Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential

Zhu, Tianyu; Ling, Hong; Ling, Zhi‐Qiang

doi:10.1186/s40364-023-00499-0

Cited by 25 publications

(14 citation statements)

References 129 publications

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“…4J ). IGF2BP3 was made up of two RNA recognition motifs (RRMs) and four K homology domains (KHs) [ 30 ]. Therefore, we established five FLAG-labeled full-length or fragmented IGF2BP3 plasmids and transfected them into the HEK293T cell line and verified them by western blot (Fig.…”

Section: Resultsmentioning

confidence: 99%

LIN28B induced PCAT5 promotes endometrial cancer progression and glycolysis via IGF2BP3 deubiquitination

Wang,

et al. 2024

Cell Death Dis

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Endometrial cancer (EC) cells exhibit abnormal glucose metabolism, characterized by increased aerobic glycolysis and decreased oxidative phosphorylation. Targeting cellular glucose metabolism in these cells could be an effective therapeutic approach for EC. This study aimed to assess the roles of LIN28B, PCAT5, and IGF2BP3 in the glucose metabolism, proliferation, migration, and invasion of EC cells. LIN28B highly expressed in EC, binds and stabilizes PCAT5. PCAT5, overexpressed in EC, and its 1485-2288nt region can bind to the KH1-2 domain of IGF2BP3 to prevent MKRN2 from binding to the K294 ubiquitination site of IGF2BP3, thus stabilizing IGF2BP3. Finally, IGF2BP3 promotes the aerobic glycolysis, proliferation, migration and invasion of EC cells by stabilizing the key enzymes of glucose metabolism HK2 and PKM2. Taken together, our data reveal that the LIN28B/PCAT5/IGF2BP3 axis is critical for glucose reprogramming and malignant biological behavior in EC cells. Therefore, targeting this axis may contribute to the development of a novel therapeutic strategy for EC metabolism.

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Section: Resultsmentioning

confidence: 99%

LIN28B induced PCAT5 promotes endometrial cancer progression and glycolysis via IGF2BP3 deubiquitination

Wang,

et al. 2024

Cell Death Dis

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“…Recent findings indicate that the involvement of IGF2BP1/2/3, known as m6A readers, in the regulation of RNA stability plays a crucial role in tumor initiation, progression, and evolution. This disruption of normal expression and critical cellular signaling bioprocesses, including oncogenes and tumor suppressors, ultimately leads to the development and advancement of tumorigenesis [ 66 – 68 ]. In the present study, we identified a crucial regulatory network involving IGF2BP3 and altered HMGB1 through m6A modulation pattern, which is associated with BLCA progression.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies, including our own, have shown that IGF2BP3 is a cancer-causing factor and frequently exhibits high levels of expression in various types of cancer [ 68 ]. In a recent study, it was found that circNFATC3 has the ability to attach to IGF2BP3, resulting in an increase in the stability of IGF2BP3 by obstructing the ubiquitin E3 ligase TRIM25 from causing ubiquitination.…”

Section: Discussionmentioning

confidence: 99%

IGF2BP3 prevent HMGB1 mRNA decay in bladder cancer and development

Lv,

Wei,

Zhang

et al. 2024

Cell Mol Biol Lett

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Background IGF2BP3 functions as an RNA-binding protein (RBP) and plays a role in the posttranscriptional control of mRNA localization, stability, and translation. Its dysregulation is frequently associated with tumorigenesis across various cancer types. Nonetheless, our understanding of how the expression of the IGF2BP3 gene is regulated remains limited. The specific functions and underlying mechanisms of IGF2BP3, as well as the potential benefits of targeting it for therapeutic purposes in bladder cancer, are not yet well comprehended. Methods The mRNA and protein expression were examined by RT-qPCR and western blotting, respectively. The methylation level of CpG sites was detected by Bisulfite sequencing PCR (BSP). The regulation of IGF2BP3 expression by miR-320a-3p was analyzed by luciferase reporter assay. The functional role of IGF2BP3 was determined through proliferation, colony formation, wound healing, invasion assays, and xenograft mouse model. The regulation of HMGB1 by IGF2BP3 was investigated by RNA immunoprecipitation (RIP) and mRNA stability assays. Results We observed a significant elevation in IGF2BP3 levels within bladder cancer samples, correlating with more advanced stages and grades, as well as an unfavorable prognosis. Subsequent investigations revealed that the upregulation of IGF2BP3 expression is triggered by copy number gain/amplification and promoter hypomethylation in various tumor types, including bladder cancer. Furthermore, miR-320a-3p was identified as another negative regulator in bladder cancer. Functionally, the upregulation of IGF2BP3 expression exacerbated bladder cancer progression, including the proliferation, migration, and invasion of bladder cancer. Conversely, IGF2BP3 silencing produced the opposite effects. Moreover, IGF2BP3 expression positively correlated with inflammation and immune infiltration in bladder cancer. Mechanistically, IGF2BP3 enhanced mRNA stability and promoted the expression of HMGB1 by binding to its mRNA, which is a factor that promotes inflammation and orchestrates tumorigenesis in many cancers. Importantly, pharmacological inhibition of HMGB1 with glycyrrhizin, a specific HMGB1 inhibitor, effectively reversed the cancer-promoting effects of IGF2BP3 overexpression in bladder cancer. Furthermore, the relationship between HMGB1 mRNA and IGF2PB3 is also observed in mammalian embryonic development, with the expression of both genes gradually decreasing as embryonic development progresses. Conclusions Our present study sheds light on the genetic and epigenetic mechanisms governing IGF2BP3 expression, underscoring the critical involvement of the IGF2BP3-HMGB1 axis in driving bladder cancer progression. Additionally, it advocates for the investigation of inhibiting IGF2BP3-HMGB1 as a viable therapeutic approach for treating bladder cancer. Graphical Abstract

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“…Multiple studies have revealed crucial small compounds to specifically target the interactions between RBPs and RNA. These inhibitors mainly target the RNA Binding domains of RBPs which are crucial for RBP-RNA interactions such as the RNA-recognition motif (RRM), hnRNP K homology (KH), and the zinc-finger domain (268)(269)(270). These molecules serve as valuable tools for the development of innovative therapies aimed at inhibiting the function of RBPs.…”

Section: Small Molecule Inhibitors Designed For Targeting Rna Binding...mentioning

confidence: 99%

Inflammation as a driver of hematological malignancies

Saluja,

Bansal,

Bhardwaj

et al. 2024

Front. Oncol.

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Hematopoiesis is a tightly regulated process that produces all adult blood cells and immune cells from multipotent hematopoietic stem cells (HSCs). HSCs usually remain quiescent, and in the presence of external stimuli like infection or inflammation, they undergo division and differentiation as a compensatory mechanism. Normal hematopoiesis is impacted by systemic inflammation, which causes HSCs to transition from quiescence to emergency myelopoiesis. At the molecular level, inflammatory cytokine signaling molecules such as tumor necrosis factor (TNF), interferons, interleukins, and toll-like receptors can all cause HSCs to multiply directly. These cytokines actively encourage HSC activation, proliferation, and differentiation during inflammation, which results in the generation and activation of immune cells required to combat acute injury. The bone marrow niche provides numerous soluble and stromal cell signals, which are essential for maintaining normal homeostasis and output of the bone marrow cells. Inflammatory signals also impact this bone marrow microenvironment called the HSC niche to regulate the inflammatory-induced hematopoiesis. Continuous pro-inflammatory cytokine and chemokine activation can have detrimental effects on the hematopoietic system, which can lead to cancer development, HSC depletion, and bone marrow failure. Reactive oxygen species (ROS), which damage DNA and ultimately lead to the transformation of HSCs into cancerous cells, are produced due to chronic inflammation. The biological elements of the HSC niche produce pro-inflammatory cytokines that cause clonal growth and the development of leukemic stem cells (LSCs) in hematological malignancies. The processes underlying how inflammation affects hematological malignancies are still not fully understood. In this review, we emphasize the effects of inflammation on normal hematopoiesis, the part it plays in the development and progression of hematological malignancies, and potential therapeutic applications for targeting these pathways for therapy in hematological malignancies.

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Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential

Cited by 25 publications

References 129 publications

LIN28B induced PCAT5 promotes endometrial cancer progression and glycolysis via IGF2BP3 deubiquitination

LIN28B induced PCAT5 promotes endometrial cancer progression and glycolysis via IGF2BP3 deubiquitination

IGF2BP3 prevent HMGB1 mRNA decay in bladder cancer and development

Inflammation as a driver of hematological malignancies

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