Reciprocal Interactions Between Apelin and Noncoding RNAs in Cancer Progression.

Apelin, a bioactive peptide that serves as an endogenous ligand for the apelin receptor (APJ), is overexpressed in various types of cancers and contributes to cancer cell proliferation, viability, migration, angiogenesis, and metastasis, as well as immune deviation. Noncoding RNAs (ncRNAs) regulate gene expression, and there is growing evidence suggesting a bidirectional crosstalk between ncRNAs (including long noncoding RNAs [lncRNAs], circular RNAs [circRNAs], and microRNAs [miRNAs]) and apelin in cancers. Certain miRNAs can directly target the apelin and inhibit its expression, thereby suppressing tumor growth. It has been indicated that miR-224, miR-195/miR-195-5p, miR-204-5p, miR-631, miR-4286, miR-637, miR-4493, and miR-214-3p target apelin mRNA and influence its expression in prostate cancer, lung cancer, esophageal cancer, chondrosarcoma, melanoma, gastric cancer, glioma, and hepatocellular carcinoma (HCC), respectively. Moreover, circ-NOTCH1, circ-ZNF264, and lncRNA BACE1-AS upregulate apelin expression in gastric cancer, glioma, and HCC, respectively. On the other hand, apelin has been shown to regulate the expression of certain ncRNAs to affect tumorigenesis. It was revealed that apelin affects the expression of circ_0000004/miR-1303, miR-15a-5p, and miR-106a-5p in osteosarcoma, lung cancer, and prostate cancer, respectively. This review explains a bidirectional interplay between ncRNAs and apelin in cancers to provide insights concerning the molecular mechanisms underlying this crosstalk and potential implications for cancer therapy.

A comprehensive review on lncRNA LOXL1-AS1: molecular mechanistic pathways of lncRNA LOXL1-AS1 in tumorigenicity of cancer cells.

Long non-coding RNAs (lncRNAs) are versatile RNAs that regulate various cellular processes, such as gene regulation, by acting as signals, decoys, guides, and scaffolds. A novel recognized lncRNA, LOXL1-antisense RNA 1 (LOXL1-AS1), is dysregulated in some diseases, including cancer, and acts as an oncogenic lncRNA in many types of cancer cells. Upregulation of LOXL1-AS1 has been involved in proliferation, migration, metastasis, and EMT, as well as inhibiting apoptosis in cancer cells. Most importantly, the malignant promoting activity of LOXL1-AS1 can be mostly mediated by sequestering specific miRNAs and inhibiting their binding to the 3´UTR of their target mRNAs, thereby indirectly regulating gene expression. Additionally, LOXL1-AS1 can decoy transcription factors and proteins and prevent their binding to their regulatory regions, inhibiting their mechanistic activity on the regulation of gene expression and signaling pathways. This review presents the mechanistic pathways of the oncogenic role of LOXL1-AS1 by modulating its target miRNAs and proteins in various cancer cells. Having information about the molecular mechanisms regulated by LOXL1-AS1 in cancer cells can open ways to find out particular prognostic biomarkers, as well as discover novel therapeutic approaches for different types of cancer.

lncRNAs: New players of cancer drug resistance via targeting ABC transporters.

Cancer drug resistance poses a significant obstacle to successful chemotherapy, primarily driven by the activity of ATP-binding cassette (ABC) transporters, which actively efflux chemotherapeutic agents from cancer cells, reducing their intracellular concentrations and therapeutic efficacy. Recent studies have highlighted the pivotal role of long noncoding RNAs (lncRNAs) in regulating this resistance, positioning them as crucial modulators of ABC transporter function. lncRNAs, once considered transcriptional noise, are now recognized for their complex regulatory capabilities at various cellular levels, including chromatin modification, transcription, and post-transcriptional processing. This review synthesizes current research demonstrating how lncRNAs influence cancer drug resistance by modulating the expression and activity of ABC transporters. lncRNAs can act as molecular sponges, sequestering microRNAs that would otherwise downregulate ABC transporter genes. Additionally, they can alter the epigenetic landscape of these genes, affecting their transcriptional activity. Mechanistic insights reveal that lncRNAs contribute to the activity of ABC transporters, thereby altering the efflux of chemotherapeutic drugs and promoting drug resistance. Understanding these interactions provides a new perspective on the molecular basis of chemoresistance, emphasizing the regulatory network of lncRNAs and ABC transporters. This knowledge not only deepens our understanding of the biological mechanisms underlying drug resistance but also suggests novel therapeutic strategies. In conclusion, the intricate interplay between lncRNAs and ABC transporters is crucial for developing innovative solutions to combat cancer drug resistance, underscoring the importance of continued research in this field.

Small molecules targeting microRNAs: new opportunities and challenges in precision cancer therapy.

Noncoding RNAs, especially miRNAs, play a pivotal role in cancer initiation and metastasis, underscoring their susceptibility to precise modulation via small molecule inhibitors. This review examines the innovative strategy of targeting oncogenic miRNAs with small drug-like molecules, an approach that can reshape the cancer treatment landscape. We review the current understanding of the multifaceted roles of miRNAs in oncogenesis, highlighting emerging therapeutic paradigms that have the potential to expand cancer treatment options. As research on small molecule inhibitors of miRNA is still in its early stages, ongoing investigative efforts and the development of new technologies and chemical matter are essential to fulfill the significant potential of this innovative approach to cancer treatment.

Guidelines for mitochondrial RNA analysis.

Mitochondria are the energy-producing organelles of mammalian cells with critical involvement in metabolism and signaling. Studying their regulation in pathological conditions may lead to the discovery of novel drugs to treat, for instance, cardiovascular or neurological diseases, which affect high-energy-consuming cells such as cardiomyocytes, hepatocytes, or neurons. Mitochondria possess both protein-coding and noncoding RNAs, such as microRNAs, long noncoding RNAs, circular RNAs, and piwi-interacting RNAs, encoded by the mitochondria or the nuclear genome. Mitochondrial RNAs are involved in anterograde-retrograde communication between the nucleus and mitochondria and play an important role in physiological and pathological conditions. Despite accumulating evidence on the presence and biogenesis of mitochondrial RNAs, their study continues to pose significant challenges. Currently, there are no standardized protocols and guidelines to conduct deep functional characterization and expression profiling of mitochondrial RNAs. To overcome major obstacles in this emerging field, the EU-CardioRNA and AtheroNET COST Action networks summarize currently available techniques and emphasize critical points that may constitute sources of variability and explain discrepancies between published results. Standardized methods and adherence to guidelines to quantify and study mitochondrial RNAs in normal and disease states will improve research outputs, their reproducibility, and translation potential to clinical application.

X and Y Differences in Melanoma Survival Between the Sexes.

Marked differences in survival from melanoma are noted between men and women that cannot be accounted for by behavioral differences. We and others have provided evidence that this difference may be due to increased expression of immune-related genes from the second X chromosome because of failure of X inactivation. In the present review, we have examined evidence for the contrary view that survival differences are due to weaker immune responses in males. One reason for this may be the loss of Y chromosomes (LOY), particularly in older males. The genes involved may have direct roles in immune responses or be noncoding RNAs that regulate both sex and autosomal genes involved in immune responses or tumor growth. Loss of the KDM6C and KDM5D demethylases appeared to common genes involved. The second factor appears to be the activation of androgen receptors (AR) on melanoma cells that increase their invasiveness and growth. Induction of T-cell exhaustion by AR that limits immune responses against melanoma appeared a common finding. The development of treatments to overcome effects related to gene loss on Y poses challenges, but several avenues related to AR signaling appear worthy of further study in the treatment of metastatic disease.

Identification of RBM15 as a prognostic biomarker in prostate cancer involving the regulation of prognostic m6A-related lncRNAs.

BACKGROUND: Long noncoding RNAs (lncRNAs) and N6-methyladenosine (m6A) modification of RNA play pivotal roles in tumorigenesis and cancer progression. However, knowledge regarding the expression patterns of m6A-related lncRNAs and their corresponding m6A regulators in prostate cancer (PCa) is limited. This study aimed to delineate the landscape of m6A-related lncRNAs, develop a predictive model, and identify the critical m6A regulators of prognostic lncRNAs in PCa. METHODS: Clinical and transcriptome data of PCa patients were downloaded from The Cancer Genome Atlas (TCGA) database. Prognostic m6A-related lncRNAs were subsequently identified through Pearson correlation and univariate Cox regression analyses. The prognostic lncRNAs were clustered into two groups by consensus clustering analysis, and a risk signature model was constructed using least absolute shrinkage and selection operator (LASSO) regression analysis of the lncRNAs. This model was evaluated using survival, clinicopathological, and immunological analyses. Furthermore, based on the constructed lncRNA-m6A regulatory network and RT-qPCR results, RBM15 was identified as a critical regulator of m6A-related lncRNAs. The biological roles of RBM15 in PCa were explored through bioinformatics analysis and biological experiments. RESULTS: Thirty-four prognostic m6A-related lncRNAs were identified and categorized into two clusters with different expression patterns and survival outcomes in PCa patients. Seven m6A lncRNAs (AC105345.1, AL354989.1, AC138028.4, AC022211.1, AC020558.2, AC004076.2, and LINC02666) were selected to construct a risk signature with robust predictive ability for overall survival and were correlated with clinicopathological characteristics and the immune microenvironment of PCa patients. Among them, LINC02666 and AC022211.1 were regulated by RBM15. In addition, RBM15 expression correlated with PCa progression, survival, and the immune response. Patients with elevated RBM15 expression were more susceptible to the drug AMG-232. Moreover, silencing RBM15 decreased the viability of PCa cells and promoted apoptosis. CONCLUSION: RBM15 is involved in the regulation of prognostic lncRNAs in the risk signature and has a robust predictive ability for PCa, making it a promising biomarker in PCa.

Identification of MicroRNAs in children with increased asthma bronchodilator usage in genetics of asthma in Costa Rica Study.

INTRODUCTION: Uncontrolled or severe asthma results in symptomatic usage of short-acting ß2-agonist (SABA) usage. MicroRNAs (miRNAs) are posttranslational regulators that can influence asthma biology. This study aims to identify miRNAs that are associated with increased SABA usage. METHODS: Small RNA sequenced from blood serum of 1,132 children with asthma aged 6 to 14 years in the Genetics of Asthma in Costa Rica Study was used for this analysis. Logistic regression identified miRNAs in patients who required increased SABA usage. These miRNA were validated for association with SABA-induced bronchodilator responsiveness (BDR). Gene target pathway analysis was performed on validated miRNAs. RESULTS: Twenty-one miRNAs were significantly associated with increased SABA usage with OR ranging from 0.87 to 1.23. Two miRNAs, miR-378a-3p and miR-144-3p, had odds ratio 1.14 (1-1.29, p = .05) and 1.11 (1.01-1.22, p = .035), respectively, for increased SABA usage and were also significantly associated with bronchodilator response. Furthermore, a linear regression analysis involving these miRNA and bronchodilator response revealed that increased miR-378a-3p correlated with decreased BDR and increased expression of miR-144-3p correlated with improving pulmonary function with bronchodilators. In gene target Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, the erythroblastosis viral oncogene signaling pathway had among one of the highest fold enrichment and p-value. CONCLUSION: Increased expression of miR-378a-3p and miR-144-3p was seen in this patient population who required increased SABA usage. There were different bronchodilatory effects seen in these two miRNAs, suggesting different potential mechanisms underlying increased SABA usage.

Role of long noncoding RNAs in the regulation of alternative splicing in glioblastoma.

Glioblastoma multiforme (GBM) is a highly severe primary brain tumor. Despite extensive research, effective treatments remain elusive. Long noncoding RNAs (lncRNAs) play a significant role in both cancer and normal biology. They influence alternative splicing (AS), which is crucial in cancer. Advances in lncRNA-specific microarrays and next-generation sequencing have enhanced understanding of AS. Abnormal AS contributes to cancer invasion, metastasis, apoptosis, therapeutic resistance, and tumor development, including glioma. lncRNA-mediated AS affects several cellular signaling pathways, promoting or suppressing cancer malignancy. This review discusses the lncRNAs regulating AS in glioblastoma and their mechanisms.

m6A modification in non-coding RNAs: Mechanisms and potential therapeutic implications in fibrosis.

N6-methyladenosine (m6A) is one of the most prevalent and reversible forms of RNA methylation, with increasing evidence indicating its critical role in numerous physiological and pathological processes. m6A catalyzes messenger RNA(mRNA) as well as regulatory non-coding RNAs (ncRNAs), such as microRNAs, long non-coding RNAs, and circular RNAs. This modification modulates ncRNA fate and cell functions in various bioprocesses, including ncRNA splicing, maturity, export, and stability. Key m6A regulators, including writers, erasers, and readers, have been reported to modify the ncRNAs involved in fibrogenesis. NcRNAs affect fibrosis progression by targeting m6A regulators. The interactions between m6A and ncRNAs can influence multiple cellular life activities. In this review, we discuss the impact of the interaction between m6A modifications and ncRNAs on the pathological mechanisms of fibrosis, revealing the possibility of these interactions as diagnostic markers and therapeutic targets in fibrosis.

Gene Expression Profile Identifies LncRNA AL355974.3 As a Potential Glioma Biomarker.

OBJECTIVE: Glioma is a central nervous system tumor arising from glial cells. Despite significant advances in diagnosis and treatment, most patients with high-grade gliomas have a poor prognosis. Many studies have shown that long noncoding RNAs (lncRNAs) may play important roles in the development, progression and treatment of many tumors, including gliomas. Molecularly targeted therapy may be a new direction for the adjuvant treatment of glioma. Therefore, we hope that by studying differentially expressed lncRNAs (DElncRNAs) in glioma, we can discover lncRNAs that can serve as biomarkers for glioma and provide better therapeutic modalities for glioma patients. METHODS: First, the expression of lncRNAs in 5 normal brain (NB) tissues and 10 glioma tissues was examined by RNA sequencing (RNA-seq). Next, we performed Kaplan-Meier analysis of data from The Cancer Genome Atlas (TCGA) database to assess the prognostic value of these variables. Finally, functional analysis of the DElncRNAs was performed by means of Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. RESULTS: RNA sequencing analysis revealed 85 upregulated miRNAs and 71 downregulated lncRNAs in low-grade glioma (LGG) and 50 upregulated lncRNAs and 70 downregulated lncRNAs in glioblastoma (GBM). Among them, AL355974.3 was the most upregulated lncRNA. LINC00632 was the most downregulated lncRNA. Second, LGG patients with higher AL355974.3 expression had worse overall survival according to Kaplan-Meier analysis of the TCGA database. Finally, bioinformatics analysis revealed that the target genes of these DElncRNAs were enriched in various biological processes and signaling pathways, such as cell metabolic and developmental processes. CONCLUSION: Our findings provide evidence that AL355974.3 may be a new biomarker for glioma.

Noncoding RNA-Mediated Epigenetic Regulation in Hepatic Stellate Cells of Liver Fibrosis.

Liver fibrosis is a significant contributor to liver-related disease mortality on a global scale. Despite this, there remains a dearth of effective therapeutic interventions capable of reversing this condition. Consequently, it is imperative that we gain a comprehensive understanding of the underlying mechanisms driving liver fibrosis. In this regard, the activation of hepatic stellate cells (HSCs) is recognized as a pivotal factor in the development and progression of liver fibrosis. The role of noncoding RNAs (ncRNAs) in epigenetic regulation of HSCs transdifferentiation into myofibroblasts has been established, providing new insights into gene expression changes during HSCs activation. NcRNAs play a crucial role in mediating the epigenetics of HSCs, serving as novel regulators in the pathogenesis of liver fibrosis. As research on epigenetics expands, the connection between ncRNAs involved in HSCs activation and epigenetic mechanisms becomes more evident. These changes in gene regulation have attracted considerable attention from researchers in the field. Furthermore, epigenetics has contributed valuable insights to drug discovery and the identification of therapeutic targets for individuals suffering from liver fibrosis and cirrhosis. As such, this review offers a thorough discussion on the role of ncRNAs in the HSCs activation of liver fibrosis.

Advances in understanding the role of lncRNA in ferroptosis.

LncRNA is a type of transcript with a length exceeding 200 nucleotides, which was once considered junk transcript with no biological function during the transcription process. In recent years, lncRNA has been shown to act as an important regulatory factor at multiple levels of gene expression, affecting various programmed cell death modes including ferroptosis. Ferroptosis, as a new form of programmed cell death, is characterized by a deficiency of cysteine or inactivation of glutathione peroxidase, leading to depletion of glutathione, aggregation of iron ions, and lipid peroxidation. These processes are influenced by many physiological processes, such as the Nrf2 pathway, autophagy, p53 pathway and so on. An increasing number of studies have shown that lncRNA can block the expression of specific molecules through decoy effect, guide specific proteins to function, or promote interactions between molecules as scaffolds. These modes of action regulate the expression of key factors in iron metabolism, lipid metabolism, and antioxidant metabolism through epigenetic or genetic regulation, thereby regulating the process of ferroptosis. In this review, we snapshotted the regulatory mechanism of ferroptosis as an example, emphasizing the regulation of lncRNA on these pathways, thereby helping to fully understand the evolution of ferroptosis in cell fate.

miR-33 deletion in hepatocytes attenuates NAFLD-NASH-HCC progression.

The complexity of the mechanisms underlying non-alcoholic fatty liver disease (NAFLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of NAFLD and the development of hepatocellular carcinoma (HCC). We report that miR-33 is elevated in the livers of humans and mice with NAFLD and that its deletion in hepatocytes (miR-33 HKO) improves multiple aspects of the disease, including steatosis and inflammation, limiting the progression to non-alcoholic steatohepatitis (NASH), fibrosis and HCC. Mechanistically, hepatic miR-33 deletion reduces lipid synthesis and promotes mitochondrial fatty acid oxidation, reducing lipid burden. Additionally, absence of miR-33 alters the expression of several known miR-33 target genes involved in metabolism and results in improved mitochondrial function and reduced oxidative stress. The reduction in lipid accumulation and liver injury resulted in decreased YAP/TAZ pathway activation, which may be involved in the reduced HCC progression in HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach to temper the development of NAFLD, NASH, and HCC in obesity.

Interaction between microRNA-195 and HuR regulates Paneth cell function in the intestinal epithelium by altering SOX9 translation.

Paneth cells at the bottom of small intestinal crypts secrete antimicrobial peptides, enzymes, and growth factors and contribute to pathogen clearance and maintenance of the stem cell niche. Loss of Paneth cells and their dysfunction occur commonly in various pathologies, but the mechanism underlying the control of Paneth cell function remains largely unknown. Here, we identified microRNA-195 (miR-195) as a repressor of Paneth cell development and activity by altering SOX9 translation via interaction with RNA-binding protein HuR. Tissue-specific transgenic expression of miR-195 (miR195-Tg) in the intestinal epithelium decreased the levels of mucosal SOX9 and reduced the numbers of lysozyme-positive (Paneth) cells in mice. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restored Paneth cell development ex vivo. miR-195 did not bind to Sox9 mRNA but it directly interacted with HuR and prevented HuR binding to Sox9 mRNA, thus inhibiting SOX9 translation. Intestinal mucosa from mice that harbored both Sox9 transgene and ablation of the HuR locus exhibited lower levels of SOX9 protein and Paneth cell numbers than those observed in miR-195-Tg mice. Inhibition of miR-195 activity by its specific antagomir improved Paneth cell function in HuR-deficient intestinal organoids. These results indicate that interaction of miR-195 with HuR regulates Paneth cell function by altering SOX9 translation in the small intestinal epithelium.NEW & NOTEWORTHY Our results indicate that intestinal epithelial tissue-specific transgenic miR-195 expression decreases the levels of SOX9 expression, along with reduced numbers of Paneth cells. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restores Paneth cell development ex vivo. miR-195 inhibits SOX9 translation by preventing binding of HuR to Sox9 mRNA. These findings suggest that interaction between miR-195 and HuR controls Paneth cell function via SOX9 in the intestinal epithelium.

Insights into non-coding RNAS: biogenesis, function and their potential regulatory roles in acute kidney disease and chronic kidney disease.

Noncoding RNAs (ncRNAs) have emerged as pivotal regulators of gene expression, and have attracted significant attention because of their various roles in biological processes. These molecules have transcriptional activity despite their inability to encode proteins. Moreover, research has revealed that ncRNAs, especially microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), are linked to pervasive regulators of kidney disease, including anti-inflammatory, antiapoptotic, antifibrotic, and proangiogenic actions in acute and chronic kidney disease. Although the exact therapeutic mechanism of ncRNAs remains uncertain, their value in treatment has been studied in clinical trials. The numerous renal diseases and the beneficial or harmful effects of NcRNAs on the kidney will be discussed in this article. Afterward, exploring the biological characteristics of ncRNAs, as well as their purpose and potential contributions to acute and chronic renal disease, were explored. This may offer guidance for treating both acute and long-term kidney illnesses, as well as insights into the potential use of these indicators as kidney disease biomarkers.

The Role of Long Noncoding RNAs in Cardiomyocyte Proliferation and Heart Regeneration After Myocardial Infarction: A Systematic Review.

Many studies support the idea that long noncoding RNAs (lncRNAs) are significantly involved in the process of cardiomyocyte (CM) regeneration following a myocardial infarction (MI). This study aimed to systematically review the emerging role of lncRNAs in cardiac regeneration by promoting CM proliferation after MI. Furthermore, the review summarized potential targets and the underlying mechanisms of lncRNAs to induce heart regeneration, suggesting utilizing lncRNAs as innovative therapeutic targets for mitigating MI injuries. We searched the PubMed, Scopus, and Web of Science databases for studies on lncRNAs that play a role in heart regeneration after MI. We used search terms that included MI, lncRNAs, CM, and proliferation. Relevant English articles published until June 11, 2023, were systematically reviewed based on inclusion and exclusion criteria. A total of 361 publications were initially identified, and after applying the inclusion and exclusion criteria, nine articles were included in this systematic review. These studies investigated the role of critical lncRNAs in cardiac regeneration after MI, including five upregulated and four downregulated lncRNAs. Acting as a competitive endogenous RNA is one of the main roles of lncRNAs in regulating genes involved in CM proliferation through binding to target microRNAs. The main molecular processes that greatly increase CM proliferation are those that turn on the Hippo/YAP1, PI3K/Akt, JAK2-STAT3, and E2F1-ECRAR-ERK1/2 signaling pathways. This systematic review highlights the significant role of lncRNAs in heart regeneration after MI and their impact on CM proliferation. The findings suggest that lncRNAs could serve as potential targets for therapeutic interventions aiming to enhance cardiac function.

Genome-wide and cell-type-selective profiling of in vivo small noncoding RNA:target RNA interactions by chimeric RNA sequencing.

Small noncoding RNAs (sncRNAs) regulate biological processes by impacting post-transcriptional gene expression through repressing the translation and levels of targeted transcripts. Despite the clear biological importance of sncRNAs, approaches to unambiguously define genome-wide sncRNA:target RNA interactions remain challenging and not widely adopted. We present CIMERA-seq, a robust strategy incorporating covalent ligation of sncRNAs to their target RNAs within the RNA-induced silencing complex (RISC) and direct detection of in vivo interactions by sequencing of the resulting chimeric RNAs. Modifications are incorporated to increase the capacity for processing low-abundance samples and permit cell-type-selective profiling of sncRNA:target RNA interactions, as demonstrated in mouse brain cortex. CIMERA-seq represents a cohesive and optimized method for unambiguously characterizing the in vivo network of sncRNA:target RNA interactions in numerous biological contexts and even subcellular fractions. Genome-wide and cell-type-selective CIMERA-seq enhances researchers' ability to study gene regulation by sncRNAs in diverse model systems and tissue types.

Comprehensive analysis of clinical and biological value of ING family genes in liver cancer.

BACKGROUND: Liver cancer (LIHC) is a malignant tumor that occurs in the liver and has a high mortality in cancer. The ING family genes were identified as tumor suppressor genes. Dysregulated expression of these genes can lead to cell cycle arrest, senescence and/or apoptosis. ING family genes are promising targets for anticancer therapy. However, their role in LIHC is still not well understood. AIM: To have a better understanding of the important roles of ING family members in LIHC. METHODS: A series of bioinformatics approaches (including gene expression analysis, genetic alteration analysis, survival analysis, immune infiltration analysis, prediction of upstream microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) of ING1, and ING1-related gene functional enrichment analysis) was applied to study the expression profile, clinical relationship, prognostic significance and immune infiltration of ING in LIHC. The relationship between ING family genes expression and tumor associated immune checkpoints was investigated in LIHC. The molecular mechanism of ING1 mediated hepatocarcinogenesis was preliminarily discussed. RESULTS: mRNA/protein expression of different ING family genes in LIHC was analyzed in different databases, showing that ING family genes were highly expressed in LIHC. In 47 samples from 366 LIHC patients, the ING family genes were altered at a rate of 13%. By comprehensively analyzing the expression, clinical pathological parameters and prognostic value of ING family genes, ING1/5 was identified. ING1/5 was related to poor prognosis of LIHC, suggesting that they may play key roles in LIHC tumorigenesis and progression. One of the target miRNAs of ING1 was identified as hsa-miR-214-3p. Two upstream lncRNAs of hsa-miR-214-3p, U91328.1, and HCG17, were identified. At the same time, we found that the expression of ING family genes was correlated with immune cell infiltration and immune checkpoint genes. CONCLUSION: This study lays a foundation for further research on the potential mechanism and clinical value of ING family genes in the treatment and prognosis of LIHC.

Expression of ITPR2 regulated by lncRNA-NONMMUT020270.2 in LPS-stimulated HT22 cells.

Background: Long non-coding RNA (lncRNA)-NONMMUT020270.2 is downregulated and co-expressed with inositol 1,4,5-trisphosphate receptor type 2 (ITPR2) in the hippocampus of Alzheimer's disease (AD) mice. However, whether the expression of ITPR2 was regulated by lncRNA-NONMMUT020270.2 remains unclear. we aimed to investigate regulating relationship of lncRNA-NONMMUT020270.2 and ITPR2. Methods: HT22 cells were firstly transfected with the pcDNA3.1-lncRNA-NONMMUT020270.2 overexpression plasmid or with the lncRNA-NONMMUT020270.2 smart silencer, and then were stimulated with lipopolysaccharide (LPS) for 24h. The mRNA expression levels of lncRNA-NONMMUT020270.2 and ITPR2 were measured by reverse transcription-quantitative PCR. Cell viability was assessed using a Cell Counting Kit 8 assay. The expression of Aß1-42 was detected by ELISA. The expression levels of p-tau, caspase-1, and inositol trisphosphate receptor (IP3R) proteins were detected by western-blotting. Nuclear morphological changes were detected by Hoechst staining. Flow cytometry and Fluo-3/AM were carried out to determine cell apoptosis and the intracellular Ca2+. Results: LPS significantly decreased cell viability, and ITPR2 mRNA and IP3R protein expression levels. While it markedly enhanced the expression levels of p-tau and Aß1-42, cell apoptosis rate, as well as intracellular Ca2+ concentration (P < 0.05). In addition, lncRNA-NONMMUT020270.2 overexpression significantly increased the expressions levels of ITPR2 mRNA and IP3R protein (P < 0.05), and inhibited expression of p-tau and Aß1-42, cell apoptosis rate, and reduced intracellular Ca2+ concentration (P < 0.05). By contrast, lncRNA-NONMMUT020270.2 silencing notably downregulated expressions levels of ITPR2 mRNA and IP3R protein (P < 0.05), and elevated expression levels of p-tau and Aß1-42, cell apoptosis rate, and intracellular Ca2+ concentration (P < 0.05). Conclusion: lncRNA-NONMMUT020270.2 was positively correlated with ITPR2 expression in LPS-induced cell. Downregulating the lncRNA-NONMMUT020270.2 and ITPR2 may promote cell apoptosis and increase intracellular Ca2+ concentration.