scholarly journals Exosomal MiR-1290 Promotes Angiogenesis of Hepatocellular Carcinoma via Targeting SMEK1

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Qiong Wang ◽  
Guanwen Wang ◽  
Lianjie Niu ◽  
Shaorong Zhao ◽  
Jianjun Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endothelial Cells ◽  
Liver Cancer ◽  
Blood Vessel ◽  
Tumor Angiogenesis ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Primary Liver Cancer ◽  
Human Endothelial Cells ◽  
Direct Target

Hepatocellular carcinoma (HCC), the most common primary liver cancer, relies on the formation of new blood vessel for growth and frequent intrahepatic and extrahepatic metastasis. Therefore, it is important to explore the underlying molecular mechanisms of tumor angiogenesis of HCC. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, the potential roles of tumor-derived exosomal microRNAs in regulating tumor angiogenesis remain to be elucidated. In this study, our miRNome sequencing demonstrated that miR-1290 was overexpressed in HCC patient serum-derived exosomes, and we found that delivery of miR-1290 into human endothelial cells enhanced their angiogenic ability. Our results further revealed that SMEK1 is a direct target of miR-1290 in endothelial cells. MiR-1290 exerted its proangiogenic function, at least in part, by alleviating the inhibition of VEGFR2 phosphorylation done by SMEK1. Collectively, our findings provide evidence that miR-1290 is overexpressed in HCC and promotes tumor angiogenesis via exosomal secretion, implicating its potential role as a therapeutic target for HCC.

scholarly journals Exosomal miR-1290 promotes angiogenesis in hepatocellular carcinoma via targeting SMEK1

2020 ◽  
Author(s):  
Qiong Wang ◽  
Guanwen Wang ◽  
Lianjie Niu ◽  
Shaorong Zhao ◽  
Jianjun Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endothelial Cells ◽  
Tumor Angiogenesis ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Primary Liver Cancer ◽  
Tumor Model ◽  
Tube Formation ◽  
Luciferase Reporter

Abstract Background: Hepatocellular carcinoma (HCC), the most common primary liver cancer, rely on the formation of new blood vessel for growth and frequent intrahepatic and extrahepatic metastasis. Therefore, it is important to explore the underlying molecular mechanisms of tumor angiogenesis of HCC. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, the potential roles of tumor-derived exosomal microRNAs in regulating tumor angiogenesis remain to be elucidated. Methods: MiRNome sequencing was performed to uncover the miRNAs that are dysregulated in HCC patient serum-derived exosomes. Expression levels of miR-1290 in tissues and cells were determined by quantitative real-time PCR. The effect of mir-1290 on proliferation was evaluated by CCK-8 assay. The angiogenic ability of cells were determined by transwell, wound-healing, tube formation and matrigel plug assays. SMMC-7721 xenograft tumor model was established in NOD-SCID nude mice using miR-1290 and NC antagomirs to determin the angiogenic effect of mir-1290 in vivo. Target protein expression was determined by western blotting. Dual luciferase reporter assay was performed to confirm the action of miR-1290 on downstream target genes including SMEK1. Results are reported as means ± S.D. and differences were tested for significance using 2-sided Student’s t-test.Results: In this study, our miRNome sequencing demonstrated that miR-1290 was overexpressed in HCC patient serum-derived exosomes, and we found that delivery of miR-1290 into human endothelial cells enhanced their angiogenic ability. Our results further revealed that SMEK1 is a direct target of miR-1290 in endothelial cells. MiR-1290 exerted its pro-angiogenic function, at least in part, by alleviating the inhibition of VEGFR2 phosphorylation done by SMEK1. Conclusions: Collectively, our findings provide evidence that miR-1290 is overexpressed in HCC and promotes tumor angiogenesis via exosomal secretion, implicating its potential role as a therapeutic target for HCC.

scholarly journals Exosomal miR-1290 promotes angiogenesis in hepatocellular carcinoma via targeting SMEK1

2019 ◽  
Author(s):  
Qiong Wang ◽  
Guanwen Wang ◽  
Lianjie Niu ◽  
Shaorong Zhao ◽  
Jianjun Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endothelial Cells ◽  
Tumor Angiogenesis ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Primary Liver Cancer ◽  
Tumor Model ◽  
Luciferase Reporter ◽  
Dependent Manner

Abstract Abstract Background: Hepatocellular carcinoma (HCC), the most common primary liver cancer, rely on the formation of new blood vessel for growth and frequent intrahepatic and extrahepatic metastasis. Therefore, it is important to explore the underlying molecular mechanisms of tumor angiogenesis of HCC. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, the potential roles of tumor-derived exosomal microRNAs in regulating tumor angiogenesis remain to be elucidated. Methods: MiRNome sequencing was performed to uncover the miRNAs that are dysregulated in HCC patient serum-derived exosomes. Expression levels of miR-1290 in tissues and cells were determined by quantitative real-time PCR. The effect of mir-1290 on proliferation was evaluated by CCK-8 assay. The angiogenic ability of cells were determined by transwell, wound-healing, tube formation and matrigel plug assays. SMMC-7721 xenograft tumor model was established in NOD-SCID nude mice using miR-1290 and NC antagomirs to determin the angiogenic effect of mir-1290 in vivo. Target protein expression was determined by western blotting. Dual luciferase reporter assay was performed to confirm the action of miR-1290 on downstream target genes including SMEK1. Results are reported as means ± S.D. and differences were tested for significance using 2-sided Student’s t-test. Results: In this study, our miRNome sequencing demonstrated that miR-1290 was overexpressed in HCC patient serum-derived exosomes, and we found that delivery of miR-1290 into human endothelial cells enhanced their angiogenic ability. Our results further revealed that SMEK1 is a direct target of miR-1290 in endothelial cells. MiR-1290 exerted its pro-angiogenic function, at least in part, by inhibiting the VEGFR2 signaling pathway in a SMEK1-dependent manner. Conclusions: Collectively, our findings provide evidence that miR-1290 is overexpressed in HCC and promotes tumor angiogenesis via exosomal secretion, implicating its potential role as a therapeutic target for HCC.

scholarly journals Anticancer Activities and Underlying Molecular Mechanisms of Novel Mangostin Glycosides in Human Hepatocellular Carcinoma Hep3B Cells

Proceedings ◽  
2019 ◽  
Vol 22 (1) ◽  
pp. 5
Author(s):  
Kim ◽  
Han ◽  
Jung
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Anticancer Agents ◽  
Molecular Mechanisms ◽  
Primary Liver Cancer ◽  
Critical Role ◽  
Single Agent ◽  
Anticancer Activities ◽  
Parent Molecule ◽  
Hep3b Cells

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Therefore, exploring effective anticancer agents and their modes of action is essential for the prevention and treatment of HCC. Glycosylation can significantly improve the physicochemical and biological properties of small molecules, such as high solubility, stability increase, and lower toxicity. In this study, for the first time, we evaluated the anticancer activities of mangostin-3-O-β-d-2-deoxyglucopyranoside (Man-3DG) and mangostin 6-O-β-d-2-deoxyglucopyranoside (Man-6DG), glycosides of mangostin, against human hepatoma Hep3B cells. Our results demonstrated that Man-3DG and Man-6DG significantly suppressed growth and migration of Hep3B cells. In addition, they induced apoptosis of Hep3B cells by regulating apoptosis-related proteins of mitochondria. Noticeably, Man-3DG and Man-6DG also caused autophage, while cotreatment of the mangostin glycosides with an autophage inhibitor 3MA enhanced the inhibitory effect on Hep3B cell growth, compared to single agent treatment. Moreover, Man-3DG and Man-6DG inhibited the c-Met signaling pathway, which plays a critical role in the pathogenesis of liver cancer. Furthermore, the mangostin glycosides decreased tumor cell-induced angiogenesis in vitro through downregulation of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). These findings suggest that Man-3DG and Man-6DG might be promising anticancer agents for HCC treatment with superior pharmacological properties than parent molecule mangostin.

scholarly journals Profiling of tumour-associated microbiota in human hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Seiga Komiyama ◽  
Takahiro Yamada ◽  
Nobuyuki Takemura ◽  
Norihiro Kokudo ◽  
Koji Hase ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Fatty Liver Disease ◽  
Primary Liver Cancer ◽  
Epithelial Barrier ◽  
Sequence Variants ◽  
Alcoholic Fatty Liver ◽  
Uncultured Bacterium ◽  
Hepatitis C Viruses ◽  
Alcoholic Fatty Liver Disease

AbstractLiver cancer is the fourth leading cause of cancer-related death. Hepatocellular carcinoma (HCC) is a primary liver cancer that results from chronic hepatitis caused by multiple predisposing factors such as viral infection, alcohol consumption, and non-alcoholic fatty liver disease. Accumulating studies have indicated that dysfunction of the gut epithelial barrier and hepatic translocation of gut microbes may be implicated in the pathogenesis of HCC. However, the translocated bacteria in HCC patients remains unclear. Here, we characterised tumour-associated microbiota in patients with liver cancer and focused on HCC. We observed that the number of amplicon sequence variants in tumour-associated microbiota was significantly higher compared with that in non-tumour regions of the liver. The tumour-associated microbiota consisted of Bacteroidetes, Firmicutes, and Proteobacteria as the dominant phyla. We identified an unclassified genus that belonged to the Bacteroides, Romboutsia, uncultured bacterium of Lachnospiraceae as a signature taxon for primary liver cancer. Additionally, we identified Ruminococcus gnavus as a signature taxon for HCC patients infected with hepatitis B and/or hepatitis C viruses. This study suggests that tumour microbiota may contribute to the pathology of HCC.

scholarly journals Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1715
Author(s):  
Macus Hao-Ran Bao ◽  
Carmen Chak-Lui Wong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Liver Cancer ◽  
Effective Treatment ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Metabolic Reprogramming ◽  
Combination Therapies ◽  
Low Oxygen ◽  
Treatment Regimens

Hypoxia, low oxygen (O2) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.

scholarly journals The Association between Diet and Hepatocellular Carcinoma: A Systematic Review

Nutrients ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 172
Author(s):  
Elena S. George ◽  
Surbhi Sood ◽  
Anna Broughton ◽  
Georgia Cogan ◽  
Megan Hickey ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Systematic Review ◽  
Liver Cancer ◽  
Dietary Pattern ◽  
Quantitative Research ◽  
Primary Liver Cancer ◽  
Healthy Eating Index ◽  
Vitamin B9 ◽  
Related Risk ◽  
Monounsaturated Fats

Globally, liver cancer is the sixth most common cause of cancer mortality, with hepatocellular carcinoma (HCC) being the most common type of primary liver cancer. Emerging evidence states that diet is recognised as a potential lifestyle-related risk factor for the development of HCC. The aim of this systematic review is to determine whether there is an association between diet and the development of HCC. Using the PRISMA guidelines, three databases (MEDLINE Complete, CINAHL and Embase) were systematically searched, and studies published until July 2020 were included. Thirty observational studies were selected. The protocol was registered with PROSPERO (CRD42019135240). Higher adherence to the Mediterranean dietary pattern, Alternative Healthy Eating Index-2010, the Urban Prudent Dietary Pattern, the Traditional Cantonese Dietary Pattern, intake of vegetables, wholegrains, fish, poultry, coffee, macronutrients such as monounsaturated fats and micronutrients such as vitamin E, vitamin B9, β-carotene, manganese and potassium were associated with a reduced risk of HCC. The results suggest a potential role of diet in the development of HCC. Further quantitative research needs to be undertaken within a range of populations to investigate diet and the relationship with HCC risk.

scholarly journals The Emerging Factors and Treatment Options for NAFLD-Related Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3740
Author(s):  
Chunye Zhang ◽  
Ming Yang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Fatty Liver ◽  
Early Stage ◽  
Primary Liver Cancer ◽  
Treatment Options ◽  
Underlying Mechanism ◽  
Diagnostic Methods ◽  
T Cell Therapy ◽  
Nonalcoholic Fatty Liver

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, followed by cholangiocarcinoma (CCA). HCC is the third most common cause of cancer death worldwide, and its incidence is rising, associated with an increased prevalence of obesity and nonalcoholic fatty liver disease (NAFLD). However, current treatment options are limited. Genetic factors and epigenetic factors, influenced by age and environment, significantly impact the initiation and progression of NAFLD-related HCC. In addition, both transcriptional factors and post-transcriptional modification are critically important for the development of HCC in the fatty liver under inflammatory and fibrotic conditions. The early diagnosis of liver cancer predicts curative treatment and longer survival. However, clinical HCC cases are commonly found in a very late stage due to the asymptomatic nature of the early stage of NAFLD-related HCC. The development of diagnostic methods and novel biomarkers, as well as the combined evaluation algorithm and artificial intelligence, support the early and precise diagnosis of NAFLD-related HCC, and timely monitoring during its progression. Treatment options for HCC and NAFLD-related HCC include immunotherapy, CAR T cell therapy, peptide treatment, bariatric surgery, anti-fibrotic treatment, and so on. Overall, the incidence of NAFLD-related HCC is increasing, and a better understanding of the underlying mechanism implicated in the progression of NAFLD-related HCC is essential for improving treatment and prognosis.

scholarly journals 452 Preliminary analysis of a real-world study (RWS) of camrelizumab treatment in primary liver cancer (PLC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A479-A480
Author(s):  
Zhendong Chen ◽  
Nianfei Wang ◽  
Dayong Luo ◽  
Bo Jiang ◽  
Mu Yuan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Group Performance ◽  
Primary Liver Cancer ◽  
Locoregional Therapy ◽  
Advanced Hepatocellular Carcinoma ◽  
Efficacy And Safety ◽  
Open Label ◽  
Patient Disposition ◽  
Ecog Ps

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized the landscape of PLC management at all evolutionary stages.1 As an anti-programmed cell death-1 (PD-1) antibody, camrelizumab monotherapy and in combination with apatinib, an anti-angiogenetic tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-2, chemotherapy or locoregional therapy, have demonstrated their efficacy in advanced hepatocellular carcinoma (HCC).2 3 4 5MethodsThis prospective, open-label, multi-center, observational RWS was conducted to evaluate efficacy and safety of camrelizumab in treatment of PLC in clinical practice. Eligible patients were histopathologically or cytologically identified HCC or intrahepatic cholangiocarcinoma, who were going to receive camrelizumab treatment, with age ≥18 ages, Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0–2 and Child-Pugh score ≤ 9. Patients were treated at clinician discretion. Three hundred patients were planned to enroll, including advanced or peri-operative PLC. The primary endpoint was progress-free survival for advanced PLC, whose efficacy was available to analysis. Efficacy was assessed per Response Evaluation Criteria in Solid Tumors version 1.1.ResultsFrom March 29, 2020 to June 10, 2021,a total of 147 eligible patients of advanced PLC were enrolled and included in this interim analysis, with 128 (87.1%) men, 130 (94.9%) ECOG PS of 0–1, 139 (94.6%) HCC, 74 (50.4%) Barcelona Clinic Liver Cancer stage C, 98 (66.7%) Child-Pugh B, and 72 (49.0%) with extrahepatic metastases, shown in table 1. Of the 147 patients, 45 (30.1%) patients were treated with camrelizumab monotherapy, 79 (53.8%) patients with combination with angiogenesis inhibitors, of which 55 (37.4%) in combination with apatinib, 21 (14.3%) patients with camrelizumab and chemotherapy. Patients, who had at least one efficacy assessment, were included in the efficacy analyses. Up to July 19, 2021, with a median follow time of 6.2 months, 132 patients were available for efficacy analyses. Patient disposition was shown in figure 1. Objective response rate (ORR) and disease control rate (DCR) were 10%/30.8%/35.3% and 75.0%/86.5%/70.6% in camrelizumab monotherapy/combined with apatinib/combined with chemotherapy, respectively. (table 2) The most common camrelizumab-treatment related adverse events (AEs) included reactive cutaneous capillary endothelial proliferation (RCCEP) (12, 8.2%), ICI-induced pneumonia (2, 1.4%), enterocolitis (2, 1.4%), and nephritis (1, 0.7%), of which all these AEs recovered. Other AEs included increase of transaminase (5, 3.4%) and hypertension (4, 2.7%). All AEs were 1–2 grade and no treatment-related death occurred.Abstract 452 Table 1Baseline characteristicsAbstract 452 Figure 1Patient dispositionAbstract 452 Table 2Confirmed tumor response assessed by investigators per RECIST v1.1ConclusionsCamrelizumab, combined with anti-angiogenetic agents or chemotherapy, or monotherapy, demonstrated good efficacy and safety in treatment of PLC.Trial RegistrationChiCTR2000034264ReferencesLlovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2021;7(1):6–28.Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol 2020;21(4):571–580.Xu J, Shen J, Gu S, et al. Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label, Phase II Trial. Clin Cancer Res 2021;27(4):1003–1011.Mei K, Qin S, Chen Z, et al. Camrelizumab in combination with apatinib in second-line or above therapy for advanced primary liver cancer: cohort A report in a multicenter phase Ib/II trial. J Immunother Cancer 2021;9(3).Qin S, Bai Y, Lim HY, et al. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol 2013;31(28):3501–3508.Ethics ApprovalThis study was approved by China registered clinical trial ethics review committee with No.ChiECRCT20200042.

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