scholarly journals Vincosamide inhibits malignant behaviors of hepatocellular carcinoma cells by activating caspase-3 activity and blocking the PI3K/AKT signaling pathway

2020 ◽  
Author(s):  
Mingyue Zhu ◽  
Haipeng Feng ◽  
Bo Lin ◽  
Ying Zhou ◽  
Yifeng Zheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Tumor Model ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Mitochondrial Morphology ◽  
Mouse Tumor ◽  
Akt Signaling Pathway ◽  
Hcc Cells

Abstract Background Vincosamide(Vinco) was first identified in the methanolic extract of the leaves of Psychotria leiocarpa, and Vinco has important anti-inflammatory effects and activity against cholinesterase. However, whether Vinco inhibits the malignant behaviors of hepatocellular carcinoma(HCC) cells is still unclear. In the present study, we explored the role of Vinco in suppressing the malignant behaviors of HCC cells. Methods MTT and trypan blue exclusion assays were applied to detect the proliferation and death of HCC cells; electron microscopy was performed to observe change in cellular mitochondrial morphology; scratch repair and Transwell assays were used to analyze the migration and invasion of HCC cells; the expression and localization of proteins were detected by laser confocal microscopy and Western blotting; and the growth of the cancer cells in vivo was assessed in a mouse tumor model. Results At a dose of 10–80 µg/ml, Vinco inhibited the proliferation of HCC cells and promoted their apoptosis in a time- and dose-independent manner but had little effect on normal liver cells. Additionally, 80 µg/ml Vinco significantly disrupted the morphology of mitochondria and suppressed the migration and invasion of HCC cells. The growth of HCC cells in the animal tumor model was significantly inhibited after treatment with Vinco (10 mg/kg/day) for 3 days. The results of the present study indicate that Vinco (10–80 µg/ml) plays novel roles in activating caspase-3, promoting the expression of PTEN, and inhibiting the phosphorylation of AKT(Ser 473) and mTOR (Thr2448) and that Vinco was able to also suppress the expression of CXCR4, Src, MMP9, EpCAM, Ras and Oct4 in HCC cells. Conclusions Vinco plays a role in inhibiting the malignant behaviors of HCC cells, and the molecular mechanism may involve in suppressing the expression of the growth-, metastasis-related factors Src, Ras, MMP9, EpCAM and CXCR4 and activating the activity of caspase-3. Vinco also blocks the PI3K/AKT signaling pathway. Thus, Vinco is an available chemotherapy for HCC patients.

Vincosamide inhibits malignant behaviors of hepatocellular carcinoma cells by activating caspase-3 activity and blocking the PI3K/AKT signaling pathway

2020 ◽  
Author(s):  
Mingyue Zhu ◽  
Haipeng Feng ◽  
Bo Lin ◽  
Ying Zhou ◽  
Yifeng Zheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Caspase 3 ◽  
Akt Signaling ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Mitochondrial Morphology ◽  
Akt Signaling Pathway ◽  
Related Factors ◽  
Hcc Cells

Abstract Background: Vincosamide(Vinco) was first identified in the methanolic extract of the leaves of Psychotria leiocarpa, and Vinco has important anti-inflammatory effects and activity against cholinesterase, Vinco also has a trait to ant-tumor. However, whether Vinco is able to inhibit the malignant behaviors of hepatocellular carcinoma(HCC) cells is still unclear. In the present study, we explored the role of Vinco in suppressing the malignant behaviors of HCC cells.Methods: MTT, trypan blue exclusion assay and the Cell Counting Kit(CCK)-8 analysis were applied to detect the proliferation and death of HCC cells; electron microscopy was performed to observe the change of cellular mitochondrial morphology; scratch repair and Transwell assays were used to analyze the migration and invasion of HCC cells; the expression and localization of proteins were detected by laser confocal microscopy and Western blotting; and the growth of the cancer cells in in vivo was assessed in a mouse tumorous model.Results: At a dose of 10-80 mg/ml, Vinco inhibited the proliferation and promoted death of HCC cells in a dose-independent manner, but had low cytotoxcity effect on normal liver cells. Additionally, 80 mg/ml of Vinco could significantly disrupt the morphology of mitochondria, suppress the migration and invasion of HCC cells. The growth of HCC cells in the animal tumorous model was significantly inhibited after treatment with Vinco (10 mg/kg/day) for 3 days. The results of the present study indicated that Vinco (10-80 mg/ml) played a role in activating caspase-3, promoting the expression of PTEN, and inhibiting the phosphorylation of AKT(Ser473) and mTOR(Thr2448), Vinco also has a trait for suppressing the expression of CXCR4, Src, MMP9, EpCAM, Ras and Oct4 in HCC cells.Conclusions: Vinco has a role in inhibiting the malignant behaviors of HCC cells; the role molecular mechanism of Vinco maybe involve in restraining expression of the growth-, metastasis-related factors Src, Ras, MMP9, EpCAM and CXCR4, and activating the activity of caspase-3. Vinco also could block PI3K/AKT signaling pathway. Thus, Vinco is an available chemotherapy for HCC patients.

scholarly journals Silence of long non-coding RNA KCNQ1OT1 inhibits the proliferation, migration and invasion of hepatocellular carcinoma cells through PI3K/AKT signaling pathway

2020 ◽  
Author(s):  
Hongliang Mei ◽  
Zhiguo Yu ◽  
Guanqi Zhang ◽  
Zhiyuan Huang ◽  
Hanjun Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Negative Impact ◽  
Akt Signaling ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Potential Biomarker

Abstract Background: KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) has been reported to be associated with hepatocellular carcinoma (HCC), which is considered as one of the most common cancers worldwide. However, the mechanism of action of KCNQ1OT1 in human HCC has not been fully explained. In this study, we aimed to explore the functional role and the potential mechanism of KCNQ1OT1 in human HCC.Methods: First, we analyzed the expression levels of KCNQ1OT1 in HCC tissues in starBase database and detected the expression of KCNQ1OT1 in HCC cell lines by quantitative real-time polymerase chain reaction assays. Next, we analyzed the role of KCNQ1OT1 in migration, invasion and proliferation of HCC by scratch wound healing, transwell and cell counting kit-8 assays. Finally, we analyzed the potential interrelationship between KCNQ1OT1 and PI3K/AKT signaling pathway through western blot assays.Results: Based on bioinformatics analyses, we found that KCNQ1OT1 was highly expressed in HCC tissues and its high expression was associated with a poor prognosis in HCC patients. We also confirmed an abnormal increase in the expression of KCNQ1OT1 in HCC cell lines. KCNQ1OT1 knockdown was found to have a negative impact on proliferation, migration and invasion of HCC cells. In addition, interference with the expression of KCNQ1OT1 reduced the phosphorylation level of AKT and the protein level of PI3K, indicating the association of KCNQ1OT1 with the PI3K/AKT signaling pathway.Conclusions: Collectively, this study confirmed the important role of KCNQ1OT1 in promoting HCC growth and revealed the inhibitory effect of KCNQ1OT1 on the PI3K/AKT signaling pathway. This work may contribute to a better understanding of HCC progression and provide a potential biomarker for HCC.

scholarly journals SERMs (selective estrogen receptor modulator), acting as estrogen receptor β agonists in hepatocellular carcinoma cells, inhibit the transforming growth factor-α-induced migration via specific inhibition of AKT signaling pathway

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262485
Author(s):  
Rie Matsushima-Nishiwaki ◽  
Noriko Yamada ◽  
Yuria Hattori ◽  
Yui Hosokawa ◽  
Junko Tachi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Estrogen Receptor ◽  
Cell Migration ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Receptor Modulator ◽  
Hcc Cells

Selective estrogen receptor modulator (SERM) interacts with estrogen receptors and acts as both an agonist or an antagonist, depending on the target tissue. SERM is widely used as a safer hormone replacement therapeutic medicine for postmenopausal osteoporosis. Regarding hepatocellular carcinoma (HCC), accumulating evidence indicates gender differences in the development, and that men are at higher morbidity risk than premenopausal women, suggesting that estrogen protects against HCC. However, it remains unclear whether SERM affects the HCC progression. Previously, we have shown that transforming growth factor (TGF)-α promotes the migration of HCC cells via p38 mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase and AKT. In the present study, we investigated whether SERM such as tamoxifen, raloxifene and bazedoxifene, affects the HCC cell migration using human HCC-derived HuH7 cells. Raloxifene and bazedoxifene but not tamoxifen, significantly suppressed the TGF-α-induced HuH7 cell migration. ERB041 and DPN, estrogen receptor (ER) β agonists, inhibited the TGF-α-induced cell migration whereas PPT, an ERα agonist, did not show the suppressive effect on the cell migration. ERB041 attenuated the TGF-α-induced phosphorylation of AKT without affecting the phosphorylation of p38 MAPK and c-Jun N-terminal kinase. Raloxifene and bazedoxifene also inhibited the phosphorylation of AKT by TGF-α. Furthermore, PHTPP, an ERβ antagonist, significantly reversed the suppression by both raloxifene and bazedoxifene of the TGF-α-induced cell migration. Taken together, our results strongly indicate that raloxifene and bazedoxifene, SERMs, suppress the TGF-α-induced migration of HCC cells through ERβ-mediated inhibition of the AKT signaling pathway.

scholarly journals TFAP4 Promotes Hepatocellular Carcinoma Invasion and Metastasis via Activating the PI3K/AKT Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Tao Huang ◽  
Qi-Feng Chen ◽  
Bo-Yang Chang ◽  
Lu-Jun Shen ◽  
Wang Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Disease Free Survival ◽  
Akt Signaling ◽  
Migration And Invasion ◽  
Akt Signaling Pathway ◽  
Invasion And Metastasis ◽  
Term Survival ◽  
Mesenchymal Transition ◽  
Tumor Tissues

Transcription factor activating enhancer binding protein 4 (TFAP4) is established as a regulator of human cancer genesis and progression. Overexpression of TFAP4 indicates poor prognosis in various malignancies. The current study was performed to quantify TFAP4 expression as well as to further determine its potential prognostic value and functional role in patients with hepatocellular carcinoma (HCC). We identified that the expression of TFAP4 mRNA in 369 tumor tissues was higher than that in 160 normal liver tissues. Upregulated TFAP4 expressions were discovered in HCC cell lines compared to the healthy liver cell line, and similarly, the levels of TFAP4 were higher in tumor tissues than its expression in paratumor tissues. High mRNA and protein expression of TFAP4 was associated with worse overall survival (OS) and disease-free survival (DFS). Additionally, TFAP4 expression emerged as a risk factor independently affecting both OS and DFS of HCC patients. Functional studies demonstrated that TFAP4 increased HCC cell migration and invasion. Further investigations found that TFAP4 promotes invasion and metastasis by inducing epithelial-mesenchymal transition (EMT) and regulating MMP-9 expression via activating the PI3K/AKT signaling pathway in HCC. In conclusion, our study demonstrated that TFAP4 is a valuable prognostic biomarker in determining the likelihood of tumor metastasis and recurrence, as well as the long-term survival rates of HCC patients. Exploring the regulatory mechanism of TFAP4 will also contribute to the development of new prevention and treatment strategies for HCC.

scholarly journals Pharmacological Mechanisms Underlying the Hepatoprotective Effects of Ecliptae herba on Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Botao Pan ◽  
Wenxiu Pan ◽  
Zheng Lu ◽  
Chenglai Xia
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Network Pharmacology ◽  
Akt Signaling Pathway ◽  
Active Ingredients ◽  
Hepatoprotective Effects ◽  
Hcc Cells

Background. The number of hepatocellular carcinoma (HCC) cases worldwide has increased significantly. As a traditional Chinese medicine (TCM) with a long history, Ecliptae herba (EH) has been widely used in HCC patients in China, but its hepatoprotective mechanism is still unclear. Methods. In this study, we applied a network pharmacology-based strategy and experimental verification to systematically unravel the underlying mechanisms of EH against HCC. First, six active ingredients of EH were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) by the ADME method. Subsequently, 52 potential targets of 6 active ingredients acting on HCC were screened from various databases, including TCMSP, DGIdb, SwissTargetPrediction, CTD, and GeneCards. Then, by constructing protein-protein interaction (PPI) network from STRING, we displayed the intricate connections among these 52 targets through Cytoscape software. We also applied enrichment analysis, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, to provide an outline and set of concepts for describing gene functions and the advanced functions of biological systems of these 52 targets from genomic and molecular level information. Finally, molecular docking and biological experiments were used to reconfirm these results. Results. We hypothesized that EH might exert anti-HCC activity by acting on hub genes, including RELA, MMP9, PTGS2, ESR1, EGFR, AR, AKT1, HIF1A, AHR, CYP3A4, ABCG2, and MMP2. Moreover, based on GO and KEGG analysis, we speculated that EH may exert hepatoprotective effects on HCC through the following mechanisms: regulation of the PI3K-AKT signaling pathway to promote apoptosis and inhibit the abnormal proliferation of HCC, downregulation of HIF-1A expression by activating the HIF-1 signaling pathway, prevention of HCC by regulating lipid metabolism, and inhibition of nonalcoholic fatty liver disease (NAFLD) by the cytochrome P450 subfamily. Subsequent biological experiments verified that EH inhibits the PI3K-AKT signaling pathway through its active ingredients, quercetin, and wedelolactone, thereby inhibiting the proliferation of HCC cells and promoting the apoptosis of HCC cells. Conclusions. The network pharmacological strategy provides an efficient method to systematically explore the pharmacological mechanism of EH in HCC. Our study demonstrated that the anti-HCC proliferation activity of EH is mainly exerted by two active ingredients (quercetin and wedelolactone), which inhibit the proliferation of HCC cells (HepG2 and Huh-7) by inhibiting PI3K-AKT signaling.

scholarly journals Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition

2021 ◽  
Vol 9 ◽  
Author(s):  
Cong Wang ◽  
Chuzhi Shang ◽  
Xiaohong Gai ◽  
Tao Song ◽  
Shaoshan Han ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Epithelial To Mesenchymal Transition ◽  
Akt Signaling ◽  
The Cancer Genome Atlas ◽  
Luciferase Reporter ◽  
Akt Signaling Pathway ◽  
Mesenchymal Transition ◽  
Hcc Cells

BackgroundSulfatase 2 (SULF2) removes the 6-O-sulfate groups from heparan sulfate proteoglycans (HSPG) and consequently alters the binding sites for various signaling molecules. Here, we elucidated the role of SULF2 in the differentiation of hepatic stellate cells (HSCs) into carcinoma-associated fibroblasts (CAFs) in the hepatocellular carcinoma (HCC) microenvironment and the mechanism underlying CAF-mediated HCC growth.MethodsThe clinical relevance of SULF2 and CAFs was examined using in silico and immunohistochemical (IHC) analyses. Functional studies were performed to evaluate the role of SULF2 in the differentiation of HSCs into CAFs and elucidate the mechanism underlying CAF-mediated HCC growth. Mechanistic studies were performed using the chromatin immunoprecipitation, luciferase reporter, and RNA immunoprecipitation assays. The in vitro findings were verified using the nude HCC xenograft mouse model.ResultsThe Cancer Genome Atlas (TCGA) database and IHC analyses revealed that the expression of CAF markers, which was positively correlated with that of SULF2 in the HCC tissues, predicted unfavorable postsurgical outcomes. Co-culturing HSCs with HCC cells expressing SULF2 promoted CAF differentiation. Additionally, CAFs repressed HCC cell apoptosis by activating the SDF-1/CXCR4/PI3K/AKT signaling pathway. Meanwhile, SULF2-induced CAFs promoted epithelial-to-mesenchymal transition (EMT) of HCC cells by modulating the SDF-1/CXCR4/OIP5-AS1/miR-153-3p/SNAI1 axis. Studies using HCC xenograft mouse models demonstrated that OIP5-AS1 induced EMT by upregulating SNAI1 and promoted HCC growth in vivo.ConclusionThese data indicated that SULF2 secreted by the HCC cells induced the differentiation of HSCs into CAFs through the TGFβ1/SMAD3 signaling pathway. SULF2-induced CAFs attenuated HCC apoptosis by activating the SDF-1/CXCR4/PI3K/AKT signaling pathway and induced EMT through the SDF-1/CXCR4/OIP5-AS1/miR-153-3p/SNAI1 axis. This study revealed a novel mechanism involved in the crosstalk between HCC cells and CAFs in the tumor microenvironment, which can aid in the development of novel and efficient therapeutic strategies for primary liver cancer.

scholarly journals AEG-1/miR-221 Axis Cooperatively Regulates the Progression of Hepatocellular Carcinoma by Targeting PTEN/PI3K/AKT Signaling Pathway

2019 ◽  
Vol 20 (22) ◽  
pp. 5526 ◽  
Author(s):  
Maheshkumar Kannan ◽  
Sridharan Jayamohan ◽  
Rajesh Kannan Moorthy ◽  
Siva Chander Chabattula ◽  
Mathan Ganeshan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Migration Assay ◽  
Cycle Arrest ◽  
Significant Expression ◽  
Induced Apoptosis ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is the third leading malignancy worldwide, causing mortality in children and adults. AEG-1 is functioned as a scaffold protein for the proper assembly of RNA-induced silencing complex (RISC) to optimize or increase its activity. The increased activity of oncogenic miRNAs leads to the degradation of target tumor suppressor genes. miR-221 is an oncogenic miRNA, that plays a seminal role in carcinogenesis regulation of HCC. However, the molecular mechanism and biological functions of the miR-221/AEG-1 axis have not been investigated extensively in HCC. Here, the expression of miR-221/AEG-1 and their target/associate genes was analyzed by qRT-PCR and Western blot. The role of the miR-221/AEG-1 axis in HCC was evaluated by proliferation assay, migration assay, invasion assay, and flow cytometry analysis. The expression level of miR-221 decreased in AEG-1 siRNA transfected HCC cells. On the other hand, there were no significant expression changes of AEG-1 in miR-221 mimic and miR-221 inhibitor transfected HCC cells and inhibition of miR-221/AEG-1 axis decreased cell proliferation, invasion, migration, and angiogenesis and induced apoptosis, cell cycle arrest by upregulating p57, p53, PTEN, and RB and downregulating LSF, MMP9, OPN, Bcl-2, PI3K, AKT, and LC3A in HCC cells. Furthermore, these findings suggest that the miR-221/AEG-1 axis plays a seminal oncogenic role by modulating PTEN/PI3K/AKT signaling pathway in HCC. In conclusion, the miR-221/AEG-1 axis may serve as a potential target for therapeutics, diagnostics, and prognostics of HCC.

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