AP4 induces JNK1 and a miR‐22‐3p/FOSL1 feed‐forward loop to activate AP‐1 and promote colorectal cancer metastasis DOI Creative Commons
Jinjiang Chou, Markus Kaller, Matjaž Rokavec

и другие.

Cancer Communications, Год журнала: 2024, Номер 44(3), С. 433 - 437

Опубликована: Янв. 15, 2024

Dear Editor, Colorectal cancer (CRC) is the third most deadly worldwide [1]. The mortality of CRC has remained high due to limited treatment options for metastatic (mCRC) [2]. Epithelial-mesenchymal transition (EMT) an important contributor mCRC c-MYC proto-oncogene (MYC)-induced transcription factor AP4 (TFAP4/AP4) a driver EMT, thereby presumably facilitates [3, 4]. mitogen-activated protein kinase (MAPK)/c-Jun N-terminal (JNK)/activator protein-1 (AP-1) pathway been implicated in regulation EMT and [5]. Here, we analyzed whether regulates components MAPK/JNK/AP-1 after MYC activation using cells rendered AP4-deficient by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) approach. detailed methods are shown Supplementary file. First, grouped MYC-induced changes mRNA expression observed cell line DLD-1 wild-type 1/pRTR-c-MYC-VSV (AP4-WT1 DLD-1/pRTR-c-MYC-VSV) into 6 non-overlapping clusters (Supplementary Figure S1A, left), with cluster 1 representing mRNAs down-regulated, 2-6 different patterns up-regulated activation. MAPK signaling were strongly over-represented right). targets MIR22 host gene (MIR22HG) E-cadherin (CDH1) down-regulated AP4-WT1 DLD-1/pRTR-c-MYC-VSV S1B). effectors, including c-Fos (FOS), c-Jun (JUN) c-JunB (JUNB), 6. Additional components. such as (JNK1), (MAP3K1), 13 (MAP3K13), 3 (MAP2K3), 7 (MAP2K7) FOS-like (FOSL1) found 3-5 Interestingly, MAP3K13, MAP2K7, JNK1 FOSL1 induced AP4-dependent manner S1C-D). Notably, FOSL1, MAP2K7 also activating 48 or 72 hours (Figure 1A) showed AP4-binding sites (CAGCTG) occupancy S2A). Therefore, these genes represent direct targets. MAP3K13 phosphorylated activation, whereas levels unchanged 1B). Furthermore, at promoters was confirmed quantitative real-time polymerase chain reaction-chromatin immunoprecipitation (qChIP) analysis 1C). nascent decreased SW480 S2B). Ectopic S2C). activates through MAP3K13/MAP2K7/JNK1 cascade. CRCs liver metastasis significantly more often FOSL1-positive [6], colon tissues [7]. Thus, AP4-induced clinically relevant CRC. trend towards positive correlation 471 primary samples Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) cohort independent patient (GSE13294) S2D). dimerization results formation AP-1 [8]. Consistently, activity ectopic 1D, S2E). In addition, lower S2F). Taken together, show that directly inducing FOSL1. Next, relevance EMT. inhibitor DB07268 partially abrogated induction vimentin (VIM) repression CDH1 lines S3A), indicating AP4-mediated contributes VIM [3]. suppressed migration invasion 1E, S3B-C). largely proliferation S3D). mediates migration, AP4. We have previously represses tumor-suppressive miRNA miR-22-3p, which up-regulation mediator DNA damage checkpoint (MDC1), miR-22-3p target, [9]. Since identified seed-match sequence (SMS) 3'-untranslated region (3'-UTR), investigated regulated via 1F). Indeed, 3'-UTR reporter repressed mutation SMS refractory 1G). S4A) effectively basal 1H, S4B). generated MIR22-/- (MIR22-knockout [KO]) ΔSMS S4C). elevated MIR22-deficient 1I, S4D). MIR22-deficiency increased SMS-dependent S4E) enhanced S4F). intrinsic higher 1J, S4G). half-life (t1/2) prolonged 1K). failed repress 1L, S4H), expression, attenuated 1M). targeting essential maintaining low allows be indirectly MIR22. determined functional effects on cells. cells, silencing compromised S5A). effect 1N, S5B-C), Silencing S5D). concomitant siRNA-mediated S5E). demonstrate FOSL1-mediated required proliferation. CRCs, displayed lymph node metastasis, lung xenograft model [10]. deregulation miR-22-3p/FOSL1 axis may mCRC. non-metastatic allowed form metastases non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice non-invasive bioluminescence imaging 1O-P) histological S6A, sufficient convert from state. efficiently prevented 1Q, S6A left). metastases. Similar obtained inhibition 1R-S, S6B-C). conclusion, induces directly, well indirectly, miR-22-3p. AP4, coherent, regulatory feed-forward loop. These regulations converge 1T), ultimately promotes invasion, enhancing formation. future, findings exploited prevention and/or Heiko Hermeking conceived, planned supervised project; Hermeking, Jinjiang Chou Markus Kaller designed experiments; performed experiments results; bioinformatics analysis; Matjaz Rokavec mouse experiments. Fangteng Liu histochemically evaluated mice. wrote manuscript. All authors read approved final grateful Raffaele Conca (Dr. von Haunersches Children's Hospital, Munich) fluorescence-activated sorting Chunfeng Ursula Götz technical assistance. declare they no competing interests. Not applicable. This work supported German Aid/Deutsche Krebshilfe grants (70114235 70112245) Hermeking. Animal experimentations analyses Government Upper Bavaria, Germany (55.2-2532.vet_02-18-57). Please note: publisher not responsible content functionality any supporting information supplied authors. Any queries (other than missing content) should directed corresponding author article.

Язык: Английский

Curcumin in the treatment of urological cancers: Therapeutic targets, challenges and prospects DOI
Mehrdad Hashemi, Sepideh Mirzaei,

Maryamsadat Barati

и другие.

Life Sciences, Год журнала: 2022, Номер 309, С. 120984 - 120984

Опубликована: Сен. 20, 2022

Язык: Английский

Процитировано

29
YTHDF3 mediates HNF1α regulation of cervical cancer radio‐resistance by promoting RAD51D translation in an m6A‐dependent manner DOI
Hui Du,

Nai‐Yi Zou,

Hong‐Ling Zuo

и другие.

FEBS Journal, Год журнала: 2022, Номер 290(7), С. 1920 - 1935

Опубликована: Ноя. 16, 2022

Radiotherapy, as an important primary treatment, has effectively improved the survival of patients with cervical cancer (CC). Some patients, however, do not benefit optimally from radiotherapy because radio‐resistance. Therefore, identifying radio‐resistance biomarkers and unravelling underlying mechanisms is critical importance for these patients. In present study, we found significant upregulation hepatocyte nuclear factor 1‐alpha (HNF1α) expression in radio‐resistant tissues cell lines. Depletion HNF1α reduced overexpression promoted resistance CC cells to irradiation vitro vivo . positively regulated DNA repair protein RAD51 homologue 4 (RAD51D) at level but mRNA level. Mechanistically, enhanced YTH domain‐containing family 3 (YTHDF3) transcription, which turn RAD51D N 6 ‐methyladenosine (m6A) modification. YTHDF3 mediates regulation by promoting translation m6A‐dependent manner. The HFN1α/YTHDF3/RAD51D regulatory axis was play a role conferring cells. conclusion, dysregulation may promote Blocking this pathway provide therapeutic benefits against

Язык: Английский

Процитировано

20
Increased expression of miR-194-5p through the circPVRL3/miR-194-5p/SOCS2 axis promotes proliferation and metastasis in pancreatic ductal adenocarcinoma by activating the PI3K/AKT signaling pathway DOI Creative Commons

Bojing Chi,

Yao Zheng,

Fuming Xie

и другие.

Cancer Cell International, Год журнала: 2022, Номер 22(1)

Опубликована: Дек. 20, 2022

MicroRNAs (miRNAs), as an indispensable type of non-coding RNA (ncRNA), participate in diverse biological processes. However, the specific regulatory mechanism certain miRNAs pancreatic ductal adenocarcinoma (PDAC) remains unclear.

Язык: Английский

Процитировано

19
Non-coding RNAs participate in interactions between senescence and gastrointestinal cancers DOI Creative Commons
Zhaozhe Liu,

Fa-He Ji,

Ying Piao

и другие.

Frontiers in Genetics, Год журнала: 2025, Номер 15

Опубликована: Янв. 3, 2025

Relationships between cellular senescence and gastrointestinal cancers have gained prominence in recent years. The currently accepted theory suggests that cancer occurrence exhibit "double-edged sword" effects. Cellular is related to via four "meta-hallmarks" i.e., genomic instability, epigenetic alterations, chronic inflammation, dysbiosis, along with two "antagonistic hallmarks" telomere attrition stem cell exhaustion. These relationships are characterized by both agonistic antagonistic elements, but the existence of an intricate dynamic balance remains unknown. Non-coding RNAs (ncRNAs) vital roles post-transcriptional regulation, how they participate be fully investigated. In this article, we systematically review ncRNAs (including microRNAs (miRNAs), long (lncRNAs), circularRNAs (circRNAs)) interactions cancers. Our aim elucidate a triangular relationship "ncRNAs-senescence-gastrointestinal cancers" which considered these three elements as equal important standing. We keen identify prognostic or therapeutic targets for from, aging-related ncRNAs, discover novel strategies treat manage elderly. seek clarify complex where "senescence-gastrointestinal interactions.

Язык: Английский

Процитировано

0
Cellular Senescence in Tumor Immune Escape: Mechanisms, Implications, and Therapeutic Potential DOI
You Li, Qinghua Wu

Critical Reviews in Oncology/Hematology, Год журнала: 2025, Номер unknown, С. 104628 - 104628

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Regulatory Network Inference of Induced Senescent Midbrain Cell Types Reveals Cell Type-Specific Senescence-Associated Transcriptional Regulators DOI Creative Commons
Taylor Russo, Jonathan Plessis‐Belair, Roger B. Sher

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 6, 2025

Abstract Cellular senescence of brain cell types has become an increasingly important perspective for both aging and neurodegeneration, specifically in the context Parkinson’s Disease (PD). The characterization classical hallmarks is a widely debated topic, whereby which phenotype being investigated, such as type, inducing stressor, and/or model system, extremely aspect to consider when defining senescent cell. Here, we describe type-specific profile through investigation various canonical markers five human midbrain lines using chronic 5-Bromodeoxyuridine (BrdU) treatment DNA damage-induced senescence. We used principal component analysis (PCA) subsequent regulatory network inference define unique common profiles well revealed senescence-associated transcriptional regulators (SATRs). Functional one identified regulators, transcription factor AP4 (TFAP4), further highlights type-specificity expression hallmarks. Our data indicates that SATRs modulate induced key play role PD.

Язык: Английский

Процитировано

0
Emerging Roles for Transcription Factors During Mitosis DOI Creative Commons
Samuel Flashner, Jane Azizkhan‐Clifford

Cells, Год журнала: 2025, Номер 14(4), С. 263 - 263

Опубликована: Фев. 12, 2025

The genome is dynamically reorganized, partitioned, and divided during mitosis. Despite their role in organizing interphase chromatin, transcription factors were largely believed to be mitotic spectators evicted from chromatin mitosis, only able reestablish position on DNA upon entry into G1. However, a panoply of evidence now contradicts this early belief. Numerous are known remain active mitosis achieve diverse purposes, including chromosome condensation, regulation the centromere/kinetochore function, control centrosome homeostasis. Inactivation results segregation errors, key features cancer. Moreover, production centromere-derived transcripts also play roles maintaining chromosomal stability. Finally, many associated with instability through poorly defined mechanisms. Herein, we will review emerging focus promoting faithful sister chromatids.

Язык: Английский

Процитировано

0
HDGF Knockout Suppresses Colorectal Cancer Progression and Drug Resistance by Modulating the DNA Damage Response DOI Creative Commons

Riya Su,

Qin Wang, Qun Hu

и другие.

Biomolecules, Год журнала: 2025, Номер 15(2), С. 282 - 282

Опубликована: Фев. 14, 2025

Colorectal cancer (CRC) is a highly heterogeneous gastrointestinal malignancy. Despite significant advances in molecular targeted therapies for CRC recent years, the increase overall survival rates patients remains limited. Therefore, there an urgent need to explore novel drug targets. Herein, we show that heparin binding growth factor (HDGF) expressed CRC, and its overexpression associated with poor disease-free interval. Additionally, reveal HDGF knockout reduces proliferation, migration, invasion, while enhancing apoptosis cells, thereby validating as potential therapeutic target CRC. Mechanistically, found modulates DNA damage response and, by recruiting C-terminal protein-interacting protein (CtIP), it facilitates homologous recombination repair influence sensitivity. Furthermore, propose may serve recognition H3K36me3, participating of damaged transcriptionally active genes, thus maintaining genomic stability

Язык: Английский

Процитировано

0
Long Non-coding RNA MIR22HG Alleviates Ischemic Acute Kidney Injury by Targeting the miR-134-5p/NFAT5 axis DOI Creative Commons
Jingdong Li, Zhaogang Dong,

Liting Tang

и другие.

Inflammation, Год журнала: 2025, Номер unknown

Опубликована: Март 17, 2025

Acute kidney injury (AKI), often triggered by ischemia–reperfusion (I/R) injury, is a critical condition characterized rapid loss of renal function, leading to high morbidity and mortality. Despite extensive research, therapeutic options for ischemic AKI remain limited, understanding the molecular mechanisms involved crucial developing targeted therapies. Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators gene expression cellular processes in various diseases, including cancer injury. This study investigates role lncRNA MIR22HG mitigating during AKI. Using vivo vitro models I/R-induced mice hypoxia/reoxygenation (H/R)-treated cells, we demonstrated that significantly downregulated conditions. Functional assays showed overexpression these led reduced cell apoptosis, inflammation, improved function. Mechanistically, exerted its protective effects negatively regulating miR-134-5p, which turn alleviated upregulating NFAT5, transcription factor known mitigate stress. Furthermore, dual-luciferase RNA pull-down confirmed direct interactions between well miR-134-5p NFAT5. Additionally, loss-and-gain-of-function upregulation mitigated inflammation Collectively, results our highlight potential targeting MIR22HG/miR-134-5p/NFAT5 axis treatment AKI, providing new insights into regulation survival repair

Язык: Английский

Процитировано

0
Genetic targets related to aging for the treatment of coronary artery disease DOI Creative Commons
Kai Huang, Zijun Chen, Ruting Wang

и другие.

BMC Medical Genomics, Год журнала: 2025, Номер 18(1)

Опубликована: Апрель 9, 2025

Coronary Artery Disease (CAD) is the most common cardiovascular disease worldwide, threatening human health, quality of life and longevity. Aging a dominant risk factor for CAD. This study aims to investigate potential mechanisms aging-related genes CAD, make molecular drug predictions that will contribute diagnosis treatment. We downloaded gene expression profile circulating leukocytes in CAD patients (GSE12288) from Gene Expression Omnibus database, obtained differentially expressed aging through "limma" package GenaCards tested their biological functions. Further screening related characteristic (ARCGs) using least absolute shrinkage selection operator random forest, generating nomogram charts ROC curves evaluating diagnostic efficacy. Immune cells were estimated by ssGSEA, then combine ARCGs with immune clinical indicators based on Pearson correlation analysis. Unsupervised cluster analysis was used construct clusters assess functional characteristics between clusters. The DSigDB database employed explore targeted drugs ARCGs, docking carried out Autodock Vina. Finally, single-cell data (GSE159677) arterial intima further signature different cell subpopulations. identified 8 associated which HIF1A FGFR3 up while NOX4, TCF7L2, HK3, CDK18, TFAP4, ITPK1 down patients. Based this, can be divided into two clusters, among A mainly involves pathways such as ECM receptor interaction focal adhesion; B amimo sugar nucleotide metabolism pyrimidine metabolism. In addition, results showed retinoic acid resveratrol had good binding affinity targets genes. ITPK1, specifically types atherosclerotic tissues. Our several may involved pathogenesis progression Further, candidate molecule inhibiting these targets.

Язык: Английский

Процитировано

0