scholarly journals Molecular targets of Yangyin Fuzheng Jiedu Prescription in the treatment of hepatocellular carcinoma based on network pharmacology analysis

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Fengna Yan ◽  
Miaomiao Feng ◽  
Xinhui Wang ◽  
Peng Wang ◽  
Yuqing Xie ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Total Bilirubin Level ◽  
Scratch Test ◽  
Network Pharmacology ◽  
Tunel Staining ◽  
Red Blood Cell Count ◽  
Independent Risk Factors ◽  
Hcc Cells

Abstract Background Yangyin Fuzheng Jiedu Prescription (YFJP) is a traditional Chinese medicine (TCM) indicated for the treatment of hepatocellular carcinoma (HCC). Its potential targets and molecular mechanisms are not clear. Therefore, this study intends to explore the molecular mechanism of YFJP based on network pharmacology analysis and in vitro validation. Methods and results Through univariate and multivariate analyses and survival analysis in HCC patients with or without YFJP treatment we found that drinking alcohol, alfafeto protein ≥ 400 ng/l, baseline portal vein tumor thrombus and total bilirubin level ≥ 18.8 μM) were independent risk factors for poor prognosis, while red blood cell count ≥ 4 × 109/l and TCM treatment were independent protective factors. Besides, YFJP prolonged the cumulative survival of HCC patients. Using online pharmacological methods, we obtained 58 relevant compounds and molecular 53 targets. By using scratch test, Transwell assay, EdU assay, and TUNEL staining, we found that YFJP-containing serum repressed the migration, invasion and proliferation of HCC cells in vitro, and induced cell apoptosis. Moreover, YFJP diminished the gene expression of TP53, CCND1, p-EGFR, EGF, VEGFA, JUN, IL6, COX-2, AKT1, and MAPK1 in HCC cells, but elevated the expression of ESR1 and CASP3. Conclusions Taken together, results showed that YFJP attenuated HCC progression through mediating effects on HCC-related genes.

scholarly journals Bioinformatic and experimental findings to indicate anti-cancer targets and mechanisms of calycosin against nasopharyngeal carcinoma

2020 ◽  
Author(s):  
Fangxian Liu ◽  
Qijin Pan ◽  
Liangliang Wang ◽  
Shijiang Yi ◽  
Peng Liu ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Cell Number ◽  
Network Pharmacology ◽  
Tunel Staining ◽  
Pharmacological Targets ◽  
Experimental Findings

Abstract Background: Calycosin is a naturally-occurring phytoestrogen that reportedly exerts anti- nasopharyngeal carcinoma (NPC) effects. Nevertheless, the molecular mechanisms for anti-NPC using calycosin remain unrevealed. Methods: Thus, a network pharmacology was used to uncover anti-NPC pharmacological targets and mechanisms of calycosin. Additionally, validated experiments were conducted to validate the bioinformatic findings of calycosin for treating NPC. Results: As results, bioinformatic assays showed that the predictive pharmacological targets of calycosin against NPC were TP53, MAPK14, CASP8, MAPK3, CASP3, RIPK1, JUN, ESR1, respectively. And the top 20 biological processes and pharmacological mechanisms of calycosin against NPC were identified accordingly. In clinical data, NPC samples showed positive expression of MAPK14, reduced TP53, CASP8 expressions. In studies in vitro and in vivo, calycosin-dosed NPC cells resulted in reduced cell proliferation, promoted cell apoptosis. In TUNEL staining, calycosin exhibited elevated apoptotic cell number. And immunostaining assays resulted in increased TP53, CASP8 positive cells, and reduced MAPK14 expressions in calycosin-dosed NPC cells and tumor-bearing nude mice. Conclusion: Altogether, these bioinformatic findings reveal optimal pharmacological targets and mechanisms of calycosin against NPC, following with representative identification of human and preclinical experiments. Notably, some of original biotargets may be potentially used to treat NPC.

Integrating Network Pharmacology and Experimental Models to Investigate the Efficacy of Coptidis and Scutellaria Containing Huanglian Jiedu Decoction on Hepatocellular Carcinoma

2020 ◽  
Vol 48 (01) ◽  
pp. 161-182 ◽  
Author(s):  
Jihan Huang ◽  
Wei Guo ◽  
Fan Cheung ◽  
Hor-Yue Tan ◽  
Ning Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Experimental Models ◽  
Network Pharmacology ◽  
Disease Networks ◽  
Cycle Arrest ◽  
Single Target ◽  
Induced Apoptosis

Unlike Western medicines with single-target, the traditional Chinese medicines (TCM) always exhibit diverse curative effects against multiple diseases through its “multi-components” and “multi-targets” manifestations. However, discovery and identification of the major therapeutic diseases and the underlying molecular mechanisms of TCM remain to be challenged. In the current study, we, for the first time, applied an integrated strategy by combining network pharmacology with experimental evaluation, for exploration and demonstration of the therapeutic potentials and the underlying possible mechanisms of a classic TCM formula, Huanglian Jiedu decoction (HLJDD). First, the herb–compound, compound–protein, protein–pathway, and gene–disease networks were constructed to predict the major therapeutic diseases of HLJDD and explore the underlying molecular mechanisms. Network pharmacology analysis showed the top one predicted disease of HLJDD treatment was cancer, especially hepatocellular carcinoma (HCC) and inflammation-related genes played an important role in the treatment of HLJDD on cancer. Next, based on the prediction by network pharmacology analysis, both in vitro HCC cell and in vivo orthotopic HCC implantation mouse models were established to validate the curative role of HLJDD. HLJDD exerted its antitumor activity on HCC in vitro, as demonstrated by impaired cell proliferation and colony formation abilities, induced apoptosis and cell cycle arrest, as well as inhibited migratory and invasive properties of HCC cells. The orthotopic HCC implantation mouse model further demonstrated the remarkable antitumour effects of HLJDD on HCC in vivo. In conclusion, our study demonstrated the effectiveness of integrating network pharmacology with experimental study for discovery and identification of the major therapeutic diseases and the underlying molecular mechanisms of TCM.

scholarly journals Long noncoding RNA CASC2c inhibited cell proliferation in hepatocellular carcinoma by inactivated ERK1/2 and Wnt/β-catenin signaling pathway

2019 ◽  
Vol 22 (3) ◽  
pp. 302-310 ◽  
Author(s):  
Q. Y. Li ◽  
K. Yang ◽  
F. G. Liu ◽  
X. G. Sun ◽  
L. Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Cancer Susceptibility ◽  
Vital Role ◽  
Migration And Invasion ◽  
Tumor Tissues ◽  
Hcc Cells

Abstract Purpose Long non-coding RNAs (lncRNAs) have been shown to play important roles in tumorigenesis, but their biological functions and the underlying molecular mechanisms remain unclear. Alternative splicing of five exons results in three transcript variants of cancer susceptibility 2 (CASC2): the lncRNAs CASC2a, CASC2b, and CASC2c. CASC2a/b have been found to have crucial regulatory functions in a number of malignancies, but few studies have examined the effects of CASC2c in cancers. The objective of the study was to investigate the role of CASC2c in the proliferation and apoptosis of hepatocellular carcinoma (HCC) cells. Methods This study first investigated the expression levels of CASC2c in tumor tissues, corresponding non-tumor tissues and cells using quantitative real-time polymerase chain reaction. The function and underlying molecular mechanism of CASC2c in human HCC were investigated in QGY-7703 cell line, as well as in gastric cancer (GC) cell and colorectal cancer (CRC) cell. Results In the present work, we observed that CASC2c was significantly down-regulated in HCC tissues and cells. Moreover, its overexpression remarkably inhibited the growth, migration, and invasion of HCC cells in vitro and promoted their apoptosis. Furthermore, we demonstrated that CASC2c overexpression decreased p-ERK1/2 levels in HCC, GC, and CRC cells. Interestingly, while overexpression of CASC2c decreased β-catenin expression in HCC and GC cells, it increased that in CRC cells. Conclusion The lncRNA–CASC2c has a vital role in tumorigenesis and cancer progression, and may serve as a biomarker or therapeutic target in cancer treatment via down-regulation of the ERK1/2 and Wnt/β-catenin signaling pathways.

scholarly journals Downregulation of CRABP2 Inhibit the Tumorigenesis of Hepatocellular Carcinoma In Vivo and In Vitro

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Qingmin Chen ◽  
Ludong Tan ◽  
Zhe Jin ◽  
Yahui Liu ◽  
Ze Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Retinoic Acid ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Tumor Stage ◽  
Migration And Invasion ◽  
Hcc Cells

Cellular retinoic acid-binding protein 2 (CRABP2) binds retinoic acid (RA) in the cytoplasm and transports it into the nucleus, allowing for the regulation of specific downstream signal pathway. Abnormal expression of CRABP2 has been detected in the development of several tumors. However, the role of CRABP2 in hepatocellular carcinoma (HCC) has never been revealed. The current study aimed to investigate the role of CRABP2 in HCC and illuminate the potential molecular mechanisms. The expression of CRABP2 in HCC tissues and cell lines was detected by western blotting and immunohistochemistry assays. Our results demonstrated that the expression levels of CRABP2 in HCC tissues were elevated with the tumor stage development, and it was also elevated in HCC cell lines. To evaluate the function of CRABP2, shRNA-knockdown strategy was used in HCC cells. Cell proliferation, metastasis, and apoptosis were analyzed by CCK-8, EdU staining, transwell, and flow cytometry assays, respectively. Based on our results, knockdown of CRABP2 by shRNA resulted in the inhibition of tumor proliferation, migration, and invasion in vitro, followed by increased tumor apoptosis-related protein expression and decreased ERK/VEGF pathway-related proteins expression. CRABP2 silencing in HCC cells also resulted in the failure to develop tumors in vivo. These results provide important insights into the role of CRABP2 in the development and development of HCC. Based on our findings, CRABP2 may be used as a novel diagnostic biomarker, and regulation of CRABP2 in HCC may provide a potential molecular target for the therapy of HCC.

scholarly journals Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma

2022 ◽  
Vol 41 (1) ◽  
Author(s):  
Yuanjun Lu ◽  
Yau-Tuen Chan ◽  
Hor-Yue Tan ◽  
Cheng Zhang ◽  
Wei Guo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Bioinformatics Analyses ◽  
Sorafenib Treatment ◽  
Hcc Cells

Abstract Background Drug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development of drug resistance. The key miRNA regulators related to the clinical outcome of sorafenib treatment and their molecular mechanisms remain to be identified. Methods The clinical significance of miRNA-related epigenetic changes in sorafenib-resistant HCC was evaluated by analyzing publicly available databases and in-house human HCC tissues. The biological functions of miR-23a-3p were investigated both in vitro and in vivo. Proteomics and bioinformatics analyses were conducted to identify the mechanisms that regulating miR-23a-3p. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were used to validate the binding relationship of miR-23a-3p and its targets. Results We found that miR-23a-3p was the most prominent miRNA in HCC, which was overexpressed in sorafenib non-responders and indicated poor survival and HCC relapse. Sorafenib-resistant cells exhibited increased miR-23a-3p transcription in an ETS Proto-Oncogene 1 (ETS1)-dependent manner. CRISPR-Cas9 knockout of miR-23a-3p improved sorafenib response in HCC cells as well as orthotopic HCC tumours. Proteomics analysis suggested that sorafenib-induced ferroptosis was the key pathway suppressed by miR-23a-3p with reduced cellular iron accumulation and lipid peroxidation. MiR-23a-3p directly targeted the 3′-untranslated regions (UTR) of ACSL4, the key positive regulator of ferroptosis. The miR-23a-3p inhibitor rescued ACSL4 expression and induced ferrotoptic cell death in sorafenib-treated HCC cells. The co-delivery of ACSL4 siRNA and miR-23a-3p inhibitor abolished sorafenib response. Conclusion Our study demonstrates that ETS1/miR-23a-3p/ACSL4 axis contributes to sorafenib resistance in HCC through regulating ferroptosis. Our findings suggest that miR-23a-3p could be a potential target to improve sorafenib responsiveness in HCC patients.

scholarly journals NT157 Inhibits Hepatocellular Carcinoma Growth and Sensitizes Cells to Sorafenib

2021 ◽  
Author(s):  
Yu Wang ◽  
Si-Zhe Yu ◽  
Shi-Rong Zhang ◽  
Jia Hou ◽  
Min Jiao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Advanced Hepatocellular Carcinoma ◽  
Downstream Signaling ◽  
Potential Strategy ◽  
Induced Apoptosis ◽  
Hcc Cells

Abstract Background: Sorafenib has been recognized as the standard therapy for advanced hepatocellular carcinoma (HCC). Besides, efficacy of sorafenib was unsatisfactory and vast patients are resistant to sorafenib. Thus, molecular mechanisms underlying regulation of sorafenib resistance and seeking potential strategy to improve its efficacy have attracted much attention. As a small-molecule inhibitor of IGF-1R, NT157 has potent antitumor activity against some human cancers. However, whether NT157 has potential anti-tumor effects and its molecular mechanisms in HCC remain poorly understood. Methods: We assessed the effects and explored the mechanism of NT157 and sorafenib as single agents or in combination with sorafenib in HCC cells and mouse model. Further, we further demonstrated that NT157 reversed resistance to sorafenib in HCC.Results: Here, we found NT157 inhibited HCC growth and induced apoptosis in vitro and in vivo. In terms of mechanism, NT157 phosphorylated IRS-1 through ERK-MAPK signaling to be degraded by the ubiquitin-proteasome pathway, lowered p-AKT to deactivate IGF-1R signaling to inhibit proliferation and induce apoptosis. Surprisingly, we further demonstrated that NT157 acted synergistically with sorafenib to inhibit proliferation and contributed to sensitize HCC cells to sorafenib by down-regulation of p-AKT. Conclusions: Overall, our findings provide a translational rationale for inhibition of IGF-1R and downstream signaling pathways by NT157 as a novel targeted therapy alone or combined with sorafenib in HCC.

scholarly journals ZRANB1 Drives Hepatocellular Carcinoma Progression through SP1-LOXL2 Axis

2021 ◽  
Author(s):  
Peiyi Xie ◽  
Qing Li ◽  
Qing Chao ◽  
Jiayu Fang ◽  
Jing Xie ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Lysyl Oxidase ◽  
Expression Patterns ◽  
Rna Seq ◽  
Loss Of Function ◽  
Close Relationship ◽  
Hcc Cells

Abstract BackgroundDeubiquitinase (DUB) zinc finger RANBP2-type containing 1 (ZRANB1/TRABID) has been reported to have a close relationship with cancers. However, its underlying role and molecular mechanisms in hepatocellular carcinoma (HCC) remain elusive. MethodsGene and protein expression of ZRANB1 in HCC tissues were determined by qRT-PCR, western blot and immunohistochemistry. A series of gain- and loss-of-function assays were used to investigated the role of ZRANB1 in HCC cells progression. Moreover, RNA-seq were used to identify the downstream targets of ZRANB1 in HCC cells. The interaction between ZRANB1 and SP1 was examined through co-IP experiment and in vitro ubiquitination assay.ResultsZRANB1 was highly expressed in HCC tissues and ZRANB1 can regulate HCC cell growth and metastasis in vitro and in vivo. Through RNA-seq, we identified that Lysyl oxidase-like 2 (LOXL2) was the most significantly downregulated gene after ZRANB1 knockdown. Furthermore, the scatter plots indicated a significant positive correlation between ZRANB1 and LOXL2 expression in clinical HCC specimens. Additionally, LOXL2 was essential for ZRANB1-mediated HCC growth and metastasis. More importantly, specificity protein 1 (SP1) was critical in ZRANB1-mediated regulation of LOXL2 expression. Mechanistically, ZRANB1 bound with SP1 directly and stabilized the SP1 protein by deubiquitinating it. The expression patterns of ZRANB1, SP1 and LOXL2 were evaluated in HCC patients. ConclusionZRANB1 overexpression facilitates the carcinogenesis of HCC through stabilizing and upregulating SP1 to promote LOXL2 expression, suggesting ZRANB1 can be novel prognostic biomarker for HCC treatment.

scholarly journals Computational and In Vitro Analysis of Plumbagin’s Molecular Mechanism for the Treatment of Hepatocellular Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Yanfei Wei ◽  
Yuning Lin ◽  
Wanjun Chen ◽  
Shasha Liu ◽  
Lijie Jin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Network Pharmacology ◽  
Therapeutic Effects ◽  
Anticancer Properties ◽  
Vitro Analysis ◽  
Mapk Signaling Pathways

Hepatocellular carcinoma (HCC) is the fifth most common malignant tumor and the second leading cause of cancer-related death in the world. Plumbagin (PL) is a small molecule naphthoquinone compound isolated from Plumbago zeylanica L. that has important anticancer properties, but its mechanism requires further investigation. In this study, we used a comprehensive network pharmacology approach to study the mechanism of action of PL for the treatment of HCC. The method includes the construction of multiple networks; moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to identify biological processes and signaling pathways. Subsequently, in vitro experiments were performed to verify the predicted molecular mechanisms obtained from the network pharmacology-based analysis. Network pharmacological analysis showed that PL may exert anti-HCC effects by enhancing reactive oxygen species (ROS) production to generate oxidative stress and by regulating the PI3K/Akt and MAPK signaling pathways. In vitro experiments confirmed that PL mainly mediates the production of ROS, regulates the PI3K/Akt and MAPK signaling pathways to promote apoptosis and autophagy, and shows significant therapeutic effects on HCC. In conclusion, our work proposes a comprehensive systems pharmacology approach to explore the potential mechanism of PL for the treatment of HCC.

scholarly journals PNO1 regulates autophagy and apoptosis of hepatocellular carcinoma via the MAPK signaling pathway

2021 ◽  
Author(s):  
Zhiqiang Han ◽  
Dongming Liu ◽  
Lu Chen ◽  
Yuchao He ◽  
Xiangdong Tian ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Rna Seq ◽  
Hcc Cells

Abstract Background Some studies have reported that the activated ribosomes are positively associated with malignant tumors, especially in hepatocellular carcinoma (HCC). The RNA-binding protein PNO1, as a critical ribosome has been rarely reported in human tumors. Thus, the roles of PNO1 in HCC should be explored. Methods We collected 150 formalin-fixed and paraffin-embedded (FFPE) samples and 8 fresh samples to explore the expression and prognosis of PNO1 in HCC by immunohistochemistry, Western Blotting and RT-PCR. Public databases (TCGA and GEO) were used to verify the expression and prognosis. The functions of PNO1 in HCC was verified by in vitro and in vivo experiments. The underlying molecular mechanisms of PNO1 were examined by RNA-seq analysis and a series of functional experiments. Results PNO1 expression was considerably higher in HCC tissues and the higher expression of PNO1 was associated with poor prognosis of HCC patients. In vitro experiments indicated that PNO1 overexpression promoted proliferation and depressed apoptosis of HCC cells. In addition, high expression of PNO1 increased autophagy of HCC cells. Consistent results were also observed in vivo experiments. The results of the RNA-seq analysis indicted that PNO1 as an oncogene promoted HCC progression through the MAPK signaling pathway. The results were also verified by in vivo experiments. Conclusions PNO1 was overexpressed in HCC, promoted autophagy and inhibited apoptosis of HCC cells via the MAPK signaling pathway.

scholarly journals M6A-Mediated Upregulation of LINC00106 Promotes Stemness and Metastasis Properties of Hepatocellular Carcinoma via Sponging Let7f

2021 ◽  
Vol 9 ◽  
Author(s):  
Wenjin Liang ◽  
Yan Wang ◽  
Qinyu Zhang ◽  
Min Gao ◽  
Haizhou Zhou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Side Population ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Transcript Stability ◽  
Hcc Cells

Background: Hepatocellular carcinoma (HCC) cells exhibit the stemness property, which makes the patient with HCC prone to tumor recurrence and metastasis. Despite the prominent regulatory role of long non-coding RNAs (lncRNAs) in tumor stemness, the roles and molecular mechanisms of LINC00106 in HCC are poorly understood.Methods: LINC00106, let7f and periostin expression levels in tissue specimens and cell lines were assessed through qRT-PCR and immunohistochemistry (IHC). Various in vivo and in vitro assays, namely sphere/colony formation, proportion of side population cells (SP%), invasion, migration, western blot, and murine xenograft model were employed for assessing the stemness and metastatic properties of HCC cells. Luciferase reporter assays, RNA-seq, RNA pull-down, RNA immunoprecipitation (RIP) were conducted to clarificate the target gene and analyze the underlying mechanisms.Results: LINC00106 was prominently upregulated in tissues and cell lines of HCC. Patients having a high LINC00106 level exhibited a poor outcome. Under in vivo and in vitro conditions, the stemness and metastatic properties of HCC cells were augmented by LINC00106. Additionally, LINC00106 was found to sponge let7f to upregulate periostin, which lead to the activation of periostin-associated PI3K-AKT signaling pathway. Moreover, m6A methylation was found to cause LINC00106 upregulation while maintaining LINC00106 RNA transcript stability.Conclusion: m6A methylation triggers the upregulation of LINC00106, which promotes the stemness and metastasis properties in HCC cells by sponging let7f, thereby resulting in periostin activation. The findings indicate the potential of LINC00106 as a diagnostic marker and therapeutic target for HCC.

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