Preliminary investigation of the role of BTB domain-containing 3 gene in the proliferation and metastasis of hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is the 6th prevalent cancer and the 4th leading cause of cancer related deaths all over the world. A major challenge for sorafenib, the standard chemotherapeutic agent in HCC treatment, is the chemo-resistance. Objective: This study was conducted to evaluate the role of dantrolene as a possible antineoplastic agent in HCC, and in chemo-sensitization of sorafenib via targeting Ca+2/PI3K pathway. Methods: HCC was induced in rats using a single dose of diethyl nitrosamine (DENA) (200 mg/kg, ip), followed by phenobarbital sodium (0.05%) in drinking water for 18 weeks. At the end of 18th week, rats were allocated into 4 groups (10 rats/each), one group was left without treatment (DENA group) and the other three groups were treated with either sorafenib, dantrolene, or their combination for further 4 weeks. One day after last injection, serum and liver tissues were collected. Liver tissue p53, VEGF, MMP-9, Cyclin D1, PI3K, and, serum AFP were assessed using immunoassay. Hepatic and serum Ca+2 were also computed. Furthermore, Ki67 was assessed immunohistochemically. Results: Dantrolene exhibited synergistic effect when used in combination with sorafenib compared to either drug alone (p <0.05) through decreasing p53, VEGF, MMP-9, Cyclin D1, and Ki-67. In addition, dantrolene was evidenced to have an inhibitory effect on Ca+2/PI3K pathway that mediates its antineoplastic action when used alone or in combination with sorafenib. Conclusion: Dantrolene exerted antineoplastic effect as well as augmented sorafenib antineoplastic activity via intervention of Ca+2/PI3K pathway, manifested by ameliorating angiogenesis, apoptosis, proliferation and metastasis.

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Long non-coding RNA ZEB1-AS1 promotes proliferation and metastasis of hepatocellular carcinoma cells by targeting miR-299-3p/E2F1 axis

The Journal of Biochemistry ◽

10.1093/jb/mvab042 ◽

2021 ◽

Author(s):

Baiyin Mu ◽

Chenlan Lv ◽

Qingli Liu ◽

Hong Yang

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Non Coding Rna ◽

Tumorigenesis And Progression ◽

Novel Biomarkers ◽

Proliferation And Metastasis ◽

Long Non Coding Rna

Abstract There is emerging evidence that dysregulation of long non-coding RNAs (lncRNAs) is associated with hepatocellular carcinoma (HCC). Zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) functions as an oncogenic regulator in various malignancies. Nonetheless, the potential role of ZEB1-AS1 in HCC remains poorly elucidated. Herein, qRT-PCR was employed for examining ZEB1-AS1, miR-299-3p and E2F1 mRNA expressions in HCC cells and tissues. MTT assay was performed to evaluate cell proliferation. Transwell assay was utilized for evaluating cancer cell migration and invasion. Western blot was employed for measuring E2F1 protein expression. What’s more, dual-luciferase reporter assay was utilized for verifying the targeting relationships between ZEB1-AS1 and miR-299-3p, as well as E2F1 and miR-299-3p. It was demonstrated that, in HCC tissues and cells, ZEB1-AS1 expression was markedly increased, and meanwhile, its high expression level is related to the unfavorable clinicopathologic indicators. ZEB1-AS1 overexpression facilitated HCC cell proliferation, migration and invasion, while its knockdown led to the opposite effects. In terms of mechanism, we discovered that ZEB1-AS1 could decoy miR-299-3p and up-regulate E2F1 expression. This work reveals the functions and mechanism of ZEB1-AS1 in HCC tumorigenesis and progression, which provides novel biomarkers and therapeutic targets for HCC.

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microR-505/heterogeneous nuclear ribonucleoprotein M inhibits hepatocellular carcinoma cell proliferation and induces cell apoptosis through the Wnt/β-catenin signaling pathway

Biomarkers in Medicine ◽

10.2217/bmm-2019-0511 ◽

2020 ◽

Vol 14 (11) ◽

pp. 981-996

Author(s):

Xiaobin Chi ◽

Yi Jiang ◽

Yongbiao Chen ◽

Lizhi Lv ◽

Jianwei Chen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Signaling Pathway ◽

Cell Apoptosis ◽

Heterogeneous Nuclear Ribonucleoprotein ◽

Apoptosis Assay ◽

Proliferation And Metastasis ◽

Novel Strategy ◽

Nuclear Ribonucleoprotein

Aim: This study aimed to investigate the expression of microRNA-505 (miR-505) and explore its clinical significance, biological function and mechanisms in hepatocellular carcinoma (HCC). Methods: Expression of miR-505 was measured in 128 paired HCC tissues and five cell lines by quantitative real-time polymerase chain reaction (qRT-PCR). MTT assay, Transwell migration, invasion assays and apoptosis assay were performed to explore the functional role of miR-505. The target gene of miR-505 was assessed using the bioinformatics assay and the related signaling pathway was confirmed using western blot. Results: Expression of miR-505 in HCC serum and tissues were downregulated. The overexpression of miR-505 in HCC cells inhibited cell proliferation and metastasis, as well as enhanced cell apoptosis by directly downregulating heterogeneous nuclear ribonucleoprotein M ( HNRNPM). The activity of the Wnt/β-catenin signaling pathway was suppressed by the overexpression of miR-505 but was promoted by the upregulation of HNRNPM. Conclusion: The results suggest that the regulation of miR-505/ HNRNPM may be a novel strategy to improve the targeted therapy of HCC.

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Accumulation of AGO2 facilitates tumor proliferation and metastasis through upregulating Survivin, Vimentin and Snail in human hepatocellular carcinoma

10.21203/rs.2.17899/v1 ◽

2019 ◽

Author(s):

Yang Yang ◽

Qi Mei

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Xenograft Model ◽

Proliferation And Metastasis ◽

Interfering Rna ◽

Cell Proliferation And Metastasis

Abstract Background：Argonaute 2 (AGO2), a typical member of the Ago gene family, plays a pivotal role in hepatocellular carcinoma (HCC) tumorgenesis through regulating the short interfering RNA-mediated gene silencing. However, the underlined mechanism needs clarified. Herein, we found that AGO2 was frequently upregulated in human HCC cancerous tissues compared with non-cancerous tissues. Methods: Clinical analyses were performed to determine the relation between the expression level of AGO2 and prognosis in HCC patients. By using CRISPR/Cas9 approach in SMMC-7721 cells and establishing xenograft model in nude mice, we further identified the role of AGO2 in HCC. Gene expression microarray analysis was used to reveal the changes of gene expression profile mediated by AGO2 depletion in SMMC-7721 cells. Results: We observed that the overexpression of AGO2 was associated with poor prognosis in HCC patients. The knockout of AGO2 inhibited tumor cell proliferation and metastasis in vivo and in vitro. We also identified that AGO2 facilitates HCC tumorigenesis through modulating Survivin, Vimentin and Snail expression. Conclusions: Therefore, this study not only demonstrates that accumulation of AGO2 promotes cell proliferation and metastasis in HCC, but also provides a novel molecular mechanism in HCC progression.

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Role of activated hepatic stellate cells in proliferation and metastasis of hepatocellular carcinoma

Hepatology Research ◽

10.1111/hepr.12356 ◽

2014 ◽

Vol 45 (3) ◽

pp. 326-336 ◽

Cited By ~ 22

Author(s):

Nan Lin ◽

Zhiju Chen ◽

Yi Lu ◽

Yangzhu Li ◽

Kunpeng Hu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Proliferation And Metastasis ◽

Activated Hepatic Stellate Cells

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USP1-dependent RPS16 protein stability drives growth and metastasis of human hepatocellular carcinoma cells

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02008-3 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Yuning Liao ◽

Zhenlong Shao ◽

Yuan Liu ◽

Xiaohong Xia ◽

Yuanfei Deng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Carcinoma Cells ◽

Deubiquitinating Enzymes ◽

Poor Survival ◽

Clinical Observations ◽

Inhibition Of Growth ◽

Proliferation And Metastasis ◽

Novel Strategy ◽

Human Hepatocellular Carcinoma Cells

Abstract Background Hepatocellular carcinoma (HCC) remains a medical challenge due to its high proliferation and metastasis. Although deubiquitinating enzymes (DUBs) play a key role in regulating protein degradation, their pathological roles in HCC have not been fully elucidated. Methods By using biomass spectrometry, co-immunoprecipitation, western blotting and immunofluorescence assays, we identify ribosomal protein S16 (RPS16) as a key substrate of ubiquitin-specific peptidase 1 (USP1). The role of USP1-RPS16 axis in the progression of HCC was evaluated in cell cultures, in xenograft mouse models, and in clinical observations. Results We show that USP1 interacts with RPS16. The depletion of USP1 increases the level of K48-linked ubiquitinated-RPS16, leading to proteasome-dependent RPS16 degradation. In contrast, overexpression of USP1-WT instead of USP1-C90A (DUB inactivation mutant) reduces the level of K48-linked ubiquitinated RPS16, thereby stabilizing RPS16. Consequently, USP1 depletion mimics RPS16 deficiency with respect to the inhibition of growth and metastasis, whereas transfection-enforced re-expression of RPS16 restores oncogenic-like activity in USP1-deficient HCC cells. Importantly, the high expression of USP1 and RPS16 in liver tissue is a prognostic factor for poor survival of HCC patients. Conclusions These findings reveal a previously unrecognized role for the activation of USP1-RPS16 pathway in driving HCC, which may be further developed as a novel strategy for cancer treatment.

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