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.

Zinc finger protein 191 inhibits hepatocellular carcinoma metastasis through discs large 1-mediated yes-associated protein inactivation

Hepatology ◽  
2016 ◽  
Vol 64 (4) ◽  
pp. 1148-1162 ◽  
Author(s):  
Di Wu ◽  
Guoyuan Liu ◽  
Yufeng Liu ◽  
Hexige Saiyin ◽  
Chenji Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Zinc Finger ◽  
Zinc Finger Protein ◽  
Protein Inactivation ◽  
Finger Protein ◽  
Discs Large ◽  
Carcinoma Metastasis

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 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 Upregulation of CENPM promotes hepatocarcinogenesis through mutiple mechanisms

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Yusha Xiao ◽  
Rahmathullah Mohamed Najeeb ◽  
Dong Ma ◽  
Kang Yang ◽  
Qiu Zhong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Hepatoma Cell ◽  
Single Gene ◽  
Gene Set Enrichment Analysis ◽  
Negative Regulator ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion

Abstract Background Hepatocellular carcinoma (HCC) still remains a dominating medical challenge in early diagnosis and clinical therapy. Centromere protein M (CENPM) has been proved to be over-expressed in HCC tissues, but carcinogenic mechanism of CENPM contributing to liver cancer is poorly understood. Methods In this study, we first explored mRNA and protein levels of CENPM in HCC samples, matching adjacent non-tumor tissues and six hepatoma cell lines by polymerase chain reaction (PCR), western blotting and immunohistochemistry (IHC). Clinical data of HCC patients downloaded from The Cancer Genome Atlas (TCGA) were also analyzed. The character of CENPM concerned with HCC progression through several functional experimentations in vitro and in vivo was researched. Bioinformatics was carried out to further discover biological functions of CENPM. Results CENPM was positively up-regulated in HCC and connected with a poor prognosis. Silencing CENPM repressed cell proliferation in vivo and in vitro, and knock-down CENPM inhibited cell migration and invasion. Additionally, depletion of CENPM can promote cell apoptosis and arrested cell cycle. Furthermore, single-gene gene set enrichment analysis (GSEA) analysis indicated that CENPM was linked to the P53 signaling pathway and cell cycle pathway, and our research supported this prediction. Finally, we also found that miR-1270 was a negative regulator and participated in post-transcriptional regulation of CENPM, and hepatitis B virus X protein (HBx) can promote hepatocellular carcinoma by suppressing miR1270. Conclusion CENPM was closely associated with HCC progression and it could be considered as a new possible biomarker along with a therapeutic target for HCC.

Members of the microRNA-17-92 cluster exhibit a cell-intrinsic antiangiogenic function in endothelial cells

Blood ◽  
2010 ◽  
Vol 115 (23) ◽  
pp. 4944-4950 ◽  
Author(s):  
Carmen Doebele ◽  
Angelika Bonauer ◽  
Ariane Fischer ◽  
Alexander Scholz ◽  
Yvonne Reiss ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Angiogenesis ◽  
Janus Kinase ◽  
Negative Regulator ◽  
3 Dimensional ◽  
Small Noncoding Rnas ◽  
A Cell ◽  
Sprout Formation

Abstract MicroRNAs are endogenously expressed small noncoding RNAs that regulate gene expression on the posttranscriptional level. The miR-17-92 cluster (encoding miR-17, -18a, -19a/b, -20a, and miR-92a) is highly expressed in tumor cells and is up-regulated by ischemia. Whereas miR-92a was recently identified as negative regulator of angiogenesis, the specific functions of the other members of the cluster are less clear. Here we demonstrate that overexpression of miR-17, -18a, -19a, and -20a significantly inhibited 3-dimensional spheroid sprouting in vitro, whereas inhibition of miR-17, -18a, and -20a augmented endothelial cell sprout formation. Inhibition of miR-17 and miR-20a in vivo using antagomirs significantly increased the number of perfused vessels in Matrigel plugs, whereas antagomirs that specifically target miR-18a and miR-19a were less effective. However, systemic inhibition of miR-17/20 did not affect tumor angiogenesis. Further mechanistic studies showed that miR-17/20 targets several proangiogenic genes. Specifically, Janus kinase 1 was shown to be a direct target of miR-17. In summary, we show that miR-17/20 exhibit a cell-intrinsic antiangiogenic activity in endothelial cells. Inhibition of miR-17/20 specifically augmented neovascularization of Matrigel plugs but did not affect tumor angiogenesis indicating a context-dependent regulation of angiogenesis by miR-17/20 in vivo.

Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1

Blood ◽  
2013 ◽  
Vol 121 (3) ◽  
pp. 519-529 ◽  
Author(s):  
Guangwei Liu ◽  
Xuelian Hu ◽  
Bo Sun ◽  
Tao Yang ◽  
Jianfeng Shi ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Negative Regulator ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific ◽  
Neutrophil Differentiation ◽  
Deficient Mice

Abstract Neutrophils are critically involved in host defense and tissue damage. Intrinsic molecular mechanisms controlling neutrophil differentiation and activities are poorly defined. Herein we found that p53-induced phosphatase 1(Wip1) is preferentially expressed in neutrophils among immune cells. The Wip1 expression is gradually up-regulated during the differentiation of myeloid precursors into mature neutrophils. Wip1-deficient mice and chimera mice with Wip1−/− hematopoietic cells had an expanded pool of neutrophils with hypermature phenotypes in the periphery. The in vivo and in vitro studies showed that Wip1 deficiency mainly impaired the developing process of myeloid progenitors to neutrophils in an intrinsic manner. Mechanism studies showed that the enhanced development and maturation of neutrophils caused by Wip1 deficiency were mediated by p38 MAPK-STAT1 but not p53-dependent pathways. Thus, our findings identify a previously unrecognized p53-independent function of Wip1 as a cell type-specific negative regulator of neutrophil generation and homeostasis through limiting the p38 MAPK-STAT1 pathway.

scholarly journals Shed antigen-induced blocking effect on CAR-T cells targeting Glypican-3 in Hepatocellular Carcinoma

2021 ◽  
Vol 9 (4) ◽  
pp. e001875
Author(s):  
Luan Sun ◽  
Fang Gao ◽  
Zhanhui Gao ◽  
Lei Ao ◽  
Na Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Negative Regulator ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

BackgroundGlypican-3 (GPC3), a cell surface glycoprotein that is pathologically highly expressed in hepatocellular carcinoma (HCC), is an attractive target for immunotherapies, including chimeric antigen receptor (CAR) T cells. The serum GPC3 is frequently elevated in HCC patients due to the shedding effect of cell surface GPC3. The shed GPC3 (sGPC3) is reported to block the function of cell-surface GPC3 as a negative regulator. Therefore, it would be worth investigating the potential influence of antigen shedding in anti-GPC3 CAR-T therapy for HCC.MethodsIn this study, we constructed two types of CAR-T cells targeting distinct epitopes of GPC3 to examine how sGPC3 influences the activation and cytotoxicity of CAR-T cells in vitro and in vivo by introducing sGPC3 positive patient serum or recombinant sGPC3 proteins into HCC cells or by using sGPC3-overexpressing HCC cell lines.ResultsBoth humanized YP7 CAR-T cells and 32A9 CAR-T cells showed GPC3-specific antitumor functions in vitro and in vivo. The existence of sGPC3 significantly inhibited the release of cytokines and the cytotoxicity of anti-GPC3 CAR-T cells in vitro. In animal models, mice carrying Hep3B xenograft tumors expressing sGPC3 exhibited a worse response to the treatment with CAR-T cells under both a low and high tumor burden. sGPC3 bound to CAR-T cells but failed to induce the effective activation of CAR-T cells. Therefore, sGPC3 acted as dominant negative regulators when competed with cell surface GPC3 to bind anti-GPC3 CAR-T cells, leading to an inhibitory effect on CAR-T cells in HCC.ConclusionsWe provide a proof-of-concept study demonstrating that GPC3 shedding might cause worse response to CAR-T cell treatment by competing with cell surface GPC3 for CAR-T cell binding, which revealed a new mechanism of tumor immune escape in HCC, providing a novel biomarker for patient enrolment in future clinical trials and/or treatments with GPC3-targeted CAR-T cells.

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 Mice lacking JunB are osteopenic due to cell-autonomous osteoblast and osteoclast defects

2004 ◽  
Vol 164 (4) ◽  
pp. 613-623 ◽  
Author(s):  
Lukas Kenner ◽  
Astrid Hoebertz ◽  
F. Timo Beil ◽  
Niamh Keon ◽  
Florian Karreth ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Osteoblast Differentiation ◽  
Essential Gene ◽  
Bone Sialoprotein ◽  
Negative Regulator ◽  
Autonomous Function ◽  
A Cell ◽  
Osteoblast Markers

Because JunB is an essential gene for placentation, it was conditionally deleted in the embryo proper. JunBΔ/Δ mice are born viable, but develop severe low turnover osteopenia caused by apparent cell-autonomous osteoblast and osteoclast defects before a chronic myeloid leukemia-like disease. Although JunB was reported to be a negative regulator of cell proliferation, junBΔ/Δ osteoclast precursors and osteoblasts show reduced proliferation along with a differentiation defect in vivo and in vitro. Mutant osteoblasts express elevated p16INK4a levels, but exhibit decreased cyclin D1 and cyclin A expression. Runx2 is transiently increased during osteoblast differentiation in vitro, whereas mature osteoblast markers such as osteocalcin and bone sialoprotein are strongly reduced. To support a cell-autonomous function of JunB in osteoclasts, junB was inactivated specifically in the macrophage–osteoclast lineage. Mutant mice develop an osteopetrosis-like phenotype with increased bone mass and reduced numbers of osteoclasts. Thus, these data reveal a novel function of JunB as a positive regulator controlling primarily osteoblast as well as osteoclast activity.

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