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Background N6-Methyladenosine (m6A) modification has been implicated in multiple processes for colon cancer development. IGF2BP3 was a newly reported m6A reader, whereas its role in colon cancer remains unclear. Methods The expression of m6A associated enzymes and total m6A level were measured by Western Blotting analysis and m6A RNA Methylation Quantification Kit respectively. Cell cycle was analyzed by flowcytometry. The interaction of IGF2BP3 and related targets was analyzed by RNA immunoprecipitation (RIP) and m6A RNA immunoprecipitation (MeRIP) assays. Results We investigated all m6A regulated enzymes in colon cancer and found only the overexpression of IGF2BP3 was associated with cancer progression and survival based on The Cancer Genome Atlas (TCGA) databases. Additionally, we also demonstrated IGF2BP3 was associated with DNA replication in the cell cycle. Knockdown of IGF2BP3 significantly repressed percentage of S phase of cell cycle as well as cell proliferation. Further research demonstrated IGF2BP3 bound to the mRNA of Cyclin D1 (CCND1, checkpoint of G1/S phase of cell cycle) and reduced its mRNA stability via reading m6A modification in the CDS region. Overexpression of Cyclin D1 in IGF2BP3 down-regulated cells completely rescued the inhibited percentage of S phase in cell cycle as well as cell proliferation. Additionally, we also demonstrated a similar role of IGF2BP3 at VEGF. IGF2BP3 bound to the mRNA of VEGF and reads m6A modification, thus regulated both expression and stability of VEGF mRNA. Knockdown of IGF2BP3 repressed angiogenesis in colon cancer via regulating VEGF. Conclusion Knockdown of IGF2BP3 repressed DNA replication in the S phase of cell cycle and angiogenesis via reading m6A modification of CCND1 and VEGF respectively. IGF2BP3 was a possible prognosis marker and potential therapeutic target of colon cancer.

Background Laryngeal cancer has the highest mortality rate among head and neck tumours. RNA N6-methyladenosine (m6A) is the most plentiful and variable in mammalian mRNA. Yet, the m6A regulatory mechanism underlying the carcinogenesis or progression of LSCC remains poorly understood. Methods The m6A RNA methylation quantification kit was used to detect tissue methylation levels. m6A microarray analysis, mRNA transcriptomic sequencing (mRNA-seq), and proteomics were used to determine RBM15, TMBIM6, and IGF2BP3. Immunohistochemical (IHC), quantitative real-time PCR (qRT-PCR) and Western blot were used to investigate RBM15, TMBIM6, and IGF2BP3 expression in tissue samples and cell lines. The biological effects of RBM15 were detected both in vitro and in vivo. The combination relationship between RBM15/IGF2BP3 and TMBIM6 was verified by RNA immunoprecipitation (RIP) assay, Methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNase Mazf, and luciferase report assay. RNase Mazf was used to determine the methylation site on TMBIM6 mRNA. Hoechst staining assay was used to confirm the apoptotic changes. The actinomycin D verified TMBIM6 stability. Results The global mRNA m6A methylation level significantly increased in LSCC patients. RBM15, as a “writer” of methyltransferase, was significantly increased in LSCC and was associated with unfavorable prognosis. The knockdown of RBM15 reduced the proliferation, invasion, migration, and apoptosis of LSCC both in vitro and in vivo. The results were reversed after overexpressing RBM15. Mechanically, TMBIM6 acted as a downstream target of RBM15-mediated m6A modification. Furthermore, RBM15-mediated m6A modification of TMBIM6 mRNA enhanced TMBIM6 stability through IGF2BP3-dependent. Conclusion Our results revealed the essential roles of RBM15 and IGF2BP3 in m6A methylation modification in LSCC, thus identifying a novel RNA regulatory mechanism.

Background Gliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis. Circular RNAs (circRNA), a newly found type of endogenous noncoding RNA, characterized by high stability, abundance, conservation, have been shown to play an important role in the pathophysiological processes and TME remodelling of various tumours. Methods CircRNA sequencing analysis was performed to explore circRNA expression profiles in normal and glioma tissues. The biological function of a novel circRNA, namely, circNEIL3, in glioma development was confirmed both in vitro and in vivo. Mechanistically, RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), luciferase reporter, and co-immunoprecipitation assays were conducted. Results We identified circNEIL3, which could be cyclized by EWS RNA-binding protein 1(EWSR1), to be upregulated in glioma tissues and to correlate positively with glioma malignant progression. Functionally, we confirmed that circNEIL3 promotes tumorigenesis and carcinogenic progression of glioma in vitro and in vivo. Mechanistically, circNEIL3 stabilizes IGF2BP3 (insulin-like growth factor 2 mRNA binding protein 3) protein, a known oncogenic protein, by preventing HECTD4-mediated ubiquitination. Moreover, circNEIL3 overexpression glioma cells drives macrophage infiltration into the tumour microenvironment (TME). Finally, circNEIL3 is packaged into exosomes by hnRNPA2B1 and transmitted to infiltrated tumour associated macrophages (TAMs), enabling them to acquire immunosuppressive properties by stabilizing IGF2BP3 and in turn promoting glioma progression. Conclusions This work reveals that circNEIL3 plays a nonnegligible multifaceted role in promoting gliomagenesis, malignant progression and macrophage tumour-promoting phenotypes polarization, highlighting that circNEIL3 is a potential prognostic biomarker and therapeutic target in glioma.

Background More and more studies have shown that circular RNAs (circRNAs) play a critical regulatory role in many cancers. However, the potential molecular mechanism of circRNAs in prostate cancer (PCa) remains largely unknown. Methods Differentially expressed circRNAs were identified by RNA sequencing. The expression of hsa_circ_0003258 was evaluated using quantitative real-time PCR and RNA in situ hybridization. The impacts of hsa_circ_0003258 on the metastasis of PCa cells were investigated by a series of in vitro and in vivo assays. Lastly, the underlying mechanism of hsa_circ_0003258 was revealed by Western blot, biotin-labeled RNA pulldown, RNA immunoprecipitation, luciferase assays and rescue experiments. Results Increased expression of hsa_circ_0003258 was found in PCa tissues and was associated with advanced TNM stage and ISUP grade. Overexpression of hsa_circ_0003258 promoted PCa cell migration by inducing epithelial mesenchymal transformation (EMT) in vitro as well as tumor metastasis in vivo , while knockdown of hsa_circ_0003258 exerts the opposite effect. Mechanistically, hsa_circ_0003258 could elevate the expression of Rho GTPase activating protein 5 (ARHGAP5) via sponging miR-653-5p. In addition, hsa_circ_0003258 physically binds to insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) in the cytoplasm and enhanced HDAC4 mRNA stability, in which it activates ERK signalling pathway, then triggers EMT programming and finally accelerates the metastasis of PCa. Conclusions Upregulation of hsa_circ_0003258 drives tumor progression through both hsa_circ_0003258/miR-653-5p/ARHGAP5 axis and hsa_circ_0003258/IGF2BP3 /HDAC4 axis. Hsa_circ_0003258 may act as a promising biomarker for metastasis of PCa and an attractive target for PCa intervention.

MicroRNAs are evolutionarily conserved, small non-coding RNAs that play critical post-transcriptional regulatory roles in skeletal muscle development. We previously found that miR-9-5p is abundantly expressed in chicken skeletal muscle. Here, we demonstrate a new role for miR-9-5p as a myogenic microRNA that regulates skeletal muscle development. The overexpression of miR-9-5p significantly inhibited the proliferation and differentiation of skeletal muscle satellite cells (SMSCs), whereas miR-9-5p inhibition had the opposite effect. We show that insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is a target gene of miR-9-5p, using dual-luciferase assays, RT-qPCR, and Western Blotting, and that it promotes proliferation and differentiation of SMSCs. In addition, we found that IGF2BP3 regulates IGF-2 expression, using overexpression and knockdown studies. We show that Akt is activated by IGF2BP3 and is essential for IGF2BP3-induced cell development. Together, our results indicate that miR-9-5p could regulate the proliferation and differentiation of myoblasts by targeting IGF2BP3 through IGF-2 and that this activity results in the activation of the PI3K/Akt signaling pathway in skeletal muscle cells.

Acquired resistance remains a bottleneck for molecular‐targeted therapy in advanced hepatocellular carcinoma (HCC). Metabolic adaptation and epigenetic remodeling are recognized as hallmarks of cancer that may contribute to acquired resistance. In various lenvatinib‐resistant models, increased glycolysis leads to lactate accumulation and lysine lactylation of IGF2BP3. This lactylation is crucial for capturing PCK2 and NRF2 mRNAs, thereby enhancing their expression. This process reprograms serine metabolism and strengthens the antioxidant defense system. Additionally, altered serine metabolism increases the availability of methylated substrates, such as S‐adenosylmethionine (SAM), for N6‐methyladenosine (m6A) methylation of PCK2 and NRF2 mRNAs. The lactylated IGF2BP3‐PCK2‐SAM‐m6A loop maintains elevated PCK2 and NRF2 levels, enhancing the antioxidant system and promoting lenvatinib resistance in HCC. Treatment with liposomes carrying siRNAs targeting IGF2BP3 or the glycolysis inhibitor 2‐DG restored lenvatinib sensitivity in vivo. These findings highlight the connection between metabolic reprogramming and epigenetic regulation and suggest that targeting metabolic pathways may offer new strategies to overcome lenvatinib resistance in HCC. This study reveals that in lenvatinib‐resistant hepatocellular carcinoma, increased glycolysis results in lactate accumulation and lysine lactylation of IGF2BP3, which increase the expression of PCK2 and NRF2. This leads to a reprogramming of serine metabolism, S‐adenosylmethionine (SAM) production, RNA m6A modification, and the antioxidant system. The IGF2BP3 lactylation‐PCK2‐SAM‐m6A loop sustains the upregulation of PCK2 and NRF2 expression and ultimately confers lenvatinib resistance.

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

Accumulating evidence indicates that N6-methyladenosine (m.sup.6A) modification of circular RNAs (circRNAs) plays a pivotal role in regulating cancer progression. However, in head and neck squamous cell carcinoma (HNSCC), the biological functions and underlying mechanisms of m.sup.6A modification in circRNAs remain insufficiently elucidated. In this study, we analyzed the association between the expression of IGF2BP3–an upstream mâ¶A reader–and clinical outcomes of HNSCC patients, followed by investigating the interaction between IGF2BP3 and circHECTD2 as well as the effect of mâ¶A modification on this interaction. Additionally, we explored the molecular mechanism by which IGF2BP3 and circHECTD2 regulate HNSCC progression, focusing on their roles in modulating microRNAs (miRNAs) and target mRNAs, and validated the functional impacts of the IGF2BP3/circHECTD2 axis on HNSCC cell proliferation, invasion, and metastasis. We found high expression of the mâ¶A reader IGF2BP3 was significantly associated with poor clinical outcomes in HNSCC patients. Further experiments showed that IGF2BP3 directly bound to circHECTD2 and stabilized it, and mâ¶A modification of circHECTD2 enhanced this binding and stabilization effect. Mechanistically, circHECTD2 functioned as a competing endogenous RNA (ceRNA) to sponge hsa-miR-4310 and hsa-miR-7157-5p, thereby preventing the miRNA-mediated degradation of SMAD2 mRNA. Ultimately, the IGF2BP3/circHECTD2/SMAD2 axis was shown to promote HNSCC cell proliferation, invasion, and metastasis. We delineate an m.sup.6A-dependent IGF2BP3/circHECTD2/SMAD2 regulatory axis that contributes to HNSCC malignancy. Elevated IGF2BP3 expression correlates with poor patient outcome and enhances circHECTD2 stability through m6A-facilitated binding; circHECTD2 in turn acts as a ceRNA to sequester hsa-miR-4310 and hsa-miR-7157-5p, thereby maintaining SMAD2 expression. Functionally, this axis promotes HNSCC cell proliferation, invasion and metastasis. Collectively, these findings suggest that IGF2BP3 and circHECTD2 may serve as promising prognostic biomarkers and therapeutic targets for HNSCC.

RNA binding proteins (RBPs) play a key role in genome regulation. Here we report the post-transcript regulation of IGF2BP3, which belongs to the insulin-like growth factor 2 mRNA binding protein family. We used iRIP-seq and RNA-seq to analyze the transcript regulation and alternative splicing on IGF2BP3 treated with overexpression cells and control. Overexpressed IGF2BP3 has broadly increased genes expression which involved in G-protein coupled receptor signaling pathway, positive regulation of cell proliferation, and signal transduction. IGF2BP3 regulated alternative splicing of multiple genes mainly clustered at response to hypoxia, negative regulation of transcription, and embryonic development. This study first provides alternative splicing analysis on transcription level of IGF2BP3 regulation, which laid the foundation for later research on IGF2BP3 critical functions.

Background Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) poses a major challenge to therapeutic efficacy in castration-resistant prostate cancer (CRPC). Although circular RNAs (circRNAs) have emerged as critical regulators in cancer biology, their involvement in PARPi resistance remains largely uncharacterized. Objective This study aims to elucidate the molecular mechanism by which hsa_circ_0038737 modulates PARPi resistance in CRPC through post-transcriptional regulatory pathways. Methods We employed a comprehensive set of in vitro and in vivo approaches, including qRT-PCR, RNA sequencing, RNA-protein pull-down, RNA immunoprecipitation, functional assays, and xenograft/organoid models, to investigate the biological function and mechanistic role of hsa_circ_0038737 in CRPC progression and therapeutic response. Results We identified hsa_circ_0038737 as a nuclear-enriched circRNA significantly upregulated in CRPC, with expression levels correlating with poor prognosis and aggressive clinical features. Mechanistically, hsa_circ_0038737 interacts with RNA-binding protein (RBP) IGF2BP3, enhancing the stability of DNPH1 mRNA, a nucleotide sanitizer critical for DNA repair. The circRNA-RBP-mRNA regulatory axis promotes PARPi resistance by facilitating DNA damage repair capacity. Moreover, we revealed that reverse-complementary Alu elements mediate circRNA biogenesis, with HNRNPDL facilitating this process. Pharmacologic inhibition of DNPH1 effectively restored PARPi sensitivity both in vitro and in vivo. Conclusion Our findings reveal a novel hsa_circ_0038737/IGF2BP3/DNPH1 axis driving PARPi resistance in CRPC, offering promising potential biomarkers and therapeutic targets to overcome resistance and improve treatment outcomes in advanced prostate cancer. Keywords: Castration-resistant prostate cancer (CRPC), Circular RNA (circRNA), PARP inhibitor, IGF2BP3, DNPH1 stabilization