Urologic malignancies, encompassing cancers of the kidney, bladder, and prostate, represent approximately 25 % of all cancer cases. Recent advances have enhanced our understanding of PVT1's crucial functions. Long noncoding RNAs influence both the onset and development of cancer, as well as epigenetic alterations. Recent findings have focused on PVT1's mechanism of action across several malignancies, particularly urologic cancers. Understanding the various functions of PVT1 linked to cancer is necessary for the development of cancer detection and treatment when PVT1 is dysregulated. Furthermore, recent advancements in genomic and epigenetic research have elucidated the complex regulatory networks that control PVT1 expression. Comprehending the intricate role of PVT1 Understanding the complex function of PVT1 in urologic cancers has substantial clinical implications. Here, we summarize some of the most recent findings about the carcinogenic effects of PVT1 signaling pathways and the possible treatment strategies for urological malignancies that target these pathways.

Exosomes are extracellular vesicles with a diameter ranging from 40 to 160 nm. They are produced by hepatocytes, cholangiocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs) and Kupffer cells in liver tissue. The secretion of exosomes might vary in quantity and composition in reaction to multiple triggers and various stages of disease. They transport various payloads, such as proteins, DNAs, and RNAs, and enable cell interaction to regulate myriad physiological and pathological processes in liver tissue. Long non-coding RNAs (lncRNAs) are a crucial component of exosomes with an excellent capability to regulate multiple cellular activities such as differentiation, development, metabolism, proliferation, apoptosis, and activation. With the advancements in transcriptomic and genomic study methods and database management technology, the functions and mechanisms of exosomal lncRNAs in liver diseases have been well-studied. This article delves into the detailed role of exosomal lncRNAs in liver disease onset and progression, ranging from hepatocellular carcinoma (HCC) to liver fibrosis drug-induced liver damage (DILI) and steatotic liver diseases.

Hepatocellular carcinoma (HCC) significantly affects the patient's physical and mental health. Long non-coding RNA plasmacytoma variant translocation 1 (lncRNA PVT1) has been associated with the progression of HCC. However, the current effectiveness of HCC treatment is considered insufficient, and the scope of its therapeutic targets is highly limited. The purpose of this investigation is to investigate the pathogenic mechanism of PVT1 in HCC and assess its potential for gene therapy in HCC.

This study assessed cycle phases and proliferative capacity of HCC cells through flow cytometry, CCK-8 assay, EdU, and colony formation assays. Chromatin Immunoprecipitation (ChIP) and Dual-Luciferase Reporter Assays were conducted to investigate the interactions among the promoter and PVT1, PVT1 and its target miRNAs, as well as miRNAs and their target genes. BALB/c nude mice were employed to establish models for studying the proliferation and metastasis of HCC in vivo.

The data revealed that TGF-β1 upregulates PVT1, while Smad3 functions as a transcription factor to modulate PVT1. PVT1, in turn, upregulates Smad6 and NRG1 (Neuregulin 1). Moreover, PVT1 combines with miR-186-5p and miR-143-3p, while miR-186-5p inhibits Smad6 and miR-143-3p inhibits NRG1. Further, in vivo and in vitro analyses revealed that PVT1 stimulates the expression of Smad6, thereby promoting the proliferation of HCC. In addition, PVT1 also promotes the spread of HCC by upregulating NRG1.

This study validated that PVT1 activated by TGF-β1/Smad3 facilitates HCC progression and metastasis by upregulating the miR-186-5p/Smad6 and miR-143-3p/NRG1 axes, indicating its potential as a biological target for treating HCC.

Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality. Many lncRNAs play important regulatory roles in the pathogenesis of HCC, but the mechanism of action of LINC00342 in the progression of HCC remains unclear. In this study, we assessed 24 pairs of HCC tissues and adjacent normal tissues as well as HCC cells and a nude mouse model of HCC. Gene and protein expression was evaluated by flow cytometry, CCK-8, RIP, colony formation assay, and TUNEL staining. This study revealed that LINC00342 was highly expressed in HCC tissues and cells. LINC00342 knockdown significantly inhibited the proliferation and migration of HCC cells, promoted apoptosis, inhibited tumor growth in vivo, and increased the sensitivity of HCC cells to cisplatin. The opposite effect was observed in LINC00342-overexpressing cells. Mechanistically, ZNF384 and m6A methylation can promote the transcription and stability of LINC00342, and LINC00342 can bind to DAPK1, which inhibits Cyt C release and the activation of caspase family proteins to accelerate HCC progression. Our study indicated that the inhibition of LINC00342 expression may represent a new breakthrough for HCC treatment.

Liver metastases are frequently observed in various malignancies, including hepatocellular carcinoma, colorectal cancer, pancreatic cancer, and melanoma. As hepatic resident macrophages, Kupffer cells play a crucial role in resisting liver metastasis by phagocytosing and clearing invading tumor cells. However, the molecular mechanisms regulating Kupffer cell phagocytosis and liver metastasis remain largely unknown. Here, we demonstrate that the MIR670 host gene (MIR670HG) significantly suppresses tumor liver metastasis by enhancing phagocytosis of various tumor cells by Kupffer cells. CD24 was identified as a downstream target and critical mediator of MIR670HG in promoting Kupffer cell phagocytosis and inhibiting tumor liver metastasis. Further investigations revealed that MIR670HG interacts with the m6A reader FXR1 and DNA 5-methylcytosine dioxygenase TET1 in an m6A modification-dependent manner. These interactions reduce the binding of TET1 to CD24 promoter, leading to increased DNA methylation at CD24 promoter and transcriptional suppression of CD24. Mutation of the m6A modification site abolishes the ability of MIR670HG to suppress CD24, promote Kupffer cell phagocytosis, and inhibit liver metastasis. In clinical tissue samples, MIR670HG expression negatively correlated with CD24 and liver metastasis. These findings suggest that m6A-modified MIR670HG promotes phagocytosis of tumor cells by Kupffer cells and suppresses liver metastasis by epigenetically downregulating CD24.

Non-alcoholic fatty liver disease (NAFLD) involves abnormal fat accumulation in the liver, mainly as triglycerides. It ranges from steatosis to non-alcoholic steatohepatitis (NASH), which can lead to inflammation, cellular damage, liver fibrosis, cirrhosis, or hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) are crucial for regulating gene expression across various conditions. LncRNAs are emerging as potential putative diagnostic markers for NAFLD-associated HCC.

We used two human and two mouse datasets from the Gene Expression Omnibus to analyze the expression profiles of mRNAs and lncRNAs. We created a network linking lncRNAs, miRNAs, and mRNAs to investigate the relationships among these RNA types. Additionally, we identified NAFLD-related lncRNAs from existing literature. We then quantified the expression levels of four specific lncRNAs, including PVT1, DUBR, SNHG17, and SNHG14, in the serum of 92 Egyptian participants using qPCR. Finally, we performed a Receiver Operating Characteristic analysis to evaluate the diagnostic potential of the candidate lncRNAs.

Our data suggests that maternally expressed gene 3 (MEG3), H19, and DPPA2 Upstream Binding RNA (DUBR) were significantly upregulated, and plasmacytoma variant translocation 1 (PVT1) was markedly downregulated. PVT1 showed the highest diagnostic accuracy for both NAFLD and NASH. The combined panels of PVT1 +H19 for NAFLD and PVT1 +H19 +DUBR for NASH demonstrated high diagnostic potential. Uniquely, PVT1 can distinguish between NAFLD and NASH. PVT1 exhibited strong diagnostic potential for NAFLD and NASH, individually and in combination with other lncRNAs.

Our study identifies four lncRNAs as putative biomarkers with high specificity and accuracy, individually or combined, for differentiating between NAFLD and NASH. Healthy volunteers with PVT1 possess the highest diagnostic accuracy and significantly discriminate between NAFLD and NASH.

Cancer stands as a leading cause of mortality and poses an escalating threat to global health. Epigenetic dysregulation is pivotal in the onset and advancement of cancer. Recent research on RNA 5-methylcytosine (m5C) methylation has underscored its significant role in cancer. RNA m5C methylation is a key component in gene expression regulation and is intricately linked to cancer development, offering valuable insights for cancer diagnosis, treatment, and prognosis. This review provides an in-depth examination of the three types of regulators associated with RNA m5C methylation and their biological functions. It further investigates the expression and impact of RNA m5C methylation and its regulators in cancer, focusing on their mechanisms in cancer progression and clinical relevance. The current research on inhibitors targeting RNA m5C methylation-related regulators remains underdeveloped, necessitating further exploration and discovery.

CircRNA is stable due to its ring structure and is abundant in humans, which not only exists in various tissues and biofluids steadily but also plays a significant role in the physiology and pathology of human beings. CircPVT1, an endogenous circRNA, has recently been identified from the PVT1 gene located in the cancer risk region 8q24. CircPVT1 is reported to be highly expressed in many different tumors, where it affects tumor cell proliferation, apoptosis, invasion, and migration. We summarize the biosynthesis and biological functions of circPVT1 and analyze the relationship between circPVT1 and tumors as well as its significance to tumors. Further, it's noteworthy for the diagnosis, treatment, and prognosis of cancer patients. Therefore, circPVT1 is likely to become an innovative tumor marker.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies in the world. Oncofetal proteins are the optimal diagnostic biomarkers and therapeutic targets for HCC. As the most abundant modification in RNA, N6-methyladenosine (m6A) has been reported to be involved in HCC initiation and progression. However, whether m6A has oncofetal characteristics remains unknown.

Gene expression in HCC tissues and cells was detected using qPCR. The level of m6A methylation was determined using methylated RNA immunoprecipitation assay. The biological roles of NUTM2B-AS1 in HCC were detected using Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine incorporation, and spheroid formation assays. The mechanisms underlying the roles of NUTM2B-AS1 were explored using RNA immunoprecipitation (RIP), chromatin isolation by RNA purification (ChIRP), chromatin immunoprecipitation (ChIP), and assay for transposase-accessible chromatin (ATAC).

NUTM2B-AS1 was identified as a novel oncofetal long noncoding RNA that was upregulated in the fetal liver and HCC and silenced in adult liver tissues. METTL3 and METTL16 induce m6A hypermethylation of NUTM2B-AS1. The m6A methylation levels of NUTM2B-AS1 exhibit oncofetal characteristics. m6A methylation upregulates NUTM2B-AS1 expression by increasing NUTM2B-AS1 transcript stability. m6A-methylated NUTM2B-AS1 promotes HCC cell proliferation and stemness via epigenetically activating BMPR1A expression. NUTM2B-AS1 specifically binds to BMPR1A promoter. m6A-methylated NUTM2B-AS1 is recognized by the m6A reader YTHDC2, which further binds to the H3K4 methyltransferase MLL1. m6A-methylated NUTM2B-AS1 recruits YTHDC2 and MLL1 to BMPR1A promoter, leading to increased H3K4me3 and chromatin accessibility at BMPR1A promoter. Functional rescue assays suggest that BMPR1A is a critical mediator of the oncogenic role of m6A-methylated NUTM2B-AS1 in HCC.

METTL3- and METTL16-mediated m6A methylation of NUTM2B-AS1 is a novel oncofetal molecular event in HCC that promotes HCC stemness via epigenetically activating BMPR1A transcription.

Despite strides in diagnostic and therapeutic approaches for ESCC, patient survival rates remain relatively low. Recent studies highlight the pivotal role of long non-coding RNAs (lncRNAs) in regulating diverse cellular activities in humans. Dysregulated lncRNAs have emerged as potential diagnostic indicators across various cancers, including ESCC. However, further research is necessary to effectively leverage ESCC-associated lncRNAs in clinical settings. Understanding their clinical significance for ESCC diagnosis and their mechanisms can pave the way for more effective therapeutic strategies. Our qRT-PCR analysis revealed significant downregulation of SOX2-OT (~ 2.02-fold) and NEAT1 (~ 1.53-fold) in ESCC blood samples. These lncRNAs show potential as biomarkers for distinguishing ESCC patients from healthy individuals, with ROC curves and AUC values of 0.736 for SOX2-OT and 0.621 for NEAT1. Further analysis examined the correlation between SOX2-OT and NEAT1 expression and various clinicopathological factors, including age, gender, smoking, alcohol use, hot beverage intake, tumor grade, and TNM stages. In-silico studies highlighted their roles in miRNA sponging via mTOR and MAPK pathways, while co-expression network analysis identified associated genes. This research paves the way for future studies on ESCC prognosis using SOX2-OT and NEAT1 as predictive markers. By thoroughly investigating the functions of these lncRNAs, we aim to deepen our understanding of their potential as diagnostic markers and their role in facilitating effective therapeutic interventions for esophageal squamous cell carcinoma (ESCC) within clinical contexts.

The expression of the long noncoding RNA (lncRNA) TPTE pseudogene 1 (TPTEP1) is significantly downregulated in ovarian cancer (OC). However, the function and mechanism of the lncRNA TPTEP1 in OC have not been identified. To investigate the expression of the lncRNA TPTEP1, we analysed a publicly available dataset and 20 pairs of OC and normal ovarian samples tissue from the First Affiliated Hospital of Anhui Medical University. Functional assays were used to determine the role of the lncRNA TPTEP1 in OC progression. Furthermore, Western blot, FISH, RNA pull-down, mass spectrometry and RNA immunoprecipitation approaches were used to determine the mechanism by which the lncRNA TPTEP1 affects OC progression. Animal experiments were used to determine the role of the lncRNA TPTEP1 in ovarian tumorigenicity in vivo. The expression of the lncRNA TPTEP1 in OC tissues was significantly lower than that in normal tissues and low expression of the lncRNA TPTEP1 was significantly correlated with advanced FIGO stage and the presence of malignant ascites in OC patients. In vitro and in vivo, regulation of the expression of the lncRNA TPTEP1 caused changes in OC cell proliferation, migration, invasion and apoptosis. Mechanistically, we found that TPTEP1 directly binds to the polypyrimidine tract-binding protein 1 (PTBP1) protein and inhibits PI3K/AKT signalling. The lncRNA TPTEP1 inhibits PI3K/AKT signalling by directly binding PTBP1, possibly indicating the molecular mechanism underlying its biological function. With further research, these findings may aid in the development of clinically useful strategies for the treatment of OC.

Long-stranded non-coding RNAs (lncRNA) have important roles in disease as transcriptional regulators, mRNA processing regulators and protein synthesis factors. However, traditional methods for detecting lncRNA are time-consuming and labor-intensive, and the functions of lncRNA are still being explored. Here, we present a surface enhanced Raman spectroscopy (SERS) based biosensor for the detection of lncRNA associated with liver cancer (LC) as well as in situ cellular imaging. Using the dual SERS probes, quantitative detection of lncRNA (DAPK1-215) can be achieved with an ultra-low detection limit of 952 aM by the target-triggered assembly of core-satellite nanostructures. And the reliability of this assay can be further improved with the R2 value of 0.9923 by an internal standard probe that enables the signal dynamic calibration. Meanwhile, the high expression of DAPK1-215 mainly distributed in the cytoplasm was observed in LC cells compared with the normal ones using the SERS imaging method. Moreover, results of cellular function assays showed that DAPK1-215 promoted the migration and invasion of LC by significantly reducing the expression of the structural domain of death associated protein kinase. The development of this biosensor based on SERS can provide a sensitive and specific method for exploring the expression of lncRNA that would be a potential biomarker for the screening of LC.

Hepatocellular carcinoma (HCC) is the most common digestive malignancyin the world, which is frequently diagnosed at late stage with a poor prognosis. For most patients with advanced HCC, the therapeutic options arelimiteddue to cancer occurrence of drug resistance. Hepatic cancer stem cells (CSCs) account for a small subset of tumor cells with the ability of self-renewal and differentiationin HCC. It is widely recognized that the presence of CSCs contributes to primary and acquired drug resistance. Therefore, hepatic CSCs-targeted therapy is considered as a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC. In this article, we review drug resistance in HCC and provide a summary of potential targets for CSCs-based therapy. In addition, the development of CSCs-targeted therapeuticsagainst drug resistance in HCC is summarized in both preclinical and clinical trials. The in-depth understanding of CSCs-related drug resistance in HCC will favor optimization of the current therapeutic strategies and gain encouraging therapeutic outcomes.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer with a high death rate in the world. The molecular mechanisms related to the pathogenesis of HCC have not been precisely defined so far. Hence, this review aimed to address the potential cross-talk between noncoding RNAs (ncRNAs) and programmed cell death in HCC. All related papers in the English language up to June 2023 were collected and screened. The searched keywords in scientific databases, including Scopus, PubMed, and Google Scholar, were HCC, ncRNAs, Epigenetic, Programmed cell death, Autophagy, Apoptosis, Ferroptosis, Chemoresistance, Tumor recurrence, Prognosis, and Prediction. According to the reports, ncRNAs, comprising long ncRNAs, microRNAs, circular RNAs, and small nucleolar RNAs can affect cell proliferation, migration, invasion, and metastasis, as well as cell death-related processes, such as autophagy, ferroptosis, necroptosis, and apoptosis in HCC by regulating cancer-associated genes and signaling pathways, for example, phosphoinositide 3-kinase/Akt, extracellular signal-regulated kinase/MAPK, and Wnt/β-catenin signaling pathways. It seems that ncRNAs, as epigenetic regulators, can be utilized as biomarkers in diagnosis, prognosis, survival and recurrence rates prediction, chemoresistance, and evaluation of therapeutic response in HCC patients. However, more scientific evidence is suggested to be accomplished to confirm these results.

For the first time, a subset of small cancer cells identified in acute myeloid leukemia has been termed Cancer Stem Cells (CSCs). These cells are notorious for their robust proliferation, self-renewal abilities, significant tumor-forming potential, spread, and resistance to treatments. CSCs are a global concern, as it found in numerous types of cancer, posing a real-world challenge today. Our review encompasses research on key CSC markers, signaling pathways, and MicroRNA in three types of cancer: breast, colon, and liver. These factors play a critical role in either promoting or inhibiting cancer cell growth. The reviewed studies have shown that as cells undergo malignant transformation, there can be an increase or decrease in the expression of different Cluster of Differentiation (CD) markers on their surface. Furthermore, alterations in essential signaling pathways, such as Wnt and Notch1, may impact CSC proliferation, survival, and movement, while also providing potential targets for cancer therapies. Additionally, some research has focused on MicroRNAs due to their dual role as potential therapeutic biomarkers and their ability to enhance CSCs' response to anti-cancer drugs. MicroRNAs also regulate a wide array of cellular processes, including the self-renewal and pluripotency of CSCs, and influence gene transcription. Thus, these studies indicate that MicroRNAs play a significant role in the malignancy of various tumors. Although the gathered information suggests that specific CSC markers, signaling pathways, and MicroRNAs are influential in determining the destiny of cancer cells and could be advantageous for therapeutic strategies, their precise roles and impacts remain incompletely defined, necessitating further investigation.

Recent studies have shown that NOP2, a nucleolar protein, is up-regulated in various cancers, suggesting a potential link to tumor aggressiveness and unfavorable outcomes. This study examines NOP2's role in lung adenocarcinoma (LUAD), a context where its implications remain unclear. Utilizing bioinformatics, we assessed 513 LUAD and 59 normal tissue samples from The Cancer Genome Atlas (TCGA) to explore NOP2's diagnostic and prognostic significance in LUAD. Additionally, in vitro experiments compared NOP2 expression between Beas-2b and A549 cells. Advanced databases and analytical tools, including LINKEDOMICS, STRING, and TISIDB, were employed to further elucidate NOP2's association with LUAD. Our findings indicate a significantly higher expression of NOP2 mRNA and protein in A549 cells compared to Beas-2b cells (P < 0.001). In LUAD, elevated NOP2 levels were linked to decreased Overall Survival (OS) and advanced clinical stages. Univariate Cox analysis revealed that high NOP2 expression correlated with poorer OS in LUAD (P < 0.01), a finding independently supported by multivariate Cox analysis (P < 0.05). The relationship between NOP2 expression and LUAD risk was presented via a Nomogram. Additionally, Gene Set Enrichment Analysis (GSEA) identified seven NOP2-related signaling pathways. A focal point of our research was the interplay between NOP2 and tumor-immune interactions. Notably, a negative correlation was observed between NOP2 expression and the immune infiltration levels of macrophages, neutrophils, mast cells, Natural Killer (NK) cells, and CD8 + T cells in LUAD. Moreover, the expression of NOP2 was related to the sensitivity of various chemotherapeutic drugs. In vitro, we found that downregulating NOP2 can decrease the proliferation, migration and invasion of A549 cells. Furthermore, NOP2 can regulate Caspase3-mediated apoptosis. Collectively, particularly regarding prognosis, immune infiltration and vitro experiments, these findings suggest NOP2's potential of serving as a poor-prognostic biomarker for LUAD and aggravating the malignancy of lung adenocarcinoma cells.

Hepatocellular carcinoma (HCC) is a prevalent liver malignancy with complex etiology and generally poor prognosis. Recently, long non-coding RNAs (lncRNAs), non-protein-coding RNA molecules exceeding 200 nucleotides, have emerged as pivotal players in HCC, influencing its initiation, progression, invasion, and metastasis. These lncRNAs modulate gene expression at epigenetic, transcriptional, and post-transcriptional levels, actively participating in the pathological and physiological processes of HCC. Understanding the intricate relationship between lncRNAs and HCC is important for improving prognosis and reducing mortality. This review summarizes advancements in elucidating the role of lncRNAs in HCC pathogenesis.

Hepatocellular carcinoma (HCC) presents a significant global health threat, particularly in regions endemic to hepatitis B and C viruses, and because of the ongoing pandemic of obesity causing metabolic-dysfunction-related fatty liver disease (MAFLD), a precursor to HCC. The molecular intricacies of HCC, genetic and epigenetic alterations, and dysregulated signaling pathways facilitate personalized treatment strategies based on molecular profiling. Epigenetic regulation, encompassing DNA methyltion, histone modifications, and noncoding RNAs, functions as a critical layer influencing HCC development. Long noncoding RNAs (lncRNAs) are spotlighted for their diverse roles in gene regulation and their potential as diagnostic and therapeutic tools in cancer. In this review, we explore the pivotal role of lncRNAs in HCC, including MAFLD and viral hepatitis, the most prevalent risk factors for hepatocarcinogenesis. The dysregulation of lncRNAs is implicated in HCC progression by modulating chromatin regulation and transcription, sponging miRNAs, and influencing structural functions. The ongoing studies on lncRNAs contribute to a deeper comprehension of HCC pathogenesis and offer promising routes for precision medicine, highlighting the utility of lncRNAs as early biomarkers, prognostic indicators, and therapeutic targets.

Cancer stemness and osteosarcoma (OS) malignant progression are closely associated. However, the molecular mechanisms underlying this association have not been fully demonstrated. Long noncoding RNAs (lncRNAs) are an intriguing class of widely prevalent endogenous RNAs involved in OS progression, the vast majority of which have not been characterized functionally. Here, we identified tumor promoter lncRNA WAC-AS1 to be highly expressed in OS tumors and associated with worse survival. Further analysis revealed that WAC-AS1 increased tumorsphere formation of OS cells and promoted metastasis, as confirmed by cell proliferation, transwell and wound healing assays. MiR-5047 was identified as a downstream target of WAC-AS1. Subsequently, based on bioinformatics analysis, RIP assay and luciferase reporter assay, SOX2 mRNA was verified as a target of miR-5047. WAC-AS1 enhanced OS cell proliferation and stemness via acting as a ceRNA by binding to miR-5047, thereby increasing SOX2 expression. In addition, SOX2 bound to the promoter region of WAC-AS1 and promoted its transcription, thereby forming a positive feedback loop to regulate OS malignancy. Taken together, our findings show WAC-AS1 is a tumor promoter and a key regulator of OS cell stemness and metastasis via a miR-5047/SOX2 axis.

The unique expression pattern endows oncofetal genes with great value in cancer diagnosis and treatment. However, only a few oncofetal genes are available for clinical use and the underlying mechanisms that drives the fetal-like reprogramming of cancer cells remain largely unknown.

Microarray assays and bioinformatic analyses were employed to screen for potential oncofetal long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC). The expression levels of MIR4435-2HG, NOP58 ribonucleoprotein (NOP58), insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) and stem markers were detected by quantitative polymerase chain reaction. The 2'-O-methylation (2'-O-Me) status of rRNA were detected through reverse transcription at low dNTP concentrations followed by PCR. The regulation of MIR4435-2HG by IGF2BP1 was explored by RNA immunoprecipitation (RIP), methylated RIP (MeRIP) and dual-luciferase assays. The interaction between MIR4435-2HG and NOP58 was investigated by RNA Pulldown, RIP and protein stability assays. In vitro and in vivo function assays were performed to detect the roles of MIR4435-2HG/NOP58 in HCC.

MIR4435-2HG was an oncofetal lncRNA associated with poor prognosis in HCC. Functional experiments showed that overexpression of MIR4435-2HG remarkably enhanced the stem-cell properties of HCC cells, promoting tumorigenesis in vitro and in vivo. Mechanically, MIR4435-2HG directly bound NOP58 and IGF2BP1. IGF2BP1 upregulated MIR4435-2HG expression in HCC through N6-methyladenosine (m6A) modification. Moreover, MIR4435-2HG protected NOP58 from degradation, which raised rRNA 2'-O-Me levels and promoted internal ribosome entry site (IRES)-dependent translation of oncogenes.

This study identified an oncofetal lncRNA MIR4435-2HG, characterized the role of MIR4435-2HG/NOP58 in stemness maintenance and proliferation of HCC cells, and confirmed m6A as a 'driver' that reactivated MR4435-2HG expression in HCC.

Renal cancer stem cells (RCSCs) derived from clear cell renal cell carcinoma (ccRCC) tissues with higher microvessel density (MVD) have strong stemness and endothelial progenitor cells-like (EPCs-like) characteristics. A high level of lncRNA PVT1 expression is essential for simultaneously retaining strong RCSC stemness and EPCs-like characteristics. PVT1 binds with TAZ protein and prevents its phosphorylation, which promotes RCSC stemness. Moreover, RCSCs support endothelial differentiation and angiogenesis, which are mediated via the PVT1/miR-15b/KDR axis. This report provides insight into the determinants of RCSC impact on stemness and highlights the critical role of RCSC in angiogenesis. The presented findings suggest that targeting RCSC through PVT1 expression may be a new treatment strategy for ccRCC.

Colorectal cancer (CRC) is the third most common cause of cancer-related deaths. The five-year relative survival rate for CRC is estimated to be approximately 90% for patients diagnosed with early stages and 14% for those diagnosed at an advanced stages of disease, respectively. Hence, the development of accurate prognostic markers is required. Bioinformatics enables the identification of dysregulated pathways and novel biomarkers. RNA expression profiling was performed in CRC patients from the TCGA database using a Machine Learning approach to identify differential expression genes (DEGs). Survival curves were assessed using Kaplan-Meier analysis to identify prognostic biomarkers. Furthermore, the molecular pathways, protein-protein interaction, the co-expression of DEGs, and the correlation between DEGs and clinical data have been evaluated. The diagnostic markers were then determined based on machine learning analysis. The results indicated that key upregulated genes are associated with the RNA processing and heterocycle metabolic process, including C10orf2, NOP2, DKC1, BYSL, RRP12, PUS7, MTHFD1L, and PPAT. Furthermore, the survival analysis identified NOP58, OSBPL3, DNAJC2, and ZMYND19 as prognostic markers. The combineROC curve analysis indicated that the combination of C10orf2 -PPAT- ZMYND19 can be considered as diagnostic markers with sensitivity, specificity, and AUC values of 0.98, 1.00, and 0.99, respectively. Eventually, ZMYND19 gene was validated in CRC patients. In conclusion, novel biomarkers of CRC have been identified that may be a promising strategy for early diagnosis, potential treatment, and better prognosis.

Clear cell Renal Cell Carcinoma (ccRCC) is a highly heterogeneous disease, making it challenging to predict prognosis and therapy efficacy. In this study, we aimed to explore the role of 5-methylcytosine (m5C) RNA modification in ccRCC and its potential as a predictor for therapy response and overall survival (OS). We established a novel 5-methylcytosine RNA modification-related gene index (M5CRMRGI) and studied its effect on the tumor microenvironment (TME) using single-cell sequencing data for in-depth analysis, and verified it using spatial sequencing data. Our results showed that M5CRMRGI is an independent predictor of OS in multiple datasets and exhibited outstanding performance in predicting the OS of ccRCC. Distinct mutation profiles, hallmark pathways, and infiltration of immune cells in TME were observed between high- and low-M5CRMRGI groups. Single-cell/spatial transcriptomics revealed that M5CRMRGI could reprogram the distribution of tumor-infiltrating immune cells. Moreover, significant differences in tumor immunogenicity and tumor immune dysfunction and exclusion (TIDE) were observed between the two risk groups, suggesting a better response to immune checkpoint blockade therapy of the high-risk group. We also predicted six potential drugs binding to the core target of the M5CRMRGI signature via molecular docking. Real-world treatment cohort data proved once again that high-risk patients were appropriate for immune checkpoint blockade therapy, while low-risk patients were appropriate for Everolimus. Our study shows that the m5C modification landscape plays a role in TME distribution. The proposed M5CRMRGI-guided strategy for predicting survival and immunotherapy efficacy, we reported here, might also be applied to more cancers other than ccRCC.

Long non-coding RNAs (lncRNAs) have been shown to be associated with the pathogenesis of different kinds of diseases and play important roles in various biological processes. Although numerous lncRNAs have been found, the functions of most lncRNAs and physiological/pathological significance are still in its infancy. Meanwhile, their expression patterns and regulation mechanisms are also far from being fully understood.

In order to reveal functional lncRNAs and identify the key lncRNAs, we develop a new sparse independence component analysis (ICA) method to identify lncRNA-mRNA-miRNA expression co-modules based on the competitive endogenous RNA (ceRNA) theory using the sample-matched lncRNA, mRNA and miRNA expression profiles. The expression data of the three RNA combined together is approximated sparsely to obtain the corresponding sparsity coefficient, and then it is decomposed by using ICA constraint optimization to obtain the common basis and modules. Subsequently, affine propagation clustering is used to perform cluster analysis on the common basis under multiple running conditions to obtain the co-modules for the selection of different RNA elements.

We applied sparse ICA to Liver Hepatocellular Carcinoma (LIHC) dataset and the experiment results demonstrate that the proposed sparse ICA method can effectively discover biologically functional expression common modules.

It may provide insights into the function of lncRNAs and molecular mechanism of LIHC. Clinical and Translational Impact Statement-The results on LIHC dataset demonstrate that the proposed sparse ICA method can effectively discover biologically functional expression common modules, which may provide insights into the function of IncRNAs and molecular mechanism of LIHC.

Super-enhancer (SE) plays a vital role in the determination of cell identity and fate. Up-regulated expression of coding genes is frequently associated with SE. However, the transcription dysregulation driven by SE, from the viewpoint of long non-coding RNA (lncRNA), remains unclear. Here, SE-associated lncRNAs in HCC are comprehensively outlined for the first time. This study integrally screens and identifies several novel SE-associated lncRNAs that are highly abundant and sensitive to JQ1. Especially, HSAL3 is identified as an uncharacterized SE-driven oncogenic lncRNA, which is activated by transcription factors HCFC1 and HSF1 via its super-enhancer. HSAL3 interference negatively regulates NOTCH signaling, implying the potential mechanism of its tumor-promoting role. The expression of HSAL3 is increased in HCC samples, and higher HSAL3 expression indicates an inferior overall survival of HCC patients. Furthermore, siHSAL3 loaded nanoparticles exert anti-tumor effect on HCC in vitro and in vivo. In conclusion, this is the first comprehensive survey of SE-associated lncRNAs in HCC. HSAL3 is a novel SE-driven oncogenic lncRNA, and siHSAL3 loaded nanoparticles are therapeutic candidates for HCC. This work sheds lights on the merit of anchoring SE-driven oncogenic lncRNAs for HCC treatment.

Hepatocellular carcinoma (HCC) is a symptomatic disease involed multi-stage program. Here, we elucidated the molecular mechanism of LncTUG1 in the regulation of HCC evolvement. And that may in all likelyhood supply a innovative latent target for HCC's diagnoses and prognosis. LncRNA TUG1, miR-144-3p, RRAGD and mTOR signaling pathway were screened as target genes in the database, and their expression levels at the cytological level were verified utilized qRT-PCR, Western Blot and immunohistochemistry. Then, we adopted CCK-8, Transwell and flow cytometry assays to estimate cell proliferation, invasion and apoptosis. By use of luciferase reporter assay, the relationships of LncRNA TUG1, miR-144-3p and RRAGD was confirmed. In addition, the LncRNA TUG1-miR-144-3p-RRAGD-mTOR signaling pathway in HCC cells was verified adopted rescue experiment and confirmed by xenotransplantation animal experiment. LncTUG1 in HCC tissues from three databases were identified and further verified through qRT-PCR in HCC cells (Huh7, Hep3B). Knockdown the LncTUG1 could increase apoptosis and inhibite invasion and proliferation in HCC cells. Using inhibitors and activators of the mTOR/S6K pathway, LncTUG1 was confirmed to regulate HCC progression by the mTOR/S6K pathway. Luciferase reporter assay demonstrated that TUG1 negatively regulates miR-144-3p. Furthermore, miR-144-3p negativly regulates RRAGD by way of interacting with the 3'UTR of the RRAGD mRNA in HCC utilized luciferase reporter assay. In vivo, we also discovered that neoplasm weight and tumor volume reduced significantly in subcutaneous xenograft nude mouse models derived from sh-LncTUG1-expressing Huh7 cells. And the expressions of p-mTOR, p-S6K and RRAGD were decreased obviously while the miR144-3p increased in subcutaneous xenograft nude mouse models. In a word, the research suggests that LncTUG1 targets miR-144-3p while miR-144-3p binds to RRAGD mRNA, which induces mTOR/S6K pathway activation and promotes the progression of HCC.

Cancer is one of the leading causes of death worldwide, primarily due to the dearth of efficient therapies that result in long-lasting remission. This is especially true in cases of metastatic cancer where drug resistance causes the disease to recur after treatment. One of the factors contributing to drug resistance, metastasis, and aggressiveness of the cancer is cancer stem cells (CSCs) or tumor-initiating cells. As a result, CSCs have emerged as a potential target for drug development. In the present review, we have examined and highlighted the lncRNAs with their regulatory functions specific to CSCs. Moreover, we have discussed the difficulties and various methods involved in identifying lncRNAs that can play a particular role in regulating and maintaining CSCs. Interestingly, this review only focuses on those lncRNAs with strong functional evidence for CSC specificity and the mechanistic role that allows them to be CSC regulators and be the focus of CSC-specific drug development.

Hepatocellular carcinoma (HCC) remains a global health challenge, representing the third leading cause of cancer deaths worldwide. Although therapeutic advances have been made in the few last years, the prognosis remains poor. Thus, there is a dire need to develop novel therapeutic strategies. In this regard, two approaches can be considered: (1) the identification of tumor-targeted delivery systems and (2) the targeting of molecule(s) whose aberrant expression is confined to tumor cells. In this work, we focused on the second approach. Among the different kinds of possible target molecules, we discuss the potential therapeutic value of targeting non-coding RNAs (ncRNAs), which include micro interfering RNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). These molecules represent the most significant RNA transcripts in cells and can regulate many HCC features, including proliferation, apoptosis, invasion and metastasis. In the first part of the review, the main characteristics of HCC and ncRNAs are described. The involvement of ncRNAs in HCC is then presented over five sections: (a) miRNAs, (b) lncRNAs, (c) circRNAs, (d) ncRNAs and drug resistance and (e) ncRNAs and liver fibrosis. Overall, this work provides the reader with the most recent state-of-the-art approaches in this field, highlighting key trends and opportunities for more advanced and efficacious HCC treatments.

Near 70% of hepatocellular carcinoma (HCC) recurrence is early recurrence within 2-year post surgery. Long non-coding RNAs (lncRNAs) are intensively involved in HCC progression and serve as biomarkers for HCC prognosis. The aim of this study is to construct a lncRNA-based signature for predicting HCC early recurrence.

Data of RNA expression and associated clinical information were accessed from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) database. Recurrence associated differentially expressed lncRNAs (DELncs) were determined by three DEG methods and two survival analyses methods. DELncs involved in the signature were selected by three machine learning methods and multivariate Cox analysis. Additionally, the signature was validated in a cohort of HCC patients from an external source. In order to gain insight into the biological functions of this signature, gene sets enrichment analyses, immune infiltration analyses, as well as immune and drug therapy prediction analyses were conducted.

A 4-lncRNA signature consisting of AC108463.1, AF131217.1, CMB9-22P13.1, TMCC1-AS1 was constructed. Patients in the high-risk group showed significantly higher early recurrence rate compared to those in the low-risk group. Combination of the signature, AFP and TNM further improved the early HCC recurrence predictive performance. Several molecular pathways and gene sets associated with HCC pathogenesis are enriched in the high-risk group. Antitumor immune cells, such as activated B cell, type 1 T helper cell, natural killer cell and effective memory CD8 T cell are enriched in patients with low-risk HCCs. HCC patients in the low- and high-risk group had differential sensitivities to various antitumor drugs. Finally, predictive performance of this signature was validated in an external cohort of patients with HCC.

Combined with TNM and AFP, the 4-lncRNA signature presents excellent predictability of HCC early recurrence.

Long non-coding RNAs have been implicated in various cancers as they regulate critical cellular processes such as proliferation, migration, invasion, and apoptosis in tumorous tissues. lncRNA-PNUTS is newly reported as an alternatively-spliced lncRNA from PNUTS pre-mRNA that promotes oncogenesis in breast cancer. However, whether LncRNA-PNUTS plays a role in other forms of cancers, such as liver cancer, remains unknown.

In the current study, we investigated the potential role of lncRNA-PNUTS in hepatocellular carcinoma (HCC). The levels of lncRNA-PNUTS in tumorous tissues obtained from HCC patients were measured. The potential impacts of lncPNUTS on metastasis and invasion were investigated through gain- or loss- of function experiments in cell models of liver cancers, as well as other cellular assays such as trans-well assays and wound-healing assays.

Here, we report that lncPNUTS was upregulated in human HCC tissues. Loss- and gain-of-function experiments indicated lncPNUTS promoted metastasis and invasion. In addition, ZEB1, which is involved in the activation of epithelial-mesenchymal-transition (EMT), was identified as a downstream target of lncPNUTS.

Our findings indicated lncPNUTS promotes HCC cancer cell metastasis and invasion via targeting ZEB1 to activate the EMT pathway, suggesting that lncPNUTS is a potential prognostic marker and therapeutic target for HCC patients.

To explore the functions of the polymorphisms in 5-methylcytosine (m5C) modification-related coding genes on the susceptibility of pediatric acute lymphoblastic leukemia (ALL).

Case-control study and multinomial logistic regression analysis were performed to construct models to evaluate the susceptibility of pediatric ALL. The relationship between five functional SNPs in m5C modification-coding genes and pediatric ALL risk was analyzed. Genotyping of 808 cases and 1,340 healthy samples from South China was identified using a TaqMan assay; odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the relationship between the five selected SNPs and pediatric ALL susceptibility.

Among the five analyzed SNPs, NOL1 rs3764909 and NSUN4 rs10252 variants significantly increased the susceptibility of pediatric ALL, while NSUN3 rs7653521, NSUN5 rs1880948, and NSUN6 rs3740102 variants were not associated with the risk of ALL. Stratification analyses demonstrated that NOL1 rs3764909 C>A exhibited a significant association with increased pediatric ALL risk in subgroups of common B ALL, pre-B ALL, T-cell ALL, low and middle risk, other gene fusion types, non-gene fusion, hypodiploid, normal diploid, primitive lymphocytes in marrow < 5% on week 12, and minimal residual disease (MRD) <0.01% on week 12 after induced therapy; NSUN4 rs10252 G>A was related to increased risk of ALL children in subgroups of age ≥ 120 months, normal white blood cell (WBC) number, middle risk, non-gene fusion, MRD ≥ 0.01 on days 15-19, and primitive lymphocytes in marrow < 5% on day 33 after induced therapy. Compared with the reference haplotype CAGTA, children who harbored haplotypes CCGTG and ACATA were remarkably related to increased ALL susceptibility. rs3764909 and rs10252 varieties of alleles were not associated with MRD levels after the selected chemotherapeutics.

In conclusion, NOL1 rs3764909 and NSUN4 rs10252 variants were enhanced by pediatric ALL risk and were suggested to be potential biomarkers for pediatric ALL.

All cell types express long non-coding RNAs (lncRNAs), which have the potential to play a role in carcinogenesis by altering the levels of their expression. Squamous cell carcinoma of the esophagus (ESCC) is a deadly disease with a poor prognosis and a high frequency of lymphatic metastases. Understanding the functional role and signaling pathways of two neighboring lncRNAs, CCAT1 and PVT1, in this oncogene's pathogenesis may help us determine ESCC. Furthermore, it is still unclear whether these lncRNAs are linked to the clinicopathological characteristics of patients with ESCC.

For this study, we used biopsy from the Imam Khomeini Cancer Institute's tumor bank in Tehran, Iran to obtain 40 ESCC tumor samples and their normal margin counterparts. The expression levels of the CCAT1, PVT1, and c-MYC genes were assessed using quantitative Real-Time RT-PCR. Additionally, demographic data and clinical-pathologic characteristics, such as tumor grade, tumor stage, lymph node, and metastasis, were taken into consideration. Graphpad prism version 8 was used for bioinformatics analyses.

Comparing ESCC tissues to non-tumor tissues, we found significant upregulation of PVT1, CCAT1, and c-MYC. Patients with ESCC who had increased PVT1 expression also had higher rates of advanced stage and lymph node metastasis, whereas increased CCAT1 expression was only linked to advanced stage and wasn't associated with lymph node metastasis. In predicting ESCC, CCAT1 (p < 0.05) was found to be an important factor. Overall survival was reduced by c-MYC and PVT1 overexpression (p < 0.001), according to Kaplan-Meier analysis. PVT1, CCAT1, and c-MYC were found to interact with 23 miRNAs with high and medium score classes, as shown in a bioinformatics study. We summarized the experimentally proven interactions between c-MYC, PVT1, and CCAT1 and other miRNAs, lncRNAs, and proteins.

This is the first report that CCAT1, PVT1 and c-MYC have been found to be up-regulated simultaneously in ESCC. It is possible that these genes may be involved in ESCC as a result of these findings. Therefore, as consequence, more research is needed to determine whether or not these lncRNAs play an oncogenic role in ESCC development and progression, as well as the regulatory mechanisms that control them.

Microvascular invasion (MVI) is an independent detrimental risk factor for tumor recurrence and poor survival in hepatocellular carcinoma (HCC). Competitive endogenous RNA (ceRNA) networks play a pivotal role in the modulation of carcinogenesis and progression among diverse tumor types. However, whether the ceRNA mechanisms are engaged in promoting the MVI process in patients with HCC remains unknown.

A ceRNA regulatory network was constructed based on RNA-seq data of patients with HCC from The Cancer Genome Atlas (TCGA) database. In total, 10 hub genes of the ceRNA network were identified using four algorithms: "MCC," "Degree," "Betweenness," and "Stress." Transcriptional expressions were verified by in situ hybridization using clinical samples. Interactions between ceRNA modules were validated by luciferase reporting assay. Logistic regression analysis, correlation analysis, enrichment analysis, promoter region analysis, methylation analysis, and immune infiltration analysis were performed to further investigate the molecular mechanisms and clinical transformation value.

The ceRNA regulatory network featuring a tumor invasion phenotype consisting of 3 long noncoding RNAs, 3 microRNAs, and 93 mRNAs was constructed using transcriptional data from the TCGA database. Systemic analysis and experimentally validation identified a ceRNA network (PVT1/miR-1258/DUSP13 axis) characterized by lipid regulatory potential, immune properties, and abnormal methylation states in patients with HCC and MVI. Meanwhile, 28 transcriptional factors were identified as potential promotors of PVT1 with 3 transcriptional factors MXD3, ZNF580, and KDM1A promising as therapeutic targets in patients with HCC and MVI. Furthermore, miR-1258 was an independent predictor for MVI in patients with HCC.

The PVT1/DUSP13 axis is significantly associated with MVI progression in HCC patients. This study provides new insight into mechanisms related to lipids, immune phenotypes, and abnormal epigenetics in oncology research.

Osteosarcoma, the most common pediatric bone tumor, is an aggressive heterogeneous malignancy defined by complex chromosomal aberrations. Overall survival rates remain at ~70%, but patients with chemoresistant or metastatic disease have extremely poor outcomes of <30%. A subgroup of tumors harbor amplification of chromosome 8q24.2 and increased expression of the oncogenic long noncoding RNA (lncRNA) Plasmacytoma Variant Translocation-1 (PVT-1), which is associated with an extremely poor clinical prognosis. This study demonstrates that PVT-1 is critical for osteosarcoma tumor-initiation potential. Chromatin Hybridization by RNA Purification analysis identified Tripartite-Motif Containing Family 28 (TRIM28) as a novel PVT-1 binding partner. Mechanistically, co-immunoprecipitation studies showed the PVT-1/TRIM28 complex binds and increases SUMOylation of phosphatidylinositol 3-kinase catalytic subunit type 3 (Vps34), which leads to enhanced ubiquitination and degradation of tumor suppressor complex 2 (TSC2), thus contributing to increased self-renewal and stem cell phenotypes. Furthermore, we identified that osteosarcoma cells with increased PVT-1 have enhanced sensitivity to the SUMOylation inhibitor, TAK-981. Altogether, this study elucidated a role for PVT-1 in the enhancement of cancer stem-like behaviors, including migration and invasion, in osteosarcoma, and identified the novel PVT-1/TRIM28 axis signaling cascade as a potential therapeutic target for osteosarcoma treatment.

Oncogenes or tumor suppressor genes are rarely mutated in several pediatric tumors and some early stage adult cancers. This suggests that an aberrant epigenetic reprogramming may crucially affect the tumorigenesis of these tumors. Compelling evidence support the hypothesis that cancer stem cells (CSCs), a cell subpopulation within the tumor bulk characterized by self-renewal capacity, metastatic potential and chemo-resistance, may derive from normal stem cells (NSCs) upon an epigenetic deregulation. Thus, a better understanding of the specific epigenetic alterations driving the transformation from NSCs into CSCs may help to identify efficacious treatments to target this aggressive subpopulation. Moreover, deepening the knowledge about these alterations may represent the framework to design novel therapeutic approaches also in the field of regenerative medicine in which bioengineering of NSCs has been evaluated. Here, we provide a broad overview about: 1) the role of aberrant epigenetic modifications contributing to CSC initiation, formation and maintenance, 2) the epigenetic inhibitors in clinical trial able to specifically target the CSC subpopulation, and 3) epigenetic drugs and stem cells used in regenerative medicine for cancer and diseases.