Cell Death & Disease
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2026
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IF 12.2
Ge Yutong,Yu Tao,Yu Shaokun,Sun Ao,Zhang Shiyu,Zhang Meiling,Wang Qian,Liu Jia,Zhang Xuan,Zeng Lulin,Lu Kaihua
Tumor-associated macrophages (TAMs) enriched in tumor microenvironment (TME) promote immune evasion and poor prognosis. Mitochondrial dysfunction, especially branched-chain amino acid (BCAA) metabolic reprogramming, has been confirmed to be involved in regulating TAMs function. The mitochondria-related protein MTFR2 was significantly upregulated in LUAD and closely associated with reduced survival. We conducted flow cytometry, multiplex immunofluorescence, immunohistochemistry on LUAD tissues, combined with analysis of public single-cell sequencing datasets, to characterize the TME features under MTFR2 dysregulation. Transcriptomics, metabolomics, and proteomics analyses revealed BCAA metabolic reprogramming, which was driven by MTFR2 binding to Leu125 within the β8 strand of VDAC1 and promoting its oligomerization. This interaction triggered mtDNA release into the cytoplasm, activating the TLR9-NF-κB pathway to upregulate BCAT1. Elevated concentrations of BCAA metabolites such as α-ketoisocaproate (KIC) and α-keto-β-methylvalerate (KMV) in the TME promoted M2 polarization and infiltration of TAMs by in vitro co-culture, 3D spheroid, and organoid models, and polarized M2 macrophages reciprocally promoted LUAD progression. Our findings establish a LUAD associated MTFR2-VDAC1-BCAT1 axis regulating the BCKAs-M2 axis in TAMs. Notably, targeting BCAT1 or depleting macrophages blocked this loop, offering a potential combination therapy for LUAD.
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高影响因子
PHARMACOLOGICAL RESEARCH
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2022
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IF 10.334
Xiaona Xie,Xueding Cai,Feng Zhou,Yaozhe Li,Qianzi Liu,Luqiong Cai,Wenjing Zhu,Jinqiu Wei,Chenying Jin,Zitian Liu,Chunhui Jiang,Haiyang Zhao,Lehe Yang,Chengguang Zhao,Xiaoying Huang
Lung adenocarcinoma (LUAD) is associated with poor prognosis. Identifying novel cancer targets and helpful therapeutic strategies remains a serious clinical challenge. This study detected differentially expressed genes in The Cancer Genome Atlas (TCGA) LUAD data collection. We also identified a predictive DNA biomarker, G protein-coupled receptor 37 (GPR37), which was verified as a prognostic biomarker with a critical role in tumor progression. In human LUAD specimens and microarray analyses, we determined that GPR37 was significantly upregulated and associated with a poor prognosis. GPR37 downregulation markedly inhibited the proliferation and migration of LUAD both in vitro and in vivo . Mechanistically, GPR37 could bind to CDK6, thereby facilitating tumor progression in LUAD by inducing cell cycle arrest at the G1 phase. GPR37 also facilitates tumorigenesis in xenograft tumors in vivo . High-throughput screening for GPR37-targeted drugs was performed using the Natural Products Library, which revealed the potential of Hypocrellin B to inhibit GPR37 and cell growth in LUAD. We demonstrated that Hypocrellin B suppressed LUAD cell proliferation and migration both in vitro and in vivo via GPR37 inhibition. Collectively, our findings reveal the role of GPR37 in LUAD progression and migration and the potential of GPR37 as a target for the treatment of LUAD. Thus, the specific inhibition of GPR37 by the natural product Hypocrellin B may possess the potential for the treatment of LUAD.
研究领域:
肿瘤学
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分子生物学
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药理学
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癌症遗传学
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高影响因子
Cancer Communications
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2026
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IF 28.4
Chenchen Hu,Feiming Hu,Changjian Shao,Yuanli He,Liping Su,Daimei Shi,Lingying Yu,Yuanjie Sun,Jing Wang,Xiyang Zhang,Hongtao Duan,Junqi Zhang,Yubo Sun,Dongbo Jiang,Xiaolong Yan,Shuya Yang,Kun Yang
Background: Lung cancer remains a major global health burden. RNA-binding proteins (RBPs) play crucial roles in post-transcriptional gene regulation, and their dysregulation is frequently implicated in tumorigenesis. The present study aimed to elucidate the molecular network governed by the highly expressed RBP TIMELESS in lung adenocarcinoma (LUAD) and determine its mechanistic role in LUAD progression. Methods: The Cancer Genome Atlas-LUAD, Gene Expression Omnibus, and single-cell RNA sequencing datasets were analyzed to identify aberrantly expressed RBP genes. The RBP gene TIMELESS exhibited the most significant effect on LUAD cell death and was selected for further study. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation sequencing and RNA sequencing were employed to identify ferroptosis-related targets directly bound by TIMELESS. Molecular mechanisms underlying the TIMELESS-mediated regulation of ferroptosis in LUAD were investigated via immunoprecipitation–mass spectrometry, glutathione S -transferase pull-down, immunofluorescence–fluorescence in situ hybridization, RNA immunoprecipitation, poly(A)-tail, and RNA stability assays. In an orthotopic lung cancer mouse model treated with erastin (a ferroptosis inducer) and programmed cell death protein 1 (PD-1) blockade, the role of TIMELESS in therapeutic response was assessed via flow cytometry and multiplex immunofluorescence (mIF). Infiltrating immune cells in LUAD were analyzed by tissue microarrays (TMAs) via mIF. Results: TIMELESS significantly affected LUAD cell proliferation and death, and TIMELESS knockdown significantly enriched RNA-binding and ferroptosis pathways. Transferrin (TF) was identified as a direct TIMELESS target governing ferroptosis. TIMELESS was revealed to bind Ccr4-Not transcription complex subunit 3 (CNOT3) to promote TF mRNA degradation. TIMELESS depletion combined with erastin and PD-1 blockade enhances efficacy, prolongs survival, increases T cell and M1 macrophage infiltration, and reduces M2 macrophage infiltration. Further, high TIMELESS expression was inversely correlated with ferroptosis marker 4-hydroxynonenal but positively correlated with programmed cell death ligand 1 (PD-L1), reduced T cell and M1 macrophage infiltration, and increased M2 macrophage infiltration. Conclusions: TIMELESS recruits CNOT3 to accelerate TF mRNA degradation, thereby suppressing ferroptosis and promoting LUAD growth. These findings suggest that the TIMELESS/TF regulatory axis may be a promising therapeutic target for LUAD.
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高影响因子
PULMONARY PHARMACOLOGY & THERAPEUTICS
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2023
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IF 3.2
Tao Wang,Xu Zhu,Kai Wang,Jianglun Li,Xiao Hu,Peng Lin,Jian Zhang
Background Cisplatin remains a common chemotherapy drug for lung adenocarcinoma (LUAD) in clinical treatment. Long-term use of cisplatin in patients may lead to acquired drug resistance, resulting in poor prognoses of patients. NEIL3 was a glycosylase-encoding gene highly expressed in LUAD. NEIL3 can repair telomerase DNA damage in the S phase. Nevertheless, there are few reports on whether NEIL3 is involved in cisplatin resistance and its related mechanisms in LUAD. Methods The expression of NEIL3 in LUAD patients was analyzed by bioinformatics. The regulator upstream of NEIL3 was predicted via hTFtarget. The possibly involved pathways of NEIL3 were obtained by performing Gene Set Enrichment Analysis. qRT-PCR and western blot were applied to test the expression level of genes and protein LUAD cells. Dual - luciferase assay and chromatin immunoprecipitation (ChIP) assay were conducted to validate the binding relationship between MAZ and NEIL3. Cell function assays were performed to test the DNA damage, cell viability, cell migration and invasion, and cell cycle of LUAD cells in the treatment group. Results NEIL3 and its upstream regulatory factor MAZ were highly expressed in LUAD tissue, and NEIL3 was enriched in cell cycle and mismatch repair pathways. Dual-luciferase assay and ChIP assay proved that MAZ could target NEIL3. Cell experiments identified that MAZ/NEIL3 axis could repress DNA damage to advance cisplatin resistance of cancer cells, and foster cell migration and invasion in LUAD. Conclusion MAZ-activated NEIL3 could propel the cisplatin resistance in LUAD by repressing DNA damage.
研究领域:
肿瘤学
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分子生物学
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基因组学
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高影响因子
IET Nanobiotechnology
·
2023
·Vol. 17
·期 3
·224-233
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IF 2.3
Junjie Zhao,Niu Niu,Fan Yang,Haitao Liu,Weibo Qi
Background Multidrug resistance is the biggest barrier on the way to chemotherapy for lung adenocarcinoma (LUAD). For some LUAD patients with cisplatin (DDP) resistance and poor prognoses, the authors put forward RNA nanoparticles (NPs) carrying miR-301b-3p Inhibitor. Methods The NPs were composed of miR-301b-3p, A549 aptamer (A549apt), and Cyanine 5 in a bottom-up manner with a 3-way-junction (3WJ) structure. Diameter, assembly process, and morphology of NPs were observed by Dynamic Light Scattering, Native-Polyacrylamide Gel Electrophoresis, and Atomic Force Microscopy. Cell internalisation, toxicity, proliferation, migration, invasion, and apoptosis were assayed by confocal laser scanning microscope, CCK8, colony formation assay, Transwell, western blot, and flow cytometry. Results 3WJ-apt-miR was evenly distributed, with diameter of 19.61 ± 0.49 nm and triangular branching structures. The accurate delivery of this NP in vivo was ensured by A549 aptamer featuring specific targeting, with smaller side effects than traditional chemotherapy. Such nanomaterials were effectively internalized by cancer cells, with normal cell activity intact. Cancer cell proliferation, invasion, and migration were suppressed, and DDP sensitivity was enhanced, causing DNA damage and facilitating apoptosis of DDP-resistant cells. Conclusion Based on RNA self-assembling, the authors researched the effect of miRNA on DDP sensitivity in LUAD regarding gene regulation. 3WJ-apt-miR paves the way for clinical tumour therapy.
研究领域:
癌症生物学
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纳米技术
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分子生物学
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药学
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基因治疗
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高影响因子
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