Ox-LDL-mediated ILF3 overexpression in gastric cancer progression by activating the PI3K/AKT/mTOR signaling pathway

D, Sun; Zhang, Mingxiang; Wei, Meng; Wang, Zhaoyang; Wen, Quan; Liu, Peng; Zhong, Xin; Liang, Yize; Chen, Yuanyuan; Huang, Yadong; Yu, Wenbin

doi:10.18632/aging.204051

Cited by 8 publications

(9 citation statements)

References 86 publications

(88 reference statements)

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“…Consequently, the suppression of ILF3 resulted in decreased PD-L1, thereby enhancing the cytotoxicity of activated CD8 + T cells towards GC cells, which triggered an immune response and played a therapeutic role in GC, which align with the existing research on hepatocellular carcinoma. Previous research has demonstrated that simvastatin effectively impedes the proliferation, migration, and invasive capacity of gastric cancer cells by targeting ILF3, a potential target for statins in the treatment of gastric cancer [29]. So further exploration revealed that simvastatin effectively suppressed the expression of PD-L1 through ILF3, consequently augmenting the cytotoxicity of CD8 + T cells to GC cells.…”

Section: Discussionmentioning

confidence: 99%

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Simvastatin inhibits PD-L1 via ILF3 to enhance CD8 + T cell-mediated ferroptosis in gastric cancer cells

Sun,

Cui,

Yang

et al. 2024

Preprint

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Background Immunotherapy is vital in the comprehensive treatment of gastric cancer (GC). However, the prognosis of GC patients remains unfavorable, necessitating to exploration of novel therapeutic approaches and medications. Methods PD-L1 expression was observed using small interfering RNA and plasmid to knock down and overexpress ILF3, respectively. The expression of ILF3, PD-L1, and ferroptosis marker molecules (SLC7A11 and GPX4) was detected upon simvastatin stimulation of gastric cancer cells co-cultured with activated CD8+ T cells. To assess the impact of ILF3 and simvastatin stimulation on the induction of ferroptosis in gastric cancer cells by CD8+ T cells, various assays including CCK8, MTT, ROS, Fe2+, MDA, GSH, and LPO were conducted. Cleavage under targets and Tagmentation (CUT&Tag) was employed to validate the mechanism of simvastatin by regulating ILF3 expression. Whole genome sequencing and KEGG analysis reveal that ILF3 regulates PD-L1 expression through the DEPTOR/mTOR signaling pathway. Results Statin treatment decreased the serum levels of ILF3 and PD-L1. This study found that ILF3 was positively correlated with the expression of PD-L1, and the knockdown of ILF3 effectively inhibited the expression of PD-L1, thus enhancing the cytotoxicity of CD8+ T cells to gastric cancer cells. Meanwhile, simvastatin inhibited the expression of PD-L1 through ILF3, which enhanced the induction of ferroptosis in gastric cancer cells by CD8+ T cells. Further studies found that simvastatin inhibited ILF3 expression by decreasing the acetylation level at residue site H3K14 in ILF3, while ILF3 inhibited PD-L1 expression through the DEPTOR/mTOR pathway. Conclusions Simvastatin further recruited CD8+ T cells to enhance anti-tumor immunity by inhibiting PD-L1 expression by ILF3 and induced GC cells to undergo ferroptosis to achieve synergistic immunotherapy. This study elucidated the new mechanism of statins to improve GC immunotherapeutic effect. It revealed a new theoretical basis for using statins in GC treatment to improve the prognosis of GC patients.

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Section: Discussionmentioning

confidence: 99%

“…IHC was performed as previously described [29]. IHC staining was performed with ILF3, DEPTOR, mTOR, 4NHE, GPX4, PD-L1, and CD8 primary antibodies.…”

Section: Ihcmentioning

confidence: 99%

Simvastatin inhibits PD-L1 via ILF3 to enhance CD8 + T cell-mediated ferroptosis in gastric cancer cells

Sun,

Cui,

Yang

et al. 2024

Preprint

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“…Tumor-derived cytokines such as IL-6 and IL-27 have promoted PD-L1+CD8+ T cells development through STAT1/STAT3 signaling ( 38 , 39 ). ILF3 promotes the production of several tumors and is closely related to cellular senescence ( 40 , 41 ). We also explored small molecules to target these transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Establishment and validation of exhausted CD8+ T cell feature as a prognostic model of HCC

Shi

Liu

et al. 2023

Front. Immunol.

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ObjectivesThe exhausted CD8+T (Tex) cells are a unique cell population of activated T cells that emerges in response to persistent viral infection or tumor antigens. Tex cells showed the characteristics of aging cells, including weakened self-renewal ability, effector function inhibition, sustained high expression of inhibitory receptors including PD-1, TIGIT, TIM-3, and LAG-3, and always accompanied by metabolic and epigenetic reprogramming. Tex cells are getting more and more attention in researching immune-related diseases and tumor immunotherapy. However, studies on Tex-related models for tumor prognosis are still lacking. We hope to establish a risk model based on Tex-related genes for HCC prognosis.MethodsTex-related GEO datasets from different pathologic factors (chronic HBV, chronic HCV, and telomere shortening) were analyzed respectively to acquire differentially expressed genes (DEGs) by the ‘limma’ package of R. Genes with at least one intersection were incorporated into Tex-related gene set. GO, KEGG, and GSEA enrichment analyses were produced. Hub genes and the PPI network were established and visualized by the STRING website and Cytoscape software. Transcription factors and targeting small molecules were predicted by the TRUST and CLUE websites. The Tex-related HCC prognostic model was built by Cox regression and verified based on different datasets. Tumor immune dysfunction and exclusion (TIDE) and SubMap algorithms tested immunotherapy sensitivity. Finally, qRT-PCR and Flow Cytometry was used to confirm the bioinformatic results.ResultsHub genes such as AKT1, CDC6, TNF and their upstream transcription factor ILF3, Regulatory factor X-associated protein, STAT3, JUN, and RELA/NFKB1 were identified as potential motivators for Tex. Tex-related genes SLC16A11, CACYBP, HSF2, and ATG10 built the HCC prognostic model and helped with Immunotherapy sensitivity prediction.ConclusionOur study demonstrated that Tex-related genes might provide accurate prediction for HCC patients in clinical decision-making, prognostic assessment, and immunotherapy. In addition, targeting the hub genes or transcription factors may help to reverse T cell function and enhance the effect of tumor immunotherapy.

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“…Traditionally linked to cardiovascular health, LDL has been long recognized as a risk factor for atherosclerosis and coronary artery disease 7 . However, recent studies have expanded our comprehension of LDL, moving beyond its role in cardiovascular disease and initiating a paradigm shift in our perception of lipids' involvement in cancer biology 8–10 …”

Section: Introductionmentioning

confidence: 99%

“…7 However, recent studies have expanded our comprehension of LDL, moving beyond its role in cardiovascular disease and initiating a paradigm shift in our perception of lipids' involvement in cancer biology. [8][9][10] The advent of transcriptomics and single-cell sequencing has revolutionized our understanding of cancer biology, offering unprecedented insights into the molecular dynamics within tumours at a resolution never before achievable. 11 Transcriptomics provides a comprehensive overview of gene expression patterns, facilitating the identification of key regulatory networks driving melanoma progression and resistance mechanisms against therapies.…”

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confidence: 99%

Deciphering cutaneous melanoma prognosis through LDL metabolism: Single‐cell transcriptomics analysis via 101 machine learning algorithms

Xie,

Wu,

Zhang

et al. 2024

Experimental Dermatology

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Cutaneous melanoma poses a formidable challenge within the field of oncology, marked by its aggressive nature and capacity for metastasis. Despite extensive research uncovering numerous genetic and molecular contributors to cutaneous melanoma development, there remains a critical knowledge gap concerning the role of lipids, notably low‐density lipoprotein (LDL), in this lethal skin cancer. This article endeavours to bridge this knowledge gap by delving into the intricate interplay between LDL metabolism and cutaneous melanoma, shedding light on how lipids influence tumour progression, immune responses and potential therapeutic avenues. Genes associated with LDL metabolism were extracted from the GSEA database. We acquired and analysed single‐cell sequencing data (GSE215120) and bulk‐RNA sequencing data, including the TCGA data set, GSE19234, GSE22153 and GSE65904. Our analysis unveiled the heterogeneity of LDL across various cell types at the single‐cell sequencing level. Additionally, we constructed an LDL‐related signature (LRS) using machine learning algorithms, incorporating differentially expressed genes and highly correlated genes. The LRS serves as a valuable tool for assessing the prognosis, immunity and mutation status of patients with cutaneous melanoma. Furthermore, we conducted experiments on A375 and WM‐115 cells to validate the function of PPP2R1A, a pivotal gene within the LRS. Our comprehensive approach, combining advanced bioinformatics analyses with an extensive review of current literature, presents compelling evidence regarding the significance of LDL within the cutaneous melanoma microenvironment.

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Ox-LDL-mediated ILF3 overexpression in gastric cancer progression by activating the PI3K/AKT/mTOR signaling pathway

Cited by 8 publications

References 86 publications

Simvastatin inhibits PD-L1 via ILF3 to enhance CD8 + T cell-mediated ferroptosis in gastric cancer cells

Simvastatin inhibits PD-L1 via ILF3 to enhance CD8 + T cell-mediated ferroptosis in gastric cancer cells

Establishment and validation of exhausted CD8+ T cell feature as a prognostic model of HCC

Deciphering cutaneous melanoma prognosis through LDL metabolism: Single‐cell transcriptomics analysis via 101 machine learning algorithms

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