibit TGF-β-induced EMT in CRC through TGF-β/Smad mediated Snail/E-cadherin expression.

scholarly journals Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1340 ◽  
Author(s):  
Olaia Martinez-Iglesias ◽  
Alba Casas-Pais ◽  
Raquel Castosa ◽  
Andrea Díaz-Díaz ◽  
Daniel Roca-Lema ◽  
...  
Keyword(s):  
Small Molecule ◽  
Ubiquitin Ligase ◽  
Epithelial To Mesenchymal Transition ◽  
Tumour Progression ◽  
E3 Ubiquitin Ligase ◽  
Therapeutic Drug ◽  
Mesenchymal Transition ◽  
E Cadherin

The requirement of the E3 ubiquitin-ligase Hakai for the ubiquitination and subsequent degradation of E-cadherin has been associated with enhanced epithelial-to-mesenchymal transition (EMT), tumour progression and carcinoma metastasis. To date, most of the reported EMT-related inhibitors were not developed for anti-EMT purposes, but indirectly affect EMT. On the other hand, E3 ubiquitin-ligase enzymes have recently emerged as promising therapeutic targets, as their specific inhibition would prevent wider side effects. Given this background, a virtual screening was performed to identify novel specific inhibitors of Hakai, targeted against its phosphotyrosine-binding pocket, where phosphorylated-E-cadherin specifically binds. We selected a candidate inhibitor, Hakin-1, which showed an important effect on Hakai-induced ubiquitination. Hakin-1 also inhibited carcinoma growth and tumour progression both in vitro, in colorectal cancer cell lines, and in vivo, in a tumour xenograft mouse model, without apparent systemic toxicity in mice. Our results show for the first time that a small molecule putatively targeting the E3 ubiquitin-ligase Hakai inhibits Hakai-dependent ubiquitination of E-cadherin, having an impact on the EMT process. This represents an important step forward in a future development of an effective therapeutic drug to prevent or inhibit carcinoma tumour progression.

scholarly journals Detachment-induced E-cadherin expression promotes 3D tumor spheroid formation but inhibits tumor formation and metastasis of lung cancer cells

2017 ◽  
Vol 313 (5) ◽  
pp. C556-C566 ◽  
Author(s):  
Phattrakorn Powan ◽  
Sudjit Luanpitpong ◽  
Xiaoqing He ◽  
Yon Rojanasakul ◽  
Pithi Chanvorachote
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Formation ◽  
Lung Cancer Cells ◽  
Tumor Spheroid ◽  
Mesenchymal Transition ◽  
E Cadherin

The epithelial-to-mesenchymal transition is proposed to be a key mechanism responsible for metastasis-related deaths. Similarly, cancer stem cells (CSCs) have been proposed to be a key driver of tumor metastasis. However, the link between the two events and their control mechanisms is unclear. We used a three-dimensional (3D) tumor spheroid assay and other CSC-indicating assays to investigate the role of E-cadherin in CSC regulation and its association to epithelial-to-mesenchymal transition in lung cancer cells. Ectopic overexpression and knockdown of E-cadherin were found to promote and retard, respectively, the formation of tumor spheroids in vitro but had opposite effects on tumor formation and metastasis in vivo in a xenograft mouse model. We explored the discrepancy between the in vitro and in vivo results and demonstrated, for the first time, that E-cadherin is required as a component of a major survival pathway under detachment conditions. Downregulation of E-cadherin increased the stemness of lung cancer cells but had an adverse effect on their survival, particularly on non-CSCs. Such downregulation also promoted anoikis resistance and invasiveness of lung cancer cells. These results suggest that anoikis assay could be used as an alternative method for in vitro assessment of CSCs that involves dysregulated adhesion proteins. Our data also suggest that agents that restore E-cadherin expression may be used as therapeutic agents for metastatic cancers.

scholarly journals Krüppel-Like Factor 4 Inhibits Pancreatic Cancer Epithelial-to-Mesenchymal Transition and Metastasis by Down-Regulating Caveolin-1 Expression

2018 ◽  
Vol 46 (1) ◽  
pp. 238-252 ◽  
Author(s):  
Zhonglin Zhu ◽  
Zhilong Yu ◽  
Jianfeng Wang ◽  
Lisheng Zhou ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Disease Stage ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
Klf4 Expression ◽  
Public Datasets ◽  
E Cadherin

Background/Aims: Krüppel-like factor 4 (KLF4), a member of the KLF family of zinc finger transcription factors, has been identified as a tumor suppressor gene in a variety of tumors. However, the molecular mechanisms by which KLF4 inhibits epithelial-to-mesenchymal transition (EMT) and metastasis in pancreatic cancer remain unclear. Methods: KLF4 expression in pancreatic cancer was analyzed using public datasets (Oncomine and The Cancer Genome Atlas). The expression of KLF4, caveolin-1 (Cav-1), E-cadherin, and vimentin, and their correlations with clinicopathological characteristics were evaluated by immunohistochemistry in pancreatic cancer tissues. The biological functions and underlying mechanisms of KLF4 expression on EMT and metastasis were also investigated in vitro and in vivo. Results: Public datasets showed that KLF4 expression was significantly decreased in pancreatic cancer and correlated with the depth of invasion and disease stage. The expression of KLF4, Cav-1, E-cadherin, and vimentin protein in pancreatic cancer tissues was closely associated with pathological grade, disease stage, and metastasis. KLF4 expression was also positively correlated with E-cadherin expression and negatively correlated with vimentin expression, whereas Cav-1 expression was negatively associated with E-cadherin expression and positively correlated with vimentin expression. Knockdown of KLF4 expression promoted EMT and facilitated pancreatic cancer cell growth and metastasis in vitro and in vivo. In addition, immunohistochemistry (IHC) results indicated that KLF4 expression was negatively correlated with Cav-1 expression. Furthermore, down-regulating KLF4 expression increased Cav-1 and vimentin expression and decreased E-cadherin expression. Mechanistically, KLF4 could transcriptionally inhibit Cav-1 expression by binding directly to the promoter domain of Cav-1. Conclusions: KLF4 inhibits pancreatic cancer EMT and metastasis by down-regulating Cav-1 expression, suggesting that the KLF4/Cav-1 signaling pathway may be a novel diagnostic and therapeutic target.

scholarly journals PPP3CB Inhibits Migration of G401 Cells via Regulating Epithelial-to-Mesenchymal Transition and Promotes G401 Cells Growth

2019 ◽  
Vol 20 (2) ◽  
pp. 275 ◽  
Author(s):  
Lei Chen ◽  
Qingling He ◽  
Yamin Liu ◽  
Yafei Wu ◽  
Dongsheng Ni ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Migration ◽  
Tumor Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Phosphatase Domain ◽  
Mesenchymal Transition ◽  
In Vivo Experiments ◽  
E Cadherin

PPP3CB belongs to the phosphoprotein phosphatases (PPPs) group. Although the majority of the PPP family play important roles in the epithelial-to-mesenchymal transition (EMT) of tumor cells, little is known about the function of PPP3CB in the EMT process. Here, we found PPP3CB had high expression in kidney mesenchymal-like cells compared with kidney epithelial-like cells. Knock-down of PPP3CB downregulated epithelial marker E-cadherin and upregulated mesenchymal marker Vimentin, promoting the transition of cell states from epithelial to mesenchymal and reorganizing the actin cytoskeleton which contributed to cell migration. Conversely, overexpression of PPP3CB reversed EMT and inhibited migration of tumor cells. Besides, in vitro and in vivo experiments indicated that the loss of PPP3CB suppressed the tumor growth. However, the deletion of the phosphatase domain of PPP3CB showed no effect on the expression of E-cadherin, migration, and G401 cell proliferation. Together, we demonstrate that PPP3CB inhibits G401 cell migration through regulating EMT and promotes cell proliferation, which are both associated with the phosphatase activity of PPP3CB.

scholarly journals Colorectal cancer-derived exosomal miR-106b-3p promotes metastasis by down-regulating DLC-1 expression

2020 ◽  
Vol 134 (4) ◽  
pp. 419-434 ◽  
Author(s):  
He Liu ◽  
Yanlong Liu ◽  
Ping Sun ◽  
Kaiming Leng ◽  
Yi Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Expression Profiles ◽  
High Serum ◽  
Mouse Lung ◽  
Mesenchymal Transition ◽  
Paired Serum ◽  
Underlying Mechanisms

Abstract Cancer-derived exosomal miRNAs play an important role in the development of metastasis, but the effects and underlying mechanisms remain unclear. In the present study, we investigated the miRNA expression profiles of 5 paired serum exosomal samples from metastatic colorectal cancer (mCRC) and non-mCRC patients via RNA sequencing. After we evaluated the differentially expressed miRNAs in 80 CRC patients, miR-106b-3p was selected as a metastasis-associated miRNA of CRC. We showed that the expression level of serum exosomal miR-106b-3p was significantly higher in CRC patients with metastasis than those without metastasis. Additionally, high serum exosomal miR-106b-3p expression in patients was correlated with a poor prognosis. Coculture of low-metastatic CRC cells with high-metastatic CRC cell-derived exosomes promoted cell migration, invasion, and epithelial-to-mesenchymal transition (EMT), which was caused by the transport and transduction of miR-106b-3p in vitro. Moreover, exosomal miR-106b-3p promoted lung metastasis of CRC cells in vivo. In addition, we demonstrated that miR-106b-3p regulated metastasis by targeting deleted in liver cancer-1 (DLC-1). A negative correlation was also identified between miR-106b-3p and DLC-1 expression in human CRC tumour tissues and in mouse lung metastatic lesions. Collectively, our study indicated that metastasis-associated miR-106b-3p from serum exosomes could be used as a potential prognostic biomarker and therapeutic target for CRC patients.

scholarly journals Isoliquiritigenin Reverses Epithelial-Mesenchymal Transition Through Modulation of the TGF-β/Smad Signaling Pathway in Endometrial Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1236
Author(s):  
Hsin-Yuan Chen ◽  
Yi-Fen Chiang ◽  
Jia-Syuan Huang ◽  
Tsui-Chin Huang ◽  
Yin-Hwa Shih ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Signaling Pathway ◽  
Cancer Cell ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Smad Signaling Pathway ◽  
E Cadherin

Endometrial cancer is a common gynecological cancer with a poor prognosis, mostly attributed to tumor metastasis. Epithelial–mesenchymal transition (EMT) can be mediated via transforming growth factor beta (TGF-β) signaling pathway, facilitating the ability of cancer cell invasion and migration. Isoliquiritigenin (ISL) is a flavonoid derived from licorice with reported antineoplastic activities. This study aims to investigate the anti-metastatic potential of ISL on endometrial cancer both in vitro and in vivo. First, human endometrial cancer cell lines (HEC-1A, Ishikawa, and RL95-2) were treated with ISL and then subjected to functional assays such as migration assay as well as molecular analyses including immunoblotting, immunofluorescence and RT-qPCR. In addition, HEC-1A-LUC cells were implanted into female nude mice and treated with ISL by intraperitoneal injection for four weeks. Results showed that ISL inhibited cell migration and reversed the effect of TGF-β on the expression of E-cadherin, N-cadherin, vimentin, α-SMA, p-Smad3, and TWIST1/2 In vitro. Interestingly, In vivo study revealed that ISL reduced peritoneal dissemination and serum level of TGF-β1, as well as decreased the expression levels of N-cadherin, p-Smad2/3, TWIST1/2, while increased E-cadherin. Overall, ISL reverses the EMT through targeting the TGF-β/Smad signaling pathway and features a potential therapeutic treatment for metastatic endometrial cancer.

scholarly journals 20(S)-ginsenoside Rh2 as agent for the treatment of LMN-CRC via regulating epithelial–mesenchymal transition

2020 ◽  
Vol 40 (3) ◽  
Author(s):  
Yihang Yuan ◽  
Jue Wang ◽  
Ming Xu ◽  
Yunpeng Zhang ◽  
Zhiqiang Wang ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Potential Effect ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Ginsenoside Rh2 ◽  
Mesenchymal Transition ◽  
Underlying Mechanisms

Abstract The lymph node metastasis of colorectal cancer (LMN-CRC) seriously threatens the prognosis of patients. Chemotherapy, as the most common treatment, results in severe bone marrow suppression. 20(S)-ginsenoside Rh2 (SGRh2), a major effective constituent of ginseng, has demonstrated therapeutic effects on a variety of diseases, including some tumours. SGRh2 treatment had no effect on other organs. Therefore, ginsenosides are considered a safe and effective antineoplastic drug. However, the effects of SGRh2 on LMN-CRC remain unknown. The present study investigated the potential effect of SGRh2 on LMN-CRC in vitro and in vivo. SW480 and CoLo205 cell lines were treated with SGRh2. SGRh2 dose-dependently decreased CRC cell proliferation by CCK-8, colony formation and Edu assays. The Transwell and scratch assays revealed that SGRh2 inhibits the migratory and invasive abilities of CRC cells in a dose-dependent manner. Furthermore, the results of Western blotting revealed that SGRh2 decreased the expression of matrix metalloproteinase (MMP)-2 and MMP9. In terms of the underlying mechanisms, SGRh2 regulates CRC metastasis by affecting epithelial–mesenchymal transition (EMT), which significantly up-regulated epithelial biomarkers (E-cadherin) and down-regulated mesenchymal biomarkers (N-cadherin and vimentin) and EMT transcriptional factors (Smad-3, Snail-1, and Twist-1). In vivo, SGRh2 significantly inhibited LMN-CRC without affecting other normal organs. Immunohistochemical results showed that SGRh2 treats LMN-CRC by regulating EMT. These results demonstrate that SGRh2 has therapeutic potential for LMN-CRC.

Chickpea (Cicer arietinum L.) Lectin Exhibit Inhibition of ACE-I, α-amylase and α-glucosidase Activity

2019 ◽  
Vol 26 (7) ◽  
pp. 494-501 ◽  
Author(s):  
Sameer Suresh Bhagyawant ◽  
Dakshita Tanaji Narvekar ◽  
Neha Gupta ◽  
Amita Bhadkaria ◽  
Ajay Kumar Gautam ◽  
...  
Keyword(s):  
Biological Effects ◽  
Exchange Chromatography ◽  
Health Concern ◽  
Carbohydrate Binding ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ic50 Values ◽  
Chickpea Lectin

Background: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated. Methods: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic. Results: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 ҝg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. β-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril. Conclusion: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans.

scholarly journals HDAC4 promotes nasopharyngeal carcinoma progression and serves as a therapeutic target

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Chun Cheng ◽  
Jun Yang ◽  
Si-Wei Li ◽  
Guofu Huang ◽  
Chenxi Li ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Tumor Growth ◽  
Therapeutic Target ◽  
Histone Deacetylases ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
E Cadherin

AbstractHistone deacetylases (HDACs) are involved in tumor progression, and some have been successfully targeted for cancer therapy. The expression of histone deacetylase 4 (HDAC4), a class IIa HDAC, was upregulated in our previous microarray screen. However, the role of HDAC4 dysregulation and mechanisms underlying tumor growth and metastasis in nasopharyngeal carcinoma (NPC) remain elusive. Here, we first confirmed that the HDAC4 levels in primary and metastatic NPC tissues were significantly increased compared with those in normal nasopharyngeal epithelial tissues and found that high HDAC4 expression predicted a poor overall survival (OS) and progression-free survival (PFS). Functionally, HDAC4 accelerated cell cycle G1/S transition and induced the epithelial-to-mesenchymal transition to promote NPC cell proliferation, migration, and invasion in vitro, as well as tumor growth and lung metastasis in vivo. Intriguingly, knockdown of N-CoR abolished the effects of HDAC4 on the invasion and migration abilities of NPC cells. Mechanistically, HDAC3/4 binds to the E-cadherin promoter to repress E-cadherin transcription. We also showed that the HDAC4 inhibitor tasquinimod suppresses tumor growth in NPC. Thus, HDAC4 may be a potential diagnostic marker and therapeutic target in patients with NPC.

scholarly journals Operative ubiquitin-specific protease 22 deubiquitination confers a more invasive phenotype to cholangiocarcinoma

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Yu Tian ◽  
Bo Tang ◽  
Chengye Wang ◽  
Yan Wang ◽  
Jiakai Mao ◽  
...  
Keyword(s):  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Sirtuin 1 ◽  
Mesenchymal Transition ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Paired Tumour

AbstractOncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-β-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

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