Necroptosis enhances ‘don’t eat me’ signal and induces macrophage extracellular traps to promote pancreatic cancer liver metastasis

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Июль 18, 2024

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with dismal prognosis due to distant metastasis, even in the early stage. Using RNA sequencing and multiplex immunofluorescence, here we find elevated expression of mixed lineage kinase domain-like pseudo-kinase (MLKL) enhanced necroptosis pathway PDAC from liver metastasis T-stage (T1M1) patients comparing non-metastatic (T1M0) patients. Mechanistically, MLKL-driven recruits macrophages, enhances tumor CD47 ‘don’t eat me’ signal, induces macrophage extracellular traps (MET) formation for CXCL8 activation. further initiates epithelial–mesenchymal transition (EMT) upregulates ICAM-1 promote endothelial adhesion. METs also degrades matrix, that eventually supports metastasis. Meanwhile, targeting reduces vivo. Our study thus reveals facilitates by evading immune surveillance, suggest blockade, combined MLKL inhibitor GW806742X, may be promising neoadjuvant immunotherapy overcoming T1M1 dilemma reviving opportunity radical surgery.

Язык: Английский

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NEAT1_1 confers gefitinib resistance in lung adenocarcinoma through promoting AKR1C1-mediated ferroptosis defence

Cell Death Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Март 12, 2024

Abstract Gefitinib is one of the most extensively utilized epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for treating advanced lung adenocarcinoma (LUAD) patients harboring EGFR mutation. However, emergence drug resistance significantly compromised clinical efficacy EGFR-TKIs. Gaining further insights into molecular mechanisms underlying gefitinib holds promise developing novel strategies to overcome and improve prognosis in LUAD patients. Here, we identified that inhibitory on EGFR-mutated cells was partially dependent induction ferroptosis, ferroptosis protection resulted resistance. Among suppressors, aldo-keto reductase family 1 member C1 (AKR1C1) exhibited significant upregulation gefitinib-resistant strains predicted poor progression-free survival (PFS) overall (OS) who received first-generation EGFR-TKI treatment. Knockdown AKR1C1 reversed by re-sensitizing gefitinib-mediated ferroptosis. The decreased expression miR-338-3p contributed aberrant cells. Furthermore, upregulated long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1_1 (NEAT1_1) sponged neutralize its suppression AKR1C1. Dual-luciferase reporter assay miRNA rescue experiment confirmed NEAT1_1/miR-338-3p/AKR1C1 axis Gain- loss-of-function assays demonstrated promoted resistance, proliferation, migration, invasion This study reveals effects axis-mediated defence LUAD. Thus, targeting might be a strategy overcoming

Язык: Английский

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Glycolysis reprogramming in CAFs promotes oxaliplatin resistance in pancreatic cancer through circABCC4 mediated PKM2 nuclear translocation

Cell Death and Disease, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 23, 2025

Язык: Английский

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EIF4E-mediated biogenesis of circPHF14 promotes the growth and metastasis of pancreatic ductal adenocarcinoma via Wnt/β-catenin pathway

Molecular Cancer, Год журнала: 2025, Номер 24(1)

Опубликована: Фев. 26, 2025

CircRNAs are critically involved in the development and progression of various cancers. However, their functions mechanisms pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. CircPHF14 (hsa_circ_0079440) was identified through analysis RNA sequencing data from PDAC normal adjacent tissues. The biological circPHF14 were then evaluated using CCK8, EdU, transwell, colony formation, wound healing assays, as well orthotopic xenograft liver metastasis models. interaction between PABPC1, which enhance stability WNT7A mRNA, investigated pull-down, mass spectrometry, Immunoprecipitation (RIP), actinomycin D assays. role EIF4E promoting biogenesis examined RIP, western blotting. In this study, we observed a significant upregulation both clinical samples cell lines. Functionally, enhanced proliferation vitro vivo. Mechanistically, interacted with PABPC1 to stabilize thereby activating Wnt/β-catenin pathway, subsequently upregulated SNAI2 initiated Epithelial-Mesenchymal Transition (EMT) PDAC. Additionally, found bind PHF14 pre-mRNA, facilitating biogenesis. Finally, developed lipid nanoparticle (LNP) formulation encapsulating sh-circPHF14 plasmids confirmed its anti-tumor efficacy patient-derived (PDX) model. EIF4E-mediated stabilizes mRNA via activates growth These findings indicate that holds promise biomarker therapeutic target for

Язык: Английский

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N6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1

Journal of Experimental & Clinical Cancer Research, Год журнала: 2024, Номер 43(1)

Опубликована: Апрель 20, 2024

Refractoriness to surgical resection and chemotherapy makes intrahepatic cholangiocarcinoma (ICC) a fatal cancer of the digestive system with high mortality poor prognosis. Important function invests circRNAs tremendous potential in biomarkers therapeutic targets. Nevertheless, it is still unknown how contribute evolution ICC. CircRNAs paired ICC adjacent tissues were screened by sequencing. To explore impact on development, experiments involving gain loss conducted. Various experimental techniques, including quantitative real-time PCR (qPCR), western blotting, RNA immunoprecipitation (RIP), luciferase reporter assays, pull-down, chromatin (ChIP), ubiquitination assays so employed identify molecular regulatory role circRNAs. Herein, we reported new circRNA, which originates from exon 9 15 SLCO1B3 gene (named circSLCO1B3), orchestrated progression promoting tumor proliferation, metastasis immune evasion. We found that circSLCO1B3 was highly overexpressed related lymphatic metastasis, sizes, differentiation. Mechanically, not only promoted proliferation via miR-502-5p/HOXC8/SMAD3 axis, but also eradicated anti-tumor immunity suppressing ubiquitin-proteasome-dependent degradation PD-L1 E3 ubiquitin ligase SPOP. further methyltransferase like 3 (METTL3) mediated m6A methylation stabilizes its expression. Our findings indicate prognostic marker target patients. Taken together, m6A-modified correlated prognosis enhancing potentiating HOXC8 expression, inducing evasion antagonizing degradation. These results suggest for

Язык: Английский

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Single‐cell RNA sequencing reveals the mechanism of PI3K/AKT/mTOR signaling pathway activation in lung adenocarcinoma by KRAS mutation

The Journal of Gene Medicine, Год журнала: 2024, Номер 26(1)

Опубликована: Янв. 1, 2024

Abstract Background Aberrant activation of the phosphatidlinositol 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target rapamycin (mTOR) signaling pathway has been shown to play an important role in lung adenocarcinoma (LUAD). The effect KRAS mutations, one signatures LUAD, on PI3K/AKT/mTOR LUAD remains unclear. Methods Seurat package and principal component analysis were used for cell categorization single‐cell RNA sequencing data LUAD. AUCell score was assess activity pathway. Meanwhile, using gene expression profiles mutation Cancer Genome Atlas dataset, patients categorized into KRAS‐mutant (KRAS‐MT) KRAS‐wild‐types (KRAS‐WT), corresponding enrichment scores calculated set analysis. Finally, subpopulation cells with highest identified, copy number variation profile this inscribed inferCNV CMap database utilized make predictions drugs targeting subpopulation. Results There is higher epithelial high KRAS, PIK3CA, AKT1 PDPK1. In particular, we found significantly levels associated KRAS‐MT than KRAS‐WT. We identified a GRB2 + presence amplified genes within its able subpopulations, such as wortmannin, palbociclib angiogenesis inhibitor. Conclusions present study provides basic theory result mutations.

Язык: Английский

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CircUCK2(2,3) promotes cancer progression and enhances synergistic cytotoxicity of lenvatinib with EGFR inhibitors via activating CNIH4–TGFα–EGFR signaling

Cellular & Molecular Biology Letters, Год журнала: 2025, Номер 30(1)

Опубликована: Янв. 30, 2025

Circular (circ)RNAs have emerged as crucial contributors to cancer progression. Nonetheless, the expression regulation, biological functions, and underlying mechanisms of circRNAs in mediating hepatocellular carcinoma (HCC) progression remain insufficiently elucidated. We identified circUCK2(2,3) through circRNA sequencing, RT-PCR, Sanger sequencing. CircUCK2(2,3) levels were measured two independent HCC cohorts using quantitative real-time PCR (qRT-PCR). explored functions gain- loss-of-function assays. Techniques such RNA-sequencing, RNA immunoprecipitation (RIP), polysome fractionation, pulldown, dual luciferase reporter assay, inhibitors EGFR downstream signaling, CRISPR-Cas9, medium transfer assays employed investigate regulatory protumoral activities circUCK2(2,3). Additionally, vitro cytotoxic patient-derived xenograft (PDX) models assessed effects on synergy lenvatinib inhibitors. is upregulated tissues serves an risk factor for poor recurrence-free survival. The its host gene, UCK2, but regulated by upstream promoter flanking inverted complementary sequences. Functionally, enhances proliferation, migration, invasion, both vivo. Mechanistically, sponging miR-149-5p, increases CNIH4 levels, which turn amplifies TGFα secretion, resulting activation pAKT pERK signaling pathways. Moreover, overexpression sensitizes cells inhibitors, synergistic cytotoxicity combined inhibitor treatment. regulates a novel oncogenic pathway, miR-149-5p-CNIH4-TGFα-EGFR, HCC, presenting viable therapeutic target biomarker precision treatment HCC.

Язык: Английский

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DDX21 Controls Cell Cycle Progression and Autophagy in Pancreatic Cancer Cells

Cancers, Год журнала: 2025, Номер 17(4), С. 570 - 570

Опубликована: Фев. 7, 2025

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer. Late diagnosis and acquisition of chemoresistance contribute to its dismal prognosis. While surgical resection improved the clinical outcome patients, only ~20% them are eligible due advanced disease at diagnosis. Thus, development new therapeutic approaches master priority for an management this The helicase DDX21 was proposed as prognostic marker in several tumors, including PDAC. Methods:DDX21 expression evaluated PDAC samples cell lines; RNA sequencing bioinformatics analyses DDX21-depleted PANC-1 silenced cells; functional autophagy, cycle proliferation. Results: expressed higher levels liver metastasis patients. Transcriptomics cells revealed enrichment genes involved autophagy progression. inactivation by interference enhanced basal autophagic flux altered reducing rate G1-S transition. Coherently, proliferation clonogenic activity significantly reduced. Conclusions: Our results support oncogenic role uncover regulation autophagy.

Язык: Английский

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CircRNA hsa_circ_0004781 promoted cell proliferation by acting as a sponge for miR-9-5p and miR-338-3p and upregulating KLF5 and ADAM17 expression in pancreatic ductal adenocarcinoma

Cancer Cell International, Год журнала: 2025, Номер 25(1)

Опубликована: Фев. 19, 2025

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types solid tumor, and novel strategies must be developed for treating it. Previous studies predominantly utilized circular RNA (circRNA) expression plasmids incorporating Alu elements to facilitate indirect circRNA. Methods Public databases bioinformatics tools were used identify hsa_circ_0004781 that highly expressed in PDAC its potential microRNA (miRNA) targets corresponding mRNA targets. Real hsa_circ_0004781, which identical native form without any exogenous sequences, was prepared through vitro transcription by using a ribozyme ion-pair reversed-phase high-performance liquid chromatography (IP-RP HPLC). The biological functions evaluated loss-of-function gain-of-function approaches with circRNA real hsa_circ_0004781. Results Knockdown inhibited proliferation migration cells, whereas overexpression produced opposite effects. Hsa_circ_0004781 identified as sponge miR-9-5p miR-338-3p, negatively correlated these miRNAs. Among Kruppel-like factor 5 ( KLF5 ) disintegrin metalloproteinase domain 17 ADAM17 survival patients inversely regulated Furthermore, exhibited same effects those plasmids. Conclusions This study first use circRNAs validate results obtained suggest an oncogene, promoting cells miR-9-5p/ miR-338-3p/ axes. Therefore, might therapeutic target PDAC.

Язык: Английский

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Circular RNA in Pancreatic Cancer: Biogenesis, Mechanism, Function and Clinical Application

International Journal of Medical Sciences, Год журнала: 2025, Номер 22(7), С. 1612 - 1629

Опубликована: Фев. 28, 2025

Circular RNAs (circRNAs) are a class of novel RNA molecules featured by single-strand covalently closed circular structure, which not only extensively found in eukaryotes and highly conserved, but also conduct paramount roles the occurrence progression pancreatic cancer (PC) through diverse mechanisms. As recent studies have demonstrated, circRNAs typically exhibit tissue-specific cell specific expression patterns, with strong potential as biomarkers for disease diagnosis prognosis. On basis their localization interactions DNA, RNA, proteins, considered to possess biological functions acting microRNA (miRNA) sponges, binding protein (RBP) transcriptional regulators, molecular scaffolds translation templates. that account, further addressing technical difficulties detection research filling gaps knowledge will definitely push ahead this comparatively young field bring forefront clinical practice. Thus, review systematically summarizes biogenesis, function, mechanisms, therapeutic targets PC.

Язык: Английский

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