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The PKCα/ZFP64/CSF1 Axis restricts Tumor Response to Anti-PD1 by driving Macrophage M2 Polarization in Hepatocellular Carcinoma [RNA-seq 1]

ABSTRACT: Despite remarkable achievements, majority of hepatocellular carcinoma (HCC) patients fail to respond to anti-PD1 therapy. Here, we showed that ZFP64 was frequently upregulated in HCC tissues of anti-PD1 resistance patients. Elevated ZFP64 levels triggered tumor progression and induced an immunosuppressive microenvironment. Mechanistically, ZFP64 transcriptionally activated colony-stimulating factor 1 (CSF1) by directly binding to its promoter, and secreted CSF1 driving the shift of macrophages into an alternatively activated phenotype. Importantly, the PKCα was revealed to phosphorylate ZFP64 at S226, resulting in its nuclear translocation to transcribe the CSF1 gene. Particularly, we proposed firstly that the PKCα/ZFP64/CSF1 axis was a critical pathway in fostering immune evasion and anti-PD1 tolerance and inhibiting this axis with lenvatinib or Gö6976 surmounted the anti-PD1 resistance in HCC. Our study indicates that the ZFP64 is an emerging indicator in predicting anti-PD1 efficacy, and reveals the PKCα/ZFP64/CSF1 axis is a suitable target for anti-PD1 combination therapy in HCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181946 | GEO | 2024/08/04

REPOSITORIES: GEO

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The PKCα/ZFP64/CSF1 Axis restricts Tumor Response to Anti-PD1 by driving Macrophage M2 Polarization in Hepatocellular Carcinoma

Project description:Despite remarkable achievements, majority of hepatocellular carcinoma (HCC) patients fail to respond to anti-PD1 therapy. Here, we showed that ZFP64 was frequently upregulated in HCC tissues of anti-PD1 resistance patients. Elevated ZFP64 levels triggered tumor progression and induced an immunosuppressive microenvironment. Mechanistically, ZFP64 transcriptionally activated colony-stimulating factor 1 (CSF1) by directly binding to its promoter, and secreted CSF1 driving the shift of macrophages into an alternatively activated phenotype. Importantly, the PKCα was revealed to phosphorylate ZFP64 at S226, resulting in its nuclear translocation to transcribe the CSF1 gene. Particularly, we proposed firstly that the PKCα/ZFP64/CSF1 axis was a critical pathway in fostering immune evasion and anti-PD1 tolerance and inhibiting this axis with lenvatinib or Gö6976 surmounted the anti-PD1 resistance in HCC. Our study indicates that the ZFP64 is an emerging indicator in predicting anti-PD1 efficacy, and reveals the PKCα/ZFP64/CSF1 axis is a suitable target for anti-PD1 combination therapy in HCC.

2024-08-04 | GSE181436 | GEO

The PKCα/ZFP64/CSF1 Axis restricts Tumor Response to Anti-PD1 by driving Macrophage M2 Polarization in Hepatocellular Carcinoma [RNA-seq 2]

2024-08-04 | GSE181947 | GEO

The PKCα/ZFP64/CSF1 Axis restricts Tumor Response to Anti-PD1 by driving Macrophage M2 Polarization in Hepatocellular Carcinoma

Project description:The PKCα/ZFP64/CSF1 Axis restricts Tumor Response to Anti-PD1 by driving Macrophage M2 Polarization in Hepatocellular Carcinoma

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The PKCα/ZFP64/CSF1 Axis restricts Tumor Response to Anti-PD1 by driving Macrophage M2 Polarization in Hepatocellular Carcinoma [RNA-seq 1]

Project description:The PKCα/ZFP64/CSF1 Axis restricts Tumor Response to Anti-PD1 by driving Macrophage M2 Polarization in Hepatocellular Carcinoma [RNA-seq 1]

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The PKCα/ZFP64/CSF1 Axis restricts Tumor Response to Anti-PD1 by driving Macrophage M2 Polarization in Hepatocellular Carcinoma [RNA-seq 2]

Project description:The PKCα/ZFP64/CSF1 Axis restricts Tumor Response to Anti-PD1 by driving Macrophage M2 Polarization in Hepatocellular Carcinoma [RNA-seq 2]

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Altered dermal architecture in PKCα-/- skin

Project description:Global gene expression analysis in PKCα-/- mouse skin reveals structural changes in the dermis and defective wound granulation tissue. The skin's mechanical integrity is maintained by an organised and robust dermal extracellular matrix (ECM). Resistance to mechanical disruption hinges primarily on homeostasis of the dermal collagen fibril architecture which is regulated, at least in part, by members of the small leucine-rich proteoglycan (SLRP) family. This array study presents data linking protein kinase C alpha (PKCα) to the regulated expression of multiple ECM components including SLRPs.

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PKCα-LSD1-NF-κB Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response [RNA-Seq]

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2018-01-31 | GSE100216 | GEO

PKCα-LSD1-NF-κB Signaling Cascade Is Crucial for Epigenetic Control of the Inflammatory Response [ChIP-Seq]

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The AXL-PYK2-PKCα axis as a nexus of stemness circuits in TNBC

Project description:Cancer stem cells (CSCs) are implicated in tumor initiation, metastasis and drug resistance, and are considered as attractive targets for cancer therapy. We identified a clinically relevant signaling nexus mediated by PYK2 and its impact on stemness in triple negative breast cancer (TNBC). PYK2 depletion in multiple mesenchymal TNBC cell lines markedly reduced the expression of PKCα and AXL proteins and reduced the number of mammosphere-forming cells and cells harboring CSCs characteristic markers. PYK2 and PKCα cooperate at a convergence point of multiple stemness-inducing pathways to regulate AXL levels and concomitantly the levels/activation of key transcription factors implicated in stemness including STAT3, TAZ, FRA1 and SMAD3 as well as the pluripotent transcription factors Nanog and Oct4, and in-turn affect their target genes. Targeting the AXL-PYK2-PKCα circuit could be a promising strategy to eliminate CSCs in TNBC and possibly overcome drug resistance.

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