scholarly journals Metadherin–PRMT5 complex enhances the metastasis of hepatocellular carcinoma through the WNT–β-catenin signaling pathway

2019 ◽  
Vol 41 (2) ◽  
pp. 130-138 ◽  
Author(s):  
Kai Zhu ◽  
Yuanfei Peng ◽  
Jinwu Hu ◽  
Hao Zhan ◽  
Liuxiao Yang ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Arginine Methyltransferase ◽  
Mesenchymal Transition ◽  
Functional Assays ◽  
In Vivo Experiments ◽  
Hcc Cells

Abstract Accumulating data suggest that metadherin (MTDH) may function as an oncogene. Our previous study showed that MTDH promotes hepatocellular carcinoma (HCC) metastasis via the epithelial-mesenchymal transition. In this study, we aim to further elucidate how MTDH promotes HCC metastasis. Using Co-immunoprecipitation (co-IP) and mass spectrometry, we found that MTDH can specifically bind to protein arginine methyltransferase 5 (PRMT5). Further functional assays revealed that PRMT5 overexpression promoted the proliferation and motility of HCC cells and that knockout of PRMT5 impeded the effect of MTDH. The immunohistochemistry assay/tissue microarray results showed that when MTDH was overexpressed in HCC cells, PRMT5 translocated from the nucleus to the cytoplasm, with the subsequent translocation of β-catenin from the cytoplasm to the nucleus and upregulation of the WNT–β-catenin signaling pathway. Further in vivo experiments suggested that PRMT5 and β-catenin played a pivotal role in MTDH-mediated HCC metastasis. We therefore concluded that the MTDH–PRMT5 complex promotes HCC metastasis by regulating the WNT–β-catenin signaling pathway.

scholarly journals MicroRNA-3163 targets ADAM-17 and enhances the sensitivity of hepatocellular carcinoma cells to molecular targeted agents

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Bin Yang ◽  
Chunping Wang ◽  
Hui Xie ◽  
Yiwu Wang ◽  
Jiagan Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Notch Signaling Pathway ◽  
Advanced Hepatocellular Carcinoma ◽  
Targeted Agents ◽  
Mesenchymal Transition ◽  
Molecular Targeted Agents ◽  
Hcc Cells

Abstract Molecular targeted agents, such as sorafenib, remain the only choice of an antitumor drug for the treatment of advanced hepatocellular carcinoma (HCC). The Notch signaling pathway plays central roles in regulating the cellular injury/stress response, anti-apoptosis, or epithelial–mesenchymal transition process in HCC cells, and is a promising target for enhancing the sensitivity of HCC cells to antitumor agents. The ADAM metalloprotease domain-17 (ADAM-17) mediates the cleavage and activation of Notch protein. In the present study, microRNA-3163 (miR-3163), which binds to the 3′-untranslated region of ADAM-17, was screened using online methods. miRDB and pre-miR-3163 sequences were prepared into lentivirus particles to infect HCC cells. miR-3163 targeted ADAM-17 and inhibited the activation of the Notch signaling pathway. Infection of HCC cells with miR-3163 enhanced their sensitivity to molecular targeted agents, such as sorafenib. Therefore, miR-3163 may contribute to the development of more effective strategies for the treatment of advanced HCC.

scholarly journals hGC33-Modified and Sorafenib-Loaded Nanoparticles have a Synergistic Anti-Hepatoma Effect by Inhibiting Wnt Signaling Pathway

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Jing Shen ◽  
Wenpeng Cai ◽  
Yongfang Ma ◽  
Ruyue Xu ◽  
Zhen Huo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Wnt Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Mapk Pathway ◽  
Wnt Signaling Pathway ◽  
Mesenchymal Transition ◽  
Specific Tumor ◽  
Induced Signal ◽  
Hcc Cells

AbstractDelivery of tumor-specific inhibitors is a challenge in cancer treatment. Antibody-modified nanoparticles can deliver their loaded drugs to tumor cells that overexpress specific tumor-associated antigens. Here, we constructed sorafenib-loaded polyethylene glycol-b-PLGA polymer nanoparticles modified with antibody hGC33 to glypican-3 (GPC3 +), a membrane protein overexpressed in hepatocellular carcinoma. We found that hGC33-modified NPs (hGC33-SFB-NP) targeted GPC3+ hepatocellular carcinoma (HCC) cells by specifically binding to GPC3 on the surface of HCC cells, inhibited Wnt-induced signal transduction, and inhibited HCC cells in G0/1 by down-regulating cyclin D1 expression, thus attenuating HCC cell migration by inhibiting epithelial–mesenchymal transition. hGC33-SFB-NP inhibited the migration, cycle progression, and proliferation of HCC cells by inhibiting the Ras/Raf/MAPK pathway and the Wnt pathway in tandem with GPC3 molecules, respectively. hGC33-SFB-NP inhibited the growth of liver cancer in vivo and improved the survival rate of tumor-bearing mice. We conclude that hGC33 increases the targeting of SFB-NP to HCC cells. hGC33-SFB-NP synergistically inhibits the progression of HCC by blocking the Wnt pathway and the Ras/Raf/MAPK pathway.

MiR-92a-3p promotes the malignant progression of hepatocellular carcinoma by mediating the PI3K/AKT/mTOR signaling pathway

2021 ◽  
Vol 27 ◽  
Author(s):  
Libing Wang ◽  
Mingxin Cui ◽  
Fengzhi Qu ◽  
Daming Cheng ◽  
Jingkun Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Western Blot ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Mesenchymal Transition ◽  
Diagnosis And Prognosis ◽  
Potential Biomarker ◽  
Hcc Cells

Background: As one of the most common cancers in the world, hepatocellular carcinoma (HCC) usually has a poor prognosis. Many HCC patients are usually diagnosed at advanced stages. Therefore, new potential biomarkers for the diagnosis and prognosis of HCC are urgently needed. More and more studies have shown that miR-92a-3p can regulate the occurrence and development of a variety of cancers, but its clinical significance and molecular mechanism in HCC are still elusive. Here, we tried to clarify the regulatory mechanism of miR-92a-3p in HCC. Methods: In this study, we conducted qRT-PCR and revealed that miR-92a-3p was notably upregulated in HCC cells. MTT, flow cytometry, wound healing, Transwell invasion assays and western blot were conducted to uncover that overexpressed miR-92a-3p could boost the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of HCC cells while inhibiting cell apoptosis. In addition, the proteins associated with PI3K/AKT/mTOR pathway were also detected by western blot. Results: It was suggested that miR-92a-3p could activate the PI3K/AKT/mTOR signaling pathway. Conclusion: These results suggest that miR-92a-3p plays a tumor-promoting role in HCC and may be a potential biomarker for the diagnosis and prognosis of HCC.

scholarly journals ENO3 Inhibits Growth and Metastasis of Hepatocellular Carcinoma via Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Honglei Cui ◽  
Danfeng Guo ◽  
Xiaodan Zhang ◽  
Yaohua Zhu ◽  
Zhihui Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Noncancerous Tissue ◽  
Mesenchymal Transition ◽  
Proliferation And Metastasis ◽  
Hcc Cells

β-enolase (ENO3) is a metalloenzyme that functions during glycolysis and has been revealed ectopic expression in different cancers. However, the function and underlying modulatory mechanisms of ENO3 in hepatocellular carcinoma (HCC) are still elusive. Here, we discovered that ENO3 was remarkably down-regulated in human HCC tissue in contrast to those in noncancerous tissue. Moreover, low expression of ENO3 was related to the poor prognosis of HCC patients. Overexpression of ENO3 suppressed proliferative, migratory, and invasive abilities of HCC cells both in vitro and in vivo, whereas knocking down ENO3 led to the opposite effect. In addition, we revealed that ENO3 repressed the epithelial-mesenchymal transition (EMT) process with its biomarker variations. Mechanistic research unveiled that ENO3 suppressed the Wnt/β-catenin signal, which subsequently modulated the transcription of its target genes associated with the proliferation and metastasis capacity of HCC cells. Taken together, our study uncovered that ENO3 acted as a tumor inhibitor in HCC development and implied ENO3 as a promising candidate for HCC treatment.

scholarly journals miR-4458 inhibits the epithelial–mesenchymal transition of hepatocellular carcinoma cells by suppressing the TGF-β signaling pathway via targeting TGFBR1

2020 ◽  
Vol 52 (5) ◽  
pp. 554-562
Author(s):  
Yuke Zhang ◽  
Kun Shi ◽  
Hang Liu ◽  
Wei Chen ◽  
Yunhai Luo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Mesenchymal Transition ◽  
Gene Assay ◽  
Hcc Cells

Abstract Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. MicroRNAs play a pivotal role in the progression of various cancers. To date, very little attention has been paid to miR-4458. Therefore, the aim of our study was to explore the function and underlying molecular mechanism of miR-4458 in HCC. We found that the expression of miR-4458 was reduced in HCC tissues and cell lines. Forced overexpression of miR-4458 inhibited the migration, invasion, and epithelial–mesenchymal transition (EMT) of HCC cells, while downregulation of miR-4458 promoted the aggressive phenotype. Furthermore, transforming growth factor beta receptor 1 (TGFBR1), the modulator of the TGF-β signaling pathway, was verified to be a novel target gene of miR-4458 by dual-luciferase reporter gene assay. Upregulated miR-4458 dramatically abolished TGFBR1 and p-Smad2/3 expression, thus blocking the TGF-β signaling pathway. Moreover, restoration of TGFBR1 partially rescued the miR-4458-mediated suppressive effect on the migration, invasion, and EMT and reactivated the TGF-β signaling pathway in HCC cells. In summary, our findings first demonstrated a mechanism of miR-4458 in HCC cell migration, invasion, and EMT by regulating the TGF-β signaling pathway via directly targeting TGFBR1.

scholarly journals miR-631 Inhibits Intrahepatic Metastasis of Hepatocellular Carcinoma by Targeting PTPRE

2020 ◽  
Vol 10 ◽  
Author(s):  
Bingqing Chen ◽  
Zhibin Liao ◽  
Yongqiang Qi ◽  
Hongwei Zhang ◽  
Chen Su ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Tyrosine Phosphatase ◽  
Intrahepatic Metastasis ◽  
Mesenchymal Transition ◽  
Downstream Target ◽  
Pathological Development ◽  
Hcc Cells

MicroRNAs (miRNAs) have been reported to play critical roles in the pathological development of hepatocellular carcinoma (HCC), one of the most common cancers in the world. Our study aims to explore the expression, function and mechanism of miR-631 in HCC. Our findings are that expression of miR-631 is significantly down-regulated in HCC tissue compared with that in adjacent non-cancerous tissue, and low expression of miR-631 in HCC tissue is associated with cirrhosis, multiple tumors, incomplete tumor encapsulation, poor tumor differentiation, and high TNM stage. Our test results showed that miR-631 could inhibit migration, invasion, epithelial–mesenchymal transition (EMT) and intrahepatic metastasis of HCC. Receptor-type protein tyrosine phosphatase epsilon (PTPRE) as a downstream target of miR-631 could promote migration, invasion and EMT of HCC cells. Besides, the expression of PTPRE had a negative correlation with the expression of miR-631 both in vivo and in vitro, and increasing expression of PTPRE could reverse inhibitory effects of miR-631 in HCC cells. In sum, our study first demonstrated that miR-631 targeted PTPRE to inhibit intrahepatic metastasis in HCC. We gain insights from these findings into the mechanism of miRNAs regulation in HCC metastasis and further introduce a novel therapeutic target for HCC treatment.

scholarly journals Bromodomain-containing protein 9 promotes the growth and metastasis of human hepatocellular carcinoma by activating the TUFT1/AKT pathway

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Changwei Dou ◽  
Liankang Sun ◽  
Liang Wang ◽  
Jian Cheng ◽  
Weiding Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Disease Free Survival ◽  
Akt Pathway ◽  
Akt Inhibitor ◽  
Mesenchymal Transition ◽  
Hep3b Cells ◽  
Hcc Cells

Abstract Bromodomain-containing protein 9 (BRD9) has a critical role in human squamous cell lung cancer, acute myeloid leukemia, and malignant rhabdoid tumors. However, the expression and biological role of BRD9 in hepatocellular carcinoma (HCC) is poorly understood. In this study, BRD9 expression was found to be elevated in HCC through data mining of public databases. Next, we confirmed that the expression of BRD9 was increased in HCC tissues compared with that in adjacent non-tumor tissues. The upregulated level of BRD9 was also observed in HCC cells in comparison to LO2 cells. The increased BRD9 expression was correlated with unfavorable clinicopathological features. A high level of BRD9 predicted a poorer overall survival and disease-free survival of HCC patients. Functionally, BRD9 overexpression facilitated the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of Hep3B cells. Conversely, either BRD9 depletion or pharmacological inhibition of BRD9 resulted in the reduced proliferation and invasiveness of HCCLM3 cells. In addition, the BRD9 knockdown restrained the growth and metastasis of HCCLM3 cells in vivo. Mechanistically, BRD9 positively regulated TUFT1 expression and AKT activation in HCC cells. ChIP-qPCR analysis indicated that BRD9 promoted the binding of P300 acetyltransferase to the TUFT1 promoter and epigenetically regulated TUFT1 expression by increasing H3K27Ac in the promoter. Notably, either TUFT1 knockdown or AKT inhibitor (MK2206) abrogated the promoting effects of BRD9 on the proliferation, migration, invasion, and EMT of Hep3B cells. The forced expression of TUFT1 abolished the effects of BRD9 knockdown on the growth and metastasis of HCCLM3 cells. Altogether, these data indicate that BRD9 promotes the growth and metastasis of HCC cells by activating the TUFT1/AKT pathway and may serve as a promising biomarker and therapeutic target for HCC.

scholarly journals Cezanne enhances epithelial mesenchymal transition and prevents anthracycline-induced apoptosis via AKT/mTOR signaling in hepatocellular carcinoma

2021 ◽  
Author(s):  
Xiao-Ping Zhong ◽  
Jiahong Wang ◽  
Jie Mei ◽  
Lianghe Lu ◽  
Yihong Ling ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Mtor Inhibitor ◽  
Epithelial Mesenchymal Transition ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Mesenchymal Transition

Abstract Background Anthracycline resistance have hindered the efficacy of transcatheter arterial chemoembolization (TACE). Translational research is therefore in need to find potential combinations by studying the resistance mechanism of anthracycline. In our published work, we found Cezanne could predict the efficacy of adjuvant TACE (ad-TACE) and induce epithelium mesenchymal transition (EMT) in hepatocellular carcinoma (HCC). We hereby conduct a sequential investigation to reveal the role of Cezanne on EMT and its potential to retard resistance. Methods The response of Cezanne in patients treated with adjuvant TACE after hepatectomy was evaluated. Functional assays were used to examine the resistance function of Cezanne to anthracyclin. In-situ tumorigenesis models and intraperitoneal perfusion chemotherapy experiment were used for in vivo verification. Results High expression of Cezanne correlated to a better outcome. Multivariate analysis showed low expression of Cezanne and the application of postoperative ad-TACE therapy were independent prognostic risk factors. However, patient outcome was significantly shorter in high Cezanne group of ad-TACE patients. In vitro assays revealed that HCC functions were inhibited after overexpressing Cezanne (OE-Cezanne). After treated with epirubicin, however, OE-Cezanne cell lines did not respond to treatment. In vivo experiment was consistent with in vitro assays. Besides, high Cezanne transforms cell morphology and is correlated to the activation of EMT related genes. Gene set analysis showed that Cezanne can regulate PI3K/AKT/mTOR signaling pathway. Therefore, mTOR inhibitor Rapamycin can reverse the resisting effect of Cezanne on HCC cell lines. Conclusions Adjuvant anthracycline-based TACE treatment after curative surgery can reduce the recurrence rate in HCC patients. However, in patients with high Cezanne expression, the efficacy of TACE may be undermined by EMT inducement. We discovered Cezanne modulates EMT by activating the AKT/mTOR signaling pathway and provided evidence for the rationale of combining mTOR inhibitor with TACE to prevent recurrence in HCC patients.

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