Protein Kinase / suppresses liver cancer by repressing autophagy and oxidative phosphorylation in hepatocytes [DH]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE147800 | GEO | 2020/06/30
REPOSITORIES: GEO
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Project description:Oxidative stress plays a critical role in liver tissue damage and in hepatocellular carcinoma (HCC) initiation and progression. However, the mechanisms that regulate autophagy and metabolic reprogramming during the generation of reactive oxygen species (ROS), and how ROS promotes tumorigenesis, still need to be fully understood. We show that protein kinase C (PKC) / loss in hepatocytes promotes autophagy and oxidative phosphorylation. This results in ROS generation, which through NRF2 drives HCC cell autonomously and non-autonomously. Although PKC/ promotes tumorigenesis in oncogene-driven cancer models, emerging evidence demonstrate that it is a tumor suppressor in more complex carcinogenic processes. Consistently, PKC / levels negatively correlate with HCC histological tumor grade, establishing this kinase as a tumor suppressor in liver cancer.
2020-06-30 | GSE147778 | GEO
Project description:Hepatocellular carcinoma (HCC) is frequently characterized by metabolic and immune remodeling in the tumor microenvironment. We previously discovered that liver-specific deletion of fructose-1, 6-bisphphotase 1 (FBP1), a gluconeogenic enzyme ubiquitously suppressed in HCC tissues, promotes liver tumorigenesis, and induces metabolic and immune perturbations closely resembling human HCC. However, the underlying mechanisms remain incompletely understood. Here we reported that FBP1-deficient livers exhibit diminished amounts of natural killer (NK) cells and accelerated tumorigenesis. Using the diethylnitrosamine-induced HCC mouse model, we analyzed potential changes in the immune cell populations purified from control and FBP1-depleted livers and found that NK cells were strongly suppressed. Mechanistically, FBP1 attenuation in hepatocytes derepresses an EZH2-dependent transcriptional program to inhibit PKLR expression. This leads to reduced levels of PKLR cargo proteins sorted into hepatocyte-derived EVs, dampened activity of EV-targeted NK cells, and accelerated liver tumorigenesis. Our study demonstrated that hepatic FBP1 depletion promotes HCC-associated immune remodeling, partly through the transfer of hepatocyte-secreted, PKLR-attenuated EVs to NK cells.
2023-03-11 | PXD026822 | Pride
Project description:SOCS1 is a tumor suppressor in hepatocellular carcinoma. Recently we showed that loss of SOCS1 in hepatocytes promotes NRF2 activation. Here we investigated how SOCS1 expression affected oxidative stress response in HCC cells. Murine Hepa1-6 cells expressing SOCS1 (Hepa-SOCS1) or control vector (Hepa-Vector) were treated with cisplatin or tert-butyl hydroperoxide (t-BHP). Induction of NRF2 and its target genes, oxidative stress, lipid peroxidation, cell survival and cellular proteome profiles were evaluated. NRF2 induction was significantly reduced in Hepa-SOCS1 cells. The gene and protein expression of NRF2 targets were differentially induced in Hepa-Vector cells but markedly suppressed in Hepa-SOCS1 cells. Hepa-SOCS1 cells displayed increased induction of reactive oxygen species (ROS) but reduced lipid peroxidation. Nonetheless, Hepa-SOCS1 cells treated with cisplatin or t-BHP showed reduced survival. GCLC, poorly induced in Hepa-SOCS1 cells, showed a strong positive correlation with NFE2L2 and an inverse correlation with SOCS1 in the TCGA-LIHC transcriptomic data. Proteomic analysis of Hepa-Vector and Hepa-SOCS1 cells revealed that SOCS1 differentially modulated many proteins involved in diverse molecular pathways including those implicated in mitochondrial ROS generation and detoxification by peroxiredoxin and thioredoxin systems. Our findings indicate that maintaining sensitivity to oxidative stress is an important tumor suppression mechanism of SOCS1 in HCC.
2024-05-22 | PXD047908 | Pride
Project description:Autophagy is a starvation response that facilitates cell survival under metabolic stress and yet defects in autophagy promote tumorigenesis. While the role of understarvation is relatively clearer, its mechanistic role in tumorigenesis is poorly understood. We show that defective autophagy promotes protein damage and accumulation of p62, a marker for protein damage accumulation that is cleared through autophagy pathway. The failure to eliminate p62 in autophagy-defective cells, leads to deregulation of cell signalling and gene expression and ultimately promotes tumorigenesis. Thus defective-autophagy is a mechanism for p62 accumulation commonly observed in human tumors. Keywords: Autophagy, p62, Signal transduction, NF-kB, tumorigenesis.
2009-03-12 | GSE15182 | GEO
Project description:Transforming growth factor beta-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death and carcinogenesis. Hepatocyte-specific deletion of TAK1 in Tak1_Hep mice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using kinase dead knock-in D138N mutation in Tak1_Hep mice inhibits the expression of liver tumor biomarkers, liver fibrosis and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single cell RNA-seq, we discover that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+ macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-non-autonomously, in the development of liver fibrosis and HCC, independent of cell death and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation.
2020-07-08 | GSE148859 | GEO
Project description:PTEN, a widely investigated tumor suppressor, has at least two longer translational variants, PTEN and . However, the regulation and precise roles of endogenous PTEN/ in tumorigenesis remain greatly unknown. Here we show that USP9X and FBXW11 selectively regulate the stability of PTEN/ but not PTEN proteins by deubiqitination and ubiquitination respectively. USP9X promotes and FBXW11 suppresses tumorigenesis mediated by PTEN/. In contrast to the current paradigm for PTEN as a tumor suppressor, PTEN/ promote tumorigenesis of cancer cells in a phosphatase-independent manner. Mechanistically, PTEN/ localized in the nucleus regulate expressions of tumor-promoting genes such as NOTCH3 in the similar way as the H3K4 presenter WDR5. Further, PTEN/ but not PTEN directly interact with WDR5 to promote trimethylation of H3K4 and maintain a tumor-promoting signature. Taken together, our results indicate that PTEN/ are a double-edged sword for carcinogenesis, suggesting that reinterpretation of the importance of PTEN gene in carcinogenesis is warranted.
2019-11-14 | PXD013196 | Pride
Project description:Hepatocyte-nuclear-factor-4? (??Hnf4?) is a transcription factor that controls epithelial cell polarity and maturation during embryogenesis. Hnf4? conditional deletion during post-natal development results in minor consequences on intestinal epithelium integrity but promotes activation of the Wnt/?-catenin pathway. Here we show that Hnf4? does not act as a tumor suppressor gene but is crucial to promote gut tumorigenesis in mice. Polyp multiplicity in ApcMin mice that lacks Hnf4? is suppressed in comparison to littermate ApcMin controls. Analysis of microarray gene expression profiles from mice lacking Hnf4? in the intestinal epithelium identifies its novel function in regulating the expression of reactive oxygen species (ROS) detoxifying genes. This role is supported with the demonstration that HNF4? is functionally involved in the protection against spontaneous and 5-fluorouracil chemotherapy-induced production of intracellular ROS in colorectal cancer cell lines. The analysis of a colorectal cancer patient cohort establishes that HNF4? is significantly up-regulated at both gene transcript and protein levels in tumors relative to adjacent benign epithelial resections. Several genes involved in ROS neutralization are also up-regulated in correlation with HNF4? expression. All together, the findings point to the nuclear receptor HNF4? as a potential therapeutic target to eradicate aberrant epithelial cell resistance to ROS production during intestinal tumorigenesis. HNF4alpha was conditionally knockout in the mouse epithelial intestine with the 12.4-kb VillinCRE. A total of 3 control and 3 mutant littermates individuals were sacrificed at 7 months of age. The distal jejunum was harvested and Total RNA was isolated from each individuals. Each RNA sample was independently used to generate probes to screen affymetrix chips.
2011-01-01 | E-GEOD-20968 | biostudies-arrayexpress
Project description:Background: Tumor necrosis factor α-induced protein 1 (TNFAIP1) is frequently downregulated in cancer cell lines and promotes cancer cell apoptosis. However, its role, clinical significance and molecular mechanisms in hepatocellular carcinoma (HCC) are unknown. Methods: The expression of TNFAIP1 in HCC tumor tissues and cell lines was measured by Western blot and immunohistochemistry. The effects of TNFAIP1 on HCC proliferation, apoptosis, metastasis, angiogenesis and tumor formation were evaluated by Cell Counting Kit-8 (CCK8), Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL), transwell, tube formation assay in vitro and nude mice experiments in vivo. The interaction between TNFAIP1 and CSNK2B was validated by liquid chromatography-tandem mass spectrometry (LC-MS/MS), Co-immunoprecipitation and Western blot. The mechanism of how TNFAIP1 regulated nuclear factor-kappaB (NF-κB) pathway was analyzed by dual-luciferase reporter, immunofluorescence, quantitative Real-time polymerase chain reaction (RT-qPCR) and Western blot. Findings: The TNFAIP1 expression is significantly decreased in HCC tissues and cell lines, and negatively correlated with the increased HCC histological grade. Overexpression of TNFAIP1 inhibits HCC cell proliferation, metastasis, angiogenesis and promotes cancer cell apoptosis both in vitro and in vivo, whereas the knockdown of TNFAIP1 in HCC cell displays opposite effects. Mechanistically, TNFAIP1 interacts with CSNK2B and promotes its ubiquitin-mediated degradation with Cul3, causing attenuation of CSNK2B-dependent NF-κB trans-activation in HCC cell. Moreover, the enforced expression of CSNK2B counteracts the inhibitory effects of TNFAIP1 on HCC cell proliferation, migration, and angiogenesis in vitro and in vivo. Interpretation: Our results support that TNFAIP1 can act as a tumor suppressor of HCC by modulating TNFAIP1/CSNK2B/NF-κB pathway, implying that TNFAIP1 may represent a potential marker and a promising therapeutic target for HCC. Fund: This work was supported in part by the financial support from the China Natural Science Foundation (No. 81972642, No. 81601122 and No. 81770389), Hunan Natural Science Foundation (No. 2017JJ3205), Cooperative Innovation Center of Engineering and New Products for Developmental Biology of Hunan Province (No. 20134486), and the Scientific Research Fund of Hunan Provincial Education Department (17B162).
2020-05-26 | PXD016378 | Pride
Project description:Tumors often undergo stress and need to reprogram their metabolism to survive and grow under nutrient challenging conditions. The stroma could play a critical role in this process by providing nutrients or signals to support the epithelial compartment of the tumor. Autophagy has been shown to play key roles both in the stroma and in the epithelium. However, how autophagy adaptors, such as p62, participate in the mechanisms whereby the stroma supports tumor progression is not yet fully understood. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation through a metabolic reprogramming orchestrated by the direct control of ATF4 stability by p62-mediated polyubiquitination. This, in turn, activates the flux of glucose carbons through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine-mediated stromal cell growth and tumor epithelial proliferation, independent of autophagy. This supports a new model in which p62 directly targets nuclear transcription factors to control metabolic reprograming in the microenvironment to repress tumorigenesis, and emerges as global tumor suppressor.
2018-02-14 | GSE94367 | GEO
Project description:Tumors often undergo stress and need to reprogram their metabolism to survive and grow under nutrient challenging conditions. The stroma could play a critical role in this process by providing nutrients or signals to support the epithelial compartment of the tumor. Autophagy has been shown to play key roles both in the stroma and in the epithelium. However, how autophagy adaptors, such as p62, participate in the mechanisms whereby the stroma supports tumor progression is not yet fully understood. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation through a metabolic reprogramming orchestrated by the direct control of ATF4 stability by p62-mediated polyubiquitination. This, in turn, activates the flux of glucose carbons through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine-mediated stromal cell growth and tumor epithelial proliferation, independent of autophagy. This supports a new model in which p62 directly targets nuclear transcription factors to control metabolic reprograming in the microenvironment to repress tumorigenesis, and emerges as global tumor suppressor.
2018-02-14 | GSE94343 | GEO