Ppm1d truncating mutations promote the development of genotoxic stress-induced AML DOI Creative Commons
Monika Burócziová, Petr Daněk, Anna Oravetzova

et al.

Leukemia, Journal Year: 2023, Volume and Issue: 37(11), P. 2209 - 2220

Published: Sept. 14, 2023

Abstract Hematopoietic stem cells (HSCs) ensure blood cell production during the life-time of an organism, and to do so they need balance self-renewal, proliferation, differentiation, migration in a steady state as well response stress or injury. Importantly, aberrant proliferation HSCs leads hematological malignancies, thus, tight regulation by various tumor suppressor pathways, including p53, is essential. Protein phosphatase magnesium-dependent 1 delta (PPM1D) negative regulator p53 promotes survival upon induction genotoxic stress. Truncating mutations last exon PPM1D lead stable, enzymatically active protein are commonly associated with clonal hematopoiesis. Using transgenic mouse model, we demonstrate that truncated reduces self-renewal basal conditions but development aggressive AML after exposure ionizing radiation. Inhibition suppressed colony growth leukemic progenitor carrying PPM1D, remarkably, it provided protection against irradiation-induced growth. Altogether, affects HSC maintenance, disrupts normal hematopoiesis, its inhibition could be beneficial context therapy-induced AML.

Language: Английский

Global burden of hematologic malignancies and evolution patterns over the past 30 years DOI Creative Commons
Nan Zhang,

Jinxian Wu,

Qian Wang

et al.

Blood Cancer Journal, Journal Year: 2023, Volume and Issue: 13(1)

Published: May 17, 2023

Abstract Hematologic malignancies are among the most common cancers, and understanding their incidence death is crucial for targeting prevention, clinical practice improvement, research resources appropriately. Here, we investigated detailed information on hematological period 1990–2019 from Global Burden of Disease study. The age-standardized rate (ASIR), (ASDR), corresponding estimated annual percentage changes (EAPC) were calculated to assess temporal trends in 204 countries territories over past 30 years. Globally, incident cases hematologic have been increasing since 1990, reaching 1343.85 thousand 2019, but ASDR all types has declining. leukemia, multiple myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma 4.26, 1.42, 3.19, 0.34 per 100,000 population respectively, with showing significant decline. However, trend varies by gender, age, region, country’s economic situation. burden generally higher men, this gender gap decreases after peaking at a given age. regions largest ASIR Central Europe, Eastern East Asia, Caribbean, respectively. In addition, proportion deaths attributed high body-mass index continued rise across regions, especially socio-demographic indices (SDI). Meanwhile, leukemia occupational exposure benzene formaldehyde was more widespread areas low SDI. Thus, remain leading cause global tumor burden, growing absolute numbers sharp several measures three decades. results study will inform analysis disease specific develop appropriate policies these modifiable risks.

Language: Английский

Citations

156
Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential DOI Creative Commons
Tianyu Zhu, Lian‐Lian Hong, Zhi‐Qiang Ling

et al.

Biomarker Research, Journal Year: 2023, Volume and Issue: 11(1)

Published: June 6, 2023

N6-methyladenosine (m6A) is the most prevalent and well-characterized internal chemical modification in eukaryotic RNA, influencing gene expression phenotypic changes by controlling RNA fate. Insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) preferentially function as m6A effector proteins, promoting stability translation of m6A-modified RNAs. IGF2BPs, particularly IGF2BP1 IGF2BP3, are widely recognized oncofetal predominantly expressed cancer rather than normal tissues, playing a critical role tumor initiation progression. Consequently, IGF2BPs hold potential for clinical applications serve good choice targeted treatment strategies. In this review, we discuss functions mechanisms readers explore therapeutic targeting human cancer.

Language: Английский

Citations

46
The role of RNA methylation in tumor immunity and its potential in immunotherapy DOI Creative Commons
Yan Li,

Haoer Jin,

Qingling Li

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: June 20, 2024

Abstract RNA methylation, a prevalent post-transcriptional modification, has garnered considerable attention in research circles. It exerts regulatory control over diverse biological functions by modulating splicing, translation, transport, and stability. Notably, studies have illuminated the substantial impact of methylation on tumor immunity. The primary types encompass N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), 3-methylcytidine (m3C). Compelling evidence underscores involvement regulating microenvironment (TME). By affecting translation stability through "writers", "erasers" "readers", influence dysregulation immune cells factors. Consequently, plays pivotal role immunity mediating various behaviors, encompassing proliferation, invasion, metastasis, etc. In this review, we discussed mechanisms several methylations, providing comprehensive overview their roles underlying within among immunocytes. exploring how these modifications mediate evasion, also examine potential applications immunotherapy. This review aims to provide novel insights strategies for identifying targets advancing cancer immunotherapy efficacy.

Language: Английский

Citations

32
Targeting IGF2BP3 in Cancer DOI Open Access
Xin Liu, Jiayu Chen, Wenliang Chen

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(11), P. 9423 - 9423

Published: May 29, 2023

RNA-binding proteins (RBPs) can regulate multiple pathways by binding to RNAs, playing a variety of functions, such as localization, stability, and immunity. In recent years, with the development technology, researchers have discovered that RBPs play key role in N6-methyladenosine (m6A) modification process. M6A methylation is most abundant form RNA eukaryotes, which defined on sixth N atom adenine RNA. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) one components m6A proteins, plays an important decoding marks performing various biological functions. IGF2BP3 abnormally expressed many human cancers, often associated poor prognosis. Here, we summarize physiological organisms describe its mechanism tumors. These data suggest may be valuable therapeutic target prognostic marker future.

Language: Английский

Citations

29
CircNFATC3 promotes the proliferation of gastric cancer through binding to IGF2BP3 and restricting its ubiquitination to enhance CCND1 mRNA stability DOI Creative Commons

Feifei Yang,

Qiang Ma, Bo Huang

et al.

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: June 20, 2023

Abstract Background Insulin like growth factor II mRNA binding protein 3 (IGF2BP3) is an RNA with multiple roles in regulation of gene expression at the post-transcriptional level and implicated tumorigenesis progression numerous cancers including gastric cancer (GC). Circular RNAs (circRNAs) are a diverse endogenous noncoding population that have important regulatory cancer. However, circRNAs regulate IGF2BP3 GC largely unknown. Methods CircRNAs bound to were screened cells using immunoprecipitation sequencing (RIP-seq). The identification localization circular nuclear activated T (circNFATC3) identified Sanger sequencing, RNase R assays, qRT-PCR, nuclear-cytoplasmic fractionation RNA-FISH assays. CircNFATC3 human tissues adjacent normal measured by qRT-PCR ISH. biological role circNFATC3 was confirmed vivo vitro experiments. Furthermore, RIP, RNA-FISH/IF, IP rescue experiments performed uncover interactions between circNFATC3, cyclin D1 (CCND1). Results We GC-associated circRNA, interacted IGF2BP3. significantly overexpressed positively associated tumor volume. Functionally, proliferation decreased after knockdown vitro. Mechanistically, cytoplasm, which enhanced stability preventing ubiquitin E3 ligase TRIM25-mediated ubiquitination, thereby enhancing axis IGF2BP3-CCND1 promoting CCND1 stability. Conclusions Our findings demonstrate promotes stabilizing enhance Therefore, potential novel target for treatment GC.

Language: Английский

Citations

25
IGF2BPs as novel m6A readers: Diverse roles in regulating cancer cell biological functions, hypoxia adaptation, metabolism, and immunosuppressive tumor microenvironment DOI Creative Commons

Meiqi Duan,

Haiyang Liu, Shasha Xu

et al.

Genes & Diseases, Journal Year: 2023, Volume and Issue: 11(2), P. 890 - 920

Published: July 20, 2023

m6A methylation is the most frequent modification of mRNA in eukaryotes and plays a crucial role cancer progression by regulating biological functions. Insulin-like growth factor 2 mRNA-binding proteins (IGF2BP) are newly identified 'readers'. They belong to family RNA-binding proteins, which bind sites on different RNA sequences stabilize them promote progression. In this review, we summarize mechanisms upstream factors regulate IGF2BP cancer. The current literature analyzed here reveals that cell proliferation, survival, chemoresistance, inhibit apoptosis, also associated with glycolysis, angiogenesis, immune response tumor microenvironment. Therefore, discovery their as 'readers' characteristic re-expression IGF2BPs cancers, it important elucidate mechanism action immunosuppressive We describe detail regulatory interaction network downstream target RNAs discuss potential clinical applications diagnostic prognostic markers, well recent advances biology therapeutic value.

Language: Английский

Citations

25
Distributions and Trends of the Global Burden of Colorectal Cancer Attributable to Dietary Risk Factors over the Past 30 Years DOI Open Access
Yuxing Liang, Nan Zhang, Miao Wang

et al.

Nutrients, Journal Year: 2023, Volume and Issue: 16(1), P. 132 - 132

Published: Dec. 30, 2023

Dietary risk has always been a major factor for colorectal cancer (CRC). However, the contribution of dietary factors to CRC at level region, gender, and age not fully characterized. Based on Global Burden Disease (GBD) 2019 study, death rates, age-standardized mortality rates (ASDRs), estimated annual percentage changes (EAPCs) were calculated assess trends attributable over past 30 years. Globally, cases increased 1,085,797 in 2019, number deaths attributed 365,752 representing approximately one-third all CRC-related fatalities. Overall, ASDR risks was 4.61 per 100,000 with slight downward trend (EAPC = -0.29). Notably, there is rising early-onset associated factors. To alleviate burdens, it recommended elevate intake whole grains, milk, calcium, fiber while reducing consumption red processed meats. The results will improve understanding, provide guidance diet different regions, groups worldwide.

Language: Английский

Citations

25
IGF2BP3 enhances lipid metabolism in cervical cancer by upregulating the expression of SCD DOI Creative Commons

Chenying Han,

Chenchen Hu,

Tianyue Liu

et al.

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(2)

Published: Feb. 14, 2024

Abstract Cervical cancer (CC) is the most common gynecologic malignancy, which seriously threatens health of women. Lipid metabolism necessary for tumor proliferation and metastasis. However, molecular mechanism relationship between CC lipid remains poorly defined. We revealed expression IGF2BP3 in exceeded adjacent tissues, was positively associated with stage using human tissue microarrays. The Cell Counting Kit-8, colony formation assay, 5-ethynyl-2′-deoxyuridine transwell assays, wound-healing flow cytometry assessed role metastasis cells. Besides, exploring participating IGF2BP3-driven used RNA-seq, determined SCD as target IGF2BP3. Further, droplets, cellular triglyceride (TG) contents, fatty acids were accessed to discover that can enhance CC. Moreover, RIP assay methylated RNA immunoprecipitation experiments seeked aimed-gene-binding specificity. Lastly, knockdown restrained growth metabolism, after overexpression rescued influence vitro vivo nude mouse tumor-bearing model. Mechanistically, regulated mRNA m6A modifications via IGF2BP3-METTL14 complex, thereby enhanced proliferation, metastasis, metabolism. Our study highlights plays a crucial progression represents therapeutic latent strategy. It potential tactic blocks metabolic pathway relevant purpose treating

Language: Английский

Citations

14
Small molecule inhibitors targeting m6A regulators DOI Creative Commons

Guotai Feng,

Yongya Wu, Yuan Hu

et al.

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: May 6, 2024

As the most common form of epigenetic regulation by RNA, N

Language: Английский

Citations

12
m6A‐dependent upregulation of DDX21 by super‐enhancer‐driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia DOI Creative Commons

Yanchun Zhao,

Yutong Zhou,

Qian Yu

et al.

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(4)

Published: April 1, 2024

Abstract Background Acute myeloid leukaemia (AML) is a haematological malignancy with unfavourable prognosis. Despite the effectiveness of chemotherapy and targeted therapy, relapse or drug resistance remains major threat to AML patients. N6‐methyladenosine (m 6 A) RNA methylation super‐enhancers (SEs) are extensively involved in leukaemogenesis AML. However, potential relationship between m A SEs has not been elaborated. Methods Chromatin immunoprecipitation (ChIP) sequencing data from Gene Expression Omnibus (GEO) cohort were analysed search SE‐related genes. The mechanisms A‐binding proteins IGF2BP2 IGF2BP3 on DDX21 explored via methylated (MeRIP) assays, (RIP) assays luciferase reporter assays. Then we elucidated roles through functional vitro vivo. Finally, co‐immunoprecipitation (Co‐IP) ChIP performed investigate downstream DDX21. Results We identified two SE‐associated transcripts High enrichment H3K27ac, H3K4me1 BRD4 was observed IGF2BP3, whose expression driven by SE machinery. enhanced stability mRNA an A‐dependent manner. highly expressed patients, which indicated poor survival. Functionally, knockdown inhibited cell proliferation, promoted apoptosis led cycle arrest. Mechanistically, recruited transcription factor YBX1 cooperatively trigger ULK1 expression. Moreover, silencing could reverse promoting effects overexpression cells. Conclusions Dysregulation SE‐IGF2BP2/IGF2BP3‐DDX21 axis facilitated progression Our findings provide new insights into link modification, elucidate regulatory DDX21, reveal underlying

Language: Английский

Citations

9