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LINC01138 is associated with clinical outcomes in patients with HCC. a The flow chart for selecting candidate lincRNAs in HCC; four lincRNAs were identified for further study. b The copy numbers of LINC01138 were determined in 72 pairs of HCC tissues and adjacent normal tissues using qPCR. c Fold-change of LINC01138 copy number variations in 72 paired tissues (deletion, blue; no-change, yellow; amplification, red.). d The RNA levels of LINC01138 were quantified in 120 pairs of HCC tissues and adjacent normal tissues using qPCR. e Fold-changes of expression of LINC01138 in 120 paired tissues (downexpression, blue; no-change, yellow; upexpression, red.). f Clinical significance of LINC01138 in patients with HCC; high LINC01138 expression positively correlated with tumour size (≥5 cm), AFP (>200 ng/ml) and HBsAg-positive patients. g Kaplan–Meier analyses of the correlation between LINC01138 RNA levels and the overall survival in 120 patients with HCC. Patients were stratified for the analysis by the median value. Values are expressed as the median with interquartile range in b, d, f
Source publication
Recurrent chromosomal aberrations have led to the discovery of oncogenes or tumour suppressors involved in carcinogenesis. Here we characterized an oncogenic long intergenic non-coding RNA in the frequent DNA-gain regions in hepatocellular carcinoma (HCC), LINC01138 (long intergenic non-coding RNA located on 1q21.2). The LINC01138 locus is frequent...
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CRISPR/Cas9 is a popular genome editing technology. Although widely used, little is known about how this prokaryotic system behaves in humans. An unwanted consequence of eukaryotic Cas9 expression is off-target DNA binding leading to mutagenesis. Safer clinical implementation of CRISPR/Cas9 necessitates a finer understanding of the regulatory mecha...
Citations
... In lung cancer, IGF2BP3 has been reported to have the ability to regulate the alternative splicing of Pyruvate kinase M (PKM), suggesting that IGF2BP3 may play a role in regulating glucose metabolism reprogramming [22]. In addition, IGF2BP3 has been found to be frequently post-transcriptionally regulated [23,24]. However, it is unknown whether IGF2BP3 is post-transcriptionally regulated in EC or is involved in glucose metabolism. ...
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.
... plays an essential role in HCC tumor growth and metastasis. 4,[26][27][28][29] However, the regulation of PRMT5 in HCC remains little explored. ...
... One recent study reported that LINC01138 interacts with PRMT5 and blocks its ubiquitination and degradation in HCC. 29 In this study, we found that SMYD4 interacts with the TIM barrel and Rossmann fold of PRMT5 and leads to lysine monomethylation of PRMT5. The TIM barrel domain is the binding region for MEP50. ...
Both lysine and arginine methyltransferases are thought to be promising therapeutic targets for malignant tumors, yet how these methyltransferases function in malignant tumors, especially hepatocellular carcinoma (HCC), has not been fully elucidated. Here, we reported that SMYD4, a lysine methyltransferase, acts as an oncogene in HCC. SMYD4 was highly upregulated in HCC and promoted HCC cell proliferation and metastasis. Mechanistically, PRMT5, a well‐known arginine methyltransferase, was identified as a SMYD4‐binding protein. SMYD4 monomethylated PRMT5 and enhanced the interaction between PRMT5 and MEP50, thereby promoting the symmetrical dimethylation of H3R2 and H4R3 on the PRMT5 target gene promoter and subsequently activating DVL3 expression and inhibiting expression of E‐cadherin, RBL2, and miR‐29b‐1‐5p. Moreover, miR‐29b‐1‐5p was found to inversely regulate SMYD4 expression in HCC cells, thus forming a positive feedback loop. Furthermore, we found that the oncogenic effect of SMYD4 could be effectively suppressed by PRMT5 inhibitor in vitro and in vivo. Clinically, high coexpression of SMYD4 and PRMT5 was associated with poor prognosis of HCC patients. In summary, our study provides a model of crosstalk between lysine and arginine methyltransferases in HCC and highlights the SMYD4‐PRMT5 axis as a potential therapeutic target for the treatment of HCC.
... In terms of peptide production from lncRNAs, lncRNA-00998-encoded SMIM30 promotes SRC/YES1 membrane anchoring and activates the MAPK pathway 3 . LncRNA-01138 acts as an RBP sponge, inhibiting ubiquitin/ proteasome-dependent degradation by physically interacting with arginine methyltransferase 5 (PRMT5) to increase PRMT5 turnover 4 . Multiple lines of evidence suggest that lncRNAs act as decoys or sponges for miRNAs, increasing oncogene expression in HCC. ...
UPF1, a novel posttranscriptional regulator, regulates the abundance of transcripts, including long noncoding RNAs (lncRNAs), and thus plays an important role in cell homeostasis. In this study, we revealed that UPF1 regulates the abundance of hepatocellular carcinoma upregulated EZH2-associated lncRNA (lncRNA-HEIH ) by binding the CG-rich motif, thereby regulating hepatocellular carcinoma (HCC) tumorigenesis. UPF1-bound lncRNA-HEIH was susceptible to degradation mediated by UPF1 phosphorylation via SMG1 and SMG5. According to analysis of RNA-seq and public data on patients with liver cancer, the expression of lncRNA-HEIH increased the levels of miR-194-5p targets and was inversely correlated with miR-194-5p expression in HCC patients. Furthermore, UPF1 depletion upregulated lncRNA-HEIH , which acts as a decoy of miR-194-5p that targets GNA13, thereby promoting GNA13 expression and HCC proliferation. The UPF1/lncRNA-HEIH/miR-194-5p/GNA13 regulatory axis is suggested to play a crucial role in cell progression and may be a suitable target for HCC therapy.
... Signi cantly, an expanding body of evidence suggests that lncRNAs play an indispensable role in the progression of various cancer types, in uencing aspects such as proliferation, metastasis, chemoradiotherapy resistance and immunosuppression. LINC01138 is highly expressed in hepatocellular carcinoma tissues and promotes cell proliferation and metastasis [15]. LncRNA XIST boosts proliferation and self-renewal of cancer stem cells in breast cancer through IL-6/STAT3 signaling [16]. ...
5-Fluorouracil (5-FU) resistance has always been a formidable obstacle in the adjuvant treatment of advanced colorectal cancer (CRC), significantly compromising the patients’ prognosis. In recent years, long non-coding RNAs (lncRNAs) have emerged as key regulators in various pathophysiological processes, particularly in cancers. However, the precise molecular mechanisms governed by these molecules in 5-FU resistance remain insufficiently elucidated. In this study, RNA-seq combined with weighted gene correlation network analysis (WGCNA) confirmed the close association of GAS6-AS1 with TRG grades. GAS6-AS1 expression was positively correlated with advanced clinicopathological features and poor prognosis in CRC. GAS6-AS1 increased the 50% inhibiting concentration (IC50) of 5-FU, enhanced cell proliferation, and accelerated G1/S transition in CRC cells, both with and without 5-FU, both in vitro and in vivo. Mechanistically, GAS6-AS1 enhanced the stability of MCM3 mRNA by recruiting PCBP1, consequently increasing MCM3 expression. Furthermore, PCBP1 and MCM3 counteracted the effects of GAS6-AS1 on 5-FU resistance. Notably, the PDX model indicated that combining chemotherapeutic drugs with GAS6-AS1 knockdown yielded superior outcomes in vivo. Taken together, our findings elucidate that GAS6-AS1 directly binds to PCBP1, enhancing MCM3 expression and thereby promoting 5-FU resistance in CRC. GAS6-AS1 may serve as a robust biomarker and potential therapeutic target for combination drug therapy in CRC.
... HTT toxicity Altered expression of HTT [71] AKT-ERK signaling, cell cycle progression Altered expression of PTEN [72] Cell cycle progression, stemness Altered RNA Splicing [73,74] mTOR signaling Methylation (hnRNPA1) [75] DNA instability response Altered expression of RNF168 [76] Cell migration, cell cycle progression, and apoptosis Altered expression of LRP12 [62] AKT signaling and metastasis Methylation of PKB [77] Lungs Metastasis Altered expression of EMT genes [78] Metastasis Altered expression of SHARPIN [79] Metastasis Altered expression of FGFR3/miR-99 family [80] Metastasis Methylation of KLF5 [81] Liver Lipid metabolism Methylation of SREBP [47] ERK signaling Altered expression of BTG2 [82] PRMY5 deprivation PRMT5 activity of LINC01138 [83] WNT-β-Catenin signaling Altered cofactor binding of LYRIC [84] Spleen NA Altered stability of MYC [85] Pancreas Glucose metabolism, cell cycle progression Altered stability of MYC [86,87] Bone Type I interferon signaling Altered expression (interferon gene) [88,89] Prostate AR, ERG signaling Altered methylation (AR) [90,91] Ovary NA Altered methylation (E2F1) [92] Heart Transcriptional activity Methylation (GATA4) [45] Breast Stemness Altered expression of C-MYC, KLF4, and OCT4 [93] Stemness Altered expression of FOXP1 [94] Metastasis and invasion Altered expression of AKT genes [78] Metastasis and AKT signaling Methylation of AKT [95] Cell cycle progression Methylation of KLF4 [96] Cell migration Methylation of ZNF326 [97] NA Methylation of PDCD4 [98] Abbreviations: AKT-ERK, alpha serine/threonine-protein-extracellular-regulated kinase; AR, androgen receptor; E2F1, E2 promoter binding factor 1; EMT, epithelial-mesenchymal transition; ERG, ETS-related gene; FGFR3, fibroblast growth factor 3; FOXP1, forkhead box protein P1; FUS, fused in sarcoma; GSK3β-NF-kβ, glycogen synthase kinase; hnRNPA1, heterogeneous nuclear ribonucleoprotein A1; HTT, huntingtin protein; KLF4, Kruppellike factor 4; LRP12, low-density lipoprotein receptor-related protein 12; LINC01138, long non-coding RNA; miR-99, microRNA99; mTOR, mammalian target of rapamycin; OCT4, octamer binding protein 4; PKB, protein kinase B; PDCD4, program cell death protein 4; SREBP, sterol regulatory element-binding protein; ZNF326, zinc finger protein 326. ...
Simple Summary
Medulloblastoma is the most prevalent intracerebellar pediatric brain tumor, accounting for approximately 20% of all childhood brain tumors and over 60% of embryonal brain tumors. MYC-driven medulloblastoma has extreme metastatic potential and is often resistant to multipronged treatment. PRMT5 plays a key role in cell functions and processes in MYC-driven medulloblastoma by stabilizing the MYC protein. RMT5 inhibitors can potentially disrupt MYC’s function, impeding tumor progression and offering a target therapeutic approach to treat MYC-amplified medulloblastoma. Here, we highlight the challenges that must be addressed in future drug development.
Abstract
MYC amplification or overexpression is most common in Group 3 medulloblastomas and is positively associated with poor clinical outcomes. Recently, protein arginine methyltransferase 5 (PRMT5) overexpression has been shown to be associated with tumorigenic MYC functions in cancers, particularly in brain cancers such as glioblastoma and medulloblastoma. PRMT5 regulates oncogenes, including MYC, that are often deregulated in medulloblastomas. However, the role of PRMT5-mediated post-translational modification in the stabilization of these oncoproteins remains poorly understood. The potential impact of PRMT5 inhibition on MYC makes it an attractive target in various cancers. PRMT5 inhibitors are a promising class of anti-cancer drugs demonstrating preclinical and preliminary clinical efficacies. Here, we review the publicly available preclinical and clinical studies on PRMT5 targeting using small molecule inhibitors and discuss the prospects of using them in medulloblastoma therapy.
... Interestingly, we found a family of protein arginine methyltransferases (PRMTs) to be potential targets of IGF2BPs. It has been reported that IGFBP2 stabilizes PRMT6 mRNA [32], IGFBP1/3 indirectly enhance the protein stability of PRMT5 [33], and there is also a regulatory relationship between PRMT3 and IGFBP1 [34]. Starbase 3.0 (https://starbase.sysu.edu.cn/) ...
Recurring evidence suggests that fasting has extensive antitumor effects in various cancers, including papillary thyroid carcinoma (PTC). However, the underlying mechanism of this relationship with PTC is unknown. In this study, we study the effect of fasting on glycolysis and mitochondrial function in PTC. We find that fasting impairs glycolysis and reduces mitochondrial dysfunction in vitro and in vivo and also fasting in vitro and fasting mimicking diets (FMD) in vivo significantly increase the expression of lncRNA-protein kinase C theta antisense RNA 1 (PRKCQ-AS1), during the inhibition of TPC cell glycolysis and mitochondrial function. Moreover, lncRNA PRKCQ-AS1 was significantly lower in PTC tissues and cells. In addition, PRKCQ-AS1 overexpression increased PTC cell glycolysis and mitochondrial function; PRKCQ-AS1 knockdown has the opposite effect. On further mechanistic analysis, we identified that PRKCQ-AS1 physically interacts with IGF2BPs and enhances protein arginine methyltransferases 7 (PRMT7) mRNA, which is the key player in regulating glycolysis and mitochondrial function in PTC. Hence, PRKCQ-AS1 inhibits tumor growth while regulating glycolysis and mitochondrial functions via IGF2BPs/PRMT7 signaling. These results indicate that lncRNA PRKCQ-AS1 is a key downstream target of fasting and is involved in PTC metabolic reprogramming. Further, the PRKCQ-AS1/IGF2BPs/PRMT7 axis is an ideal therapeutic target for PTC diagnosis and treatment.
... RNA sequencing (RNA-seq) was performed according to the manufacturer's instructions [13]. Briefly, total RNA was extracted by the Trizol reagent (Invitrogen, Carlsbad, CA, USA) from platinum-resistant and platinum-sensitive OC tissues. ...
Background Increasing evidences has indicated that primary and acquired resistance of ovarian cancer (OC) to platinum
is mediated by multiple molecular and cellular factors. Understanding these mechanisms could promote the therapeutic
efciency for patients with OC.
Methods Here, we screened the expression pattern of circRNAs in samples derived from platinum-resistant and platinumsensitive OC patients using RNA-sequencing (RNA-seq). The expression of hsa_circ_0010467 was validated by Sanger
sequencing, RT-qPCR, and fuorescence in situ hybridization (FISH) assays. Overexpression and knockdown experiments
were performed to explore the function of hsa_circ_0010467. The efects of hsa_circ_0010467 on enhancing platinum treatment were validated in OC cells, mouse model and patient-derived organoid (PDO). RNA pull-down, RNA immunoprecipitation (RIP), and dual-luciferase reporter assays were performed to investigate the interaction between hsa_circ_0010467
and proteins.
Results Increased expression of hsa_circ_0010467 is observed in platinum-resistant OC cells, tissues and serum exosomes,
which is positively correlated with advanced tumor stage and poor prognosis of OC patients. Hsa_circ_0010467 is found to
maintain the platinum resistance via inducing tumor cell stemness, and silencing hsa_circ_0010467 substantially increases
the efcacy of platinum treatment on inhibiting OC cell proliferation. Further investigation reveals that hsa_circ_0010467
acts as a miR-637 sponge to mediate the repressive efect of miR-637 on leukemia inhibitory factor (LIF) and activates the
LIF/STAT3 signaling pathway. We further discover that AUF1 could promote the biogenesis of hsa_circ_0010467 in OC.
Conclusion Our study uncovers the mechanism that hsa_circ_0010467 mediates the platinum resistance of OC through
AUF1/hsa_circ_0010467/miR-637/LIF/STAT3 axis, and provides potential targets for the treatment of platinum-resistant
OC patients.
... However, the link with m7G methylation modification, especially with METTL1 / WDR4 acting lncRNA, has not been studied. In the METTL1 / WDR4 associated lncRNA risk signature, MYLK-AS1 promotes HCC progression by regulating the miR-424-5p/E2F7 axis and VEGFR-2 signaling pathway [40]; LINC01138 can interact with PRMT5 and promote metastasis and proliferation of HCC by enhancing its protein stability [41]. There are no pilot studies for the other seven lncRNA risk signature genes, including ZNF529-AS1, PRRT3-AS1, AL031985.3, ...
N7 methylguanosine (m7G) has a crucial role the development of hepatocellular carcinoma (HCC). This study aimed to investigate the impact of the m7G methylation core genes (METTL1 and WDR4) and associated RNA risk signatures on HCC. we found m7G methylation core genes (METTL1 and WDR4) were upregulated in four HCC cell lines, and downregulation of METTL1 and WDR4 attenuated HCC cell proliferation, migration, and invasion. Moreover, METTL1 and WDR4 are upregulated in HCC tissues, and that there is a significant positive correlation between them. METTL1 and WDR4 were identified as independent prognostic markers for HCC by employing overall survival (OS), disease-specific survival (DSS), Progression Free Interval survival (PFI), and univariate/multivariate Cox analyses. We identified 1479 coding RNAs (mRNAs) and 232 long non-coding RNAs (lncRNAs) associated with METTL1 / WDR4 by using weighted coexpression network analysis (WGCNA) and co-clustering analysis. The least absolute shrinkage and selection operator (lasso) were used to constructing mRNA and lncRNA risk signatures associated with the METTL1 / WDR4. These risk were independent poor prognostic factors in HCC. Furthermore, we found that METTL1 / WDR4 expression and mRNA / lncRNA risk scores were closely associated with TP53 mutations. Clinicopathological features correlation results showed that METTL1 / WDR4 expression and mRNA / lncRNA risk score were associated with the stage and invasion depth (T) of HCC. To predict the overall survival of HCC individuals, we constructed a nomogram with METTL1/WDR4 expression, mRNA/lncRNA risk score, and clinicopathological features. In addition, we combined single-cell sequencing datasets and immune escape-related checkpoints to construct an immune escape-related protein–protein interaction(PPI) network. In conclusion, M7G methylated core genes (METTL1 and WDR4) and associated RNA risk signatures are associated with prognosis and immune escape in HCC.
... [11][12][13] It activates signal pathways related to cell growth and promotes the differentiation, proliferation, invasion, and metastasis of HCC cells. [14][15][16][17][18] In colon cancer, IGF2BP3 acts as a N 6 -methyladenosine reader to regulate the tumor cell cycle. 19 IGF2BP3 also promotes the expression of drug resistance genes, leading to drug resistance of tumors. ...
Background and Aims
Overexpression of IGF2BP3 is associated with the prognosis of hepatocellular carcinoma (HCC). However, its role in regulating tumor immune microenvironment (TME) is not well characterized. Here, we investigated the effects of IGF2BP3 on macrophages and CD8⁺ T cells within the TME of HCC.
Methods
The relationship between IGF2BP3 and immune cell infiltration was analyzed using online bioinformatics tools. Knockout of IGF2BP3 in mouse hepatoma cell line Hepa1-6 was established using CRISPR/Cas9 technology. In vitro cell coculture and subcutaneously implanted hepatoma mice model were used to explore the effects of IGF2BP3 on immune cells. Expression of CCL5 or transforming growth factor beta 1 (TGF-β1) was detected with quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The binding of IGF2BP3 and its target RNA was verified by trimolecular fluorescence complementation system and RNA immunoprecipitation followed by quantitative or semiquantitative polymerase chain reaction.
Results
IGF2BP3 expression was elevated in HCC and was positively correlated with macrophage infiltration. Patients with higher IGF2BP3 expression and lower macrophage infiltration had a better survival rate. We found that IGF2BP3 could bind to the mRNA of CCL5 or TGF-β1, increasing their expression, and inducing macrophage infiltration and M2 polarization while inhibiting the activation of CD8⁺ T cells. Furthermore, inhibition of IGF2BP3 combined with anti-CD47 antibody treatment significantly suppressed the growth of hepatoma in Hepa1-6 xenograft tumor mice.
Conclusions
IGF2BP3 promoted the infiltration and M2-polarization of macrophages and suppressed CD8⁺ T activation by enhancing CCL5 and TGF-β1 expression, which facilitated the progression of Hepa1-6 xenograft tumor.
... In the study of their cancer-promoting mechanisms, lncRNAs were found to be related to the methylation of m 6 A and could bind to IGF2BP to stabilize themselves. 96,142,143 A representative example is the DANCR lncRNA regulated by IGF2BP2 in an m 6 A methylation-dependent manner, which promoted the stem cell-like properties of cancer, cell proliferation, and stabilization of PC pathogenesis. 16 A recent study found that the crosstalk between IGF2BP2 and the ZFAS1 lncRNA promoted ATP hydrolysis and the Warburg effect and played an important role in mitochondrial energy metabolism in colon cancer. ...
m6A methylation is the most frequent modification of mRNA in eukaryotes and plays a crucial role in cancer progression by regulating biological functions. Insulin-like growth factor 2 mRNA-binding proteins (IGF2BP) are newly identified m6A 'readers'. They belong to a family of RNA-binding proteins, which bind to the m6A sites on different RNA sequences and stabilize them to promote cancer progression. In this review, we summarize the mechanisms by which different upstream factors regulate IGF2BP in cancer. The current literature analyzed here reveals that the IGF2BP family proteins promote cancer cell proliferation, survival, and chemoresistance, inhibit apoptosis, and are also associated with cancer glycolysis, angiogenesis, and the immune response in the tumor microenvironment. Therefore, with the discovery of their role as 'readers' of m6A and the characteristic re-expression of IGF2BPs in cancers, it is important to elucidate their mechanism of action in the immunosuppressive tumor microenvironment. We also describe in detail the regulatory and interaction network of the IGF2BP family in downstream target RNAs and discuss their potential clinical applications as diagnostic and prognostic markers, as well as recent advances in IGF2BP biology and associated therapeutic value.
