Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

Metal Nanogap Memory: Performances and Switching Mechanism.

The nanogap memory (NGM) device, emerging as a promising nonvolatile memory candidate, has attracted increasing attention for its simple structure, nano/atomic scale size, elevated operating speed, and robustness to high temperatures. In this study, nanogap memories based on Pd, Au, and Pt were fabricated by combining nanofabrication with electromigration technology. Subsequent evaluations of the electrical characteristics were conducted under ambient air or vacuum conditions at room temperature. The investigation unveiled persistent challenges associated with metal NGM devices, including (1) prolonged SET operation time in comparison to RESET, (2) the potential generation of error bits when enhancing switching speeds, and (3) susceptibility to degradation during program/erase cycles. While these issues have been encountered by predecessors in NGM device development, the underlying causes have remained elusive. Employing molecular dynamics (MD) simulation, we have, for the first time, unveiled the dynamic processes of NGM devices during both SET and RESET operations. The MD simulation highlights that the adjustment of the tunneling gap spacing in nanogap memory primarily occurs through atomic migration or field evaporation. This dynamic process enables the device to transition between the high-resistance state (HRS) and the low-resistance state (LRS). The identified mechanism provides insight into the origins of the aforementioned challenges. Furthermore, the study proposes an effective method to enhance the endurance of NGM devices based on the elucidated mechanism.

Exome sequencing identifies HELB as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer.

Rare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to collate exome sequencing data from multiple epithelial ovarian cancer case cohorts and controls in order to systematically evaluate the role of coding, loss-of-function variants across the genome in epithelial ovarian cancer risk. We assembled exome data for a total of 2,573 non-mucinous cases (1,876 high-grade serous and 697 non-high grade serous) and 13,925 controls. Harmonised variant calling and quality control filtering was applied across the different data sets. We carried out a gene-by-gene simple burden test for association of rare loss-of-function variants (minor allele frequency < 0.1%) with all non-mucinous ovarian cancer, high grade serous ovarian cancer and non-high grade serous ovarian cancer using logistic regression adjusted for the top four principal components to account for cryptic population structure and genetic ancestry. Seven of the top 10 associated genes were associations of the known ovarian cancer susceptibility genes BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH6 and PALB2 (false discovery probability < 0.1). A further four genes (HELB, OR2T35, NBN and MYO1A) had a false discovery rate of less than 0.1. Of these, HELB was most strongly associated with the non-high grade serous histotype (P = 1.3×10-6, FDR = 9.1×10-4). Further support for this association comes from the observation that loss of function variants in this gene are also associated with age at natural menopause and Mendelian randomisation analysis shows an association between genetically predicted age at natural menopause and endometrioid ovarian cancer, but not high-grade serous ovarian cancer.

Positive effect of peptide-calcium chelates from Grifola frondosa on a mouse model of senile osteoporosis.

Calcium supplementation has been shown to be efficacious in mitigating the progression of senile osteoporosis (SOP) and reducing the incidence of osteoporotic fractures resulting from prolonged calcium shortage. In this study, Grifola frondosa (GF) peptides-calcium chelate were synthesized through the interaction between peptide from GF and CaCl2. The chelation reaction was shown to involve the participation of the amino and carboxyl groups in the peptide, as revealed by scanning electron microscope, Fourier-transform infrared, and ultraviolet spectrophotometry. Furthermore, a mouse model of (SOP) induced by d-galactose was established (SCXK-2018-0004). Results demonstrated that low dosage of low-molecular weight GF peptides-calcium chelates (LLgps-Ca) could significantly improve serum index and pathological features of bone tissue and reduce bone injury. Further research suggested that LLgps-Ca could ameliorate SOP by modulating the disrupted metabolic pathway, which includes focal adhesion, extracellular matrix receptor interaction, and PI3K-Akt signaling pathway. Using Western blot, the differentially expressed proteins were further confirmed. Thus, calciumchelating peptides from GF could serve as functional calcium agents to alleviate SOP.

Climate warming impacts chewing Spodoptera litura negatively but sucking Corythucha marmorata positively on native Solidago canadensis.

Insect-plant interactions are among importantly ecological processes, and rapid environmental changes such as temperature and resource fluctuations can disrupt long-standing insect-plant interactions. While individual impacts of climate warming, atmospheric nitrogen (N) deposition, and plant provenance on insect-plant interactions are well studied, their joint effects on insect-plant interactions are less explored in ecologically realistic settings. To this end, we performed five experiments with native and invasive Solidago canadensis populations from home and introduced ranges and two insect herbivores (leaf-chewing Spodoptera litura and sap-sucking Corythucha marmorata) in the context of climate warming and N deposition. We determined leaf defensive traits, feeding preference, and insect growth and development, and quantified the possible associations among climate change, host-plant traits, and insect performance with structural equation modeling. First, native S. canadensis populations experienced higher damage by S. litura but lower damage by C. marmorata than invasive S. canadensis populations in the ambient environment. Second, warming decreased the leaf consumption, growth, and survival of S. litura on native S. canadensis populations, but did not affect these traits on invasive S. canadensis populations; warming increased the number of C. marmorata on native S. canadensis populations via direct facilitation, but decreased that on invasive S. canadensis populations via indirect suppression. Third, N addition enhanced the survival of S. litura on native S. canadensis populations, and its feeding preference and leaf consumption on invasive S. canadensis populations. Finally, warming plus N addition exhibited non-additive effects on insect-plant interactions. Based on these results, we tentatively conclude that climate warming could have contrasting effects on insect-plant interactions depending on host-plant provenance and that the effects of atmospheric N deposition on insects might be relatively weak compared to climate warming. Future studies should focus on the molecular mechanisms underlying these different patterns.

EGFR Oncogenic Mutations in NSCLC Impair Macrophage Phagocytosis and Mediate Innate Immune Evasion Through Up-Regulation of CD47.

INTRODUCTION: EGFR-mutated NSCLC is characterized by an immunosuppressive microenvironment that confers limited clinical effectiveness to anti-PD-1 or PD-L1 antibodies. Despite the discouraging outcomes of immunotherapy, novel immune checkpoints are constantly emerging, among which the specific vulnerability for therapeutic intervention in the context of EGFR-mutated NSCLC remains unresolved. METHODS: Data sets of patient- and cell line-levels were used for screening and mutual validation of association between EGFR mutation and a panel of immune checkpoint-related genes. Regulatory mechanism was elucidated through in vitro manipulation of EGFR signaling pathway and evaluated by immunoblot analysis, quantitative polymerase chain reaction, flow cytometry, immunofluorescence staining, and chromatin immunoprecipitation. In vivo investigation of different therapeutic strategies were conducted using both immunocompetent and immunodeficient mouse models. RESULTS: Among all screened immune checkpoints, CD47 emerged as the candidate most relevant to EGFR activation. Mechanistically, EGFR mutation constitutively activated downstream ERK and AKT pathways to respectively up-regulate the transcriptional factors c-Myc and NF-κB, both of which structurally bound to the promotor region of CD47 and actively transcribed this "don't eat me" signal. Impaired macrophage phagocytosis was observed on introduction of EGFR-sensitizing mutations in NSCLC cell line models, whereas CD47 blockade restored the phagocytic capacity and augmented tumor cell killing in both in vitro and in vivo models. Remarkably, the combination of anti-CD47 antibody with EGFR tyrosine kinase inhibitor revealed an additive antitumor activity compared with monotherapy of either antitumor agent in both immunocompetent and adaptive immunity-deficient mouse models. CONCLUSIONS: EGFR-sensitizing mutation facilitates NSCLC's escape from innate immune attack through up-regulating CD47. Combination therapy incorporating CD47 blockade holds substantial promise for clinical translation in developing more effective therapeutic approaches against EGFR-mutant NSCLC.

m6A-Induced lncRNA MEG3 Promotes Cerebral Ischemia-Reperfusion Injury Via Modulating Oxidative Stress and Mitochondrial Dysfunction by hnRNPA1/Sirt2 Axis.

Ischemic stroke remains one of the major causes of serious disability and death globally. LncRNA maternally expressed gene 3 (MEG3) is elevated in middle cerebral artery occlusion/reperfusion (MCAO/R) rats and oxygen-glucose deprivation/reperfusion (OGD/R)-treated neurocytes cells. The objective of this study is to investigate the mechanism underlying MEG3-regulated cerebral ischemia/reperfusion (I/R) injury. MCAO/R mouse model and OGD/R-treated HT-22 cell model were established. The cerebral I/R injury was monitored by TTC staining, neurological scoring, H&E and TUNEL assay. The levels of MEG3, hnRNPA1, Sirt2 and other key molecules were detected by qRT-PCR and western blot. Mitochondrial dysfunction was assessed by transmission Electron Microscopy (TEM), JC-1 and MitoTracker staining. Oxidative stress was monitored using commercial kits. Bioinformatics analysis, RIP, RNA pull-down assays and RNA FISH were employed to detect the interactions among MEG3, hnRNPA1 and Sirt2. The m6A modification of MEG3 was assessed by MeRIP-qPCR. MEG3 promoted MCAO/R-induced brain injury by modulating mitochondrial fragmentation and oxidative stress. It also facilitated OGD/R-induced apoptosis, mitochondrial dysfunction and oxidative stress in HT-22 cells. Mechanistically, direct associations between MEG3 and hnRNPA1, as well as between hnRNPA1 and Sirt2, were observed in HT-22 cells. MEG3 regulated Sirt2 expression in a hnRNPA1-dependent manner. Functional studies showed that MEG3/Sirt2 axis contributed to OGD/R-induced mitochondrial dysfunction and oxidative stress in HT-22 cells. Additionally, METTL3 was identified as the m6A transferase responsible for the m6A modification of MEG3. m6A-induced lncRNA MEG3 promoted cerebral I/R injury via modulating oxidative stress and mitochondrial dysfunction by hnRNPA1/Sirt2 axis.

Epidemiologic changes of a longitudinal surveillance study spanning 51 years of scrub typhus in mainland China.

Scrub typhus may be one of the world's most prevalent, neglected and serious, but easily treatable, febrile diseases. It has become a significant potential threat to public health in China. In this study we used national disease surveillance data to analyze the incidence and spatial-temporal distribution of scrub typhus in mainland China during 1952-1989 and 2006-2018. Descriptive epidemiological methods and spatial-temporal epidemiological methods were used to investigate the epidemiological trends and identify high-risk regions of scrub typhus infection. Over the 51-year period, a total of 182,991 cases and 186 deaths were notified. The average annual incidence was 0.13 cases/100,000 population during 1952-1989. The incidence increased sharply from 0.09/100,000 population in 2006 to 1.93/100,000 population in 2018 and then exponentially increased after 2006. The incidence was significantly higher in females than males (χ2 = 426.32, P < 0.001). Farmers had a higher incidence of scrub typhus than non-farmers (χ2 = 684.58, P < 0.001). The majority of cases each year were reported between July and November with peak incidence occurring during October each year. The trend surface analysis showed that the incidence of scrub typhus increased gradually from north to south, and from east and west to the central area. The spatial autocorrelation analysis showed that a spatial positive correlation existed in the prevalence of scrub typhus on a national scale, which had the characteristic of aggregated distribution (I = 0.533, P < 0.05). LISA analysis showed hotspots (High-High) were primarily located in the southern and southwestern provinces of China with the geographical area expanding annually. These findings provide scientific evidence for the surveillance and control of scrub typhus which may contribute to targeted strategies and measures for the government.

Novel gene signatures predicting and immune infiltration analysis in Parkinson's disease: based on combining random forest with artificial neural network.

BACKGROUND: Parkinson's disease (PD) ranks as the second most prevalent neurodegenerative disorder globally, and its incidence is rapidly rising. The diagnosis of PD relies on clinical characteristics. Although current treatments aim to alleviate symptoms, they do not effectively halt the disease's progression. Early detection and intervention hold immense importance. This study aimed to establish a new PD diagnostic model. METHODS: Data from a public database were adopted for the construction and validation of a PD diagnostic model with random forest and artificial neural network models. The CIBERSORT platform was applied for the evaluation of immune cell infiltration in PD. Quantitative real-time PCR was performed to verify the accuracy and reliability of the bioinformatics analysis results. RESULTS: Leveraging existing gene expression data from the Gene Expression Omnibus (GEO) database, we sifted through differentially expressed genes (DEGs) in PD and identified 30 crucial genes through a random forest classifier. Furthermore, we successfully designed a novel PD diagnostic model using an artificial neural network and verified its diagnostic efficacy using publicly available datasets. Our research also suggests that mast cells may play a significant role in the onset and progression of PD. CONCLUSION: This work developed a new PD diagnostic model with machine learning techniques and suggested the immune cells as a potential target for PD therapy.

Integration of the cancer cell secretome and transcriptome reveals potential noninvasive diagnostic markers for bladder cancer.

PURPOSE: Bladder cancer (BLCA) is a major cancer of the genitourinary system. Although cystoscopy is the standard protocol for diagnosing BLCA clinically, this procedure is invasive and expensive. Several urine-based markers for BLCA have been identified and investigated, but none has shown sufficient sensitivity and specificity. These observations underscore the importance of discovering novel BLCA biomarkers and developing a noninvasive method for detection of BLCA. Exploring the cancer secretome is a good starting point for the development of noninvasive biomarkers for cancer diagnosis. EXPERIMENTAL DESIGN: In this study, we established a comprehensive secretome dataset of five representative BLCA cell lines, BFTC905, TSGH8301, 5637, MGH-U1, and MGH-U4, by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Expression of BLCA-specific secreted proteins at the transcription level was evaluated using the Oncomine cancer microarray database. RESULTS: The expressions of four candidates-COMT, EWSR1, FUSIP1, and TNPO2-were further validated in clinical human specimens. Immunohistochemical analyses confirmed that transportin-2 was highly expressed in tumor cells relative to adjacent noncancerous cells in clinical tissue specimens from BLCA patients, and was significantly elevated in BLCA urine compared with that in urine samples from aged-matched hernia patients (controls). CONCLUSIONS: Collectively, our findings suggest TNPO2 as a potential noninvasive tumor-stage or grade discriminator for BLCA management.

In vitro study of optimal removable partial denture clasp design made from novel high-performance polyetherketoneketone.

PURPOSE: This study aimed to investigate the retentive force and deformation of double Akers' polyetherketoneketone (PEKK) clasps on removable partial dentures (RPDs) with varying designs and undercut depths. METHODS: Thirty double Akers' PEKK clasps with two different widths and heights (Groups I and II) were fabricated using computer-aided design and computer-aided manufacturing (CAD/CAM). Each design was further subdivided (n = 5) into three undercut depths (0.25, 0.50, and 0.75 mm). The retentive force of the clasps was measured after 10 years of clinical use (15,000 insertion/removal cycles), and the deformation of the clasp tips was analyzed before and after cycling. RESULTS: Clasps with 0.50-mm and 0.75-mm undercut depths exhibited greater initial retentive forces (3.15-3.51 N) compared to those in the 0.25-mm undercut group (2.40-2.80 N). Group I maintained consistent retentive forces over the cycles (P = 0.345), whereas Group II showed declining forces after the initial use (P < 0.003). In both groups, the 0.50-mm undercut exhibited a greater retentive force than the 0.25-mm (P < 0.001 and P < 0.004, respectively), with no significant differences between the 0.50-mm and 0.75-mm undercut depths. Despite a lower initial retentive force, the 0.25-mm undercut showed less deformation and clasp tip wear. CONCLUSIONS: The PEKK clasps did not exhibit significantly reduced retentive forces or permanent deformations after 15,000 fatigue cycles. These results suggest that the PEKK polymer displays superior mechanical properties as an esthetic clasp material, and clasps with 0.50-mm and 0.75-mm undercut depths are recommended for long-term clinical use.

Editorial viewpoints of scientific publishing for early-career research scientists.

While the structure and composition of the scientific manuscript is well known within scientific communities, insider knowledge such as the tricks of the trade and editorial viewpoints of scientific publishing are often less known to early-career research scientists. This article focuses on the key aspects of scientific publishing, including tips for success geared towards senior postdocs and junior faculty. It also highlights important considerations for getting manuscripts published in an efficient and successful manner.

Effects of fertilizer application on the growth of Stranvaesia davidiana D. seedlings.

Wild plants represent a potential source of urban landscape trees. Stranvaesia davidiana Dcne. is a member of the Stranvaesia Lindl. Genus, which belongs to family Rosaceae Juss. It has great ornamental value. It can contribute to urban color foliage and fruit species. However, the most effective fertilizer application strategy required for its cultivation is unknown. Therefore, we conducted an orthogonal experiment to investigate the fertilizer type and level (pure nitrogen) using ten experimental groups, including an untreated control group. Pot experiments were used to determine the growth indices of seedlings, including plant height, basal diameter, and chlorophyll content post-fertilizer treatment. This study explored the most appropriate fertiler application model for the growth of S. davidiana seedlings. The results revealed that enhanced seedling growth depended on the type and amount of fertilizer used, and their interaction. Fertilizer application increased the plant height by 2.67 cm to 12.26 cm, basal diameter by 0.39 cm to 0.75 cm, and chlorophyll content by 5.66 to 19.86. Among the different types of fertilizer, organic fertilizer increased the plant height by 0.42 cm to 9.59 cm and basal diameter by 0.01 cm to 0.05 cm, compared with the control group. Organic fertilizer had the maximum effect on seedling growth, especially at medium levels. The total growth of basal diameter and chlorophyll content was 1.58 ± 0.04 cm and 39.53 ± 2.37, respectively. Basal diameter is the most critical index in seedling reproduction . The study results suggest that the application of 4.06 g of organic fertilizer per plant was the most effective, and served as a basis for further field trials.

Comparative analysis of the retention force and deformation of PEEK and PEKK removable partial denture clasps with different thicknesses and undercut depths.

STATEMENT OF PROBLEM: The retentive force and deformation of milled polyetheretherketone (PEEK) and polyetherketoneketone (PEKK) removable partial denture (RPD) frameworks are not well understood. PURPOSE: The purpose of this in vitro study was to assess the retentive force and deformation of PEEK and PEKK Akers clasps with different designs and undercut depths. MATERIAL AND METHODS: A master model containing the first and second molar abutments was used to design Akers clasps of different cross-sectional dimensions, undercut depths (0.5 and 0.75 mm), and materials. The components of the removable partial denture framework also included an occlusal rest and were manufactured using a milling machine (n=5). The fatigue resistance of the Akers clasps was measured before and after deformation regarding the retentive forces. RESULTS: The PEEK2-U50 clasp had the largest retentive force with no significant difference among all groups before and after the insertion and removal cycle. In addition, the increased cross-sectional dimensions of the design resulted in significant differences in retentive forces between the PEEK1 and PEEK2 groups and between the PEEK and PEKK materials. CONCLUSIONS: Increasing the clasp's cross-sectional dimensions significantly impacted retentive forces, especially between different PEEK groups and between PEEK and PEKK materials.

PLK1 and its substrate MISP facilitate intrahepatic cholangiocarcinoma progression by promoting lymphatic invasion and impairing E-cadherin adherens junctions.

Intrahepatic cholangiocarcinoma (iCCA) is a subtype of CCA and has a high mortality rate and a relatively poor prognosis. However, studies focusing on increased cell motility and loss of epithelial integrity during iCCA progression remain relatively scarce. We collected seven fresh tumor samples from four patients to perform RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) to determine the transcriptome profile and chromatin accessibility of iCCA. The increased expression of cell cycle regulators, including PLK1 and its substrate MISP, was identified. Ninety-one iCCA patients were used to validate the clinical significance of PLK1 and MISP. The upregulation of PLK1 and MISP was determined in iCCA tissues. Increased expression of PLK1 and MISP was significantly correlated with tumor number, N stage, and lymphatic invasion in an iCCA cohort. Knockdown of PLK1 or MISP reduced trans-lymphatic endothelial migration and wound healing and affected focal adhesions in vitro. In cell‒cell junctions, MISP localized to adherens junctions and suppressed E-cadherin dimerization. PLK1 disrupted adherens junctions in a myosin-dependent manner. Furthermore, PLK1 and MISP promoted cell proliferation in vitro and tumorigenesis in vivo. In iCCA, PLK1 and MISP promote aggressiveness by increasing lymphatic invasion, tumor growth, and motility through the repression of E-cadherin adherens junctions.

Epigenetic regulation of asymmetric cell division by the LIBR-BRD4 axis.

Asymmetric cell division (ACD) is a mechanism used by stem cells to maintain the number of progeny. However, the epigenetic mechanisms regulating ACD remain elusive. Here we show that BRD4, a BET domain protein that binds to acetylated histone, is segregated in daughter cells together with H3K56Ac and regulates ACD. ITGB1 is regulated by BRD4 to regulate ACD. A long noncoding RNA (lncRNA), LIBR (LncRNA Inhibiting BRD4), decreases the percentage of stem cells going through ACD through interacting with the BRD4 mRNAs. LIBR inhibits the translation of BRD4 through recruiting a translation repressor, RCK, and inhibiting the binding of BRD4 mRNAs to polysomes. These results identify the epigenetic regulatory modules (BRD4, lncRNA LIBR) that regulate ACD. The regulation of ACD by BRD4 suggests the therapeutic limitation of using BRD4 inhibitors to treat cancer due to the ability of these inhibitors to promote symmetric cell division that may lead to tumor progression and treatment resistance.

miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD.

Previous studies have shown that microRNAs (miRNAs) are involved in the regulation of a variety of metabolic diseases, which related to some important signal pathways. Our aim was to explore the possible mechanism of miRNAs by revealing the differential expression of serum miRNAs in different BMI of type 2 diabetes mellitus (T2DM) patients with non-alcoholic fatty liver disease (NAFLD). We found that miR-29 decreased liver aminotransferase gamma-GGT and uric acid levels by inhibiting the expression of JNK-1 in non-obese T2DM patients with NAFLD, and down-regulated the expression of atherosclerosis-related factor lipoprotein phospholipase A2 (Lp-PLA2). Combined with bioinformatics analysis, we speculate that this may be mediated by the AMPK signaling. These findings suggest that miR-29 may be a potential targeted therapeutic strategy in T2DM patients with NAFLD.

Interplay between lncRNA RP11-367G18.1 variant 2 and YY1 plays a vital role in hypoxia-mediated gene expression and tumorigenesis.

BACKGROUND: The hypoxia-responsive long non-coding RNA, RP11-367G18.1, has recently been reported to induce histone 4 lysine 16 acetylation (H4K16Ac) through its variant 2; however, the underlying molecular mechanism remains poorly understood. METHODS: RNA pull-down assay and liquid chromatography-tandem mass spectrometry were performed to identify RP11-367G18.1 variant 2-binding partner. The molecular events were examined utilizing western blot analysis, real-time PCR, luciferase reporter assay, chromatin immunoprecipitation, and chromatin isolation by RNA purification assays. The migration, invasion, soft agar colony formation, and in vivo xenograft experiments were conducted to evaluate the impact of RP11-367G18.1 variant 2-YY1 complex on tumor progression. RESULTS: In this study, RNA sequencing data revealed that hypoxia and RP11-367G18.1 variant 2 co-regulated genes were enriched in tumor-related pathways. YY1 was identified as an RP11-367G18.1 variant 2-binding partner that activates the H4K16Ac mark. YY1 was upregulated under hypoxic conditions and served as a target gene for hypoxia-inducible factor-1α. RP11-367G18.1 variant 2 colocalized with YY1 and H4K16Ac in the nucleus under hypoxic conditions. Head and neck cancer tissues had higher levels of RP11-367G18.1 and YY1 which were associated with poor patient outcomes. RP11-367G18.1 variant 2-YY1 complex contributes to hypoxia-induced epithelial-mesenchymal transition, cell migration, invasion, and tumorigenicity. YY1 regulated hypoxia-induced genes dependent on RP11-367G18.1 variant 2. CONCLUSIONS: RP11-367G18.1 variant 2-YY1 complex mediates the tumor-promoting effects of hypoxia, suggesting that this complex can be targeted as a novel therapeutic strategy for cancer treatment.

SNHG15-Mediated Localization of Nucleolin at the Cell Protrusions Regulates CDH2 mRNA Expression and Cell Invasion.

LncRNAs are emerging as important regulators of gene expression by controlling transcription in the nucleus and by modulating mRNA translation in the cytoplasm. In this study, we reveal a novel function of lncRNA SNHG15 in mediating breast cancer cell invasion through regulating the local translation of CDH2 mRNA. We show that SNHG15 preferentially localizes at the cellular protrusions or cell leading edge and that this localization is directed by IMP1, a multifunctional protein involved in many aspects of RNA regulation. We demonstrate that SNHG15 also forms a complex with nucleolin, allowing nucleolin to be co-transported with SNHG15 to the cell protrusions, where the accumulated nucleolin is able to bind to CDH2 mRNA. Interaction with nucleolin stabilizes local CDH2 mRNA and regulates its translation, thus promoting cell invasive potential. Our findings reveal an underlying mechanism by which lncRNA could serve as a carrier to transport a protein regulator into a specific cell compartment to enhance target mRNA expression.