scholarly journals Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

2020 ◽  
Author(s):  
HanHee Jo ◽  
Yusun Park ◽  
Taehun Kim ◽  
Jisu Kim ◽  
JongSook Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Cancer Tissue ◽  
Sorafenib Treatment ◽  
Tumor Types ◽  
Related Proteins ◽  
Sirt3 Expression ◽  
Hcc Cells

Abstract Background : Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib. However, many patients with HCC show reduced sensitivity to sorafenib during treatment. SIRT3, a member of the mammalian sirtuin family, is a tumor suppressor in certain tumor types. However, only few studies have investigated the effects of SIRT3 on tumor prognosis and sorafenib sensitivity in patients with HCC. Here, we aimed to investigate the correlation between SIRT3 expression and glucose metabolism and proliferation in HCC and discover effective compounds that increase endogenous SIRT3 modulation effect of sorafenib. Methods: To determine the correlation between SIRT3 and glucose related proteins, immunostaining was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2). We also employed PD0332991 to modulate the SIRT3 expression in HCC cell and conducted functional assays. Results: SIRT3 expression was downregulated in high glycolytic and proliferative HCC cells of human patients, xenograft model and HCC cell lines. Moreover, SIRT3 expression was downregulated after sorafenib treatment, resulting in reduced drug sensitivity in HCC cell lines. To enhance the anti-tumor effect of sorafenib, we employed PD0332991 (CDK4/6-Rb inhibitor) based on the correlation between SIRT3 and phosphorylated retinoblastoma protein in HCC. Notably, combined treatment with sorafenib and PD0332991 showed an enhancement of the anti-tumor effect in HCC cells. Conclusions: Our data suggest that the modulation of SIRT3 by CDK4/6 inhibition might be useful for HCC therapy together with sorafenib, which, unfortunately, has limited efficacy and whose use is often associated with drug resistance.

scholarly journals Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

2020 ◽  
Author(s):  
HanHee Jo ◽  
Yusun Park ◽  
Taehun Kim ◽  
Jisu Kim ◽  
JongSook Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Cancer Tissue ◽  
Sorafenib Treatment ◽  
Tumor Types ◽  
Related Proteins ◽  
Sirt3 Expression ◽  
Hcc Cells

Abstract Background : Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib. However, many patients with HCC show reduced sensitivity to sorafenib during treatment. SIRT3, a member of the mammalian sirtuin family, is a tumor suppressor in certain tumor types. However, only few studies have investigated the effects of SIRT3 on tumor prognosis and sorafenib sensitivity in patients with HCC. Here, we aimed to investigate the correlation between SIRT3 expression and glucose metabolism and proliferation in HCC and discover effective compounds that increase endogenous SIRT3 modulation effect of sorafenib. Methods: To determine the correlation between SIRT3 and glucose related proteins, immunostaining was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2). We also employed PD0332991 to modulate the SIRT3 expression in HCC cell and conducted functional assays. Results: SIRT3 expression was downregulated in high glycolytic and proliferative HCC cells of human patients, xenograft model and HCC cell lines. Moreover, SIRT3 expression was downregulated after sorafenib treatment, resulting in reduced drug sensitivity in HCC cell lines. To enhance the anti-tumor effect of sorafenib, we employed PD0332991 (CDK4/6-Rb inhibitor) based on the correlation between SIRT3 and phosphorylated retinoblastoma protein in HCC. Notably, combined treatment with sorafenib and PD0332991 showed an enhancement of the anti-tumor effect in HCC cells. Conclusions: Our data suggest that the modulation of SIRT3 by CDK4/6 inhibition might be useful for HCC therapy together with sorafenib, which, unfortunately, has limited efficacy and whose use is often associated with drug resistance.

scholarly journals Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

2020 ◽  
Author(s):  
HanHee Jo ◽  
Kyung Sik Kim ◽  
Taehun Kim ◽  
Yusun Park ◽  
Jisu Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Cancer Tissue ◽  
Sorafenib Treatment ◽  
Anti Cancer ◽  
Tumor Types ◽  
Related Proteins ◽  
Sirt3 Expression

Abstract Background : : Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib. However, many patients with HCC show reduced sensitivity to sorafenib during treatment. SIRT3, a member of the mammalian sirtuin family, is a tumor suppressor in certain tumor types. To date, a few studies have investigated the effects of SIRT3 on tumor prognosis and sorafenib sensitivity in patients with HCC. Thus, this study aimed to investigate the correlation between SIRT3 expression and glucose metabolism and proliferation in HCC and to discover effective compounds that increase endogenous SIRT3 modulation effect of sorafenib. Methods: To determine the correlation between SIRT3 and glucose related proteins, immunostaining was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2). We also employed PD0332991 to modulate the SIRT3 expression in HCC cell and conducted functional assays. Results: SIRT3 expression is downregulated in high glycolytic and proliferative HCC of human patients, xenograft model and HCC cell lines. We also demonstrated that SIRT3 expression was downregulated after sorafenib treatment, resulting in reduced drug sensitivity in HCC cell lines. To enhance the anti-tumor effect of sorafenib, we employed PD0332991 (CDK4/6-Rb inhibitor) based on the correlation between SIRT3 and phospho-Rb in HCC. In addition, combined treatment with sorafenib and PD0332991 showed a synergic anti-tumor effect in HCC cells. Conclusions: Taken together, our data suggest that the modulation of SIRT3 by CDK4/6 inhibition might be used for HCC therapy together with sorafenib, which, unfortunately, has limited efficacy and whose use is often associated with drug resistance.

scholarly journals Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells

2019 ◽  
Author(s):  
HanHee Jo ◽  
Dayoung Yoo ◽  
JongSook Lee ◽  
Seon yoo Kim ◽  
Jee-in Chung ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Combined Treatment ◽  
Xenograft Model ◽  
Cancer Tissue ◽  
Sorafenib Treatment ◽  
Anti Cancer ◽  
Tumor Types ◽  
Related Proteins ◽  
Sirt3 Expression

Abstract Background : Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib. However, many patients with HCC show reduced sensitivity to sorafenib during treatment. SIRT3, a member of the mammalian sirtuin family, is a tumor suppressor in certain tumor types. To date, a few studies have investigated the effects of SIRT3 on tumor prognosis and sorafenib sensitivity in patients with HCC. Thus, this study aimed to investigate the correlation between SIRT3 expression and glucose metabolism and proliferation in HCC and to discover effective compounds that increase endogenous SIRT3 modulation effect of sorafenib. Methods: To determine the correlation between SIRT3 and glucose related proteins, immunostaining was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2). We also employed PD0332991 to modulate the SIRT3 expression in HCC cell and conducted functional assays. Results: SIRT3 expression is downregulated in high glycolytic and proliferative HCC of human patients, xenograft model and HCC cell lines. We also demonstrated that SIRT3 expression was downregulated after sorafenib treatment, resulting in reduced drug sensitivity in HCC cell lines. To enhance the anti-tumor effect of sorafenib, we employed PD0332991 (CDK4/6-Rb inhibitor) based on the correlation between SIRT3 and phospho-Rb in HCC. In addition, combined treatment with sorafenib and PD0332991 showed a synergic anti-tumor effect in HCC cells. Conclusions: Taken together, our data suggest that the modulation of SIRT3 by CDK4/6 inhibition might be used for HCC therapy together with sorafenib, which, unfortunately, has limited efficacy and whose use is often associated with drug resistance.

CDK12 inhibition mediates DNA damage and is synergistic with sorafenib treatment in hepatocellular carcinoma

Gut ◽  
2019 ◽  
Vol 69 (4) ◽  
pp. 727-736 ◽  
Author(s):  
Cun Wang ◽  
Hui Wang ◽  
Cor Lieftink ◽  
Aimee du Chatinier ◽  
Dongmei Gao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Damage ◽  
Cell Lines ◽  
Synergistic Effects ◽  
Loss Of Function ◽  
Bioinformatics Analyses ◽  
Sorafenib Treatment ◽  
Hcc Cells

ObjectivesHepatocellular carcinoma (HCC) is one of the most frequent malignancies and a major leading cause of cancer-related deaths worldwide. Several therapeutic options like sorafenib and regorafenib provide only modest survival benefit to patients with HCC. This study aims to identify novel druggable candidate genes for patients with HCC.DesignA non-biased CRISPR (clustered regularly interspaced short palindromic repeats) loss-of-function genetic screen targeting all known human kinases was performed to identify vulnerabilities of HCC cells. Whole-transcriptome sequencing (RNA-Seq) and bioinformatics analyses were performed to explore the mechanisms of the action of a cyclin-dependent kinase 12 (CDK12) inhibitor in HCC cells. Multiple in vitro and in vivo assays were used to study the synergistic effects of the combination of CDK12 inhibition and sorafenib.ResultsWe identify CDK12 as critically required for most HCC cell lines. Suppression of CDK12 using short hairpin RNAs (shRNAs) or its inhibition by the covalent small molecule inhibitor THZ531 leads to robust proliferation inhibition. THZ531 preferentially suppresses the expression of DNA repair-related genes and induces strong DNA damage response in HCC cell lines. The combination of THZ531 and sorafenib shows striking synergy by inducing apoptosis or senescence in HCC cells. The synergy between THZ531 and sorafenib may derive from the notion that THZ531 impairs the adaptive responses of HCC cells induced by sorafenib treatment.ConclusionOur data highlight the potential of CDK12 as a drug target for patients with HCC. The striking synergy of THZ531 and sorafenib suggests a potential combination therapy for this difficult to treat cancer.

scholarly journals LncRNA HOXD-AS1 functions as a ceRNA to promote hepatocellular carcinoma metastasis in zebrafish xenograft models

2021 ◽  
Author(s):  
Ying Zhang ◽  
Xiaolu Wang ◽  
Feng Qin ◽  
Shaochang Jia
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Noncoding Rna ◽  
Xenograft Model ◽  
Cerna Network ◽  
Xenograft Models ◽  
Proliferation And Invasion ◽  
Hcc Cells

Abstract Background: A few studies have shown that long noncoding RNA (lncRNA) HOXD cluster antisense RNA 1 (HOXD-AS1) plays an important role in hepatocellular carcinoma (HCC) metastasis as a competing endogenous RNA (ceRNA), but there is little in vivo evidence. This study aims to explore the zebrafish HCC xenograft as an in vivo metastasis model to verify the ceRNA network of HOXD-AS1. Methods: The quantitative reverse transcription PCR (qRT-PCR) assay was used to assess the expression level of HOXD-AS1 in HCC cell lines. Knockdown of HOXD-AS1 or miR-130a-3p was performed by transfecting small interfering RNA (siRNA) or microRNA (miRNA) inhibitor, respectively. The proliferation and invasion of HCC cells in vitro were analyzed by CCK-8 and transwell assays. The growth and metastasis of HCC cells in vivo were assessed by zebrafish xenograft models.Results: We verified that HOXD-AS1 was overexpressed in all tested HCC cell lines than the normal hepatic cells. Silence of HOXD-AS1 suppressed cell proliferation and invasion in Hep3B and Huh7 HCC cell lines in vitro. In zebrafish xenograft models, knockdown of HOXD-AS1 also reduced the growth and metastasis of the two HCC cells. Moreover, downregulation of miR-130a-3p not only increased the HCC metastasis, but also rescued the metastasis which inhibited by silence of HOXD-AS1 in vitro and in vivo.Conclusions: Our study demonstrates the metastasis role of the HOXD-AS1/miR-130a-3p ceRNA network in HCC cells in vitro and in vivo, and these findings suggest that zebrafish xenograft model could be used for ceRNA mechanism verification in tumor metastasis.

scholarly journals N-Acetyltransferase 10 Enhances Doxorubicin Resistance in Human Hepatocellular Carcinoma Cell Lines by Promoting the Epithelial-to-Mesenchymal Transition

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Xiuming Zhang ◽  
Jiang Chen ◽  
Shi Jiang ◽  
Shilin He ◽  
Yanfeng Bai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Xenograft Model ◽  
Mesenchymal Transition ◽  
Mouse Xenograft Model ◽  
Incorporation Assay ◽  
Hcc Cells

Background. N-Acetyltransferase 10 (NAT10) has been reported to be expressed at high levels in hepatocellular carcinoma (HCC); however, its role in chemoresistance is unclear. This study is aimed at investigating whether NAT10 regulates the epithelial-mesenchymal transition (EMT) and chemoresistance in HCC. Methods. HCC cell lines (Huh-7, Bel-7402, SNU387, and SNU449) were treated with remodelin, an inhibitor of NAT10, or transfected with small inhibitory RNAs (siRNAs) targeting NAT10 or Twist. The EMT was induced by hypoxia. The CCK-8 assay was used to quantify cell viability, the EdU incorporation assay to assess cell proliferation. siRNA knockdown efficiency and epithelial/mesenchymal marker expression were assessed by western blotting. Results. Knockdown of NAT10 using siRNA or inhibition of NAT10 using remodelin increased the sensitivity of HCC cell lines to doxorubicin; similar effects were observed in cells transfected with the Twist siRNA. Inhibition of NAT10 using remodelin also reversed the ability of doxorubicin to induce the EMT in HCC cells. Furthermore, inhibiting NAT10 reversed the hypoxia-induced EMT. Finally, we confirmed that combining doxorubicin with remodelin delayed tumor growth and reduced tumor cell proliferation in a mouse xenograft model of HCC. Conclusions. NAT10 may contribute to chemoresistance in HCC by regulating the EMT. The mechanism by which NAT10 regulates the EMT and doxorubicin sensitivity in HCC cells merits further investigation.

scholarly journals High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma

2021 ◽  
Author(s):  
Jianjun Xu ◽  
Zhe Su ◽  
Xiang Cheng ◽  
Shaobo Hu ◽  
Wenjie Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
T Cell Activation ◽  
Critical Role ◽  
Treatment Result ◽  
Tunel Staining ◽  
Sorafenib Treatment ◽  
Adaptive Resistance ◽  
Hcc Cells

Abstract Background Adaptive resistance and side effects of sorafenib treatment result in unsatisfied survival of patients with hepatocellular carcinoma (HCC). Palmitoyl-protein thioesterase 1 (PPT1) plays a critical role in progression of various cancers. However, its role on prognosis and immune infiltrates in HCC remains unclarified. Methods By data mining in the Cancer Genome Atlas databases, the role of PPT1 in HCC were initially investigated. Furthermore, HCC cell lines Hep 3B and Hep 1–6 were treated with DC661 against PPT1. The biological function of PPT1 was determined by CCK-8 test, colony formation assay, TUNEL staining, immunofluorescence staining, Western blotting, and PI-Annexin V apoptosis assays in vitro. Animal models of subcutaneous injection were applied to investigate the therapeutic role of targeting PPT1. Results Wefound that PPT1 levels were significantly upregulated in HCC tissues compared with normal tissues and were significantly associated with a poor prognosis. Multivariate analysis further confirmed that high expression of PPT1 was an independent risk factor for poor overall survival of HCC patients. We initially found that PPT1 was significantly upregulated in sorafenib-resistant cell lines established in this study. Upon sorafenib treatment, HCC cells acquired adaptive resistance by inducing autophagy. We found that DC661, a selective and potent small-molecule PPT1-inhibitor, induced lysosomal membrane permeability, caused lysosomal deacidification, inhibited autophagy and enhanced sorafenib sensitivity in HCC cells. Interestingly, this sensitization effect was also mediated by the induction mitochondrial pathway apoptosis. In addition, the expression level of PPT1 was associated with the immune infiltration in the HCC tumor microenvironment, and PPT1 inhibitor DC661 significantly enhanced the anti-tumor immune response by promoting dendritic cell maturation and further promoting CD8+ T cell activation. Moreover, DC661 combined with sorafenib was also very effective at treating xenograft models in immunized mice. Conclusions Our findings suggested that targeting PPT1 with DC661 in combination with sorafenib might be a novel and effective alternative therapeutic strategy for HCC.

scholarly journals Role of tight junction-associated MARVEL protein marvelD3 in migration and Epithelial–Mesenchymal Transition of hepatocellular carcinoma

2021 ◽  
Author(s):  
Yanmeng Li ◽  
Teng Li ◽  
Donghu Zhou ◽  
Jia Wei ◽  
Zhenkun Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tight Junction ◽  
Tumor Cell ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Mesenchymal Transition ◽  
And Migration ◽  
Related Proteins ◽  
Hcc Cells

Abstract BackgroundTight junction (TJ) imbalance is associated with hepatocellular carcinoma (HCC). MarvelD3, which contains a conserved MARVEL (MAL and related proteins for vesicle trafficking and membrane link) domain similarly to occludin and tricellulin, is a recently identified integral membrane protein that forms TJs. However, little is known about the possible roles of marvelD3 in epithelial–mesenchymal transition (EMT) and metastasis of HCC. We aimed to demonstrate the role of marvelD3 in inhibiting HCC EMT and migration and further explore the underlying molecular mechanisms.MethodsMarvlD3 expression was assessed in HCC and normal liver tissues. Changes in marvelD3 expression were analyzed during transforming growth factor β1 (TGF-β1) and snail/slug-induced EMT. MarvelD3 knockdown HCC cell lines were established using marvelD3-siRNA to analyze correlations between marvelD3 and EMT-related proteins. Tumor cell behaviors were analyzed in marvelD3 knockdown HCC cells. Associations between marvelD3 and genes in the nuclear factor (NF)-κB pathway were also analyzed.ResultsLoss of marvelD3 expression was significantly correlated with the occurrence and TNM stage of HCC. MarvelD3 was downregulated in HCC cells with TGF-β and snail/slug-induced EMT. Expression of marvelD3 protein was significantly associated with E-cadherin and vimentin in HCC cell lines. Knockdown of marvelD3 promoted tumor cell migration concomitant with activation of the NF-κB signaling pathway and increased matrix metallopeptidase 9 expression.ConclusionsOur study demonstrated that MarvelD3 inhibited EMT and migration of HCC cells via NF-κB signaling pathway. This suggests that marvelD3 is a novel potential biomarker for the treatment and prognosis of HCC.

scholarly journals M6A-Mediated Upregulation of LINC00106 Promotes Stemness and Metastasis Properties of Hepatocellular Carcinoma via Sponging Let7f

2021 ◽  
Vol 9 ◽  
Author(s):  
Wenjin Liang ◽  
Yan Wang ◽  
Qinyu Zhang ◽  
Min Gao ◽  
Haizhou Zhou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Side Population ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Transcript Stability ◽  
Hcc Cells

Background: Hepatocellular carcinoma (HCC) cells exhibit the stemness property, which makes the patient with HCC prone to tumor recurrence and metastasis. Despite the prominent regulatory role of long non-coding RNAs (lncRNAs) in tumor stemness, the roles and molecular mechanisms of LINC00106 in HCC are poorly understood.Methods: LINC00106, let7f and periostin expression levels in tissue specimens and cell lines were assessed through qRT-PCR and immunohistochemistry (IHC). Various in vivo and in vitro assays, namely sphere/colony formation, proportion of side population cells (SP%), invasion, migration, western blot, and murine xenograft model were employed for assessing the stemness and metastatic properties of HCC cells. Luciferase reporter assays, RNA-seq, RNA pull-down, RNA immunoprecipitation (RIP) were conducted to clarificate the target gene and analyze the underlying mechanisms.Results: LINC00106 was prominently upregulated in tissues and cell lines of HCC. Patients having a high LINC00106 level exhibited a poor outcome. Under in vivo and in vitro conditions, the stemness and metastatic properties of HCC cells were augmented by LINC00106. Additionally, LINC00106 was found to sponge let7f to upregulate periostin, which lead to the activation of periostin-associated PI3K-AKT signaling pathway. Moreover, m6A methylation was found to cause LINC00106 upregulation while maintaining LINC00106 RNA transcript stability.Conclusion: m6A methylation triggers the upregulation of LINC00106, which promotes the stemness and metastasis properties in HCC cells by sponging let7f, thereby resulting in periostin activation. The findings indicate the potential of LINC00106 as a diagnostic marker and therapeutic target for HCC.

scholarly journals CircTP63 promotes hepatocellular carcinoma progression by sponging miR-155-5p and upregulating ZBTB18

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jiantao Wang ◽  
Jinbiao Che
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Circular Rnas ◽  
Epithelial Cell Line ◽  
High Morbidity ◽  
Mrna Levels ◽  
Promoting Effect ◽  
Tumor Stages ◽  
Hcc Cells

Abstract Background Hepatocellular carcinoma (HCC) is the leading cause of tumor-related death worldwide due to high morbidity and mortality, yet lacking effective biomarkers and therapies. Circular RNAs (circRNAs) are a group of non-coding RNAs that regulate gene expression through interacting with miRNAs, implicating in the tumorigenesis and progression. A novel circRNA, circTP63, was reported to be an oncogene in HCC. However, its role in HCC remains unclear. Methods qRT-PCR was used to assess the mRNA levels of CircTP63 in 90 pairs of tumor and adjacent normal tissues from HCC patients, one human normal hepatic epithelial cell line and HCC cell lines. CCK-8, colony formation, transwell, and flow cytometry assays were performed to detect the cellular function of circTP63/miR-155-5p/ZBTB18 in HCC cells. HCC xenograft mice models were established to assess the in vivo effect of circTP63. Bioinformatic analysis, RNA pull-down and luciferase assays were used to determine the interaction among circTP63/miR-155-5p/ZBTB18. Results circTP63 was significantly upregulated in HCC tissues and cell lines. High circTP63 expression is closely associated with the tumor stages, lymph node metastasis, and poor prognosis of HCC patients. Functionally, knockdown of circTP63 inhibited cell proliferation, migration, invasion, and promoted cell apoptosis of HCC. Meanwhile, overexpression of circTP63 enhanced HCC progression. Mechanically, circTP63 was a sponge of miR-155-5p to facilitate the ZBTB18 expression, and the ZBTB18 expression in HCC tissues was negatively associated with the survival rate of HCC patients. Furthermore, rescued assays revealed that the reduced tumor-promoting effect on HCC cells induced by knockdown of circTP63 can be reversed by miR-155-5p inhibitor or ZBTB18 overexpression. Conclusion Our data highlight a critical circTP63-miR-155-5p-ZBTB18 regulatory network involved in the HCC progression, gaining mechanistic insights into the function of circRNAs in HCC progression, and providing effective biomarkers and therapeutic targets for HCC treatment.

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