IGF2 Research Articles

SUMOylation modification of FTO facilitates oxidative damage response of arsenic by IGF2BP3 in an m6A-dependent manner

N6-methyladenosine (m6A) is the most common form of internal post-transcriptional methylation observed in eukaryotic mRNAs. The abnormally increased level of m6A within the cells can be catalyzed by specific demethylase fat mass and obesity-associated protein (FTO) and stay in a dynamic and reversible state. However, whether and how FTO regulates oxidative damage via m6A modification remain largely unclear. Herein, by using both in vitro and in vivo models of oxidative damage induced by arsenic, we demonstrated for the first time that exposure to arsenic caused a significant increase in SUMOylation of FTO protein, and FTO SUMOylation at lysine (K)− 216 site promoted the down-regulation of FTO expression in arsenic target organ lung, and therefore, remarkably elevating the oxidative damage via an m6A-dependent pathway by its specific m6A reader insulin-like growth factor-2 mRNA-binding protein-3 (IGF2BP3). Consequently, these findings not only reveal a novel mechanism underlying FTO-mediated oxidative damage from the perspective of m6A, but also imply that regulation of FTO SUMOylation may serve as potential approach for treatment of oxidative damage.

Association analysis of transcriptome and quasi-targeted metabolomics reveals the regulation mechanism underlying broiler muscle tissue development at different levels of dietary guanidinoacetic acid.

The development and characteristics of muscle fibers in broilers are critical determinants that influence their growth performance, as well as serve as essential prerequisites for the production of high-quality chicken meat. Guanidinoacetic acid (GAA) is a crucial endogenous substance in animal creatine synthesis, and its utilization as a feed additive has been demonstrated the capabilities to enhance animal performance, optimize muscle yield, and augment carcass quality. The objective of this study was to investigate the regulation and molecular mechanism underlying muscle development in broilers at different levels of GAA via multiple omics analysis. The 90 Cobb broilers, aged 1 day, were randomly allocated into three treatments consisting of five replicates of six chickens each. The control group was provided with a basal diet, while the Normal GAA and High GAA groups received a basal diet supplemented with 1.2 g/kg and 3.6 g/kg of GAA, respectively. After a feeding period of 42 days, the pectoralis muscles were collected for histomorphological observation, transcriptome and metabolomic analysis. The results demonstrated that the addition of 1.2 g/kg GAA in the diet led to an augmentation in muscle fiber diameter and up-regulation of IGF1, IHH, ASB2, and ANKRD2 gene expression. However, a high dose of 3.6 g/kg GAA in the diet potentially reversed the beneficial effects on chicken breast development by excessively activating the TGF-β signaling pathway and reducing nucleotide metabolite content. These findings would provide a theoretical foundation for enhancing the performance and meat quality of broilers by incorporating GAA as a feed additive.

Abstract LB262: Reprogramming the tumor microenvironment by targeting IGF2-IGF1R signaling, enhancing viro-immunotherapy

Abstract While an FDA-approved oncolytic herpes simplex-1 virus (oHSV) has shown therapeutic promise with superior safety, accumulating clinical data revealed that its therapeutic efficacy is observed in a small subset of patients. Here, we show that NFκB-mediated Insulin-like Growth Factor 2 (IGF2)/Insulin-like Growth Factor-1 Receptor (IGF1R) signaling pathway as a key modulator for oHSV therapy-mediated tumor resistance. RNA sequencing on the oHSV-infected primary glioblastoma (GBM) and breast cancer (BC) cells identified IGF2 as one of the top 10 upregulated secretomes. Transcriptomic analysis also revealed significant upregulation/enrichment of genes related to IGF2-IGF1R-MAPK pathway in oHSV-treated tumor cells. Infection with oHSV in GBM and BC cells up-regulated IGF2 transcription via direct binding of NFκB in the IGF2 promoter 3. Compromising the IGF2-IGF1R signaling pathway using IGF2 neutralizing antibody significantlDB7 BC tumors in vivo. To circumvent this and promptly translate our findings in clinical settings, we have developed a novel oHSV, oHSV-D11mt, by incorporating modified IGF2R domain 11 into the parental oHSV genome to function as IGF2 decoy receptor as a single-agent modality. oHSV-D11mt specifically bind to IGF2 not IGF1, blocks oHSV-induced IGF2-IGF1R signaling, increases tumor cell killing, decreases oHSV-induced neutrophils/PMN-MDSCs infiltration, immune suppressive/proangiogenic cytokine secretion, and increases CD8+ cytotoxic T lymphocytes (CTLs) activation, resulting in increased virus propagation and mice survival. These findings suggest that IGF2-IGF1R signaling is a novel target to overcome oHSV therapy resistance and oHSV-D11mt could be used for improved viro-immunotherapy. Citation Format: Min Hye Noh, Alexandra Miller, Grace Nguyen, Hiroshi Nakashima, E. Antonio Chiocca, Balveen Kaur, Zhongming Zhao, Tae Jin Lee, Ji Young Yoo. Reprogramming the tumor microenvironment by targeting IGF2-IGF1R signaling, enhancing viro-immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB262.

Inhibition of IGF2BP1 attenuates the progression of endometriosis through PTBP1.

Endometriosis (EMs), manifested by pain and infertility, is a chronic inflammatory disease. The precise pathophysiology of this disease remains uncertain. Insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) and polypyrimidine tract-binding protein 1 (PTBP1) have both been found to regulate proliferation, apoptosis, and invasion. This study aimed to investigate the effects of IGF2BP1/PTBP1 in treating EMs. qRT-PCR and western blotting were employed to quantify IGF2BP1 and PTBP1 expression in six patients with EMs (mean age 33.83 years). The correlation analysis, STRING database prediction, and RNA immunoprecipitation were utilized to identify the relationship between IGF2BP1 and PTBP1. Ectopic endometrial volume, weight, HE staining, and IGF2BP1 silencing were utilized to estimate the effects of IGF2BP1 in EMs model rats. qRT-PCR, CCK-8, 5-ethynyl-2'-deoxyuridine (EDU) labeling, Transwell assay, and flow cytometry were utilized to assess the effects of IGF2BP1/PTBP1 on the proliferation, migration, invasion, and apoptosis of ectopic endometrial stromal cells (eESCs). Furthermore, western blotting was employed to evaluate expressions of PCNA, VEGF, and E-cadherin in EMs rats and eESCs. The mRNA and protein levels of IGF2BP1 and PTBP1 in the ectopic and eutopic endometrium of EMs patients were significantly increased. RNA immunoprecipitation revealed a close interaction of IGF2BP1 with PTBP1. Additionally, the endometrial volume, weight, and histopathologic scores in rats were significantly reduced after IGF2BP1 silencing. IGF2BP1 silencing also decreased the expression of PCNA and VEGF, and increased E-cadherin expression in endometrial tissues of EMs rats. Moreover, IGF2BP1 silencing inhibited proliferation, migration, and invasion and promoted apoptosis through PTBP1 in eESCs. IGF2BP1 exhibits potential beneficial properties in the management of EMs by interacting with PTBP1, thereby highlighting IGF2BP1 as a promising therapeutic target for EMs.

IGF2 promotes alveolar bone regeneration in murine periodontitis via inhibiting cGAS/STING-mediated M1 macrophage polarization

Periodontitis is a chronic inflammatory disease with the destruction of supporting periodontal tissue. This study evaluated the role of insulin-like growth factor 2 (IGF2) in periodontitis by inhibiting the polarization of M1 macrophages via the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. IGF2 was enriched in the gingival tissue of murine periodontitis model identified by RNA sequencing. IGF2 application alleviated the expression of pro-inflammatory factors and promoted osteogenesis and the expression of related genes and proteins in a dose-dependent manner in periodontitis. The result of micro-CT verified this finding. Both in vivo and in vitro results revealed that IGF2 decreased the polarization of M1 macrophages and pro-inflammatory factors by immunofluorescence staining, flow cytometry, western blotting and RT-PCR. IGF2 application promoted the osteogenic ability of periodontal ligament fibroblasts (PDLFs) indirectly via its inhibition of M1 polarization evaluated by alkaline phosphatase and alizarin red staining. Then, the cGAS/STING pathway was upregulated in periodontitis and macrophages challenged by LPS, the inhibition of which led to downregulation of M1 polarization. Furthermore, IGF2 could downregulate cGAS, STING and the phosphorylation of P65. Collectively, our study indicates IGF2 can regulate the polarization of M1 macrophages via the cGAS/STING pathway and highlights the promising future of IGF2 as a therapeutic treatment for periodontitis.

Polymorphisms of IGF-1 Gene in Indonesian Local Goat Reared Under Smallholder Farmers in Sulawesi Region

Polymorphisms of IGF-1 Gene in Indonesian Local Goat Reared Under Smallholder Farmers in Sulawesi Region

302 Targeted Inhibition of the Epigenetically Activated miR-483-5p IGF-2 Pathway as a Novel Therapeutic Strategy for Meningioma

INTRODUCTION: Meningioma is the most common primary central nervous system tumor. These are usually treated by surgical resection with curative intent, however gross total resection is not always feasible and there are many cases of recurrent and refractory disease despite adjuvant radiotherapy. Presently, there is no effective pharmacotherapeutic options for these tumors. METHODS: Small RNA sequencing was performed on meningioma tumor samples to study grade-dependent changes in microRNA expression. Gene expression was analyzed by chromatin marks, qRT-PCR and western blot. miRNA modulation, anti-IGF-2 neutralizing antibodies, and inhibitors against IGF1R were evaluated in a tumor-derived primary cultures of meningioma cells. RESULTS: Meningioma tumor samples showed high, grade-dependent expression of miR-483-5p, associated with high mRNA and protein expression of its host gene IGF-2. Inhibition of miR-483-5p reduced the growth of cultured meningioma cells, whereas a miR-483 mimic increased cell proliferation. Similarly, inhibition of this pathway with anti-IGF-2 neutralizing antibodies reduced meningioma cell proliferation. Small molecule tyrosine kinase inhibitor blockade of the IGF-2 receptor (IGF1R) resulted in rapid loss of viability of cultured meningioma tumor-derived cells, suggesting that autocrine IGF-2 feedback is obligatory for meningioma tumor cell survival and growth. The observed IGF1R-inhibitory IC50 for GSK1838705A and Ceritinib in cell-based assays along with the available pharmacokinetics data predicted that effective drug concentration could be achieved in vivo as a new medical treatment of meningioma. CONCLUSIONS: Meningioma cell growth is critically dependent on autocrine miR-483/IGF-2 stimulation and the IGF-2 pathway provides a new feasible meningioma treatment target.

Insight into Insulin-like Growth Factor-1 Receptor (IGF-1R) gene mutations: Implications for growth disorders and treatment: A review of the literature and case report

Background: Insulin-like Growth Factor -1 Receptor (IGF-1R) and its ligand, IGF-1, are crucial for human tissue growth and development. Mutations in IGF-1R and, to a lesser extent, IGF-1 genes lead to diverse growth disorders, characterized by intrauterine growth retardation and postnatal growth challenges. Case report: We present a case of a 6-year-old girl with speech and mild cognitive delays, exhibiting normal motor skills, no neurological issues, and standard vital signs. Her growth parameters indicated significant retardation, with a height standard deviation score (Ht-SDS) of -2 and an IGF-1 level of +1.8 SDS, normal thyroid function and delayed bone age. Genetic analysis identified a 3335 mbp interstitial loss in 15q26.1, encompassing the IGF-1R gene, critical for growth and development. Literature review: Analysis of 34 papers provided insight into the genetic complexities of IGF-1R and IGF-1 mutations. Studies ranged from familial cases to cohort studies, uncovering mutations including missense mutations, deletions, and copy number variations (CNVs), each associated with unique growth disorder phenotypes. Advances in diagnostic techniques like multiplex ligation-dependent probe amplification (MLPA) and whole exome sequencing (WES) have been pivotal in identifying these mutations, facilitating more targeted management approaches. Conclusions: This case and review of literature underscore the importance of an integrated genetic, endocrine, and developmental approach in managing growth hormone deficiency (GHD) and IGF-1 resistance. The variability in growth disorders and response to therapy highlights the need for personalized treatment plans, informed by genetic insights, to optimize outcomes for patients with these complex conditions.

Effects of three short-chain fatty acids on growth, intestinal microbiota composition, and ammonia tolerance of juvenile yellow catfish Pelteobagrus fulvidraco

The objective of this research was to examine how the growth, ammonia tolerance, and intestinal microbiota composition of juvenile yellow catfish are affected by dietary supplementation of isobutyric acid (IBA), isovaleric acid (IVA), and 2-methylbutyric acid (2-MBA). During the 8-week trial, four groups were fed the basal diet (Control), and the basal diet supplementation with 0.25% IBA, IVA and 2-MBA, respectively. The research shows that the yellow catfish in the IBA and 2-MBA groups had a higher weight gain rate and specific growth rate than the control group, but feed conversion ratio has the opposite trend. Dietary supplementation of IBA and 2-MBA can significantly improve digestive enzymes activities (α-amylase, lipase, and trypsin) in intestinal tract and blood health (serum albumin increased, alanine transaminase and aspartate transaminase decreased). The up-regulation of IGF-1, Myod, and MyoG gene mRNA expression levels occurred significantly in the muscle tissue of the IBA, IVA, and 2-MBA groups, but IL 1 and IL8 genes in intestinal tract were significantly down-regulated. Supplementation of IBA, IVA and 2-MBA significantly increased the relative abundance of Candidatus Arthromitus, while decreased the relative abundance of Achromobacter, most notably in IBA group. After 96-h ammonia stress, cumulative mortality in IBA group was the lowest. Supplementing the diet of yellow catfish with IBA or 2-MBA can enhance their growth, digestive enzyme activity, and blood health status. Additionally, IBA can improve ammonia tolerance, which may be related to the increase abundance of Candidatus Arthromitus in intestine.

Activation of the insulin receptor by insulin-like growth factor 2

Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin’s function. However, the molecular mechanism underlying IGF2-induced IR activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform IR (IR-B) in both the inactive and IGF2-bound active states, and short isoform IR (IR-A) in the IGF2-bound active state. Under saturated IGF2 concentrations, both the IR-A and IR-B adopt predominantly asymmetric conformations with two or three IGF2s bound at site-1 and site-2, which differs from that insulin saturated IR forms an exclusively T-shaped symmetric conformation. IGF2 exhibits a relatively weak binding to IR site-2 compared to insulin, making it less potent in promoting full IR activation. Cell-based experiments validated the functional importance of IGF2 binding to two distinct binding sites in optimal IR signaling and trafficking. In the inactive state, the C-terminus of α-CT of IR-B contacts FnIII-2 domain of the same protomer, hindering its threading into the C-loop of IGF2, thus reducing the association rate of IGF2 with IR-B. Collectively, our studies demonstrate the activation mechanism of IR by IGF2 and reveal the molecular basis underlying the different affinity of IGF2 to IR-A and IR-B.

Embryonic methionine triggers post-natal developmental programming in Japanese quail

Embryonic development is one of the most sensitive and critical stages when maternal effects may influence the offspring’s phenotype. In birds and other oviparous species, embryonic development is confined to the eggs, therefore females must deposit resources into the eggs to prepare the offspring for the prevailing post-natal conditions. However, the mechanisms of such phenotypic adjustments remain poorly understood. We simulated a maternal nutritional transfer by injecting 1 mg of l-methionine solution into Japanese quail eggs before the onset of incubation. The increase in early methionine concentration in eggs activated the insulin/insulin-like signalling and mechanistic target of rapamycin (IIS/mTOR) signalling pathways and affected post-natal developmental trajectories. Chicks from methionine-supplemented eggs had higher expression of liver IGF1 and mTOR genes at hatching but were similar in size, and the phenotypic effects of increased growth became apparent only a week later and remained up to three weeks. Circulating levels of insulin-like growth factor-1 (IGF-1) and expression of ribosomal protein serine 6 kinase 1 (RPS6K1), the mTOR downstream effector, were elevated only three weeks after hatching. These results show that specific nutritional cues may have phenotypic programming effects by sequentially activating specific nutrient-sensing pathways and achieving transgenerational phenotypic plasticity.

Beckwith–Wiedemann syndrome with juvenile fibrous nodules and lobular breast tumors: a case report and review of the literature

BackgroundBeckwith–Wiedemann syndrome (BWS) is a genomic imprinting disorder caused by diverse genetic and/or epigenetic disorders of chromosome 11p15.5. BWS presents with a variety of clinical features, including overgrowth and an increased risk of embryonal tumors. Notably however, reports of patients with BWS and breast tumors are rare, and the association between these conditions is still unclear. Insulin-like growth factor-2 (IGF2) expression is known to be associated with the development of various cancers, including breast cancer, and patients with BWS with specific subtypes of molecular defects are known to show characteristic clinical features and IGF2 overexpression.Case presentationA 17-year-old girl who had been diagnosed with BWS based on an umbilical hernia, hyperinsulinemia, and left hemihypertrophy at birth, visited our department with a gradually swelling left breast. Her left breast was markedly larger than her right breast on visual examination. Imaging examinations showed two tumors measuring about 10 cm each in the left breast, and she was diagnosed with juvenile fibroadenoma following core needle biopsy. The two breast tumors were removed surgically and the patient remained alive with no recurrence. The final diagnosis was juvenile fibroadenoma without malignant findings. Immunohistochemical staining using IGF2 antibody revealed overexpression of IGF2 in the cytoplasm of ductal epithelial cells. Because of her clinical features and IGF2 overexpression, molecular defects of 11p15.5 including a possible genetic background of paternal uniparental disomy of chromosome 11 or hypermethylation of imprinting center 1 was suspected.ConclusionsIn this case, overexpression of IGF2 suggested a possible relationship between BWS and breast tumors. Moreover, the characteristic clinical features and IGF2 staining predicted the subtype of 11p15.5 molecular defects in this patient.

Directed evolution of genetically encoded LYTACs for cell-mediated delivery

Lysosome-targeting chimeras (LYTACs) are a promising therapeutic modality to drive the degradation of extracellular proteins. However, early versions of LYTAC contain synthetic glycopeptides that cannot be genetically encoded. Here, we present our designs for a fully genetically encodable LYTAC (GELYTAC), making our tool compatible with integration into therapeutic cells for targeted delivery at diseased sites. To achieve this, we replaced the glycopeptide portion of LYTACs with the protein insulin-like growth factor 2 (IGF2). After showing initial efficacy with wild-type IGF2, we increased the potency of GELYTAC using directed evolution. Subsequently, we demonstrated that our engineered GELYTAC construct not only secretes from HEK293T cells but also from human primary T-cells to drive the uptake of various targets into receiver cells. Immune cells engineered to secrete GELYTAC thus represent a promising avenue for spatially selective targeted protein degradation.

Abstract 4390: IGFBP-6 is induced by progesterone to regulate progesterone receptor expression in breast cancer cells

Abstract Insulin-like growth factor binding protein-6 (IGFBP-6) is induced by progesterone (P4) in T-47D breast cancer cells. IGFBP-6 regulates insulin-like growth factor 2 (IGF2) by sequestering it to inhibit receptor binding and extend its extracellular half-life. IGF2 binds to insulin-like growth factor 1 receptor or insulin receptor A to promote breast cancer cell proliferation and survival. Progesterone is an ovarian steroid hormone which has complex roles in breast cancer through the actions of progesterone receptor A and B (PR-A and B). Progesterone antagonizes the actions of estradiol (E2), another steroid hormone which promotes proliferation and survival in breast cancer. T-47D cells treated with both P4 and E2 exhibit significantly reduced proliferation compared to treatment with E2 alone. To better understand the role of IGFBP-6 in progesterone signaling, T-47D cells which over-express IGFBP-6 were treated with P4, E2, or both. Overexpressing cells exhibited stronger antagonism compared to controls when co-treated with P4 and E2. RNA-interference was performed to knockdown IGFBP-6 induction in the presence of P4 and E2. Knockdown of IGFBP-6 in the presence of P4 and E2 decreases the antagonistic effects of P4. Expression of both PR-A and PR-B decreases by about 50% when IGFBP-6 is knocked down. These results indicate that IGFBP-6 increases PR expression in response to P4 stimulation. Citation Format: Francisco Javier Lariz, Pacha Botero, Kevin Houston. IGFBP-6 is induced by progesterone to regulate progesterone receptor expression in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4390.

Early nutritional programming in sterlet sturgeon (Acipenser ruthenus) with dietary soybean meal: Assessment of growth performance, body composition, and expression of GH, IGF-I, and Ghrelin genes.

This study was performed to assess the impacts of introducing diets containing different levels of soybean meal (SBM) to sterlet sturgeon (Acipenser ruthenus) larvae on growth performance, body composition, and molecular responses in the juvenile stage. The sterlet larvae (57.68 ± 0.66 mg) were weaned onto the formulated diets as follows: a control diet containing 60% fishmeal (FM), and three experimental diets with replacement levels of 15% (SBM15), 30% (SBM30), and 45% (SBM45) of FM with SBM. Then, a total of 260 fish (initial weight: 323.33 ± 11.76 mg) were fed the four different diets for 28 days in triplicates (phase 1, nutritional programming, NP). All treatments were then fed with the FM diet in phase 2 (common phase), and in phase 3 (challenge phase), all experimental groups (6.14 ± 0.08 g) were transitioned to SBM45 for 28 days. At the end of phases 1 and 2, growth performance showed no significant differences among the groups (P > 0.05), while significantly improved in SBM45 than the control at the end of phase 3 (P < 0.05). No significant differences were found among the groups in any phases for whole body composition (P > 0.05). Additionally, the total saturated fatty acids were significantly higher in SBM-based diets than FM at the end of phase 3 (P < 0.05). The mRNA of GH, IGF-I was significantly affected by variation of FM replacement level (P < 0.05). The expression level of Ghrelin was up-regulated in fish fed SBM at the end of phase 3 (P < 0.05). Our findings revealed that NP can positively enhance the adaptation of juvenile sterlet sturgeon to 45% SBM when exposed to the same diets at the larval stage. Further research is being carried out to provide valuable insights into the underlying mechanisms of digestive performance for this species.

Changes in growth performance, gene expressions related to protein absorption and hepatic metabolism of triploid crucian carp (Carassius carassius triploid) caused by dietary protein level

The aim of this study was to investigate the effects of dietary protein inclusion level on growth, protein absorption pathway and liver metabolism-related pathway in triploid crucian carp (Carassius carassius triploid). Six experimental diets with different protein levels (26%, 29%, 32%, 35%, 38%, 41%) were formulated. A total of 540 fish with an initial weight of 11.79 ± 0.09 g were randomly assigned to 18 cages and six treatments with three replicates of 30 fish each for 8 weeks feeding. The results showed that the specific growth rate (SGR) and feed efficiency (FE) of triploid crucian carp were highly positively correlated with protein content (p < 0.05). The broken-line regression analysis showed that the optimal dietary inclusion level was determined to be 39% considering SGR of triploid crucian carp. In addition, genes related to protein absorption were influenced by the protein inclusion level of dietary. The mRNA expressions of pept1, lat2, cdx2, jak2 and sp1 exhibited similar change tendency and promoted to highest expression at 41% groups, 32% followed. Furthermore, the expressions of hepatic metabolism genes tor, s6k1, igf1, ampd1 and adsl reached peak at 38% dietary protein inclusion level, while 4e-bp2 gene showed the highest expression levels at 41% dietary protein inclusion level. Finally, igf1 expression in liver and cdx2 in intestine showed high pearson coefficients with dietary protein level suggesting their expressions were significant positively regulated by dietary protein level. In conclusion, this study evidenced the influence of dietary protein level on growth, protein absorption pathway, TOR and IGF pathways of hepatic metabolism related in triploid crucian carp. 39% dietary protein inclusion level would be optimum level of triploid crucian carp dietary, which will lead to a better growth and high feed efficiency of triploid crucian carp.

The m6A reader IGF2BP2 regulates glycolytic metabolism and mediates histone lactylation to enhance hepatic stellate cell activation and liver fibrosis

Evidence for the involvement of N6-Methyladenosine (m6A) modification in the etiology and progression of liver fibrosis has emerged and holds promise as a therapeutic target. Insulin-like growth factor 2 (IGF2) mRNA-binding protein 2 (IGF2BP2) is a newly identified m6A-binding protein that functions to enhance mRNA stability and translation. However, its role as an m6A-binding protein in liver fibrosis remains elusive. Here, we observed that IGF2BP2 is highly expressed in liver fibrosis and activated hepatic stellate cells (HSCs), and inhibition of IGF2BP2 protects against HSCs activation and liver fibrogenesis. Mechanistically, as an m6A-binding protein, IGF2BP2 regulates the expression of Aldolase A (ALDOA), a key target in the glycolytic metabolic pathway, which in turn regulates HSCs activation. Furthermore, we observed that active glycolytic metabolism in activated HSCs generates large amounts of lactate as a substrate for histone lactylation. Importantly, histone lactylation transforms the activation phenotype of HSCs. In conclusion, our findings reveal the essential role of IGF2BP2 in liver fibrosis by regulating glycolytic metabolism and highlight the potential of targeting IGF2BP2 as a therapeutic for liver fibrosis.

Deciphering Breast Cancer Metastasis Cascade: A Systems Biology Approach Integrating Transcriptome and Interactome Insights for Target Discovery.

Breast cancer is the lead cause of cancer-related deaths among women globally. Breast cancer metastasis is a complex and still inadequately understood process and a key dimension of mortality attendant to breast cancer. This study reports dysregulated genes across metastatic stages and tissues, shedding light on their molecular interplay in disease pathogenesis and new possibilities for drug discovery. Comprehensive analyses of gene expression data from primary breast tumor, circulating tumor cells, and distant metastatic sites in the brain, lung, liver, and bone were conducted. Genes dysregulated across multiple stages and tissues were identified as metastatic cascade genes, and are further classified based on functional associations with metastasis-related mechanisms. Their interactions with HUB genes in interactome networks were scrutinized, followed by pathway enrichment analysis. Validation for their potential as targets included assessments for survival, druggability, prognostic marker status, secretome annotation, protein expression, and cell type marker association. Results displayed critical genes in the metastatic cascade and those specific to metastatic sites, revealing the involvement of the collagen degradation and assembly of collagen fibrils and other multimeric structure pathways in driving metastasis. Notably, pivotal cascade genes FABP4, CXCL12, APOD, and IGF1 emerged with high metastatic potential, linked to significant druggability and survival scores, establishing them as potential molecular targets. The significance of this research lies in its potential to uncover novel biomarkers for early detection, therapeutic targets, and a deeper understanding of the molecular mechanisms underpinning the metastatic cascade in breast cancer, and with an eye to precision/personalized medicine.

WITHDRAWN: Exploring the Interplay of m6A regulators in renal cell carcinoma: Molecular insights and clinical implications

BackgroundThe m6A modification of N6-methyladenosine (m6A) modification regulates gene expression and functioning by affecting RNA splicing, stability, translocation, and translation. ObjectiveThis study used comprehensive bioinformatics analysis to elucidate the mechanisms by which m6A regulators function in kidney renal clear cell carcinoma (KIRC) and their interrelationships. MethodsThe KIRC data extracted from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases was used in this study. LASSO Cox regression, protein–protein interaction analysis, univariate Cox regression, and a predictive risk model. Cox regression, Kaplan–Meier analysis, consensus clustering, CIBERSORT, gene set enrichment analysis (GSEA), ESTIMATE, immune cell infiltration, and prognostic factors were investigated in KIRC utilizing computational methods. ResultsThe results of integrated analysis showed that KIRC has unique and complex gene patterns associated with m6A and is linked to different gene patterns. These patterns included an 11.68-fold change in insulin-like growth factor-2 mRNA-binding protein 3 (IGF2BP3), a 3.35-fold change in ELAV-like RNA binding protein 2 (ELAVL2), a 2.34-fold change in fat mass- and obesity-associated protein (FTO), a 2.52-fold change in ELAVL4, and a 2.15-fold change in ELAVL3. By contrast, there was downregulation of IGF2BP2, zinc finger CCCH-type containing 14 (ZC3H14), and alpha-ketoglutarate-dependent dioxygenase (ALKBH6), with fold changes of 0.44, 0.66, and 0.68, respectively. Minor modifications ranging from 1 to 1.28 were seen in other m6A regulators. ConclusionThis study showed that m6A alteration affects KIRC tumor immunity. Moreover, m6A regulators such as IGF2BP3 have therapeutic and diagnostic potential, which could improve patient outcomes by personalized immunotherapy.

In Silico Approach to Molecular Profiling of the Transition from Ovarian Epithelial Cells to Low-Grade Serous Ovarian Tumors for Targeted Therapeutic Insights.

This paper aims to elucidate the differentially coexpressed genes, their potential mechanisms, and possible drug targets in low-grade invasive serous ovarian carcinoma (LGSC) in terms of the biologic continuity of normal, borderline, and malignant LGSC. We performed a bioinformatics analysis, integrating datasets generated using the GPL570 platform from different studies from the GEO database to identify changes in this transition, gene expression, drug targets, and their relationships with tumor microenvironmental characteristics. In the transition from ovarian epithelial cells to the serous borderline, the FGFR3 gene in the "Estrogen Response Late" pathway, the ITGB2 gene in the "Cell Adhesion Molecule", the CD74 gene in the "Regulation of Cell Migration", and the IGF1 gene in the "Xenobiotic Metabolism" pathway were upregulated in the transition from borderline to LGSC. The ERBB4 gene in "Proteoglycan in Cancer", the AR gene in "Pathways in Cancer" and "Estrogen Response Early" pathways, were upregulated in the transition from ovarian epithelial cells to LGSC. In addition, SPP1 and ITGB2 genes were correlated with macrophage infiltration in the LGSC group. This research provides a valuable framework for the development of personalized therapeutic approaches in the context of LGSC, with the aim of improving patient outcomes and quality of life. Furthermore, the main goal of the current study is a preliminary study designed to generate in silico inferences, and it is also important to note that subsequent in vitro and in vivo studies will be necessary to confirm the results before considering these results as fully reliable.