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 The Deubiquitinase OTUD3 Stabilizes ACTN4 to Activate NF-κB Signaling Pathway in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Peiyi Xie ◽  
Yanglin Chen ◽  
Hongfei Zhang ◽  
Guichao Zhou ◽  
Qing Chao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Protein Level ◽  
Loss Of Function ◽  
Downstream Target ◽  
Gene And Protein Expression ◽  
Hcc Cells

Abstract Background: OTUD3, a deubiquitinating enzyme, has emerged as important role in some cancer. It showed that OTUD3 plays suppressive role in breast cancer whereas oncogenic role in lung cancer. However, the function and mechanism of OTUD3 in hepatocellular carcinoma (HCC) progression remain elusive. Methods: Gene and protein expression of OTUD3 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 OTUD3 in HCC cells progression. Moreover, mass spectroscopic analysis and RNA-seq were used to identify the downstream targets of OTUD3 in HCC cells. The interaction between OTUD3 and ACTN4 was examined through co-IP experiment and in vitro ubiquitination assay.Results: In our research, OTUD3 was significantly overexpressed in HCC tissues and higher OTUD3 expression was correlated with bigger tumor size, more distant metastasis, and worse TNM stage. Additionally, OTUD3 promoted HCC cells growth and metastasis in vitro and in vivo. Furthermore, ACTN4 was identified as a downstream target of OTUD3 and ACTN4 protein level was significantly related to OTUD3 expression. Rescue experiments indicated that ACTN4 was essential for OTUD3-mediated HCC proliferation and metastasis in vitro and in vivo. Moreover, we identified that NF-κB signaling pathway was activated by OTUD3 through ACTN4 to promote HCC cells progression. Importantly, OTUD3 protein level was correlated with ACTN4 protein level and activity of NF-κB signaling pathway in HCC tissues. Conclusion: Our findings identify the oncogenic role of OTUD3 in HCC and suggest that OTUD3 can be considered as a pivotal prognostic biomarker and a potential therapeutic target.

scholarly journals Targeting TRIM54/Axin1/β-Catenin Axis Prohibits Proliferation and Metastasis in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Jinrong Zhu ◽  
Yongqi Wu ◽  
Shaoxi Lao ◽  
Jianfei Shen ◽  
Yijian Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Prognostic Factor ◽  
Small Molecule ◽  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Proliferation And Metastasis ◽  
Oncogenic Gene ◽  
Sustained Activation

Accumulating evidence demonstrates that dysregulation of ubiquitin-mediated degradation of oncogene or suppressors plays an important role in several diseases. However, the function and molecular mechanisms of ubiquitin ligases underlying hepatocellular carcinoma (HCC) remain elusive. In the current study, we show that overexpression of TRIM54 was associated with HCC progression. TRIM54 overexpression facilitates proliferation and lung metastasis; however, inhibition of TRIM54 significantly suppressed HCC progression both in vitro and in vivo. Mechanically, we demonstrated that TRIM54 directly interacts with Axis inhibition proteins 1 (Axin1) and induces E3 ligase-dependent proteasomal turnover of Axin1 and substantially induces sustained activation of wnt/β-catenin in HCC cell lines. Furthermore, we showed that inhibition of the wnt/β-catenin signaling pathway via small molecule inhibitors significantly suppressed TRIM54-induced proliferation. Our data suggest that TRIM54 might function as an oncogenic gene and targeting the TRIM54/Axin1/β-catenin axis signaling may be a promising prognostic factor and a valuable therapeutic target for HCC.

scholarly journals SPATS2, negatively regulated by miR-145-5p, promotes hepatocellular carcinoma progression through regulating cell cycle

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Gang Dong ◽  
Shanshan Zhang ◽  
Shen Shen ◽  
Lulu Sun ◽  
Xuemei Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
G1 Arrest ◽  
Poor Survival ◽  
Potential Therapeutic Target ◽  
Normal Tissues ◽  
Proliferation And Metastasis ◽  
And Function ◽  
Hcc Cells

Abstract Spermatogenesis associated serine rich 2 (SPATS2) has been reported to contribute to the tumorigenesis of multiple malignancies. The molecular function of SPATS2 in hepatocellular carcinoma (HCC) is still not fully understood. In this study, we aimed to investigate the expression pattern and function roles of SPATS2 in HCC. The regulation of SPATS2 expression was also explored. We found that SPATS2 was highly expressed in HCC tissues in comparison with that in adjacent normal tissues. High expression of SPATS2 was associated with vascular invasion, advanced TNM stages, tumor multiplicity, and poor survival. Functionally, SPATS2 was found to promote the proliferation and metastasis of HCC cells both in vitro and in vivo, while knockdown of SPATS2 enhanced apoptosis and G1 arrest of HCC cells in vitro. Mechanistically, bioinformatics analysis revealed that MiR-145-5p directly targeted SPATS2 and functional rescue experiments verified that MiR-145-5p overexpression could abolish the effect of SPATS2 on the regulation of HCC malignant phenotype. Taken together, our findings suggest that SPATS2 functions as an oncogene in HCC. The MiR-145-5p/SPATS2 axis provides a novel mechanism underlying HCC progression and may serve as a potential therapeutic target for HCC.

scholarly journals HBV Facilitated Hepatocellular Carcinoma Cells Proliferation by Up-Regulating Angiogenin Expression Through IL-6

2018 ◽  
Vol 46 (2) ◽  
pp. 461-470 ◽  
Author(s):  
Xiaotang Zhou ◽  
Fan Yang ◽  
Ying Yang ◽  
Ying Hu ◽  
Weixia Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Nuclear Transfer ◽  
Nuclear Translocation ◽  
Neutralizing Antibody ◽  
Rrna Synthesis ◽  
In Vivo Experiments ◽  
B Virus

Background/Aims: Patients with hepatitis B virus (HBV) infection are at a high risk of developing hepatocellular carcinoma (HCC). In this study, we aim to investigate the roles of HBV on angiogenin (ANG), as well as the effects on cell proliferation in presence of ANG down-regulation. Methods: Serum ANG was determined by ELISA. The expression of ANG mRNA and protein in HCC cell lines with or without HBV/HBx were determined. Western blot and ELISA were conducted to determine the effects of HBV/HBx on IL-6 expression. The role of IL-6 on ANG was evaluated by IL-6 recombinant protein or IL-6 neutralizing antibody. Immunofluorescence staining was used to detect the nuclear translocation of ANG. MTT was performed to evaluate the relative inhibition ratio. Result: In vivo experiments showed elevation of serum ANG in patients infected with HBV. In vitro experiments showed HBV and HBx contributed to the transcription and translation of ANG. ANG expression showed increase after IL-6 stimulation, and ANG protein decreased in the presence of IL-6 blocking with its antibody. HBV promoted nuclear translocation of ANG. Inhibiting ANG expression or blocking of nuclear transfer of ANG attenuated the 45S rRNA synthesis and cell proliferation. Conclusion: HBV and HBx protein can increase the level of ANG through IL-6. HBV and HBx contributed to the nuclear translocation of ANG. Cell proliferation was inhibited after inhibiting the expression or nuclear transfer of ANG.

scholarly journals The Effects of Resveratrol on Prostate Cancer through Targeting the Tumor Microenvironment

2021 ◽  
Vol 11 (1) ◽  
pp. 16-32
Author(s):  
Natalie Silk ◽  
Jeremy Reich ◽  
Rahul Sinha ◽  
Shivansh Chawla ◽  
Kyla Geary ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Microenvironment ◽  
Cancer Prevention ◽  
Molecular Mechanisms ◽  
The United States ◽  
In Vivo Experiments ◽  
Cancer Initiation ◽  
Proliferation And Metastasis

Prostate cancer is one of the most common cancers diagnosed in men in the United States and the second leading cause of cancer-related deaths worldwide. Since over 60% of prostate cancer cases occur in men over 65 years of age, and this population will increase steadily in the coming years, prostate cancer will be a major cancer-related burden in the foreseeable future. Accumulating data from more recent research suggest that the tumor microenvironment (TME) plays a previously unrecognized role in every stage of cancer development, including initiation, proliferation, and metastasis. Prostate cancer is not only diagnosed in the late stages of life, but also progresses relatively slowly. This makes prostate cancer an ideal model system for exploring the potential of natural products as cancer prevention and/or treatment reagents because they usually act relatively slowly compared to most synthetic drugs. Resveratrol (RSV) is a naturally occurring stilbenoid and possesses strong anti-cancer properties with few adverse effects. Accumulating data from both in vitro and in vivo experiments indicate that RSV can interfere with prostate cancer initiation and progression by targeting the TME. Therefore, this review is aimed to summarize the recent advancement in RSV-inhibited prostate cancer initiation, proliferation, and metastasis as well as the underlying molecular mechanisms, with particular emphasis on the effect of RSV on TME. This will not only better our understanding of prostate cancer TMEs, but also pave the way for the development of RSV as a potential reagent for prostate cancer prevention and/or therapy.

scholarly journals circRPS16 Promotes Proliferation and Invasion of Hepatocellular Carcinoma by Sponging miR-876-5p to Upregulate SPINK1

2021 ◽  
Vol 11 ◽  
Author(s):  
Shuwen Lin ◽  
Ye Lin ◽  
Zhongshi Wu ◽  
Wuzheng Xia ◽  
Chenglong Miao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Luciferase Reporter ◽  
Downstream Target ◽  
Proliferation And Invasion

The roles of serine protease inhibitor Kazal type 1 (SPINK1) in multiple types of cancers have been significantly documented. However, its specific roles in hepatocellular carcinoma (HCC) remain to be investigated. This study found that SPINK1 is upregulated in HCC and its upregulation correlates with poor prognosis. Besides, functional assays revealed that SPINK1 promotes cell proliferation, cell cycle, and invasion in vitro. Through bioinformatics analysis, we speculate that circRPS16 regulates SPINK1 expression by sponging miR-876-5p. This was further verified by the dual-luciferase reporter and fluorescent in situ hybridization (FISH) assays. Subsequently, rescue assays verified that circRPS16 promotes cell proliferation, cell cycle, and invasion through miR-876-5p. Importantly, silencing circRPS16 inhibited tumor growth by downregulating SPINK1 expression in vivo. Collectively, our results confirm that SPINK1 is a downstream target of circRPS16. Besides, circRPS16 and SPINK1 are oncogenic factors in HCC progression; they provide novel diagnostic and therapeutic targets for HCC patients.

scholarly journals Silencing of KNTC1 inhibits hepatocellular carcinoma cells progression via suppressing PI3K/Akt pathway

2020 ◽  
Author(s):  
Hui Tong ◽  
Junjie Xie ◽  
Xiaohui Liu ◽  
Chenghong Peng ◽  
Baiyong Shen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Regression ◽  
Annexin V ◽  
Tumor Formation ◽  
Migration Ability ◽  
Migration Assay ◽  
In Vivo Experiments ◽  
Hcc Cells

Abstract Background: Kinetochore associated 1 (KNTC1) encodes a kinetochore component in Rod-Zwilch-ZW10 (RZZ) complex which is essential for the segregation of sister chromatids during mitosis and participates in the spindle checkpoint. Recent research demonstrated that kinetochore proteins may be potential biomarkers and may contribute to the development of human malignancies. Here, we sought to identify the biological significances of KNTC1 in hepatocellular carcinoma (HCC).Methods: KNTC1 expression was studied in HCC tissues by immunohistochemistry. Lentivirus delivered short hairpin RNA (shRNA) was performed to generate KNTC1 knockdown HCC cell lines. The effects of KNTC1 on HCC cells proliferation, migration, apoptosis and tumor formation was analyzed by MTT assay, colony formation assay, wound-healing assay, transwell migration assay, annexin V assay in vitro and in nude mouse models in vivo.Results: Our immunohistochemistry experiment showed that KNTC1 was highly expressed in HCC tissues and correlated with terrible prognosis, indicating that KNTC1 acts a pivotal role in HCC development. Furthermore, shRNA KNTC1 (Lv‑shKNTC1) was applied to infect BEL-7404 and SK-HEP-1 to identify roles of KNTC1 on HCC. Lv‑shKNTC1 cells showed reduced proliferation ability, increased apoptosis and decreased migration ability. In vivo experiments suggested that xenografts grow significantly slower upon the silencing of KNTC1. Mechanistically, the protein levels of PIK3CA, p-Akt, CCND1, CDK6 are all down-regulated in Lv-KNTC1 SK-HEP-1 cells. Therefore, KNTC1 may affect the biological activity of HCC cells through PI3K/Akt signaling pathway. Conclusions: In summary, the key finding of this report highlighted the significance of KNTC1 in tumor regression of HCC, demonstrating KNTC1 as an innovative target for adjuvant treatment of HCC.

Liver X receptor inhibits the growth of hepatocellular carcinoma cells via regulating HULC/miR-134-5p/FOXM1 axis

2020 ◽  
Author(s):  
Yan Zhang ◽  
Jintao He ◽  
Teng Yang ◽  
Wenhui He ◽  
Shan Jiang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cyclin D1 ◽  
Gene Promoter ◽  
Liver X Receptor ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
In Vivo Experiments ◽  
Hcc Cells

Abstract Background Highly upregulated in liver cancer (HULC), the specifically overexpressed long non-coding RNA (lncRNA) in human hepatocellular carcinoma (HCC), can promote the growth and metastasis of HCC cells. Therefore, it will be benefit to HCC treatment by effectively downregulating HULC. Liver X receptor (LXR), a member of nuclear receptor superfamily, exerts anti-tumor effects on various human malignancies including HCC. However, it is unclear whether the anti-HCC function of LXR is involved in the regulation of HULC. Methods Quantitative real-time PCR and Western blot were used to separately examine RNA and protein levels in HCC cells. Cell counting kit-8 assay was used to detect the growth of HCC cells in vitro . Dual-luciferase reporter assays were performed to analyze the regulation of forkhead box M1 (FOXM1) by miR-134-5p and the regulation of miR-134-5p by HULC. Xenograft models were engaged to evaluate the growth of HCC cells in vivo . Results In this study, we found that activation of LXR could inhibit the growth of HCC cells by downregulating HULC. Mechanistically, LXR decreased HULC via suppressing its gene promoter activity. Moreover, HULC and FOXM1 were highly expressed while miR-134-5p was lowly expressed in HCC tissues, and the level of HULC was positively correlated with that of FOXM1 while negatively correlated with that of miR-134-5p. Additionally, miR-134-5p downregulated FOXM1 by targeting 3′-untranslated region (UTR) of its mRNA, and HULC upregulated FOXM1 and its downstream target molecule cyclin D1 through sequestrating miR-134-5p. Furthermore, activation of LXR increased miR-134-5p while decreased FOXM1 by reducing HULC in HCC cells. The in vivo experiments showed that activation of LXR repressed the growth of HCC xenografts, and decreased HULC, FOXM1 and cyclin D1 while increased miR-134-5p in the xenografts. Conclusions Our results for the first time reveal that LXR can inhibit the growth of HCC cells by regulating HULC/miR-134-5p/FOXM1 axis. The novel pathway LXR/HULC/miR-134-5p/FOXM1 may serve as a promising target in HCC treatment.

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-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.

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