Recent studies have revealed a great diversity and complexity in extracellular vesicles and particles (EVPs). The developments in techniques and the growing awareness of the particle heterogeneity have spurred active research on new particle subsets. Latest discoveries highlighted unique features and roles of non-vesicular extracellular nanoparticles (NVEPs) as promising biomarkers and targets for diseases. These nanoparticles are distinct from extracellular vesicles (EVs) in terms of their smaller particle sizes and lack of a bilayer membrane structure and they are enriched with diverse bioactive molecules particularly proteins and RNAs, which are widely reported to be delivered and packaged in exosomes. This review is focused on the two recently identified membraneless NVEPs, exomeres and supermeres, to provide an overview of their biogenesis and contents, particularly those bioactive substances linked to their bio-properties. This review also explains the concepts and characteristics of these nanoparticles, to compare them with other EVPs, especially EVs, as well as to discuss their isolation and identification methods, research interests, potential clinical applications and open questions.

Drug resistance in colorectal cancer (CRC) poses a major challenge for cancer therapy and stands as the primary cause of cancer-related mortality. The N6-methyladenosine (m6A) modification has emerged as a pivotal regulator in cancer biology, yet the precise m6A regulators that propel CRC progression and chemoresistance remain elusive. Our study established a significant correlation between m6A regulatory gene expression profiles and CRC severity. Notably, based on the knockout cellular and mouse model created by CRISPR/Cas9-mediated genome engineering, we identified m6A demethylase FTO emerged as a pivotal orchestrator of CRC chemoresistance through the regulation of NUPR1, a critical transcription factor involved in iron homeostasis via LCN2 and FTH1. Mechanistic study revealed that FTO stabilized NUPR1 mRNA by specifically targeting the +451 m6A site, thereby preventing YTHDF2-mediated degradation of NUPR1 mRNA. Moreover, the simultaneous targeting of FTO and NUPR1 dramatically enhanced the efficacy of chemotherapy in CRC cells. Our findings underscore the potential of modulating the m6A methylome to overcome chemoresistance and highlight the FTO-NUPR1 axis as a critical determinant in CRC pathobiology.

In recent years, the interplay between N6-methyladenosine (m6A) modifications and non-coding RNAs (ncRNAs) has emerged as a pivotal research area, owing to their crucial involvement in the pathophysiological mechanisms underlying various diseases. A significant hurdle in cancer therapy is therapeutic resistance, which frequently contributes to adverse patient outcomes. Recent investigations have underscored the vital role that interactions between m6A modifications and ncRNAs play in mediating cancer therapeutic resistance via the MAPK, PI3K/Akt/mTOR, Wnt/β-catenin, HIPPO, and NF-κB pathways. This review elucidates how these interactions drive tumor therapeutic resistance by modulating these pathways. By dissecting the regulatory dynamics between m6A and ncRNAs in the context of cancer therapeutic resistance, this review aims to deepen the understanding of m6A-ncRNA interaction in cancer therapeutic resistance and identify potential therapeutic targets to improve cancer treatment efficacy.

Myocardial ischemia-reperfusion damage (MIRI) is a clinical problem and lacks proven treatment approaches. As a m6A reader, hnRNPA2B1 controls RNA destiny in the pathophysiology of neurodegenerative and cancerous disorders. Recently, we found that the level of hnRNPA2B1 was elevated in patients with myocardial infarction after percutaneous coronary intervention (PCI), which was positively correlated with cTnI. However, the role of hnRNPA2B1 in MIRI is still unknown. In the present study, we investigated the mechanism underlying MIRI-induced ferroptosis by focusing on a novel function of hnRNPA2B1. Our results showed that HnRNPA2B1 was also significantly increased in cardiomyocytes of MIRI models in vitro and in vivo. Genetically deleting hnRNPA2B1 effectively mitigated myocardial injury and cardiac function during MIRI. Silencing hnRNPA2B1 in cardiomyocytes boosted cell survival and decreased ferroptosis by lowering lipid ROS, MDA, Fe2+, and raising GSH, FTH1 levels, while overexpressing hnRNPA2B1 had the opposite impact. Mechanistic investigations revealed that hnRNPA2B1 recognized and interacted with the m6A site of PFN2 mRNA at "AGACU" to enhance the stability of PFN2 mRNA transcripts. Furthermore, PFN2 knockdown resulted in decreased MDA and Fe2+ levels and an increase in FTH1 expression. Importantly, silencing PFN2 attenuated ferroptosis in cardiomyocytes overexpressing hnRNPA2B1 during OGD/R injury. Collectively, hnRNPA2B1 potentially acts as a therapeutic target of MIRI through regulating caridac ferroptosis mediated by m6A-PFN2/FTH1 pathway.

Gastrointestinal (GI) tumors represent a significant global health burden and are among the leading causes of cancer-related mortality worldwide. their drug resistance is one of the major challenges in cancer therapy. In recent years, epigenetic modifications, especially N6-methyladenosine (m6A) RNA modifications, have become a hot research topic. m6A modification plays an important role in gene expression and cancer progression by regulating RNA splicing, translation, stability, and degradation, which are regulated by "writers," "erasers" and "readers." In GI tumors, resistance to chemotherapy, targeted therapy, and immunotherapy is closely associated with m6A RNA modification. Therefore, the molecular mechanism of m6A modification and its targeted drug development provide new therapeutic strategies for overcoming drug resistance and therapeutic efficacy in GI tumors. In this review, the biological functions of m6A were explored, the specific resistance mechanisms of m6A in different types of GI tumors were explored, new ideas and targets for future treatment resistance were identified, and the limitations of this field were highlighted.

Long non-coding RNAs (lncRNAs) are a class of transcripts exceeding 200 nucleotides (nt) in length, which are broadly implicated in a broad spectrum of physiological and pathological processes, including allelic imprinting, genome packaging, chromatin remodeling, transcriptional activation and disruption, as well as the occurrence and progression of oncogenesis. N6-methyladenosine (m6 A) methylation stands as the most prevalent RNA modification, affecting multiple facets of RNA biology such as stability, splicing, transport, translation, degradation, and tertiary structure. Aberrant m6 A modifications are intimately implicated in cancer progression. In recent years, there has been a growing number of studies illuminating the dynamic interplay between lncRNAs and m6 A modifications, revealing that lncRNAs can modulate the activity of m6 A regulators, while m6 A not only affects the structural integrity but also the translational efficiency and stability of lncRNAs. Together, the interactions between lncRNAs and m6 A modifications significantly impact downstream oncogenes, cancer suppressor genes, cellular metabolism, epithelial-mesenchymal transition, angiogenesis, drug transport, DNA homology repair, and epigenetics, subsequently influencing tumorigenesis, metastasis, and drug resistance. This article endeavors to clarify the functions and mechanisms of lncRNAs and m6 A modifications interaction in cancer to provide promising insights for cancer diagnosis and therapeutic strategies.

Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) plays a vital role in angiogenesis, when its nucleic acid-binding domain is occupied by transthyretin (TTR), the neovascularization of human retinal microvascular endothelial cells (hRECs) is repressed under hyperglycemic conditions.

HnRNPA2B1-targeting peptides (THIPs) were designed based on the core fragments at the TTR-hnRNPA2B1 interface. Biacore, Langmuir equilibrium adsorption, and co-immunoprecipitation (co-IP) assays were performed to determine the association between the THIPs and hnRNPA2B1. Proliferation and DNA synthesis in hRECs were detected using CCK-8 and EdU assays. Transwell, wound healing, and tube formation assays were used to evaluate migratory and the angiogenic capacity of hRECs. Related RNA and protein expression levels were tested by quantitative PCR and western blot assays, respectively. Streptozotocin (STZ)-induced diabetic retinopathy (DR) model rats were intravitreally injected with 5 μL of AAV9 virus (1 × 1012 vg/mL) every 8 weeks, with sterile saline used as control. After 16 weeks, the retinas were extracted and subjected to Evans blue leakage and retinal trypsin digestion assays. Retinal paraffin sections were prepared and stained with hematoxylin and eosin (H&E) or subjected to immunohistochemical or immunofluorescence assays.

Biacore, Langmuir equilibrium adsorption, and co-IP analyses demonstrated that the four designed THIPs specifically recognized hnRNPA2B1. CCK-8 and EdU labeling assays showed that the THIPs inhibited proliferation and DNA synthesis in hRECs under hyperglycemia. Transwell, wound healing and tube formation assays demonstrated that the THIPs inhibited the migratory and angiogenic capacity of hRECs. Quantitative PCR and western blot assays suggested that the THIPs exerted their effects via the STAT4/miR-223-3p/FBXW7 and the downstream Notch1/Akt/mTOR axes. In vivo studies using DR model rat revealed that the intravitreal administration of THIP-4 significantly mitigated retinal leakage, capillary decellularization, pericyte loss, fibrosis, and gliosis during DR progression.

Our findings demonstrated that under hyperglycemia, THIP-4 suppressed DR progression via the STAT4/miR-223-3p/FBXW7 and Notch1/Akt/mTOR axes both in vitro and in vivo. These results indicated that THIP-4 has strong potential for clinical application in DR and other angiogenesis associated diseases.

The most common form of internal RNA modification in eukaryotes is called n6-methyladenosine (m6A) methylation. It has become more and more well-known as a research issue in recent years since it alters RNA metabolism and is involved in numerous biological processes. Currently, m6A alteration offers new opportunities in clinical applications and is intimately linked to carcinogenesis. Ferroptosis-a form of iron-dependent, lipid peroxidation-induced regulated cell death-was discovered. In the development of cancer, it has become an important factor. According to newly available data, ferroptosis regulates tumor growth, and cancer exhibits aberrant m6A levels in crucial ferroptosis regulatory components. On the other hand, m6A has multiple roles in the development of tumors, and the relationship between m6A-modified ferroptosis and malignancies is quite intricate. In this review, we first give a thorough review of the regulatory and functional roles of m6A methylation, focusing on the molecular processes of m6A through the regulation of ferroptosis in human cancer progression and metastasis, which are strongly associated to cancer initiation, progression, and drug resistance. Therefore, it is crucial to clarify the relationship between m6A-mediated regulation of ferroptosis in cancer progression, providing a new strategy for cancer treatment with substantial clinical implications.

Multidrug resistance (MDR) remains a significant barrier to effective chemotherapy and results in a poor prognosis for gastric cancer (GC). Exploring the mechanism of MDR is highly important for identifying biomarkers for MDR and developing new treatment strategies. In this study, integrative analyses of multiomics and bioinformatics data were combined with experimental validation to explore the mechanism of MDR in GC. We found that phosphoglycerate dehydrogenase (PHGDH), the key rate-limiting enzyme in the serine synthesis pathway, was significantly upregulated in MDR GC cells. PHGDH was found to perform a noncanonical function to promote MDR by activating the Wnt/β-catenin signaling pathway, and this effect is mediated by transcription factor 7-like 2 (TCF7L2), a pivotal co-activator of β-catenin in the Wnt pathway. Specifically, PHGDH stabilizes TCF7L2 mRNA by interacting with insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), a key m6A reader, in an m6A-dependent manner, thereby increasing the expression of TCF7L2. Moreover, TCF7L2 binds to the promoter of PHGDH and regulates its expression, which forms a positive feedback loop. This PHGDH/IGF2BP1-TCF7L2 loop contributes to GC MDR and is correlated with a poor prognosis of GC patients.

Ovarian carcinoma (OvCa) metastasis is initiated and boosted by tumor-stroma interactions mediated by small extracellular vesicles (sEVs) containing microRNAs (miRNAs). However, the mechanisms of sorting relevant miRNAs into tumoral sEVs remain elusive.

In this study, among the RNA-binding proteins, hnRNPA2B1 was identified as the most significant factor associated with survival in OvCa patients, and its expression was higher in omental metastases compared to paired ovarian lesions. Based on the CRISPR-Cas9 technique, orthotopic xenograft mice revealed a remarkable metastasis-inhibiting effect of hnRNPA2B1-knockdown, accompanied by diminished myofibroblast signals in the omentum. Meanwhile, after hnRNPA2B1-knockdown, OvCa-sEVs largely lost the ability to promote omental metastasis and myofibroblast activation in vivo and in vitro. High-throughput miRNA sequencing of sEV cargoes revealed that UAG motif-containing miRNAs were significantly affected by hnRNPA2B1, and RNA immunoprecipitation (RIP) verified their direct binding to hnRNPA2B1. In pull down assays, the miRNAs with mutated UAG motif exhibited decreased binding capacity to hnRNPA2B1. The myofibroblasts activated by OvCa-sEVs could promote tumor metastasis, and this effect was notably impacted by manipulating hnRNPA2B1, related sEV-miRNAs, and PI3K/AKT signaling.

These findings highlight the miRNA sorting to sEVs mediated by hnRNPA2B1 as an important mechanism involved in OvCa metastasis, which may illuminate new therapeutic strategies.

MicroRNAs (miRNAs) are a class of non-coding RNA sequences that regulate gene expression post-transcriptionally. The miR-99 family, which is highly evolutionarily conserved, comprises three homologs: miR-99a, miR-99b, and miR-100. Its members are under-expressed in most cancerous tissues, suggesting their cancer-repressing properties in multiple cancers; however, in some contexts, they also promote malignant lesion progression. MiR-99 family members target numerous genes involved in various tumor-related processes such as tumorigenesis, proliferation, cell-cycle regulation, apoptosis, invasion, and metastasis. We review the recent research on this family, summarize its implications in cancer, and explore its potential as a biomarker and cancer therapeutic target. This review contributes to the clinical translation of the miR-99 family members.

Primary or acquired mutations in RAS/RAF genes resulting in cetuximab resistance have limited its clinical application in colorectal cancer (CRC) patients. The mechanism of this resistance remains unclear. RNA sequencing from cetuximab-sensitive and -resistant specimens revealed an activation of the tryptophan pathway and elevation of IDO1 and IDO2 in cetuximab-resistant CRC patients. In vitro, in vivo, and clinical specimens confirmed the upregulation of IDO1and IDO2 and the Kyn/Trp after cetuximab treatment. Additionally, the IDO inhibitor, epacadostat, could effectively inhibit the migration and proliferation of cetuximab-resistant CRC cells while promoting apoptosis. Compared to epacadostat monotherapy, the combination of cetuximab and epacadostat showed a stronger synergistic anti-tumor effect. Furthermore, in vivo experiments confirmed that combination therapy effectively suppressed tumor growth. Mechanistically, KEGG pathway analysis revealed the activation of the IFN-γ pathway in cetuximab-resistant CRC tissues. Luciferase reporter assays confirmed the transcriptional activity of IDO1 following cetuximab treatment. Silencing IFN-γ then suppressed the upregulation induced by cetuximab. Moreover, we observed that the combination reduced the concentration of the tryptophan metabolite kynurenine, promoted the infiltration of CD8+ T lymphocytes, and enhanced the polarization of M1 macrophages within the tumor microenvironment, thereby exerting potent anti-tumor immune effects. Overall, our results confirm the remarkable therapeutic efficacy of combining cetuximab with epacadostat in cetuximab-resistant CRC. Our findings may provide a novel target for overcoming cetuximab resistance in CRC.

The liver is the most common site of metastasis of colorectal cancer (CRC), and colorectal liver metastasis is one of the major causes of CRC-related deaths worldwide. The tumor microenvironment, particularly the extracellular matrix (ECM), plays a critical role in CRC metastasis and chemoresistance. Based on findings from clinical and basic research, this review attempts to offer a complete understanding of the role of the ECM in colorectal liver metastasis and to suggest potential ways for therapeutic intervention. First, the ECMs' role in regulating cancer cell fate is explored. We then discuss the hepatic ECM fingerprint and its influence on the metastatic behavior of CRC cells, highlighting key molecular interactions that promote metastasis. In addition, we examine how changes in the ECM within the metastatic niche contribute to chemoresistance, focusing on ECM remodeling by ECM stiffening and the activation of specific signaling pathways. Understanding these mechanisms is crucial for the development of novel strategies to overcome metastasis and improve outcomes for CRC patients.

The RNA-binding protein hnRNPA2B1 acts as an m6A reader and plays a role in tumor development. This study investigates the potential mechanism of hnRNPA2B1 in colorectal cancer (CRC) progression. The expression profiles of hnRNPA2B1, circCDYL, and PHF8 in CRC cell lines were analyzed. Following si-hnRNPA2B1 transfection, CRC cell proliferation, invasion, and migration were evaluated by CCK-8 and Transwell. CDYL expression was detected after actinomycin D and RNase R treatment. RIP was conducted to assess the enrichment of hnRNPA2B1 and m6A on circCDYL. RIP and RNA pull-down assays established the interaction between circCDYL and EIF4A3/PHF8. EIF4A3 expression was evaluated using RT-qPCR and Western blot techniques. hnRNPA2B1 and PHF8 displayed high expression levels, whereas circCDYL showed low expression levels in colorectal cancer cells. Inhibition of hnRNPA2B1 reduced CRC cell proliferation, migration, and invasion. hnRNPA2B1 mechanistically elevated the m6A level of circCDYL while decreasing its expression, which in turn reduced the binding of circCDYL to EIF4A3 and enhanced PHF8 expression. In summary, hnRNPA2B1-mediated m6A modification decreases circCDYL expression, which inhibits the interaction of circCDYL with EIF4A3, enhances PHF8 expression, and ultimately facilitates CRC progression.

Long non-coding RNAs (lncRNAs) are a class of non-coding RNA molecules with transcripts longer than 200 bp, which were initially thought to be noise from genomic transcription without biological function. However, since the discovery of H19 in 1980 and Xist in 1990, increasing evidence has shown that lncRNAs regulate gene expression at epigenetic, transcriptional, and post-transcriptional levels through specific regulatory actions and are involved in the development of cancer and other diseases. Despite many lncRNAs being expressed at lower levels than those of protein-coding genes with less sequence conservation across species, lncRNAs have become an intense area of RNA research. They exert diverse biological functions such as inducing chromatin remodeling, recruiting transcriptional machinery, acting as competitive endogenous RNAs for microRNAs, and modulating protein-protein interactions. Epithelial-mesenchymal transition (EMT) is a developmental process, associated with embryonic development, wound healing, and cancer progression. In the context of oncogenesis, the EMT program is transiently activated and confers migratory/invasive and cancer stem cell (CSC) properties to tumor cells, which are crucial for malignant progression, metastasis, and therapeutic resistance. Accumulating evidence has revealed that lncRNAs play crucial roles in the regulation of tumor epithelial/mesenchymal plasticity (EMP) and cancer stemness. Here, we summarize the emerging roles and molecular mechanisms of lncRNAs in regulating tumor cell EMP and their effects on tumor initiation and progression through regulation of CSCs. We also discuss the potential of lncRNAs as diagnostic and prognostic biomarkers and therapeutic targets.

Breast cancer (BC) is the most common malignant tumor in women, and the majority of BC-related deaths are due to tumor metastasis. There is emerging evidence for the role of long noncoding RNAs (lncRNAs) in tumor progression. Nevertheless, lncRNAs that drive metastasis in patients with BC and the underlying mechanisms of lncRNAs are still largely elusive. In this study, we showed that LINC00882 was highly expressed in metastatic BC tissues, and a receiver operating characteristic (ROC) curve was able to distinguish well between BC cases with lymph node metastasis (LNM) and those without LNM. Functionally, LINC00882 promoted BC invasion and metastasis in vitro and in vivo. Mechanistically, at the transcriptional level, CEBP-β could bind directly to the LINC00882 promoter region and activate its transcription. Moreover, at the posttranscriptional level, m6A modification of LINC00882 mediated by methyltransferase-like 14 (METTL14) promoted its expression via an IGF2BP2-dependent pathway. Furthermore, 514-615 nucleotides of LINC00882 could directly interact with poly (A) binding protein cytoplasmic 1 (PABPC1) and promote the interaction between PABPC1 and ELK3 mRNA, thereby stabilizing ELK3 mRNA and enhancing the ELK3 protein level. E-cadherin expression was suppressed via ELK3-mediated transcription inhibition, subsequently activating epithelial-mesenchymal transition to promote BC metastasis. These results highlight the role of LINC00882 in BC, and LINC00882 may be a diagnostic and therapeutic target for BC.

Dental pulp regeneration is significantly aided by human dental pulp stem cells (hDPSCs). An increasing number of studies have demonstrated that circular RNAs (circRNAs) are crucial in the multidirectional differentiation of many mesenchymal stem cells, but their specific functions and mechanisms remain unknown. This work aimed at elucidating the molecular mechanism by which hsa_circ_0001599 works in hDPSCs during odontogenic differentiation. The expression of hsa_circ_0001599 in hDPSCs and dental pulp tissue was determined by using quantitative real-time PCR (qRT‒PCR). The role of hsa_circ_0001599 in the odontogenic differentiation of hDPSCs and its mechanism were studied using a variety of in vivo and in vitro assessments. The odontogenic differentiation of hDPSCs was facilitated by the overexpression of hsa_circ_0001599, which activated the PI3K/AKT signalling pathway in vitro. In vivo, hsa_circ_0001599 can promote the formation of new dentin-like structures. Mechanistically, hsa_circ_0001599 enhanced ITGA2 expression by sponging miR-889-3p. Furthermore, hsa_circ_0001599 interacts with the methylation reader hnRNPA2B1, promoting hnRNPA2B1 translocation from the nucleus to the cytoplasm and increasing ITGA2 mRNA stability. This research revealed the important role of hsa_circ_0001599 in odontogenic differentiation. Thus, hDPSCs engineered with hsa_circ_0001599 have the potential to be effective therapeutic targets for dental pulp repair and regeneration.

N(6)-methyladenosine (m6A) modification is the most abundant and prevalent internal modification in eukaryotic mRNAs. The role of m6A modification in cancer has become a hot research topic in recent years and has been widely explored. m6A modifications have been shown to regulate cancer occurrence and progression by modulating different target molecules. This paper reviews the recent research progress of m6A modifications in cancer and provides an outlook on future research directions, especially the development of molecularly targeted drugs. See also the graphical abstract(Fig. 1).

LINC00312 has shown to play a suppressive role in the development and progression of non-small cell lung cancer (NSCLC). However, the expression pattern and diagnostic role of circulating LINC00312 in NSCLC remain to be confused.

A total of 319 patients diagnosed with NSCLC and 180 healthy volunteers were enrolled from the First Affiliated Hospital of Huzhou University between January, 2022 and December, 2023. The participates were randomly assigned into the training and validation groups with a ratio of 6:4, while the remaining was named as the exosomal group. Reverse transcription-quantitative PCR (RT-qPCR) was employed to investigate the expression pattern of LINC00312 in NSCLC tissues, serum samples and cell lines. Receiver operating characteristic (ROC) curve analysis was carried out for distinguishing NSCLC from healthy volunteers.

Here, we revealed that LINC00312 was lowly expressed in NSCLC and low LINC00312 expression manifested a poor prognosis. Additionally, compared with the healthy volunteer group, a reduction of circulating LINC00312 in patients with NSCLC was observed in both the training and validation groups. Further correlation analysis indicated that circulating LINC00312 expression was tightly associated with lymph node metastasis, cancer thrombus, spread through air space (STAS) status and pathological type. Moreover, circulating LINC00312 showed a good performance to distinguish NSCLC from healthy volunteers with a higher sensitivity and specificity values. Lastly, exosomal LINC00312 level was also decreased in NSCLC compared with in healthy volunteers.

Taken together, these data unveil that circulating LINC00312 was notably downregulated in NSCLC, offering a novel non-invasive marker for diagnosis of NSCLC.

The fibrosis of pathologic scar (PS) is formed by the excessive deposition of extracellular matrix, resulting in an abnormal scar. Recent clinical tests have indicated that the regulation of PS fibroblast cells (PSF cells) proliferation can serve as an intervention measure for PS. Our work aimed to elucidate the specific mechanism of action of TCF4 on the progression of PS fibrosis.

Our study used qRT-PCR and Western blot to search for the expression of key proteins in PS clinical samples and cells. Transwell, CCK-8, and wound scratch assays were employed to analyze the proliferation and migration of PSF cells. CHIP, dual-luciferase reporter experiments, and bio-informatics analysis were used to analyze the interactions between molecules.

The analysis of PS clinical samples confirmed a positive correlation between TCF4 and miR-494-3p. This regulatory mechanism was related to the progression of PS. We verified that the overexpression of miR-494-3p or the knockdown of THBS1 both suppressed the proliferation and migration of PSF cells. Furthermore, we also confirmed the binding relationships between TCF4, miR-494-3p, and THBS1. Simultaneously, we verified the existence of the TCF4/miR-494-3p/THBS1 regulatory network in PS. This regulatory process affects the development of PS fibrosis.

Our study results indicate that TCF4, miR-494-3p, and THBS1 are abnormally expressed in PS. TCF4 increases the proliferation and migration ability of PSF cells through the miR-494-3p/THBS1 signaling pathway, which promotes the fibrosis of PS.

RNA modifications are emerging as critical cancer regulators that influence tumorigenesis and progression. Key modifications, such as N6-methyladenosine (m6A) and 5-methylcytosine (m5C), are implicated in various cellular processes. These modifications are regulated by proteins that write, erase, and read RNA and modulate RNA stability, splicing, translation, and degradation. Recent studies have highlighted their roles in metabolic reprogramming, signaling pathways, and cell cycle control, which are essential for tumor proliferation and survival. Despite these scientific advances, the precise mechanisms by which RNA modifications affect cancer remain inadequately understood. This review comprehensively examines the role RNA modifications play in cancer proliferation, metastasis, and programmed cell death, including apoptosis, autophagy, and ferroptosis. It explores their effects on epithelial-mesenchymal transition (EMT) and the immune microenvironment, particularly in cancer metastasis. Furthermore, RNA modifications' potential in cancer therapies, including conventional treatments, immunotherapy, and targeted therapies, is discussed. By addressing these aspects, this review aims to bridge current research gaps and underscore the therapeutic potential of targeting RNA modifications to improve cancer treatment strategies and patient outcomes.

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of metabolic dysfunction-associated fatty liver disease metabolic dysfunction-associated steatohepatitis , characterized by hepatic steatosis, inflammation, and fibrosis. This study investigates the role and potential mechanisms of metallothionein 1B (MT1B) in MASH through bioinformatics analysis and experimental validation. quantitative reverse transcription PCR and Western blot analyses confirm that MT1B expression is significantly downregulated in liver tissues of MASH patients, in high-fat diet-induced mouse models, and in hepatocytes induced by FFAs. Further functional experiments show that upregulation of MT1B reduces intracellular triglycerides and total cholesterol levels, lipid droplet formation, and proinflammatory factors. In vivo experiments demonstrate that specific downregulation of hepatic MT1B expression via AAV8-shMT1B injection significantly increases triglyceride and total cholesterol levels, exacerbates lipid accumulation, and markedly elevates liver fibrosis and inflammatory factor expression. RNA-seq and bioinformatics analyses show that the AKT/PI3K pathway is significantly suppressed in MT1B-overexpressing cells. Further experiments indicate that AKT inhibition can reverse the lipid metabolism disorders and inflammatory responses caused by MT1B downregulation. Additionally, Zinc can promote the nuclear translocation of MTF1, leading to its binding to the MT1B promoter, thereby upregulating MT1B expression and ultimately mitigating MASH progression. These findings suggest that zinc-regulated MT1B plays a critical role in lipid metabolism and inflammatory responses by regulating the AKT/PI3K signaling pathway, influencing MASH progression.

Significant advances in the development of new cancer therapies have given rise to multiple novel therapeutic options in chemotherapy, radiotherapy, immunotherapy, and targeted therapies. Although the development of resistance is often reported along with temporary disease remission, there is often tumor recurrence of an even more aggressive nature. Resistance to currently available anticancer drugs results in poor overall and disease-free survival rates for cancer patients. There are multiple mechanisms through which tumor cells develop resistance to therapeutic agents. To date, efforts to overcome resistance have only achieved limited success. Epitranscriptomics, especially related to m6A RNA modification dysregulation in cancer, is an emerging mechanism for cancer therapy resistance. Here, recent studies regarding the contributions of m6A modification and its regulatory proteins to the development of resistance to different cancer therapies are comprehensively reviewed. The promise and potential limitations of targeting these entities to overcome resistance to various anticancer therapies are also discussed.

RNA modification is the critical mechanism for regulating post-transcriptional processes. There are more than 150 RNA modifications reported so far, among which N6-Methyladenosine is the most prevalent one. M6A RNA modification complex consists of 'writers', 'readers' and 'erasers' which together in a group catalyze, recognize and regulate the methylation process of RNA and thereby regulate the stability and translation of mRNA. The discovery of erasers also known as demethylases, revolutionized the research on RNA modifications as it revealed that this modification is reversible. Since then, various studies have focused on discovering the role of m6A modification in various diseases especially cancers. Aberrant expression of these 'readers', 'writers', and 'erasers' is found to be altered in various cancers resulting in disturbance of cellular homeostasis. Acute leukemias are the most common cancer found in pediatric patients and account for 20% of adult cases. Dysregulation of the RNA modifying complex have been reported in development and progression of hematopoietic malignancies. Further, targeting m6A modification is the new approach for cancer immunotherapy and is being explored extensively. This review provides detailed information about current information on the role of m6A RNA modification in acute leukemia and their therapeutic potential.

Metastasis continues to negatively impact individuals diagnosed with colorectal cancer (CRC). Research has revealed the important role of long noncoding RNAs (lncRNAs) in CRC metastasis, but the underlying mechanisms remain unclear. Here, we revealed that the lncRNA small nucleolar RNA host gene 1 (SNHG1) is expressed at higher levels in metastatic CRC tissues than in primary CRC tissues, and that high lncRNA SNHG1 expression indicates poor patient outcomes. We found that lncRNA SNHG1 promotes the migration and invasion of tumor cells both in vivo and in vitro. Moreover, lncRNA SNHG1 increases serpin family A member 3 (SERPINA3) mRNA stability by interacting with the heterogeneous nuclear ribonucleoprotein D (HNRNPD) protein, and subsequently upregulates SERPINA3 expression. Moreover, HNRNPD and SERPINA3 reversed the effects of lncRNA SNHG1 knockdown on CRC cell metastasis. In conclusion, we report that the lncRNA SNHG1 recruits HNRNPD, in turn upregulating SERPINA3 expression and ultimately facilitating CRC cell migration and invasion. Targeting the lncRNA SNHG1/HNRNPD/SERPINA3 signaling pathway might be a therapeutic option for preventing CRC metastasis.

Increasing evidence demonstrate that the significant role of long non-coding RNA (lncRNA) in metastasis and the remodeling of the tumor microenvironment. However, the precise mechanisms of lncRNAs in cancer metastasis are still poorly understood. The function of lncRNA-Mir100hg in melanoma and its involvement in mediating communication between tumor stem cells and non-stemness tumor cells remains unknown. We found that Mir100hg is upregulated in melanoma stem cells (CSCs) known as OLSD. Furthermore, Mir100hg can be transferred from OLSD to non-stem cancer cells (OL) through exosomes. Once Mir100hg enters OL cells, it operates through a competitive endogenous RNA (ceRNA) mechanism. It competes with microRNAs (miR-16-5p and miR-23a-3p) by binding to them, thus preventing these miRNAs from targeting their mRNAs. As a result, the expression of glycolysis-related mRNA was restored. This ultimately enhances the metastatic capability of OL cells. In summary, our study uncovers a network used by CSCs to transfer their high metastatic activity to non-stem cancer cells through the exosomal Mir100hg. This mechanism sheds new light on the communication between heterogeneous cancer cell populations in melanoma. Importantly, it provides novel insights into the role of lncRNAs in cancer metastasis and highlights the significance of the tumor microenvironment in facilitating metastasis.

Tumor cell invasion is considered as one of the main therapeutic challenges in cancer patients, which leads to distant metastasis and reduced prognosis. Therefore, investigation of the factors involved in tumor cell invasion improves the therapeutic methods to reduce tumor metastasis. Epithelial-mesenchymal transition (EMT) process has a pivotal role in tumor cell invasion and metastasis, during which tumor cells gain the invasive ability by losing epithelial characteristics and acquiring mesenchymal characteristics. WNT/β-catenin signaling pathway has a key role in tumor cell invasion by regulation of EMT process. Long non-coding RNAs (lncRNAs) have also an important role in EMT process through the regulation of WNT/β-catenin pathway. Deregulation of lncRNAs is associated with tumor metastasis in different tumor types. Therefore, in the present review, we investigated the role of lncRNAs in EMT process and tumor cell invasion through the regulation of WNT/β-catenin pathway. It has been reported that lncRNAs mainly induced the EMT process and tumor cell invasion through the activation of WNT/β-catenin pathway. LncRNAs that regulate the WNT/β-catenin mediated EMT process can be introduced as the prognostic markers as well as suitable therapeutic targets to reduce the tumor metastasis in cancer patients.

Temozolomide (TMZ) resistance is one of the major reasons for poor prognosis in patients with glioblastoma (GBM). Long noncoding RNAs (lncRNAs) are involved in multiple biological processes, including TMZ resistance. Linc00942 is a potential regulator of TMZ sensitivity in GBM cells is shown previously. However, the underlying mechanism of TMZ resistance induced by Linc00942 is unknown. In this study, the sequence of Linc00942 by rapid amplification of cDNA ends assay in TMZ-resistant GBM cells is identified and confirmed that Linc00942 contributes to self-renewal and TMZ resistance in GBM cells. Chromatin isolation by RNA purification followed by mass spectrometry (ChIRP-MS) and followed by Western blotting (ChIRP-WB) assays shows that Linc00492 interacted with TPI1 and PKM2, subsequently promoting their phosphorylation, dimerization, and nuclear translocation. The interaction of Linc00942 with TPI1 and PKM2 leads to increased acetylation of H3K4 and activation of the STAT3/P300 axis, resulting in the marked transcriptional activation of SOX9. Moreover, the knockdown of SOX9 reversed TMZ resistance induced by Linc00492 both in vitro and in vivo. In summary, Linc00942 strongly promotes SOX9 expression by interacting with TPI1 and PKM2 is found, thereby driving self-renewal and TMZ resistance in GBM cells. These findings suggest potential combined therapeutic strategies to overcome TMZ resistance in patients with GBM.

Cancer development is thought to be closely related to aberrant epigenetic regulation, aberrant expression of specific non-coding RNAs (ncRNAs), and tumor microenvironment (TME). The m6A methylation is one of the most abundant RNA modifications found in eukaryotes, and it can determine the fate of RNA at the post-transcriptional level through a variety of mechanisms, which affects important biological processes in the organism. The m6A methylation modification is involved in RNA processing, regulation of RNA nuclear export or localisation, RNA degradation and RNA translation. This process affects the function of mRNAs and ncRNAs, thereby influencing the biological processes of cancer cells. TME accelerates and promotes cancer generation and progression during tumor development. The m6A methylation interacting with ncRNAs is closely linked to TME formation. Mutual regulation and interactions between m6A methylation and ncRNAs in TME create complex networks and mediate the progression of various cancers. In this review, we will focus on the interactions between m6A modifications and ncRNAs in TME, summarising the molecular mechanisms by which m6A interacts with ncRNAs to affect TME and their roles in the development of different cancers. This work will help to deepen our understanding of tumourigenesis and further explore new targets for cancer therapy.

MicroRNA host gene (MIRHG) lncRNA is a particular lncRNA subclass that can perform both typical and atypical lncRNA functions. The biological function of MIRHG lncRNA MIR194-2HG in cancer is poorly understood.

Loss-of-function studies were performed in vivo and in vitro to reveal the biological function of MIR194-2HG in GC. MicroRNA PCR array, northern blotting, RNA sequencing, chromatin immunoprecipitation, and rescue assays were conducted to uncover the molecular mechanism of MIR194-2HG.

In this study, we reported an atypical lncRNA function of MIR194-2HG in GC. MIR194-2HG downregulation was clinically associated with malignant progression and poor prognosis in GC. Functional assays confirmed that MIR194-2HG knockdown significantly promoted GC proliferation and metastasis in vitro and in vivo. Mechanismically, MIR194-2HG was required for the biogenesis of miR-194 and miR-192, which were reported to be tumor-suppressor genes in GC. Moreover, hepatocyte nuclear factor HNF4A directly activated the transcription of MIR194-2HG and its derived miR-194 and miR-192. Meanwhile, BTF3L4 was proved to be a common target gene of miR-192 and miR-194. Rescue assay further confirmed that MIR194-2HG knockdown promotes GC progression through maintaining BTF3L4 overexpression in a miR-194/192-dependent manner.

The dysregulated MIR194-2HG/BTF3L4 axis is responsible for GC progression. Targeting HNF4A to inhibit miR-192/194 expression may be a promising strategy for overcoming GC.

As a research hotspot in the field of molecular biology, N6-methyladenosine (m6A) modification has made progress in the treatment of colorectal cancer (CRC), leukemia and other cancers. Numerous studies have demonstrated that the tumour microenvironment (TME) regulates the level of m6A modification in the host and activates a series of complex epigenetic signalling pathways through interactions with CRC cells, thus affecting the progression and prognosis of CRC. However, with the diversity in the composition of TME factors, this action is reciprocal and complex. Encouragingly, some studies have experimentally revealed that the intestinal flora can alter CRC cell proliferation by directly acting on m6A and thereby altering CRC cell proliferation. This review summarizes the data, supporting the idea that the intestinal flora can influence host m6A levels through pathways such as methyl donor metabolism and thus affect the progression of CRC. We also review the role of m6A modification in the diagnosis, treatment, and prognostic assessment of CRC and discuss the current status, limitations, and potential clinical value of m6A modification in this field. We propose that additional in-depth research on m6A alterations in CRC patients and their TME-related targeted therapeutic issues will lead to better therapeutic outcomes for CRC patients.

Heterogeneous nuclear ribonucleoproteins (HNRNPs) represent a large family of RNA-binding proteins consisting of more than 20 members and have attracted great attention with their distinctive roles in cancer progression by regulating RNA splicing, transcription, and translation. Nevertheless, the cancer-specific modulation of HNRNPs has not been fully elucidated. The research of LC-MS/MS technology has documented that HNRNPs were widely and significantly targeted by different post-translational modifications (PTMs), which have emerged as core regulators in shaping protein functions and are involved in multiple physiological processes. Accumulating studies have highlighted that several PTMs are involved in the mechanisms of HNRNPs regulation in cancer and may be suitable therapeutic targets. In this review, we summarize the existing evidence describing how PTMs modulate HNRNPs functions on gene regulation and the involvement of their dysregulation in cancer, which will help shed insights on their clinical impacts as well as possible therapeutic tools targeting PTMs on HNRNPs.

HNRNPA2B1 is a member of the HNRNP family, which is associated with telomere function, mRNA translation, and splicing, and plays an important role in tumor development. To date, there have been no pan-cancer studies of HNRNPA2B1, particularly within the TME. Therefore, we conducted a pan-cancer analysis of HNRNPA2B1 using TCGA data. Based on datasets from TCGA, TARGET, Genotype-Tissue Expression, and Human Protein Atlas, we employed a range of bioinformatics approaches to explore the potential oncogenic role of HNRNPA2B1. This included analyzing the association of HNRNPA2B1 expression with prognosis, tumor mutation burden (TMB), microsatellite instability (MSI), immune response, and immune cell infiltration of individual tumors. We further validated the bioinformatic findings using immunohistochemistry techniques. HNRNPA2B1 was found to be differentially expressed across most tumor types in TCGA's pan-cancer database and was predictive of poorer clinical staging and survival status. HNRNPA2B1 expression was also closely linked to TMB, MSI, tumor stemness, and chemotherapy response. HNRNPA2B1 plays a significant role in the TME and is involved in the regulation of novel immunotherapies. Its expression is significantly associated with the infiltration of macrophages, dendritic cells, NK cells, and T cells. Furthermore, HNRNPA2B1 is closely associated with immune checkpoints, immune-stimulatory genes, immune-inhibitory genes, MHC genes, chemokines, and chemokine receptors. We performed a comprehensive evaluation of HNRNPA2B1, revealing its potential role as a prognostic indicator for patients and its immunomodulatory functions.

The long noncoding RNA (lncRNA)/Wingless (Wnt) axis is often dysregulated in digestive system tumors impacting critical cellular processes. Abnormal expression of specific Wnt-related lncRNAs such as LINC01606 (promotes motility), SLCO4A1-AS1 (promotes motility), and SH3BP5-AS1 (induces chemoresistance), plays a crucial role in these malignancies. These lncRNAs are promising targets for cancer diagnosis and therapy, offering new treatment perspectives. The lncRNAs, NEF and GASL1, differentially expressed in plasma show diagnostic potential for esophageal squamous cell carcinoma and gastric cancer, respectively. Additionally, Wnt pathway inhibitors like XAV-939 have demonstrated preclinical efficacy, underscoring their therapeutic potential. This review comprehensively analyzes the lncRNA/Wnt axis, highlighting its impact on cell proliferation, motility, and chemoresistance. By elucidating the complex molecular mechanisms of the lncRNA/Wnt axis, we aim to identify potential therapeutic targets for digestive system tumors to pave the way for the development of targeted treatment strategies.

Ocular melanoma, including uveal melanoma (UM) and conjunctival melanoma (CM), is the most common ocular cancer among adults with a high rate of recurrence and poor prognosis. Loss of epigenetic homeostasis disturbed gene expression patterns, resulting in oncogenesis. Herein, we comprehensively analyzed the DNA methylation, transcriptome profiles, and corresponding clinical information of UM patients through multiple machine-learning algorithms, finding that a methylation-driven gene RBMS1 was correlated with poor clinical outcomes of UM patients. RNA-seq and single-cell RNA-seq analyses revealed that RBMS1 reflected diverse tumor microenvironments, where high RBMS1 expression marked an immune active TME. Furthermore, we found that tumor cells were identified to have the higher communication probability in RBMS1+ state. The functional enrichment analysis revealed that RBMS1 was associated with pigment granule and melanosome, participating in cell proliferation as well as apoptotic signaling pathway. Biological experiments were performed and demonstrated that the silencing of RBMS1 inhibited ocular melanoma proliferation and promoted apoptosis. Our study highlighted that RBMS1 reflects a distinct microenvironment and promotes tumor progression in ocular melanoma, contributing to the therapeutic customization and clinical decision-making.

N6-methyladenosine (m6A) methylation is one of the most predominant internal RNA modifications in eukaryotes and has become a hot spot in the field of epigenetics in recent years. Cardiovascular diseases (CVDs) are a leading cause of death globally. Emerging evidence demonstrates that RNA modifications, such as the m6A modification, are associated with the development and progression of many diseases, including CVDs. An increasing body of studies has indicated that programmed cell death (PCD) plays a vital role in CVDs. However, the molecular mechanisms underlying m6A modification and PCD in CVDs remain poorly understood. Herein, elaborating on the highly complex connections between the m6A mechanisms and different PCD signaling pathways and clarifying the exact molecular mechanism of m6A modification mediating PCD have significant meaning in developing new strategies for the prevention and therapy of CVDs. There is great potential for clinical application.

N6-methyladenosine (m6A) is the most abundant modification of RNA in eukaryotic cells. Previous studies have shown that m6A is pivotal in diverse diseases especially cancer. m6A corelates with the initiation, progression, resistance, invasion, and metastasis of cancer. However, despite these insights, a comprehensive understanding of its specific roles and mechanisms within the complex landscape of cancer is still elusive. This review begins by outlining the key regulatory proteins of m6A modification and their posttranslational modifications (PTMs), as well as the role in chromatin accessibility and transcriptional activity within cancer cells. Additionally, it highlights that m6A modifications impact cancer progression by modulating programmed cell death mechanisms and affecting the tumor microenvironment through various cancer-associated immune cells. Furthermore, the review discusses how microorganisms can induce enduring epigenetic changes and oncogenic effect in microorganism-associated cancers by altering m6A modifications. Last, it delves into the role of m6A modification in cancer immunotherapy, encompassing RNA therapy, immune checkpoint blockade, cytokine therapy, adoptive cell transfer therapy, and direct targeting of m6A regulators. Overall, this review clarifies the multifaceted role of m6A modification in cancer and explores targeted therapies aimed at manipulating m6A modification, aiming to advance cancer research and improve patient outcomes.

Identifying precise biomarkers for colorectal cancer (CRC) detection and management remains challenging. Here, we developed an innovative prognostic model for CRC using cuproptosis-related long non-coding RNAs (lncRNAs).

In this retrospective study, CRC patient transcriptomic and clinical data were sourced from The Cancer Genome Atlas database. Cuproptosis-related lncRNAs were identified and used to develop a prognostic model, which helped categorize patients into high- and low-risk groups. The model was validated through survival analysis, risk curves, independent prognostic analysis, receiver operating characteristic curve analysis, decision curves, and nomograms. In addition, we performed various immune-related analyses. LncRNA expression levels were examined in normal human colorectal epithelial cells (FHC) and CRC cells (HCT-116) using quantitative polymerase chain reaction (qPCR).

Six cuproptosis-related lncRNAs were identified: ZKSCAN2-DT, AL161729.4, AC016394.1, AC007128.2, AL137782.1, and AC099850.3. The prognostic model distinguished between high-/low-risk populations, demonstrating excellent predictive ability for survival outcomes. Immunocorrelation analysis showed significant differences in immune cell infiltration and functions, immune checkpoint expression, and m6A methylation-related genes. The qPCR results showed significant upregulation of ZKSCAN2-DT, AL161729.4, AC016394.1, AC007128.2 in HCT-116 cells, while AL137782.1 and AC099850.3 expression patterns were significantly downregulated.

Cuproptosis-related lncRNAs can potentially serve as reliable diagnostic and prognostic biomarkers for CRC.