TRIB3 promotes hepatocellular carcinoma growth and predicts poor prognosis

2020 ◽  
Vol 29 (3) ◽  
pp. 307-315
Author(s):  
Xiao-Jun Wang ◽  
Fei-Fei Li ◽  
Yi-Jing Zhang ◽  
Man Jiang ◽  
Wan-Hua Ren
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Xenograft Model ◽  
Clinicopathological Characteristics ◽  
Tissue Samples ◽  
Normal Tissues ◽  
Related Family ◽  
Hcc Cells

BACKGROUND: Tribbles pseudokinase 3 (TRIB3) is a member of the tribbles-related family, which is involved a lot of cellular processes and multiple cancers, such as breast cancer, colorectal cancer, renal cell carcinomas, and lung cancer. However, the expression pattern and biological function of TRIB3 in hepatocellular carcinoma (HCC) has not yet been completely elucidated. METHODS: The expression of TRIB3 and clinicopathological characteristics were evaluated by HCC tissue microarray and qPCR analysis. Lentivirus packaging and transfection were employed to establish cell lines with TRIB3 overexpression or knockdown. The biological functions of TRIB3 in the growth of HCC were determined using MTT and crystal violet assays. Tumor growth was monitored in a xenograft model in vivo. RESULTS: The expression of TRIB3 was upregulated in HCC tissue samples compared to paired normal tissues in 45 patients examined by qPCR assay. TRIB3 expression was significantly correlated with HCC tumor size and prognosis in postoperative patients by analysis of the TRIB3 expression data and HCC clinical features. Forced expression of TRIB3 significantly promoted HCC growth in vitro. In contrast, downregulation of TRIB3 inhibited cell growth in vitro. Moreover, knockdown of TRIB3 suppressed tumorigenesis of HCC cells in vivo. CONCLUSION: TRIB3 promotes growth abilities of HCC cells both in vitro and in vivo and predicts poor prognosis of HCC patients, which serves as a prognostic marker and might provide a potential therapeutic candidate for patients with HCC.

scholarly journals Cyclin-Dependent Kinase Regulatory Subunit 2 Indicated Poor Prognosis and Facilitated Aggressive Phenotype of Hepatocellular Carcinoma

2019 ◽  
Vol 2019 ◽  
pp. 1-13
Author(s):  
Jie Zhang ◽  
Qianqian Song ◽  
Jinxia Liu ◽  
Lina Lu ◽  
Yuqing Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Disease Free Survival ◽  
Normal Liver ◽  
Regulatory Subunit ◽  
Mrna Levels ◽  
Cyclin Dependent Kinase ◽  
Normal Tissues ◽  
Hcc Cells

Cyclin-dependent kinase regulatory subunit 2 (CKS2) is a member of the cell cycle-dependent protein kinase subunit family, which is implicated as an oncogene in various malignancies. However, the clinical significance, oncogenic functions, and related mechanisms of CKS2 in hepatocellular carcinoma (HCC) remain largely unclear. In the present study, expression features and prognostic value of CKS2 were evaluated in the bioinformatic databases and HCC tissues. The effects of CKS2 on the malignant phenotypes of HCC cells were explored in vitro. According to the analyses of three bioinformatic databases, mRNA levels of CKS2 were elevated in HCC tissues compared with the normal tissues. Immunohistochemical assays found that high CKS2 expression was closely associated with liver cirrhosis (P=0.019), poor differentiation (P=0.02), portal vein invasion (P<0.001), TNM stage (P=0.019), tumor metastasis (P=0.008), and recurrence (P=0.003). The multivariate regression analyses suggested that CKS2 was an independent prognostic factor for overall survival (HR=2.088, P=0.014) and disease-free survival (HR=2.511, P=0.002) of HCC patients. Moreover, the bioinformatic analyses indicated that CKS2 might be associated with the malignant phenotypes in HCC progression. In addition, in vitro assays showed that CKS2 expression was higher in HCC cell lines than in normal liver cells. Knockdown of CKS2 remarkably repressed the proliferation, colony formation (P=0.0003), chemoresistance, migration (P=0.0047), and invasion (P=0.0012) of HCC cells. Taken together, overexpression of CKS2 was significantly correlated with poor prognosis of HCC patients and the malignant phenotypes of HCC cells, suggesting that it was a novel prognostic biomarker and potential target of 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 Upregulation of musashi1 increases malignancy of hepatocellular carcinoma via the Wnt/β-catenin signaling pathway and predicts a poor prognosis

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Qiuhua Liu ◽  
Cuijie Zhou ◽  
Bo Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Poor Prognosis ◽  
Liver Tumors ◽  
Clinicopathological Characteristics ◽  
Invasion And Migration ◽  
Potential Biomarker ◽  
Hcc Cells

Abstract Background Hepatocellular carcinoma (HCC) is a common human malignant cancer due to a high metastatic capacity and the recurrence rate is also high. This study is aim to investigate the role of musashi1 as a potential biomarker for therapy of HCC. Methods The mRNA and protein expression levels of musashi1 were detected in HCC samples and cell lines. The malignant properties of HCC cells, including proliferation, invasion and migration were measured by overexpressing or knocking down expression of musashi1. Additionally, the correlation between musashi1 and clinicopathological indexes and prognosis were analyzed. The expression of CD44 was measured and the correlation between CD44 and musashi1 was analyzed. Results In vitro cytological experiments demonstrated that musashi1 was elevated in HCC samples and cell lines and this increased expression affected cancer cell viability, migration and invasive capacity by activating of the Wnt/β-catenin signaling pathway. Analysis of clinicopathological characteristics suggested that up-regulation of musashi1 was related to metastasis potential and a poor prognosis. Besides, there was a positive correlation between CD44 and musashi1 expression. Upregulation of musashi1 in malignant liver tumors may have contributed to the maintenance of stem-cell like characteristics of HCC cells. Conclusions Upregulation of musashi1 could enhance malignant development of HCC cells and thus might be a novel marker for HCC therapy.

scholarly journals β-TrCP-mediated ubiquitination and degradation of Dlg5 regulates hepatocellular carcinoma cell proliferation

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Dongping Wang ◽  
Qi Zhang ◽  
Fenfen Li ◽  
Chan Wang ◽  
Changming Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Xenograft Model ◽  
Ubiquitin Proteasome System ◽  
Tumor Xenograft ◽  
Dependent Manner ◽  
Ubiquitin Proteasome ◽  
Novel Strategy ◽  
Hcc Cells

Abstract Background Discs large homolog 5 (Dlg5) is a member of the membrane-associated guanylate kinase (MAGUK) adaptor family of proteins and its deregulation has been implicated in the malignancy of several cancer types. Dlg5 was down-regulated in hepatocellular carcinoma (HCC) and lower Dlg5 expression was associated with poor survival of HCC patients. However, how to regulate Dlg5 remains largely unknown. Methods The co-immunoprecipitation assay was used to determine the interaction between Dlg5 and β-TrCP. The in vivo ubiquitination assay was performed to determine the regulation of Dlg5 by β-TrCP. CCK-8 and colony formation assay were implemented to detect the biological effect of Dlg5 on the growth of HCC cells in vitro. The effect of Dlg5 on HCC tumor growth in vivo was studied in a tumor xenograft model in mice. Results Here we report that Dlg5 is regulated by the ubiquitin proteasome system and depletion of either Cullin 1 or β-TrCP led to increased levels of Dlg5. β-TrCP regulated Dlg5 protein stability by targeting it for ubiquitination and subsequent destruction in a phosphorylation-dependent manner. We further demonstrated a crucial role of Ser730 in the non-canonical phosphodegron of Dlg5 in governing β-TrCP-mediated Dlg5 degradation. Importantly, failure to degrade Dlg5 significantly inhibited HCC cells proliferation both in vitro and in vivo. Conclusion Collectively, our finding provides a novel molecular mechanism for the negative regulation of Dlg5 by β-TRCP in HCC cells. It further suggests that preventing Dlg5 degradation could be a possible novel strategy for clinical treatment of HCC.

scholarly journals Exosomal hsa_circ_0004658 derived from RBPJ overexpressed-macrophages inhibits hepatocellular carcinoma progression via miR-499b-5p/JAM3

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Lei Zhang ◽  
Jing Zhang ◽  
Pengfei Li ◽  
Ting Li ◽  
Zhiqin Zhou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Xenograft Model ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Mouse Xenograft Model ◽  
Rna Immunoprecipitation ◽  
And Migration ◽  
Hcc Cells

AbstractMacrophage-derived exosomes (Mφ-Exo) have multidimensional involvement in tumor initiation, progression, and metastasis, but their regulation in hepatocellular carcinoma (HCC) is not fully understood. RBPJ has been implicated in macrophage activation and plasticity. In this study we assess the role of exosomes derived from RBPJ-overexpressed macrophages (RBPJ+/+ Mφ-Exo) in HCC. The circular RNA (circRNA) profiles in RBPJ+/+ Mφ-Exo and THP-1-like macrophages (WT Mφ)-Exo was evaluated using circRNA microarray. CCK-8, Transwell, and flow cytometry analyses were used to evaluate the function of Mφ-Exo-circRNA on HCC cells. Luciferase reporter assays, RNA immunoprecipitation, and Pearson’s correlation analysis were used to confirm interactions. A nude mouse xenograft model was used to further analyze the functional significance of Mφ-Exo-cirRNA in vivo. Our results shown that hsa_circ_0004658 is upregulated in RBPJ+/+ Mφ-Exo compared to WT Mφ-Exo. RBPJ+/+ Mφ-Exo and hsa_circ_0004658 inhibits proliferation and promotes apoptosis in HCC cells, whereas hsa_circ_0004658 knockdown stimulated cell proliferation and migration but restrained apoptosis in vitro and promotes tumor growth in vivo. The effects of RBPJ+/+ Mφ-Exo on HCC cells can be reversed by the hsa_circ_0004658 knockdown. Mechanistic investigations revealed that hsa_circ_0004658 acts as a ceRNA of miR-499b-5p, resulting in the de-repression of JAM3. These results indicate that exosome circRNAs secreted from RBPJ+/+ Mφ inhibits tumor progression through the hsa_circ_0004658/miR-499b-5p/JAM3 pathway and hsa_circ_0004658 may be a diagnostic biomarker and potential target for HCC therapy.

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 Elafin promotes tumour metastasis and attenuates the anti-metastatic effects of erlotinib via binding to EGFR in hepatocellular carcinoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Chenwei Wang ◽  
Yadi Liao ◽  
Wei He ◽  
Hong Zhang ◽  
Dinglan Zuo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Early Stage ◽  
Tissue Microarrays ◽  
Luciferase Reporter ◽  
Normal Tissues ◽  
Tumour Metastasis ◽  
Hcc Cells

Abstract Background Elafin is a serine protease inhibitor critical for host defence. We previously reported that Elafin was associated with the recurrence of early-stage hepatocellular carcinoma (HCC) after surgery. However, the exact role of Elafin in HCC remains obscure. Methods HCC tissue microarrays were used to investigate the correlation between Elafin expression and the prognosis of HCC patients. In vitro migration, invasion and wound healing assays and in vivo lung metastasis models were used to determine the role of Elafin in HCC metastasis. Mass spectrometry, co-immunoprecipitation, western blotting, and immunofluorescence staining assays were performed to uncover the mechanism of Elafin in HCC. Dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the transcriptional regulation of Elafin. Results Elafin expression was frequently increased in HCC tissues compared to normal tissues, and high Elafin expression in HCC tissues was correlated with aggressive tumour phenotypes and a poor prognosis in HCC patients. Elafin dramatically enhanced the metastasis of HCC cells both in vitro and in vivo by interacting with EGFR and activating EGFR/AKT signalling. Moreover, Elafin attenuated the suppressive effects of erlotinib on HCC metastasis. Besides, Elafin was transcriptionally regulated by Sp1 in HCC cells. Clinically, Elafin expression was positively correlated with Sp1, Vimentin, and EGFR signalling in both our HCC tissue microarrays and TCGA database analysis. Conclusions Upregulation of Elafin by Sp1 enhanced HCC metastasis via EGFR/AKT pathway, and overexpression of Elafin attenuated the anti-metastatic effects of erlotinib, suggesting a valuable prognostic biomarker and therapeutic target for HCC.

scholarly journals RETRACTED ARTICLE: α2,6-Sialylation mediates hepatocellular carcinoma growth in vitro and in vivo by targeting the Wnt/β-catenin pathway

Oncogenesis ◽  
2017 ◽  
Vol 6 (5) ◽  
pp. e343-e343 ◽  
Author(s):  
Y Zhao ◽  
A Wei ◽  
H Zhang ◽  
X Chen ◽  
L Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Xenograft Model ◽  
Migration And Invasion ◽  
Mouse Xenograft Model ◽  
Retracted Article ◽  
Underlying Mechanisms ◽  
St6gal I

Abstract Abnormal sialylation due to overexpression of sialyltransferases has been associated with tumorigenesis and tumor progression. Although ST6Gal-I influences cancer persistence and progression by affecting various receptors, the underlying mechanisms and mediators remain largely obscure, especially in hepatocellular carcinoma (HCC). We found that ST6Gal-I expression was markedly upregulated in HCC tissues and cells, high levels being associated with aggressive phenotype and poor prognosis. Furthermore, we examined the roles and mechanisms of ST6Gal-I in HCC tumorigenesis and metastasis in vitro and in vivo. ST6Gal-I overexpression promoted proliferation, migration and invasion of Huh-7 cells, whereas its knockdown restricted these abilities in MHCC97-H cells. Additionally, in a mouse xenograft model, ST6Gal-I-knockdown MHCC97-H cells formed significantly smaller tumors, implying that ST6Gal-I overexpression can induce HCC cell malignant transformation. Importantly, enhanced HCC tumorigenesis and metastasis by ST6Gal-I may be associated with Wnt/β-catenin signaling promotion, including β-catenin nuclear transition and upregulation of downstream molecules. Together, our results suggest a role for ST6Gal-I in promoting the growth and invasion of HCC cells through the modulation of Wnt/β-catenin signaling molecules, and that ST6Gal-I might be a promising marker for prognosis and therapy of HCC.

scholarly journals Downregulation of PRAME Suppresses Proliferation and Promotes Apoptosis in Hepatocellular Carcinoma Through the Activation of P53 Mediated Pathway

2018 ◽  
Vol 45 (3) ◽  
pp. 1121-1135 ◽  
Author(s):  
Hanzhang Zhu ◽  
Jingrui Wang ◽  
Junjie Yin ◽  
Bei Lu ◽  
Qijun Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Cell Apoptosis ◽  
Poor Prognosis ◽  
P53 Pathway ◽  
Tissue Samples ◽  
Potential Biomarker

Background/Aims: The expression of PRAME and its role in hepatocellular carcinoma (HCC) remain unknown. The aim of this study was to examine the functional role of PRAME in HCC development and exploring the molecular mechanism. Methods: We first detected PRAME expression in 96 human HCC tissue samples and correlated with clinicopathological characteristics and prognosis of the patients. We then established stable HCC cell lines with PRAME overexpression and knockdown followed by functional analysis in vitro. Further, we examined the relationship between PRAME and p53 pathway in vitro by using Western blotting. Finally, PRAME expression was detected to evaluate its correlation with p-p53 and p53 pathway related apoptotic proteins in xenograft tumor mouse model using immunohistochemistry. Results: PRAME expression was significantly higher in HCC tissues than in adjacent non-tumor tissues and their expression was positively correlated with alpha fetoprotein levels and tumor size. In addition, PRAME expression was associated with AJCC stage and is a potential biomarker of poor prognosis regarding 5-year overall survival in HCC. In vitro studies, we found that PRAME expression was higher in HCC cell lines than in normal hepatic cell line. Inhibited cell proliferation and increased cell apoptosis was observed in PRAME knockdown HCC cells. Futher, increased cell apoptosis was correlated with the proportion of cells in G0/G1 stage, activated p53 mediated apoptosis, and increased cyclin p21 expression. Xenograft analysis in nude mice also found that PRAME knockdown inhibited tumorigenesis while PRAME overexpression had opposite effect. Conclusions: In HCC, PRAME serves as a potential biomarker for poor prognosis and novel therapeutic target in treating this cancer. PRAME is a potential biomarker of poor prognosis in HCC. PRAME surpresses HCC cell death in vitro and in vivo by regulating p53 apoptotic signaling and may serve as a potential therapeutic target in HCC.

scholarly journals TGF-β1 Induced Deficiency of Linc00261 Promotes Epithelial-mesenchymal-transition and Stemness of Hepatocellular Carcinoma via Modulating SMAD3

2021 ◽  
Author(s):  
Zhanjun Chen ◽  
Leyang Xiang ◽  
Huohui Ou ◽  
Yinghao Fang ◽  
Yuyan Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Tumor Sphere ◽  
Non Coding Rnas ◽  
Tgf Β1 ◽  
Hcc Cells

Abstract Emerging evidence suggests that long non-coding RNAs (lncRNAs) play important roles in the metastasis and recurrence of hepatocellular carcinoma (HCC).Kinds of lncRNAs were found to be involved in regulating epithelial-mesenchymal transition (EMT) or stem-like traits in human cancers, however, the molecular mechanism and signaling pathways targeting EMT and stemness remains largely unknown. Previously, we found that linc00261 was down-regulated in HCC and associated with multiple worse clinic pathological parameters and poor prognosis. Here, we show that linc00261 was down-regulated in TGF-β1 stimulated cells, and forced expression of linc00261 attenuated EMT and stem-like traits in HCC.Linc00261 also inhibited the tumor sphere forming in vitro and decreased the tumorigenicity in vivo. Furthermore, we revealed that linc00261 suppressed the expression and phosphorylation of SMAD3 (p-SMAD3), which is a core transcriptional modulator in TGF-β1 signaling mediated EMT and the acquisition of stemness traits. A negative correlation between linc00261 and p-SMAD3 was determined in HCC samples.Conclusion: Our study revealed that linc00261suppressed EMT and stem-like traits of HCC cells by inhibiting TGF-β1/SMAD3 signaling.

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