scholarly journals Potential diagnostic and prognostic marker dimethylglycine dehydrogenase (DMGDH) suppresses hepatocellular carcinoma metastasis in vitro and in vivo

Oncotarget ◽  
2016 ◽  
Vol 7 (22) ◽  
pp. 32607-32616 ◽  
Author(s):  
Gang Liu ◽  
Guojun Hou ◽  
Liang Li ◽  
Yixue Li ◽  
Weiping Zhou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Prognostic Marker ◽  
Carcinoma Metastasis

scholarly journals ZNF191 Inhibits Hepatocellular Carcinoma Metastasis via DLG1-mediated YAP1 Inactivation

2015 ◽  
Author(s):  
Di Wu ◽  
Guoyuan Liu ◽  
Songmin Jiang ◽  
Long Yu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Zinc Finger Protein ◽  
Negative Regulator ◽  
Metastasis Suppressor ◽  
Discs Large ◽  
Chromatin Immunoprecipitation Sequencing ◽  
A Cell ◽  
Carcinoma Metastasis

Searching targets for hepatocellular carcinoma (HCC) treatment, we identified zinc finger protein 191 (ZNF191) as a suppressor against HCC metastasis. Over-expressing ZNF191 in HCC cells impaired cell motility, while ZNF191 depletion promoted HCC cell migration in vitro and metastasis in vivo through triggering yes-associated protein 1 (YAP1) signaling. Chromatin immunoprecipitation-sequencing (ChIP-seq) revealed that ZNF191 specifically bound to the promoter of Discs, Large homolog 1 (DLG1), a cell polarity maintainer and a negative regulator of YAP1. Double-knockdown experiments showed that DLG1 was not only the mediator of ZNF191 s function to suppress migration but also a link between ZNF191 and YAP1 signaling. ZNF191 was down-regulated in metastatic HCCs, correlating positively with DLG1 levels and inversely with YAP1 activation. Our findings indicate ZNF191 functions as a metastasis suppressor via DLG1-mediated YAP1 signaling inactivation.

scholarly journals C1orf61 promotes hepatocellular carcinoma metastasis and affects the therapeutic response to sorafenib

2020 ◽  
Author(s):  
You Yu ◽  
Zhimeng Wang ◽  
Zan Huang ◽  
Xianying Tang ◽  
Wenhua Li
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Therapeutic Response ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Molecular Events ◽  
Carcinoma Metastasis ◽  
And Migration

Abstract Background C1orf61 is a specific transcriptional activator that is highly up-regulated during weeks 4–9 of human embryogenesis, the period in which most organs develop. We have previously demonstrated that C1orf61 acts as a tumor activator in human hepatocellular carcinoma (HCC) tumorigenesis and metastasis. However, the underlying molecular mechanisms of tumor initiation and progression in HCC remain obscure. Methods In this study, we demonstrated that the pattern of C1orf61 expression was closely correlated with metastasis in liver cancer cells. Gene expression profiling analysis indicated that C1orf61 regulated diverse genes related to cell growth, migration, invasion and epithelial-mesenchymal transition (EMT). Results Results showed that C1orf61 promotes hepatocellular carcinoma metastasis by inducing cellular EMT in vivo and in vitro. Moreover, C1orf61-induced cellular EMT and migration are involved in the activation of the STAT3 and Akt cascade pathways. We also found that C1orf61 was associated with HBV infection-induced cell migration in HCC. In addition, C1orf61 expression improved the efficacy of the anticancer therapy sorafenib in HCC patients. For the first time, we report a regulatory pathway by which C1orf61 promoted cancer cell metastasis and regulated the therapeutic response to sorafenib. Conclusions These findings increased our understanding of the molecular events that regulate metastasis and treatment in HCC.

scholarly journals KIAA1217 Promotes Epithelial-Mesenchymal Transition and Hepatocellular Carcinoma Metastasis by Interacting with and Activating STAT3

2021 ◽  
Vol 23 (1) ◽  
pp. 104
Author(s):  
Yanhong Wang ◽  
Na Li ◽  
Yanping Zheng ◽  
Anqing Wang ◽  
Chunlei Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Adaptor Protein ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Macromolecular Protein ◽  
Carcinoma Metastasis

The survival and prognosis of hepatocellular carcinoma (HCC) are poor, mainly due to metastasis. Therefore, insights into the molecular mechanisms underlying HCC invasion and metastasis are urgently needed to develop a more effective antimetastatic therapy. Here, we report that KIAA1217, a functionally unknown macromolecular protein, plays a crucial role in HCC metastasis. KIAA1217 expression was frequently upregulated in HCC cell lines and tissues, and high KIAA1217 expression was closely associated with shorter survival of patients with HCC. Overexpression and knockdown experiments revealed that KIAA1217 significantly promoted cell migration and invasion by inducing epithelial-mesenchymal transition (EMT) in vitro. Consistently, HCC cells overexpressing KIAA1217 exhibited markedly enhanced lung metastasis in vivo. Mechanistically, KIAA1217 enhanced EMT and accordingly promoted HCC metastasis by interacting with and activating JAK1/2 and STAT3. Interestingly, KIAA1217-activated p-STAT3 was retained in the cytoplasm instead of translocating into the nucleus, where p-STAT3 subsequently activated the Notch and Wnt/β-catenin pathways to facilitate EMT induction and HCC metastasis. Collectively, KIAA1217 may function as an adaptor protein or scaffold protein in the cytoplasm and coordinate multiple pathways to promote EMT-induced HCC metastasis, indicating its potential as a therapeutic target for curbing HCC metastasis.

scholarly journals FMRP regulates STAT3 mRNA localization to cellular protrusions and local translation to promote hepatocellular carcinoma metastasis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Zhifa Shen ◽  
Bowen Liu ◽  
Biting Wu ◽  
Hongyin Zhou ◽  
Xiangyun Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Fragile X ◽  
Phosphorylation Site ◽  
Underlying Mechanism ◽  
Mrna Localization ◽  
Potential Phosphorylation Site ◽  
Mental Retardation Protein ◽  
Carcinoma Metastasis

AbstractMost hepatocellular carcinoma (HCC)-associated mortalities are related to the metastasis of cancer cells. The localization of mRNAs and their products to cell protrusions has been reported to play a crucial role in the metastasis. Our previous findings demonstrated that STAT3 mRNA accumulated in the protrusions of metastatic HCC cells. However, the underlying mechanism and functional significance of this localization of STAT3 mRNA has remained unexplored. Here we show that fragile X mental retardation protein (FMRP) modulates the localization and translation of STAT3 mRNA, accelerating HCC metastasis. The results of molecular analyses reveal that the 3′UTR of STAT3 mRNA is responsible for the localization of STAT3 mRNA to cell protrusions. FMRP is able to interact with the 3′UTR of STAT3 mRNA and facilitates its localization to protrusions. Importantly, FMRP could promote the IL-6-mediated translation of STAT3, and serine 114 of FMRP is identified as a potential phosphorylation site required for IL-6-mediated STAT3 translation. Furthermore, FMRP is highly expressed in HCC tissues and FMRP knockdown efficiently suppresses HCC metastasis in vitro and in vivo. Collectively, our findings provide further insights into the mechanism of HCC metastasis associated with the regulation of STAT3 mRNA localization and translation.

scholarly journals The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroaki Kanzaki ◽  
Tetsuhiro Chiba ◽  
Junjie Ao ◽  
Keisuke Koroki ◽  
Kengo Kanayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Erk Signaling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antitumor Effects ◽  
The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

Knockout of Ajuba Attenuates the Growth and Migration of Hepatocellular Carcinoma Cells

2020 ◽  
Vol 160 (11-12) ◽  
pp. 650-658
Author(s):  
Yichen Le ◽  
Yi He ◽  
Meirong Bai ◽  
Ying Wang ◽  
Jiaxue Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Growth ◽  
Cancer Progression ◽  
Normal Liver ◽  
Cell Growth And Migration ◽  
And Migration ◽  
Hcc Cells

Ajuba has been found to be mutated or aberrantly regulated in several human cancers and plays important roles in cancer progression via different signaling pathways. However, little is known about the role of Ajuba in hepatocellular carcinoma (HCC). Here, we found an upregulation of Ajuba expression in HCC tissues compared with normal liver tissues, while a poor prognosis was observed in HCC patients with high Ajuba expression. Knockout of Ajuba in HCC cells inhibited cell growth in vitro and in vivo, suppressed cell migration, and enhanced the cell apoptosis under stress. Moreover, re-expression of Ajuba in Ajuba-deficient cells could restore the phenotype of Ajuba-deficient cells. In conclusion, these results indicate that Ajuba is upregulated in HCC and promotes cell growth and migration of HCC cells, suggesting that Ajuba could possibly be a new target for HCC diagnosis and treatment.

scholarly journals Loss of PR55α promotes proliferation and metastasis by activating MAPK/AKT signaling in hepatocellular carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
JiangSheng Zhao ◽  
GuoFeng Chen ◽  
Jingqi Li ◽  
Shiqi Liu ◽  
Quan Jin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle Progression ◽  
Lung Metastases ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Signal Pathways ◽  
And Migration ◽  
Healthy Liver

Abstract Background PR55α plays important roles in oncogenesis and progression of numerous malignancies. However, its role in hepatocellular carcinoma (HCC) is unclear. This study aims to characterize the functions of PR55α in HCC. Methods PR55α expressions in HCC tissues and paired healthy liver samples were evaluated using Western blot and tissue microarray immunohistochemistry. We knocked down the expression of PR55α in SMMC-7721 and LM3 cell lines via small interfering and lentivirus. In vitro cell counting, colony formation, migration and invasion assays were performed along with in vivo xenograft implantation and lung metastases experiments. The potential mechanisms involving target signal pathways were investigated by RNA-sequencing. Results PR55α expression level was suppressed in HCC tissues in comparison to healthy liver samples. Decreased PR55α levels were correlated with poorer prognosis (P = 0.0059). Knockdown of PR55α significantly promoted cell proliferation and migration, induced repression of the cell cycle progression and apoptosis in vitro while accelerating in vivo HCC growth and metastasis. Mechanistic analysis indicated that PR55α silencing was involved with MAPK/AKT signal pathway activation and resulted in increased phosphorylation of both AKT and ERK1/2. Conclusions This study identifies PR55α to be a candidate novel therapeutic target in the treatment of HCC.

scholarly journals CircFAM13B promotes the proliferation of hepatocellular carcinoma by sponging miR-212, upregulating E2F5 expression and activating the P53 pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ying Xie ◽  
Xiaofeng Hang ◽  
Wensheng Xu ◽  
Jing Gu ◽  
Yuanjing Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Gene Expression Omnibus ◽  
Differentially Expressed ◽  
In Vivo Studies ◽  
Circular Rnas ◽  
Novel Target ◽  
Underlying Mechanisms

Abstract Background Most of the biological functions of circular RNAs (circRNAs) and the potential underlying mechanisms in hepatocellular carcinoma (HCC) have not yet been discovered. Methods In this study, using circRNA expression data from HCC tumor tissues and adjacent tissues from the Gene Expression Omnibus database, we identified out differentially expressed circRNAs and verified them by qRT-PCT. Functional experiments were performed to evaluate the effects of circFAM13B in HCC in vitro and in vivo. Results We found that circFAM13B was the most significantly differentially expressed circRNA in HCC tissue. Subsequently, in vitro and in vivo studies also demonstrated that circFAM13B promoted the proliferation of HCC. Further studies revealed that circFAM13B, a sponge of miR-212, is involved in the regulation of E2F5 gene expression by competitively binding to miR-212, inhibits the activation of the P53 signalling pathway, and promotes the proliferation of HCC cells. Conclusions Our findings revealed the mechanism underlying the regulatory role played by circFAM13B, miR-212 and E2F5 in HCC. This study provides a new theoretical basis and novel target for the clinical prevention and treatment of HCC.

scholarly journals KLF7/VPS35 axis contributes to hepatocellular carcinoma progression through CCDC85C-activated β-catenin pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yarong Guo ◽  
Bao Chai ◽  
Junmei Jia ◽  
Mudan Yang ◽  
Yanjun Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Luciferase Reporter ◽  
Aberrant Expression ◽  
Proliferation And Invasion ◽  
Hcc Cells

Abstract Objective Dysregulation of KLF7 participates in the development of various cancers, but it is unclear whether there is a link between HCC and aberrant expression of KLF7. The aim of this study was to investigate the role of KLF7 in proliferation and migration of hepatocellular carcinoma (HCC) cells. Methods CCK8, colony growth, transwell, cell cycle analysis and apoptosis detection were performed to explore the effect of KLF7, VPS35 and Ccdc85c on cell function in vitro. Xenografted tumor growth was used to assess in vivo role of KLF7. Chip-qPCR and luciferase reporter assays were applied to check whether KLF7 regulated VPS35 at transcriptional manner. Co-IP assay was performed to detect the interaction between VPS35 and Ccdc85c. Immunohistochemical staining and qRT-PCR analysis were performed in human HCC sampels to study the clinical significance of KLF7, VPS35 and β-catenin. Results Firstly, KLF7 was highly expressed in human HCC samples and correlated with patients’ differentiation and metastasis status. KLF7 overexpression contributed to cell proliferation and invasion of HCC cells in vitro and in vivo. KLF7 transcriptional activation of VPS35 was necessary for HCC tumor growth and metastasis. Further, co-IP studies revealed that VPS35 could interact with Ccdc85c in HCC cells. Rescue assay confirmed that overexpression of VPS35 and knockdown of Ccdc85c abolished the VPS35-medicated promotion effect on cell proliferation and invasion. Finally, KLF7/VPS35 axis regulated Ccdc85c, which involved in activation of β-catenin signaling pathway, confirmed using β-catenin inhibitor, GK974. Functional studies suggested that downregulation of Ccdc85c partly reversed the capacity of cell proliferation and invasion in HCC cells, which was regulated by VPS35 upregulation. Lastly, there was a positive correlation among KLF7, VPS35 and active-β-catenin in human HCC patients. Conclusion We demonstrated that KLF7/VPS35 axis promoted HCC cell progression by activating Ccdc85c-medicated β-catenin pathway. Targeting this signal axis might be a potential treatment strategy for HCC.

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