scholarly journals Deletion of Endonuclease V suppresses chemically induced hepatocellular carcinoma

2020 ◽  
Vol 48 (8) ◽  
pp. 4463-4479 ◽  
Author(s):  
Xiang Yi Kong ◽  
Erik Sebastian Vik ◽  
Meh Sameen Nawaz ◽  
Natalia Berges ◽  
Tuva Børresdatter Dahl ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mrna Expression ◽  
Rna Binding ◽  
Liver Tumors ◽  
Endonuclease V ◽  
Chemically Induced ◽  
Series Of Experiments ◽  
Suppressive Phenotype

Abstract Endonuclease V (EndoV) is a conserved inosine-specific ribonuclease with unknown biological function. Here, we present the first mouse model lacking EndoV, which is viable without visible abnormalities. We show that endogenous murine EndoV cleaves inosine-containing RNA in vitro, nevertheless a series of experiments fails to link an in vivo function to processing of such transcripts. As inosine levels and adenosine-to-inosine editing often are dysregulated in hepatocellular carcinoma (HCC), we chemically induced HCC in mice. All mice developed liver cancer, however, EndoV−/− tumors were significantly fewer and smaller than wild type tumors. Opposed to human HCC, adenosine deaminase mRNA expression and site-specific editing were unaltered in our model. Loss of EndoV did not affect editing levels in liver tumors, however mRNA expression of a selection of cancer related genes were reduced. Inosines are also found in certain tRNAs and tRNAs are cleaved during stress to produce signaling entities. tRNA fragmentation was dysregulated in EndoV−/− livers and apparently, inosine-independent. We speculate that the inosine-ribonuclease activity of EndoV is disabled in vivo, but RNA binding allowed to promote stabilization of transcripts or recruitment of proteins to fine-tune gene expression. The EndoV−/− tumor suppressive phenotype calls for related studies in human HCC.

scholarly journals Sirt1 deacetylates and stabilizes p62 to promote hepato-carcinogenesis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Lifeng Feng ◽  
Miaoqin Chen ◽  
Yiling Li ◽  
Muchun Li ◽  
Shiman Hu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Cell Growth ◽  
Knockout Mice ◽  
Liver Tumors ◽  
Underlying Mechanism ◽  
Carcinoma Cells ◽  
Conditional Knockout

Abstractp62/SQSTM1 is frequently up-regulated in many cancers including hepatocellular carcinoma. Highly expressed p62 promotes hepato-carcinogenesis by activating many signaling pathways including Nrf2, mTORC1, and NFκB signaling. However, the underlying mechanism for p62 up-regulation in hepatocellular carcinoma remains largely unclear. Herein, we confirmed that p62 was up-regulated in hepatocellular carcinoma and its higher expression was associated with shorter overall survival in patients. The knockdown of p62 in hepatocellular carcinoma cells decreased cell growth in vitro and in vivo. Intriguingly, p62 protein stability could be reduced by its acetylation at lysine 295, which was regulated by deacetylase Sirt1 and acetyltransferase GCN5. Acetylated p62 increased its association with the E3 ligase Keap1, which facilitated its poly-ubiquitination-dependent proteasomal degradation. Moreover, Sirt1 was up-regulated to deacetylate and stabilize p62 in hepatocellular carcinoma. Additionally, Hepatocyte Sirt1 conditional knockout mice developed much fewer liver tumors after Diethynitrosamine treatment, which could be reversed by the re-introduction of exogenous p62. Taken together, Sirt1 deacetylates p62 at lysine 295 to disturb Keap1-mediated p62 poly-ubiquitination, thus up-regulating p62 expression to promote hepato-carcinogenesis. Therefore, targeting Sirt1 or p62 is a reasonable strategy for the treatment of hepatocellular carcinoma.

scholarly journals Circular RNA UBE2Q2 promotes malignant progression of gastric cancer by regulating signal transducer and activator of transcription 3-mediated autophagy and glycolysis

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Jing Yang ◽  
Xing Zhang ◽  
Jiacheng Cao ◽  
Penghui Xu ◽  
Zetian Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Rna Binding ◽  
Synergistic Effects ◽  
Circular Rna ◽  
Circular Rnas ◽  
In Vivo Experiments ◽  
Series Of Experiments ◽  
Transcription 3

AbstractGastric cancer remains the third leading cause of cancer-related mortality worldwide. Emerging evidence has shown that circular RNAs (circRNAs) play a critical regulatory role in the occurrence and development of various cancers through sponging miRNAs or acting as RNA-binding protein (RBP) sponges. We found that circUBE2Q2 was significantly upregulated in GC tissues and cell lines. Knockdown of circUBE2Q2 inhibited proliferation, migration, invasion, and glycolysis, and increased autophagy in vitro. In addition, knockdown of circUBE2Q2 inhibited GC tumorigenicity and metastasis potential in vivo. A series of experiments were performed to confirm that circUBE2Q2 regulates GC progression via the circUBE2Q2-miR-370-3p-STAT3 axis and promotes tumor metastasis through exosomal communication. Further in vivo experiments confirmed that, combination treatment of circUBE2Q2 knocking down and STAT3 inhibitor has synergistic effects on the gastric cancer growth inhibition, which provides a possibility to enhance the sensitivity of targeted drugs to gastric cancer through targeting circUBE2Q2. Our findings revealed that circUBE2Q2 may serve as a new proliferation-promoting factor and prognostic marker in gastric cancer.

scholarly journals Chemopreventive Efficacy of Punica granatum and Silybum marianum Extracts on Chemically-induced Hepatocellular Carcinoma in Rats

2019 ◽  
Vol 7 (2) ◽  
Author(s):  
Hend Maarof Tag ◽  
Ahlem Bargougui ◽  
Sara Gamal Alshayyal ◽  
Amany Kamal ◽  
Hekmat M. Tantawy ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepg2 Cells ◽  
Punica Granatum ◽  
In Vivo Model ◽  
Control Group ◽  
Albino Rats ◽  
Silybum Marianum ◽  
Chemically Induced

Punica granatum (POM) and Silybum marianum (MT) receiving attention as potential potent anti-oxidant and anti-mutant agents. In this context, the present study was designed to highlight their effects either in vitro as well as in vivo model of induced Hepatocellular carcinoma (HCC). Human hepatoma (HepG2 cells) were treated with MT and POM to explore their antitumor activity then in vivo were carried out on thirty-six male albino rats divided into six groups (n=6). Two weeks after induction of HCC, rats were co-treated with either MT or POM ethanolic extract (500 mg/kg, orally) daily for 8 weeks. The results displayed marked reduction in the viability of HepG2 cells with IC50 equal to 48.4 and 8.6 μg/mL of POM and MT treatment respectively. Considering, in vivo experiment HCC group displayed significant elevation liver function indices (p<0.05). It also elicited depletion of liver reduced glutathione (GSH), and increased content of liver malondialdehyde (MDA) compared to control group. HCC was proved after a significantly elevated alpha-fetoprotein (AFP) level (p<0.05). All of these measurements were diminished significantly after POM and MT treatments, except the GSH level that was increased significantly. Supplementation of pomegranate and milk thistle extracts had a protective effect against chemically induced HCC. 

scholarly journals Mechanism and Molecular Network of RBM8A-Mediated Regulation of Oxaliplatin Resistance in Hepatocellular Carcinoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Rong Liang ◽  
Jinyan Zhang ◽  
Zhihui Liu ◽  
Ziyu Liu ◽  
Qian Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Binding Motif ◽  
Mesenchymal Transition ◽  
Regulatory Pathways ◽  
Wide Range

RNA-binding motif protein 8A (RBM8A) is abnormally overexpressed in hepatocellular carcinoma (HCC) and involved in the epithelial-mesenchymal transition (EMT). The EMT plays an important role in the development of drug resistance, suggesting that RBM8A may be involved in the regulation of oxaliplatin (OXA) resistance in HCC. Here we examined the potential involvement of RBM8A and its downstream pathways in OXA resistance using in vitro and in vivo models. RBM8A overexpression induced the EMT in OXA-resistant HCC cells, altering cell proliferation, apoptosis, migration, and invasion. Moreover, whole-genome microarrays combined with bioinformatics analysis revealed that RBM8A has a wide range of transcriptional regulatory capabilities in OXA-resistant HCC, including the ability to regulate several important tumor-related signaling pathways. In particular, histone deacetylase 9 (HDAC9) emerged as an important mediator of RBM8A activity related to OXA resistance. These data suggest that RBM8A and its related regulatory pathways represent potential markers of OXA resistance and therapeutic targets in HCC.

SETD3 is regulated by a couple of microRNAs and plays opposing roles in proliferation and metastasis of hepatocellular carcinoma

2019 ◽  
Vol 133 (20) ◽  
pp. 2085-2105 ◽  
Author(s):  
Liangliang Xu ◽  
Peng Wang ◽  
Xinfu Feng ◽  
Jianwei Tang ◽  
Lian Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Mrna Expression ◽  
Protein Level ◽  
Downstream Target ◽  
In Vivo Experiments ◽  
Pathological Differentiation ◽  
Important Pathway ◽  
Proliferation And Metastasis

Abstract A previous study reported that histone methyltransferase SETD3 is up-regulated in tumor tissues of hepatocellular carcinoma (HCC) and is associated with the growth of HCC. However, the clinical significance and the effect of SETD3 on HCC metastasis remain unclear. In the present study, both the protein and mRNA expression levels of SETD3 were measured in a larger cohort of HCC patients. The results showed that the protein level of SETD3 in HCC tissues was significantly higher than that in non-tumorous tissues, which was inconsistent with the mRNA expression level of SETD3. The high protein level of SETD3 in HCC tissues was significantly associated with male gender, poor pathological differentiation, liver cirrhosis and unfavorable prognosis of HCC patients. Subsequently, we demonstrated that SETD3 could be regulated at post-transcriptional step by a couple of miRNAs (miR-16, miR-195 and miR-497). Additionally, in vitro and in vivo experiments revealed that SETD3 played opposing roles in proliferation and metastasis of HCC: promoting proliferation but inhibiting metastasis. Mechanistic experiments revealed that doublecortin-like kinase 1 (DCLK1) was a downstream target of SETD3. SETD3 could increase the DNA methylation level of DCLK1 promoter to inhibit the transcription of DCLK1. Further study revealed that DCLK1/PI3K/matrix metalloproteinase (MMP) 2 (MMP-2) was an important pathway that mediated the effect of SETD3 on HCC metastasis. In conclusion, the present study revealed that SETD3 is associated with tumorigenesis and is a promising biomarker for predicting the prognosis of HCC patients after surgical resection. In addition, SETD3 plays inhibitory role in HCC metastasis partly through DCLK1/PI3K/MMP-2 pathway.

scholarly journals CPEB3-mediated MTDH mRNA translational suppression restrains hepatocellular carcinoma progression

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
He Zhang ◽  
Chendan Zou ◽  
Zini Qiu ◽  
Fang E ◽  
Qiang Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Progression ◽  
Rna Binding ◽  
Epithelial Mesenchymal Transition ◽  
Binding Protein ◽  
Mrna Translation ◽  
Luciferase Assay ◽  
Mesenchymal Transition

Abstract Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein. We had reported that CPEB3 is involved in hepatocellular carcinoma (HCC) progression. However, the underlying mechanisms of CPEB3 in HCC remain unclear. In this study, we firstly performed RNA immunoprecipitation to uncover the transcriptome-wide CPEB3-bound mRNAs (CPEB3 binder) in HCC. Bioinformatic analysis indicates that CPEB3 binders are closely related to cancer progression, especially HCC metastasis. Further studies confirmed that metadherin (MTDH) is a direct target of CPEB3. CPEB3 can suppress the translation of MTDH mRNA in vivo and in vitro. Besides, luciferase assay demonstrated that CPEB3 interacted with 3′-untranslated region of MTDH mRNA and inhibited its translation. Subsequently, CPEB3 inhibited the epithelial–mesenchymal transition and metastasis of HCC cells through post-transcriptional regulation of MTDH. In addition, cpeb3 knockout mice are more susceptible to carcinogen-induced hepatocarcinogenesis and subsequent lung metastasis. Our results also indicated that CPEB3 was a good prognosis marker, which is downregulated in HCC tissue. In conclusion, our results demonstrated that CPEB3 played an important role in HCC progression and targeting CPEB3-mediated mRNA translation might be a favorable therapeutic approach.

scholarly journals HuR Protein in Hepatocellular Carcinoma: Implications in Development, Prognosis and Treatment

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 119
Author(s):  
Vasiliki Papatheofani ◽  
Georgia Levidou ◽  
Panagiotis Sarantis ◽  
Evangelos Koustas ◽  
Michalis V. Karamouzis ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Tumors ◽  
Normal Liver ◽  
Primary Liver Tumors ◽  
The Stability ◽  
Hu Antigen R ◽  
Post Transcriptional Regulation

Hu-antigen R (HuR) is a post-transcriptional regulator that belongs to the embryonic lethal abnormal vision Drosophila-like family (ELAV). HuR regulates the stability, translation, subcellular localization, and degradation of several target mRNAs, which are implicated in carcinogenesis and could affect therapeutic options. HuR protein is consistently highly expressed in hepatocellular carcinoma (HCC) compared to the adjacent normal liver tissue and is involved in the post-transcriptional regulation of various genes implicated in liver malignant transformation. Additionally, HuR protein seems to be a putative prognosticator in HCC, predicting worse survival. This review summarizes the recent evidence regarding the role of HuR in primary liver tumors, as presented in clinical studies, in vitro experiments and in vivo animal models. In conclusion, our review supports the consistent role of HuR protein in the development, prognosis, and treatment of HCC. Additional studies are expected to expand current information and exploit its putative employment as a future candidate for more personalized treatment in these tumors.

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 lncRNA PANTR1 Upregulates BCL2A1 Expression to Promote Tumorigenesis and Warburg Effect of Hepatocellular Carcinoma through Restraining miR-587

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Xirui Ma ◽  
Ziming Mao ◽  
Jing Zhu ◽  
Huifang Liu ◽  
Fengling Chen
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Growth ◽  
Warburg Effect ◽  
Liver Tumors ◽  
Basic Research ◽  
High Morbidity ◽  
Cell Growth And Migration ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is one of the most common subtypes of malignant liver tumors, characterized by high morbidity and mortality. Due to its poor diagnosis strategy and inefficient clinical intervention, HCC has brought terrible life experiences for patients worldwide. Finding novel curative agents for HCC is urgently needed. In the current study, we hypothesized that lncRNA PANTR1 participates in HCC initiation or progression. Our study found that lncRNA PANTR1 was upregulated in HCC tumor tissues and abundantly expressed in HCC cell lines. PANTR1 knockdown inhibited cell growth and migration, promoted cell apoptosis in vitro, and suppressed tumor cell growth in vivo. Moreover, our results suggest that downregulated PANTR1 inhibited the Warburg effect in HCC cells. Underlying mechanisms of PANTR1 in HCC progression were investigated. PANTR1 acted as a competent sponge for miR-587 and downregulated miR-587 expression in HCC cells. Further, MiR-587 directly targets BCL2A1. lncRNA PANTR1 promotes HCC progression via mediating the miR-587-BCL2A1 axis. Our study identified a novel lncRNA PANTR1/miR-587/BCL2A1 axis in HCC progression. We might provide a new target for HCC basic research and clinical management.

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