scholarly journals 3,3′-Diindolylmethane Suppresses the Growth of Hepatocellular Carcinoma by Regulating Its Invasion, Migration and ER Stress-Mediated Mitochondrial Apoptosis

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1178
Author(s):  
Suvesh Munakarmi ◽  
Juna Shrestha ◽  
Hyun-Beak Shin ◽  
Geum-Hwa Lee ◽  
Yeon-Jun Jeong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Er Stress ◽  
Hepatoma Cell ◽  
Biologically Active ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Huh7 Cells ◽  
Anti Cancer

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide with limited treatment options. Biomarker-based active phenolic flavonoids isolated from medicinal plants might shed some light on potential therapeutics for treating HCC. 3,3′-diindolylmethane (DIM) is a unique biologically active dimer of indole-3-carbinol (I3C), a phytochemical compound derived from Brassica species of cruciferous vegetables—such as broccoli, kale, cabbage, and cauliflower. It has anti-cancer effects on various cancers such as breast cancer, prostate cancer, endometrial cancer, and colon cancer. However, the molecular mechanism of DIM involved in reducing cancer risk and/or enhancing therapy remains unknown. The aim of the present study was to evaluate anti-cancer and therapeutic effects of DIM in human hepatoma cell lines Hep3B and HuhCell proliferation was measured with MTT and trypan blue colony formation assays. Migration, invasion, and apoptosis were measured with Transwell assays and flow cytometry analyses. Reactive oxygen species (ROS) intensity and the loss in mitochondrial membrane potential of Hep3B and Huh7 cells were determined using dihydroethidium (DHE) staining and tetramethylrhodamine ethyl ester dye. Results showed that DIM significantly suppressed HCC cell growth, proliferation, migration, and invasion in a concentration-dependent manner. Furthermore, DIM treatment activated caspase-dependent apoptotic pathway and suppressed epithelial–mesenchymal transition (EMT) via ER stress and unfolded protein response (UPR). Taken together, our results suggest that DIM is a potential anticancer drug for HCC therapy by targeting ER-stress/UPR.

scholarly journals The Synergistic Anti-Cancer Effects of NVP-BEZ235 and Regorafenib in Hepatocellular Carcinoma

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2454
Author(s):  
Cheng-Chan Yu ◽  
Sung-Ying Huang ◽  
Shu-Fang Chang ◽  
Kuan-Fu Liao ◽  
Sheng-Chun Chiu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Western Blot ◽  
Kinase Inhibitor ◽  
Epithelial Mesenchymal Transition ◽  
Combined Treatment ◽  
Gelatin Zymography ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Mesenchymal Transition ◽  
Anti Cancer

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Regorafenib is a multi-kinase inhibitor and the second-line treatment for HCC. Since the PI3K/Akt/mTOR signaling pathway is dysregulated in HCC, we evaluated the therapeutic effects of regorafenib combined with a dual PI3K/mTOR inhibitor BEZ235 in the human HCC cell lines (n = 3). The combined treatment with BEZ235 and regorafenib enhanced the inhibition of cell proliferation and increased the expression of cleaved caspase-3 and cleaved PARP in HCC cells. Moreover, the combined treatment suppressed HCC cell migration and invasion in the transwell assay. Further, the Western blot analyses confirmed the involvement of epithelial-mesenchymal transition (EMT)-related genes such as slug, vimentin, and matrix metalloproteinase (MMP)-9/-2. Additionally, the proteinase activity of MMP-9/-2 was analyzed using gelatin zymography. Furthermore, the inhibition of phosphorylation of the Akt, mTOR, p70S6K, and 4EBP1 after combined treatment was validated using Western blot analysis. Therefore, these results suggest that the combined treatment with BEZ235 and regorafenib benefits patients with HCC.

scholarly journals Anti-Cancer Effects of Glaucarubinone in the Hepatocellular Carcinoma Cell Line Huh7 via Regulation of the Epithelial-To-Mesenchymal Transition-Associated Transcription Factor Twist1

2021 ◽  
Vol 22 (4) ◽  
pp. 1700
Author(s):  
Jihye Seo ◽  
Jain Ha ◽  
Eunjeong Kang ◽  
Haelim Yoon ◽  
Sewoong Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Wound Healing ◽  
Transcription Factor ◽  
Cell Migration ◽  
Cell Line ◽  
Intracellular Signaling ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Huh7 Cells ◽  
Anti Cancer

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is a leading cause of cancer-related deaths. As HCC has a high mortality rate and its incidence is increasing worldwide, understanding and treating HCC are crucial for resolving major public health concerns. In the present study, wound healing screening assays were performed using natural product libraries to identify natural chemicals that can inhibit cancer cell migration. Glaucarubinone (GCB) showed a high potential for inhibiting cell migration. The anti-cancer effects of GCB were evaluated using the HCC cell line, Huh7. GCB showed anti-cancer effects, as verified by wound healing, cell migration, invasion, colony formation, and three-dimensional spheroid invasion assays. In addition, cells treated with GCB showed suppressed matrix metalloproteinase activities. Immunoblotting analyses of intracellular signaling pathways revealed that GCB regulated the levels of Twist1, a crucial transcription factor associated with epithelial-to-mesenchymal transition, and mitogen-activated protein kinase. The invasive ability of cancer cells was found to be decreased by the regulation of Twist1 protein levels. Furthermore, GCB downregulated phosphorylation of extracellular signal-regulated kinase. These results indicate that GCB exhibits anti-metastatic properties in Huh7 cells, suggesting that it could be used to treat HCC.

scholarly journals microRNA-16 via Twist1 inhibits EMT induced by PM2.5 exposure in human hepatocellular carcinoma

Open Medicine ◽  
2019 ◽  
Vol 14 (1) ◽  
pp. 673-682 ◽  
Author(s):  
Hao Zhang ◽  
Zhihu Li
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Line ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Human Hepatocellular Carcinoma ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Mesenchymal Transition

AbstractEpidemiological study has confirmed that PM2.5 (particulate matter with an aerodynamic diameter less than 2.5 μm) is associated with the incidence and progression of human hepatocellular carcinoma (HCC). Accordingly, this study was undertaken to investigate the pro-metastatic effects of PM2.5 on human HCC cell line SMMC-7721 in vitro and to explore the underlying mechanisms. CCK-8 assay was performed to examine the effect of PM2.5 on the proliferation of SMMC-7721 cells; scratch wound assay and transwell matrigel system has been used to examine the effect of PM2.5 on the migration and invasion ability of SMMC-7721 cells; furthermore, effect of PM2.5 on epithelial mesenchymal transition (EMT) of SMMC-7721 cells were examined by examining the EMT markers vimentin, ɑ-smooth muscle actin (ɑ-SMA), and E-cadherin; furthermore, the roles of microRNA-16 (miR-16) and its target Twist1 in PM2.5 induced carcinogenic effects were also examined. Results of CCK-8 assay suggested that PM2.5 promoted the proliferation of SMMC-7721 cells in a dose and time dependent manner. PM2.5 also markedly promoted the migration and invasion ability of SMMC-7721 cells. Moreover, epithelial mesenchymal transition (EMT) was also triggered by PM2.5. On the other hand, microRNA-16 (miR-16) and its target Twist1 was found to be mediated by PM2.5, and miR-16 mimic could suppress the metastatic ability of SMMC-7721 cells exposure to PM2.5 via inversely regulating the expression of Twist1. Furthermore, dual Luciferase reporter assay confirmed the specifically binding of miR-16 to the predicted 3′-UTR of Twist1. The present study confirmed the pro-proliferative and pro-metastatic effect of PM2.5 on HCC cell line SMMC-7721. The possible mechanisms were EMT process induced by PM2.5 in SMMC-7721 cells, which was accompanied by a decrease in miR-16 and increase in Twist1 expression.

scholarly journals Upregulation of PD-L1 expression promotes epithelial-to-mesenchymal transition in sorafenib-resistant hepatocellular carcinoma cells

2020 ◽  
Vol 8 (5) ◽  
pp. 390-398
Author(s):  
Gui-Li Xu ◽  
Cai-Fang Ni ◽  
Han-Si Liang ◽  
Yun-Hua Xu ◽  
Wan-Sheng Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Regulatory Element ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Knock Down ◽  
Huh7 Cells ◽  
Element Binding Protein ◽  
Hcc Cells ◽  
E Cadherin

Abstract Background The epithelial-to-mesenchymal transition (EMT) status is associated with programmed death-1 ligand 1 (PD-L1) expression in various cancers. However, the role and molecular mechanism of PD-L1 in the EMT of sorafenib-resistant hepatocellular carcinoma (HCC) cells remain elusive. In this study, we aimed to investigate the regulation of PD-L1 on the EMT in sorafenib-resistant HCC cells. Methods Initially, the sorafenib-resistant HCC cell lines HepG2 SR and Huh7 SR were established. Western-blot assays were used to detect the expression of PD-L1, E-cadherin, and N-cadherin. The intervention and overexpression of PD-L1 were used to explore the role of PD-L1 in the regulation of EMT in HepG2 SR and Huh7 SR cells. Cell migration and invasion were assessed by transwell assays. PD-L1 or Sterol regulatory element-binding protein 1 (SREBP-1) overexpression and knock-down were performed in order to study the mechanism of PD-L1 in sorafenib-resistant HCC cells. Results PD-L1 expression was upregulated, whereas E-cadherin levels were downregulated and N-cadherin expression was increased in HepG2 SR and Huh7 SR cells. The cell viabilities of HepG2 and Huh7 cells were lower than those of HepG2 SR and Huh7 SR cells. PD-L1 overexpression reduced E-cadherin expression and increased N-cadherin levels, whereas PD-L1 knock-down increased E-cadherin expression and decreased N-cadherin expression. PD-L1 expression promoted EMT and the migratory and invasive abilities of HepG2 SR and Huh7 SR cells. PD-L1 promoted the EMT of sorafenib-resistant HCC cells via the PI3K/Akt pathway by activating SREBP-1 expression in HepG2 SR and Huh7 SR cells. Conclusions The findings reveal that PD-L1 expression promotes EMT of sorafenib-resistant HCC cells.

scholarly journals 3BDO Inhibits proliferation, epithelial–mesenchymal transition (EMT) and stemness via suppressing survivin in human glioblastoma cells

2021 ◽  
Author(s):  
zhaotao wang ◽  
yongping Li ◽  
minyi liu ◽  
danmin chen ◽  
yunxiang ji ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Xenograft Mouse Model

Abstract BackgroundGlioblastoma (GBM) is a tumor of the central nervous system carries an extremely poor prognosis. Unfortunately, it also is the most frequently encountered tumor in this region. These tumors arise from glioblastoma stem cells (GSCs), which are glioma cells that are known to possess high degrees of stemness. GBM invades through the process of EMT, which features loss of cell differentiation and polarity. Survivin is a type of apoptotic inhibitor that has been characterized in several malignancies such as glioma. Normal tissues rarely express survivin. On the other hand, 3-benzyl-5-((2-nitrophenoxy) methyl) dihydrofuran-2(3H)-one (3BDO) represents an autophagy inhibitor and activates the mTOR pathway. It has been reported that 3BDO shows anti-cancer activities in lung carcinoma. However, the effects of 3BDO on GBM reminds unknown. Therefore, the purpose of this study was to explore the role and molecular mechanisms that 3BDO mediates in GBM.MethodCCK-8 experiments and clone formation assay were performed to detect the cell proliferation. Transwell assay was conducted to examined cell migration and invasion. Western blotting and immunofluorescence staining was used to analyze protein expression levels. Xenograft mouse model was used to evaluate the effect of 3BDO in vivo.ResultsWe found that 3BDO inhibited U87 and U251 cell proliferation in a dose-dependent manner. Additonally, 3BDO decreased the sphere formation and stemness markers (sox2, nestin and CD133) in GSCs. 3BDO also inhibited migration, invasion and suppressed EMT markers (N-cadherin, vimentin and snail) in GBM cells. Moreover, we found that 3BDO downregulated survivin expression of survivin both in GBM cells (U87, U251) and GSCs. Furthermore, overexpression of survivin reduced the therapeutic effects of 3BDO on GBM cell EMT, invasion, migration and proliferation, as well as decreased stemness in GSCs. Finally, we demonstrated that 3BDO inhibited tumor growth in a tumor xenograft mouse model constructed using U87 cells. Similar to the in vitro findings, 3BDO diminished suvivin expression, stemness and levels of EMT makers in vivo.Conclusionsour results demonstrated that 3BDO repressed GBM via downregulating survivin-mediated stemness and EMT both in vitro and in vivo.

Emodin Inhibits the Growth and Invasion and Induces Apoptosis and Autophagy in Hepatocellular Carcinoma via PI3K/AKT/mTOR and Wnt/β-catenin Pathway

2021 ◽  
Author(s):  
binyu qin ◽  
Zhili Zeng ◽  
Jianliang Xu ◽  
Jing Shangwen ◽  
Zeng Jie Ye ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Western Blot ◽  
Hepg2 Cells ◽  
Cancer Metastasis ◽  
Migration And Invasion ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
The Impact

Abstract Background: Previous studies reported that emodin extracted from Rheum palmatum L. exerts antiproliferation and antimetastatic effects in a variety of human cancer types. However, the role of emodin in hepatocellular carcinoma (HCC) remain unknown.Methods: EdU and colony formation assays were performed to evaluate the effects of emodin on proliferation. The mobility capacities of HCC treated with emodin were evaluated using wound healing assay. Transwell invasion and migration assays were performed to evaluate anti-migratory and anti-invasive effects of emodin on HCC. Annexin V-FITC/PI was performed to analyze the apoptosis. PI stain was performed to analyze cell cycle. RNA sequencing technology was used to identify the differentially expressed genes (DEGs) induced by emodin in HCC. The impact of emodin on autophagic flux in HepG2 cells was examined by mCherry-GFP-LC3 analysis. Western blot was used to assess the protein expressions of epithelial-mesenchymal transition (EMT), autophagy, PI3K/AKT/mTOR and Wnt/β-catenin signaling pathway.Results: We found that emodin inhibited the growth of HepG2 cells in a dose- and time-dependent manner. In addition, emodin inhibited cell proliferation, induced S and G2/M phases arrest, and promoted apoptosis in HepG2 cells. The migration and invasion of HepG2 cells were also suppressed by emodin. Enrichment analysis revealed that DEGs involved in cell adhesion, cancer metastasis and cell cycle arrest. Moreover, western blot and bioinformatics analysis indicated that emodin induced autophagy and inhibited the EMT in part through suppression of the PI3K/AKT/mTOR and Wnt/β-catenin pathways. Conclusion: Our study indicated that emodin inhibited cell metastasis in HCC via the crosstalk between autophagy and EMT.

scholarly journals NCSTN promotes hepatocellular carcinoma cell growth and metastasis via β-catenin activation in a Notch1/AKT dependent manner

2020 ◽  
Author(s):  
Hui Li ◽  
Tian Lan ◽  
Lin Xu ◽  
Hailing Liu ◽  
Jinju Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Growth ◽  
Nuclear Translocation ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Gsk 3Β

Abstract Background Hepatocellular carcinoma is the third top cause of cancer-related mortalities worldwide. The prognosis of HCC patients remains poor due to rapid progression and high incidence of tumor recurrence. Nicastrin (NCSTN), a core subunit of γ-Secretase, has been reported to play a vital role in tumor progression. However, no study till now has revealed its role in HCC. Methods The expression of NCSTN was evaluated by immunohistochemical staining, Western blot, and quantitative real-time PCR. Cell counting kit-8, colony formation and cell cycle assays were used for evaluating cell growth in vitro. Transwell and wound-healing assays were used for evaluating cell migration and invasion capacity. Immunofluorescence, subcellular protein fractionation and co-immunoprecipitation were used for location analysis of β-catenin. The in vivo functions of NCSTN were illustrated by xenograft tumor models. Results NCSTN was dramatically overexpressed in HCC compared to normal liver tissues. Elevated NCSTN expression level was significantly correlated to worse overall and recurrence-free survival of HCC patients. Enhanced NCSTN expression promoted HCC cell growth, migration and invasion in vitro and in vivo. Mechanistic investigations showed that NCSTN induced epithelial-mesenchymal transition (EMT) process via upregulation of Zeb1. Subsequently, we revealed that NCSTN facilitated nuclear translocation of β-catenin, a positive transcriptional regulator of Zeb1. Using Notch and AKT inhibitors, we revealed that NCSTN promoted β-catenin activation through Notch1 and AKT signaling pathway. NCSTN increased AKT and GSK-3β phosphorylation by cleavage of Notch1, which decreased GSK-3β/β-catenin complex. The inactivation of GSK-3β inhibited the β-catenin degradation and promoted nuclear translocation of β-catenin to initiate transcription of Zeb1, resulting in malignant phenotype. Conclusions Our results demonstrated that NCSTN promoted HCC cell growth and metastasis via β-catenin-mediated upregulation of Zeb1 in a Notch1/AKT dependent manner, suggesting that NCSTN might serve as a potential prognostic marker and therapeutic target for HCC.

scholarly journals Quantitative Analysis of Tissue Secretome Reveals the Diagnostic and Prognostic Value of Carbonic Anhydrase II in Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Xiaohua Xing ◽  
Hui Yuan ◽  
Hongzhi Liu ◽  
Xionghong Tan ◽  
Bixing Zhao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Carbonic Anhydrase ◽  
Epithelial Mesenchymal Transition ◽  
Carbonic Anhydrase Ii ◽  
Migration And Invasion ◽  
Secretory Proteins ◽  
Therapeutic Effects ◽  
Absolute Quantitation ◽  
Term Survival ◽  
Mesenchymal Transition

AbstractEarly detection and intervention are key strategies to reduce mortality, increase long-term survival and improve the therapeutic effects of hepatocellular carcinoma (HCC) patients. Herein, the isobaric tag for relative and absolute quantitation (iTRAQ) quantitative proteomic strategy was used to study the secretome in conditioned media from HCC cancerous tissues, surrounding noncancerous and distal noncancerous tissues to identify diagnostic and prognostic biomarkers for HCC. In total, 22 and 49 secretory proteins were identified to be dysregulated in the cancerous and surrounding noncancerous tissues compared with the distal noncancerous tissues. Among these proteins, carbonic anhydrase II (CA2) was identified to be significantly upregulated in the secretome of cancerous tissues; correspondingly, the serum concentrations of CA2 were remarkably increased in HCC patients than that in normal populations. Interestingly, a significant increase of serum CA2 in recurrent HCC patients after radical resection was also confirmed compared with HCC patients without recurrence, and the serum level of CA2 could act as an independent prognostic factor for time to recurrence (TTR) and overall survival (OS). Regarding the mechanism, the secreted CA2 enhances the migration and invasion of HCC cells by activating the epithelial mesenchymal transition (EMT) pathway. Taken together, this study identified a novel biomarker for HCC diagnosis and prognosis and provides a valuable resource of the HCC secretome for investigating serological biomarkers.

scholarly journals Ligustrazine inhibits the proliferation and migration of ovarian cancer cells via regulating miR-211

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Hairong Zhang ◽  
Shichao Ding ◽  
Lei Xia
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Anti Cancer ◽  
And Migration ◽  
The Impact ◽  
Proliferation And Migration

Abstract Ovarian cancer (OC) is a commonly diagnosed female cancer. Ligustrazine (LSZ), a natural compound, has been reported to exert anti-cancer activity, although the mechanisms underlying the anti-cancer effects are not clear. The present study investigated the impact of LSZ on cell proliferation and migration by regulating microRNA-211 (miR-211) expression using the human ovarian cancer SK-OV-3 and OVCAR-3 cell lines. OC cells were treated with 0, 0.5, 1, and 2 mM LSZ, and quantitative real-time PCR was utilized to measure miR-211 levels in SK-OV-3 and OVCAR-3 cells with different treatment. Moreover, to further confirm the roles of miR-211 in LSZ induced anti-tumor effects, miR-211 expression was inhibited by transfection of miR-211 inhibitors in SK-OV-3 cells. Cell proliferation of transfected cells was evaluated using the CCK-8 and colony formation assay. The scratch assay was employed to assess cell migration and transwell assay was performed for evaluating the cell invasion. Protein levels of epithelial–mesenchymal transition (EMT) markers were determined by Western blotting. We found that LSZ inhibited the viability, proliferation, migration and invasion ability of SK-OV-3 and OVCAR-3 cells in a dose-dependent manner; moreover, LSZ could significantly increase the expression of miR-211 in both SK-OV-3 and OVCAR-3, and knockdown of miR-211 in SK-OV-3 cells partially abrogated the anti-tumor behavior of LSZ by promoting the viability, proliferation, migration, invasion and EMT of SK-OV-3 cells. Thus, we found that LSZ can inhibit the proliferation and migration of OC cells via regulating miR-211. Our study suggests that LSZ might be a potential and effective treatment for OC.

scholarly journals The Chinese Medicine, Jiedu Recipe, Inhibits the Epithelial Mesenchymal Transition of Hepatocellular Carcinoma via the Regulation of Smad2/3 Dependent and Independent Pathways

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Shufang Liang ◽  
Yong Zou ◽  
Jingdong Gao ◽  
Xiaolin Liu ◽  
Wanfu Lin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Chinese Herb ◽  
Migration And Invasion ◽  
Transwell Assay ◽  
Mesenchymal Transition ◽  
Huh7 Cells ◽  
Effective Therapeutic Strategy ◽  
E Cadherin

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. In China, traditional Chinese herb medicine has been widely used in the treatment of HCC. Jiedu Recipe (JR) is a common used prescription which has shown good results against HCC. However, the exact mechanisms of JR are still unknown. Therefore, we investigated the efficacy of JR on HCC in the current study. JR inhibited the cell viability of both SMMC-7721 and Huh7 cells in both time- and dose-dependent manners. Transwell assay revealed that JR decreased the number of migrated cells of SMMC-7721 cells. JR treatment increased the E-cadherin expression level and decreased the levels of p-Smad2/3 and Smad2/3. Further study showed that JR reversed the effect of TGFβ1 on the expression of E-cadherin, vimentin, N-cadherin, and MMP2/9. JR also significantly inhibited TGFβ1-induced migration and invasion of SMMC-7721 and Huh7 cells determined by wound healing assay and transwell assay. TGFβ1 treatment increased the phosphorylation of Smad2/3, p38 MAPK, JNK, ERK1/2, and Akt in SMMC-7721 cells and pretreatment with JR blocked TGFβ1-induced activation of Smad2/3 and Akt and MAPKs. In conclusion, JR inhibits liver cancer cells migration and invasion through epithelial mesenchymal transition (EMT) inhibition via Smad2/3 dependent and independent pathways, suggesting it is an effective therapeutic strategy against HCC metastasis.

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