MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

2020 ◽  
Author(s):  
Tong-tong Li ◽  
Jie Mou ◽  
Yao-jie Pan ◽  
Fu-chun Huo ◽  
Wen-qi Du ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Kinase Inhibitor ◽  
Flow Cytometric Analysis ◽  
Luciferase Reporter ◽  
Advanced Hepatocellular Carcinoma ◽  
Cell Viability Assay ◽  
Resistant Cells

Abstract Background: Kinase inhibitor sorafenib is the first-line targeted drug for advanced hepatocellular carcinoma (HCC) patients. However, the appearance of anti-cancer agents’ resistance has limited its therapeutic effect. Methods: In this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in HCC sorafenib-resistant cells and their parental cells. The biological functions of miR-138-1-3p and PAK5 in sorafenib-resistant cells and their parental cells were explored by cell viability assay, plate colony formation assay and flow cytometric analysis. The potential mechanisms of PAK5 were evaluated via co-immunoprecipitation (co-IP), immunofluorescence, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). The effects of miR-138-1-3p and PAK5 on HCC sorafenib chemoresistant characteristics were investigated by a xenotransplantation model. Results: We detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in HCC sorafenib resistance cell lines. Mechanical studies revealed that miR-138-1-3p reduced the protein expression of PAK5 by directly targeting the 3′-UTR of PAK5 mRNA. In addition, we verified that PAK5 elevated the phosphorylation and nuclear translocation of β-catenin that enhanced the transcriptional activity of multidrug resistance protein ABCB1. Conclusions: PAK5 contributed to the sorafenib chemoresistant characteristics of HCC by activity β-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated HCC sorafenib resistance, which provided a potential therapeutic target for advanced HCC patients.

scholarly journals MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Tong-tong Li ◽  
Jie Mou ◽  
Yao-jie Pan ◽  
Fu-chun Huo ◽  
Wen-qi Du ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Kinase Inhibitor ◽  
Luciferase Reporter ◽  
Advanced Hepatocellular Carcinoma ◽  
First Line Therapy ◽  
Xenotransplantation Model

Abstract Background Sorafenib is a kinase inhibitor that is used as a first-line therapy in advanced hepatocellular carcinoma (HCC) patients. However, the existence of sorafenib resistance has limited its therapeutic effect. Through RNA sequencing, we demonstrated that miR-138-1-3p was downregulated in sorafenib resistant HCC cell lines. This study aimed to investigate the role of miR-138-1-3p in sorafenib resistance of HCC. Methods In this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in sorafenib-resistant HCC cells and parental cells. The biological functions of miR-138-1-3p and PAK5 in sorafenib-resistant cells and their parental cells were explored by cell viability assays and flow cytometric analyses. The mechanisms for the involvement of PAK5 were examined via co-immunoprecipitation (co-IP), immunofluorescence, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). The effects of miR-138-1-3p and PAK5 on HCC sorafenib resistant characteristics were investigated by a xenotransplantation model. Results We detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in sorafenib-resistance HCC cell lines. Mechanistic studies revealed that miR-138-1-3p reduced the protein expression of PAK5 by directly targeting the 3′-UTR of PAK5 mRNA. In addition, we verified that PAK5 enhanced the phosphorylation and nuclear translocation of β-catenin that increased the transcriptional activity of a multidrug resistance protein ABCB1. Conclusions PAK5 contributed to the sorafenib resistant characteristics of HCC via β-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated sorafenib resistance in HCC, which provided a potential therapeutic target in advanced HCC patients.

scholarly journals Avelumab in Combination with Axitinib as First-Line Treatment in Patients with Advanced Hepatocellular Carcinoma: Results from the Phase 1b VEGF Liver 100 Trial

Liver Cancer ◽  
2021 ◽  
pp. 1-11
Author(s):  
Masatoshi Kudo ◽  
Kenta Motomura ◽  
Yoshiyuki Wada ◽  
Yoshitaka Inaba ◽  
Yasunari Sakamoto ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitor ◽  
Group Performance ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Clinical Activity ◽  
Advanced Hepatocellular Carcinoma ◽  
Recist 1.1 ◽  
Phase 1B ◽  
Grade 3

<b><i>Introduction:</i></b> Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for the treatment of advanced/metastatic hepatocellular carcinoma (aHCC). Avelumab is a human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We report the final analysis from VEGF Liver 100 (NCT03289533), a phase 1b study evaluating safety and efficacy of avelumab plus axitinib in treatment-naive patients with aHCC. <b><i>Methods:</i></b> Eligible patients had confirmed aHCC, no prior systemic therapy, ≥1 measurable lesion, Eastern Cooperative Oncology Group performance status ≤1, and Child-Pugh class A disease. Patients received avelumab 10 mg/kg intravenously every 2 weeks plus axitinib 5 mg orally twice daily until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and investigator-assessed objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) for HCC. <b><i>Results:</i></b> Twenty-two Japanese patients were enrolled and treated with avelumab plus axitinib. The minimum follow-up was 18 months as of October 25, 2019 (data cutoff). Grade 3 treatment-related adverse events (TRAEs) occurred in 16 patients (72.7%); the most common (≥3 patients) were hypertension (<i>n</i> = 11 [50.0%]), palmar-plantar erythrodysesthesia syndrome (<i>n</i> = 5 [22.7%]), and decreased appetite (<i>n</i> = 3 [13.6%]). No grade 4 TRAEs or treatment-related deaths occurred. Ten patients (45.5%) had an immune-related AE (irAE) of any grade; 3 patients (13.6%) had an infusion-related reaction (IRR) of any grade, and no grade ≥3 irAE and IRR were observed. The objective response rate was 13.6% (95% CI: 2.9–34.9%) per RECIST 1.1 and 31.8% (95% CI: 13.9–54.9%) per mRECIST for HCC. <b><i>Conclusion:</i></b> Treatment with avelumab plus axitinib was associated with a manageable toxicity profile and showed antitumor activity in patients with aHCC.

Clinical Outcomes of 2nd- and 3rd-Line Regorafenib for Advanced Hepatocellular Carcinoma

Oncology ◽  
2021 ◽  
pp. 1-8
Author(s):  
Kensuke Naruto ◽  
Tomokazu Kawaoka ◽  
Kei Amioka ◽  
Yutaro Ogawa ◽  
Kikukawa Chihiro ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Outcomes ◽  
Median Overall Survival ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Advanced Hepatocellular Carcinoma ◽  
Free Survival ◽  
Line Therapy ◽  
Unresectable Hepatocellular Carcinoma

<b><i>Introduction:</i></b> This study compared clinical outcomes of 2nd- and 3rd-line regorafenib in patients with unresectable hepatocellular carcinoma. <b><i>Methods:</i></b> In this retrospective cohort study, 48 patients were treated with regorafenib for unresectable hepatocellular carcinoma. Thirty-five and 13 patients were initiated on 2nd- and 3rd-line therapy, respectively. We assessed the responses to and safety of the therapy. <b><i>Results:</i></b> There were no statistically significant differences in clinical characteristics at the start of 2nd- or 3rd-line regorafenib therapy. The overall response rate of 2nd- and 3rd-line regorafenib was 20 and 8%, respectively. The disease control rate was 57 and 54%, respectively. Median overall survival (mOS) from the start of 2nd-line regorafenib was 17.5 months. mOS from the start of 3rd-line regorafenib was not obtained. Median progression-free survival of 2nd- and 3rd-line regorafenib was 4.9 and 2.3 months, respectively. mOS from 1st-line therapy with tyrosine kinase inhibitor plus sorafenib-regorafenib-lenvatinib was 29.5 months; that with lenvatinib-sorafenib-regorafenib was not obtained. Patients on 3rd-line therapy tended to have better Child-Pugh scores and tumor factors at the start of 1st-line therapy than other patients. <b><i>Conclusion:</i></b> Patients on 2nd- and 3rd-line regorafenib showed favorable responses. Good Child-Pugh scores and tumor factors may be associated with a better response rate and OS.

Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells

2006 ◽  
Vol 291 (5) ◽  
pp. G877-G884 ◽  
Author(s):  
Pau Sancho-Bru ◽  
Ramón Bataller ◽  
Jordi Colmenero ◽  
Xavier Gasull ◽  
Montserrat Moreno ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Portal Hypertension ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Stellate Cells ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Cell Contraction

Catecholamines participate in the pathogenesis of portal hypertension and liver fibrosis through α1-adrenoceptors. However, the underlying cellular and molecular mechanisms are largely unknown. Here, we investigated the effects of norepinephrine (NE) on human hepatic stellate cells (HSC), which exert vasoactive, inflammatory, and fibrogenic actions in the injured liver. Adrenoceptor expression was assessed in human HSC by RT-PCR and immunocytochemistry. Intracellular Ca2+ concentration ([Ca2+]i) was studied in fura-2-loaded cells. Cell contraction was studied by assessing wrinkle formation and myosin light chain II (MLC II) phosphorylation. Cell proliferation and collagen-α1(I) expression were assessed by [3H]thymidine incorporation and quantitative PCR, respectively. NF-κB activation was assessed by luciferase reporter gene and p65 nuclear translocation. Chemokine secretion was assessed by ELISA. Normal human livers expressed α1A-adrenoceptors, which were markedly upregulated in livers with advanced fibrosis. Activated human HSC expressed α1A-adrenoceptors. NE induced multiple rapid [Ca2+]i oscillations (Ca2+ spikes). Prazosin (α1-blocker) completely prevented NE-induced Ca2+ spikes, whereas propranolol (nonspecific β-blocker) partially attenuated this effect. NE caused phosphorylation of MLC II and cell contraction. In contrast, NE did not affect cell proliferation or collagen-α1(I) expression. Importantly, NE stimulated the secretion of inflammatory chemokines (RANTES and interleukin-8) in a dose-dependent manner. Prazosin blocked NE-induced chemokine secretion. NE stimulated NF-κB activation. BAY 11-7082, a specific NF-κB inhibitor, blocked NE-induced chemokine secretion. We conclude that NE stimulates NF-κB and induces cell contraction and proinflammatory effects in human HSC. Catecholamines may participate in the pathogenesis of portal hypertension and liver fibrosis by targeting HSC.

scholarly journals MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3026
Author(s):  
Hyuk Moon ◽  
Simon-Weonsang Ro
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Therapeutic Strategies ◽  
Erk Signaling ◽  
Health Concern ◽  
Alternative Mechanism ◽  
Major Health ◽  
Activating Mutations ◽  
Genetic Events

Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. Recently, the MAPK/ERK signaling pathway in HCC has gained renewed attention from basic and clinical researchers. The MAPK/ERK signaling pathway is activated in more than 50% of human HCC cases; however, activating mutations in RAS and RAF genes are rarely found in HCC, which are major genetic events leading to the activation of the MAPK/ERK signaling pathway in other cancers. This suggests that there is an alternative mechanism behind the activation of the signaling pathway in HCC. Here, we will review recent advances in understanding the cellular and molecular mechanisms involved in the activation of the MAPK/ERK signaling pathway and discuss potential therapeutic strategies targeting the signaling pathway in the context of HCC.

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 Terminalia catappaExerts Antimetastatic Effects on Hepatocellular Carcinoma through Transcriptional Inhibition of Matrix Metalloproteinase-9 by Modulating NF-κB and AP-1 Activity

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Chao-Bin Yeh ◽  
Ming-Ju Hsieh ◽  
Yih-Shou Hsieh ◽  
Ming-Hsien Chien ◽  
Pen-Yuan Lin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Matrix Metalloproteinase ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Matrix Metalloproteinase 9 ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Mrna Levels ◽  
Inhibitory Effects ◽  
Huh7 Cells ◽  
Metalloproteinase 9

High mortality and morbidity rates for hepatocellular carcinoma (HCC) in Taiwan primarily result from uncontrolled tumor metastasis. Previous studies have identified thatTerminalia catappaleaf extracts (TCE) exert hepatoprotective, antioxidative, antiinflammatory, anticancer, and antimetastatic activities. However, the effects of TCE on HCC and the underlying molecular mechanisms of its activities have yet to be fully elucidated. The present study's findings demonstrate that TCE concentration dependently inhibits human HCC migration/invasion. Zymographic and western blot analyses revealed that TCE inhibited the activities and expression of matrix metalloproteinase-9 (MMP-9). Assessment of mRNA levels, using reverse transcriptase polymerase chain reaction (PCR) and real-time PCR, and promoter assays confirmed the inhibitory effects of TCE on MMP-9 expression in HCC cells. The inhibitory effects of TCE on MMP-9 proceeded by upregulating tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as suppressing nuclear translocation and DNA binding activity of nuclear factor-kappa B (NF-κB) and activating protein-1 (AP-1) on the MMP-9 promoter in Huh7 cells. In conclusion, TCE inhibits MMP-9 expression and HCC cell metastasis and, thus, has potential use as a chemopreventive agent. Its inhibitory effects are associated with downregulation of the binding activities of the transcription factors NF-κB and AP-1.

Astaxanthin and Nrf2 signaling pathway: a novel target for new therapeutic approaches

2021 ◽  
Vol 21 ◽  
Author(s):  
Milad Ashrafizadeh ◽  
Zahra Ahmadi ◽  
Habib Yaribeygi ◽  
Thozhukat Sathyapalan ◽  
Amirhossein Sahebkar
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Haematococcus Pluvialis ◽  
Primary Source ◽  
Redox Balance ◽  
Protective Effects ◽  
Beneficial Effects ◽  
New Therapeutic Approaches ◽  
Nrf2 Signaling Pathway

: Astaxanthin (AST) is a naturally occurring compound isolated from various sources such as fungi, plants, salmon, and crab. However, Haematococcus Pluvialis, a green alga, is the primary source of this beta carotenoid compound. AST has several favourable biological and pharmacological activities such as antioxidant, anti-inflammatory, anti-tumor, anti-diabetes, hepatoprotective and neuroprotective. Nevertheless, the exact molecular mechanisms of these protective effects of AST are unclear yet. The Nrf2 signaling pathway is one of the critical candidate signaling pathways that may be involved in these beneficial effects of AST. This signaling pathway is responsible for maintaining the redox balance in the physiologic state. Upon nuclear translocation, Nrf2 signaling activates antioxidant enzymes to reduce oxidative stress and protect cells against damage. In the current study, we have reviewed the effects of AST on the Nrf2 signaling pathway, which could potentially be developed as a novel therapeutic approach for the management of various diseases.

scholarly journals SNHG 6 promotes the progression of Colon and Rectal adenocarcinoma via miR-101-3p and Wnt/β-catenin signaling pathway

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Qianwen Shao ◽  
Jing Xu ◽  
Rong Deng ◽  
Wei Wei ◽  
Bing Zhou ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Rectal Adenocarcinoma ◽  
Human Colon ◽  
Luciferase Reporter ◽  
Survival Times ◽  
Reporter Assays ◽  
Polymerase Chain ◽  
Nucleolar Rna ◽  
Mtt Assays

Abstract Background Small nucleolar RNA host gene 6 (SNHG6) regulates diverse biological processes in cancers. Potential function of SNHG6 in human colon and rectal adenocarcinoma (CRC) was evaluated. Methods Quantitative real-time polymerase chain reaction, MTT assays, Colony formation assays, Transwell assay, Western Blotting and Luciferase reporter assays were performed to measure the biological functions and potential molecular mechanisms of SNHG6 in CRC. Results SNHG6 was over-expressed in CRC, and high expression of s SNHG6 were associated with short survival times. We then identified miR-101-3p as an inhibitory target of SNHG6. Knockdown of SNHG6 significantly decreased miR-101-3p expression. Moreover, silenced SNHG6 obviously inhibited CRC cell growth, weakened cell invasion capacity and blocked the Wnt/β-catenin signaling pathway. Conclusion SNHG6 could regulate the progression of CRC via modulating the expression levels of miR-101-3p and the activity of Wnt/β-catenin signaling.

scholarly journals Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 Phase III study design

2020 ◽  
Vol 16 (21) ◽  
pp. 1525-1536 ◽  
Author(s):  
Robin Kate Kelley ◽  
Jennifer W Oliver ◽  
Saswati Hazra ◽  
Fawzi Benzaghou ◽  
Thomas Yau ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Single Agent Therapy ◽  
Treatment Naïve ◽  
Phase Iii Study ◽  
Immunomodulatory Properties

Cabozantinib is an oral tyrosine kinase inhibitor that targets VEGFR, MET and the TAM (TYRO3, AXL, MER) family of kinase receptors. In addition to their role in tumor growth and angiogenesis, cabozantinib targets promote an immune-suppressive microenvironment. Cabozantinib is approved as single-agent therapy for patients with advanced hepatocellular carcinoma who received prior sorafenib. Owing to its antitumor and immunomodulatory properties, cabozantinib is being developed in combination with immune checkpoint inhibitors. Early studies of these combinations have shown promising antitumor activity and tolerability in patients with solid tumors. Here, we describe the rationale and design of COSMIC-312, a Phase III study evaluating the safety and efficacy of cabozantinib in combination with atezolizumab (anti–PD-L1 monoclonal antibody) versus sorafenib for treatment-naive patients with advanced hepatocellular carcinoma. ClinicalTrial.gov Registration: NCT03755791

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