JOURNAL OF EXPERIMENTAL MEDICINE
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2024
·Vol. 221
·期 7
·e20240111
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IF 12.6
Xue Yun,Chen Yuting,Sun Sijia,Tong Xinyuan,Chen Yujia,Tang Shijie,Wang Xue,Bi Simin,Qiu Yuqin,Zhao Qiqi,Qin Zhen,Xu Qin,Ai Yingjie,Chen Leilei,Zhang Beizhen,Liu Zhijie,Ji Minbiao,Lang Meidong,Chen Luonan,Xu Guoliang,Hu Liang,Ye Dan,Ji Hongbin
Phenotypic plasticity is a rising cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung cancer. Here, we find that ten-eleven translocation (TET)–mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that Tet2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3–CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to–cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.
研究领域:
肿瘤学
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免疫学
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分子生物学
·
癌症生物学
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DOI
PubMed
高影响因子
IMMUNOLOGY AND CELL BIOLOGY
·
2026
·
IF 3.3
Yadi Li,Xiaoqian Zhou,Zhusheng Yang,Xiumin Yang,Aihua Wei
Psoriasis, a chronic inflammatory skin disease, involves dysregulated immune responses and keratinocyte hyperproliferation. The role of salt-inducible kinase 2 (SIK2) in modulating interleukin-23 (IL-23) secretion via C–X–C motif chemokine ligand 5 (CXCL5) in neutrophils has not been fully explored. We combined in vivo and in vitro approaches to examine SIK2's role in an imiquimod (IMQ)-induced psoriasis model and activated neutrophils. Mice underwent intradermal injections of lentiviruses overexpressing SIK2, CXCL5, or both, while in vitro experiments involved transfecting activated neutrophils with these constructs. Assessments included ear thickness, cellular and neutrophil infiltration through histological and immunofluorescence techniques, and analysis of gene and protein expressions via quantitative real-time PCR (qRT-PCR), immunohistochemistry (IHC), and Western blot. Additionally, cell viability, proliferation, and cytokine levels in N -formylmethionyl-leucyl-phenylalanine (fMLF) treated neutrophils were evaluated using cell-counting kit-8 (CCK8), 5-ethynyl-2′-deoxyuridine (EdU) incorporation, and Enzyme-Linked Immunosorbent Assay (ELISA). Overexpression of SIK2 significantly reduced ear thickness, cellular and neutrophil infiltration, IL-1β, tumor necrosis factor-alpha (TNF-α), CXCL5, IL-23 and phosphorylated Yes-associated protein (p-YAP) levels, and increased SIK2 levels in IMQ mice model, but overexpression of CXCL5 reversed these effects. In vitro , SIK2 overexpression resulted in reduced cell viability and proliferation, with corresponding reductions in IL-1β, IL-17, IL-23, and Matrix Metallopeptidase 9 levels, whereas overexpression of CXCL5 reversed these effects. Our findings suggest that SIK2 acts as a critical modulator in psoriasis by influencing CXCL5-mediated IL-23 secretion in neutrophils, underscoring the potential of SIK2 as a therapeutic target to alleviate the inflammatory responses in psoriasis.
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DOI
高影响因子
Cell Death & Disease
·
2026
·Vol. 17
·期 1
·326
·
IF 12.2
Xin Hu,Meiqi Feng,Chengjin Qi,Boran Li,Hongjuan He,Kai Li,Lu Chen,Boshu Ji,Haoran Yu,Yue Zhao,Tong Wu,Ruiheng Ma,Yuhao Dong,Yan Zhang,Qiong Wu
Investigating the epigenetic mechanisms underlying lung adenocarcinoma (LUAD) through the lens of N 4-acetylcytosine (ac4C) modification could innovate cancer treatment strategies and targets. We used biological information methods to analyze shared data, with a focus on studying N -acetyltransferase 10 (NAT10), which is the only known ac4C “writer” protein. Our analysis revealed a significant upregulation of NAT10 expression in LUAD, a finding that was corroborated by investigations in both LUAD cancer tissue samples and cell lines. Subsequently, we employed CRISPR/Cas9 technology to knock out the NAT10 gene and analyzed the resulting knockout cells using acRIP-seq and RNA-seq techniques. Our findings demonstrated different expressions of the genes C-X-C motif chemokine ligand 5 (CXCL5) and DEK proto-oncogene (DEK), and functional enrichment analysis indicated a strong association with the adhesion signaling pathway. Laboratory experiments revealed that NAT10 acts as an ac4C “writer,” promoting the acetylation of CXCL5 and DEK and thus preventing the degradation of their mRNAs. Moreover, NAT10 was found to significantly affect the number of metastases and tumor growth following the injection of cancer cells into the tail vein of mice. Our research data suggests that targeting NAT10 has the potential to serve as a diagnostic biomarker or prognostic target for developing anti-metastatic therapies aimed at disrupting the adhesion process.
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 23
·12844
·
IF 4.9
Zhining Gao,Haoyang Dai,Qinqin Zhang,Fan Yang,Chenxi Bu,Suiqing Chen
Acute liver injury (ALI) is an injury to liver tissue caused by viruses, drugs, alcohol, and oxygen deprivation, and is one of the most common and serious clinical disorders. Hydroxytyrosol (HT) is a naturally occurring polyphenolic compound isolated from forsythia and has excellent anti-inflammatory properties. However, the effect and mechanisms of HT in ALI remain unclear. We used the LPS/D-GalN induced experimental ALI mouse model and AML12 cells to reveal the efficacy and potential mechanisms of HT in ALI, and HE staining was used for the evaluation of pathologies. A biochemical assay was used to detect changes in liver function, RNA-seq was conducted to reveal the underlying mechanisms of HT for ALI, and WB, RT-qPCR, and IF were used to assess the effects of HT action. Furthermore, an in vitro ALI model against HT in AML12 cells induced by LPS/D-GalN was used to assess the HT protection mechanism. HT significant alleviated LPS/D-GalN-induced ALI in the mice by suppressing inflammatory. In terms of RNA-seq, HT improved the TNF, ECM-receptor interaction, and PI3K/AKT signaling pathway, and it downregulated the mRNA levels of VCAM-1, CXCL5, TNF-α and IL-6 in the liver. Mechanically, HT alleviated LPS/D-GalN in the mice by targeting TNF-α, thereby inhibiting the TNF-α/PI3K/AKT signaling pathway.
研究领域:
药理学
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肝病学
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分子生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Xin Jiang,Ziqing Yuan,Tingbo Ding,Ker Yu,Jibin Dong
The massive infiltration of suppressor immune cells within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is a major cause of treatment resistance. Reducing this infiltration may represent a potentially effective therapeutic strategy. Sphingomyelin synthase 2 (SMS2) is a crucial enzyme for sphingomyelin synthesis, contributing significantly to the integrity and function of the plasma membrane. In this study, we developed a self-assembling SMS2 siRNA gene expression plasmid for in vivo delivery. The SMS2 siRNA specifically inhibits SMS2 expression while preserving the expression and activity of SMS1. Administration of the self-assembling SMS2 siRNA suppresses tumor growth in a murine model of Panc02 pancreatic carcinoma, modulates the polarization of tumor-associated macrophages (TAMs), and reduces the infiltration of tumor-associated neutrophils (TANs) by regulating the NF-κB/CXCL5 pathway. Consequently, utilizing SMS2 siRNA to improve the local immunosuppressive microenvironment holds promise for pancreatic cancer therapy.
研究领域:
癌症生物学
·
分子生物学
·
免疫学
·
药理学
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DOI
PubMed
高影响因子
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