Biological Role Research Articles

Downregulation of KLF5 by EBER1 via the ERK signaling pathway in EBV-positive nasopharyngeal carcinoma cells: implications for latent EBV infection.

Nasopharyngeal carcinoma (NPC) carcinogenesis and malignant transformation are intimately associated with Epstein-Barr virus (EBV) infection. A zinc-fingered transcription factor known as Krüppel-like factor 5 (KLF5) has been shown to be aberrantly expressed in a number of cancer types. However, little is known about the regulatory pathways and roles of KLF5 in EBV-positive NPC. Our study found that KLF5 expression was significantly lower in EBV-positive NPC than in EBV-negative NPC. Further investigation revealed that EBER1, which is encoded by EBV, down-regulates KLF5 via the extracellular signal-regulated kinase (ERK) signalling pathway. This down-regulation of KLF5 by EBER1 contributes to maintaining latent EBV infection in NPC. Furthermore, we uncovered the biological roles of KLF5 in NPC cells. Specifically, KLF5 may influence the cell cycle, prevent apoptosis, and encourage cell migration and proliferation - all of which have a generally pro-cancer impact. In conclusion, these findings offer novel strategies for EBV-positive NPC patients' antitumour treatment.

AHNAK2 Promotes the Progression of Pancreatic Ductal Adenocarcinoma by Maintaining the Stability of c-MET.

Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant and rapidly progresses. The overall response rate of PDAC to current treatment methods is still unsatisfactory. Thus, identifying novel targets and clarifying the underlying mechanisms associated with PDAC progression may potentially offer additional treatment strategies. AHNAK2 is aberrantly expressed in a variety of tumors and exerts pro-tumorigenic effects. However, the biological role of AHNAK2 in PDAC remains poorly understood. The expression of AHNAK2 in PDAC and paired non-tumor tissues was detected by immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR). Lentivirus knockdown was performed to investigate the impact of AHNAK2 on the biological function of pancreatic cancer cells. The subcutaneous cell-derived xenograft (CDX) model and the KPC spontaneous mouse model with AHNAK2 silencing were used to observe the effects of AHNAK2 on tumor growth and prognosis. The expression of c-MET at protein level in response to HGF treatment was assessed using western blot. Our results demonstrated that AHNAK2 was highly expressed in PDAC clinical samples and associated with poor prognosis. Knockdown of AHNAK2 significantly inhibited the proliferation, migration, and invasion of pancreatic cancer cells. AHNAK2 knockdown or knockout resulted in tumor growth suppression and prolonged survival in mice with PDAC. In addition, AHNAK2 and c-MET expression levels showed a significant positive correlation at the post-transcriptional level. Mechanistically, AHNAK2 promoted tumor progression by preventing c-MET degradation and persistently activating the HGF/c-MET signaling pathway. Overall, our study revealed that AHNAK2 plays an important role in PDAC progression by modulating the c-MET signaling pathway, and targeting AHNAK2 may be an effective therapeutic strategy for PDAC.

LINC02257 regulates colorectal cancer liver metastases through JNK pathway

BackgroundLong noncoding RNAs (lncRNAs) have emerged as critical regulators of colorectal cancer (CRC) progression, but their roles and underlying mechanisms in colorectal cancer liver metastases (CRLMs) remain poorly understood. MethodsTo explore the expression patterns and functions of lncRNAs in CRLMs, we analyzed the expression profiles of lncRNAs in CRC tissues using the TCGA database and examined the expression patterns of lncRNAs in matched normal, CRC, and CRLM tissues using clinical samples. We further investigated the biological roles of LINC02257 in CRLM using in vitro and in vivo assays, and verified its therapeutic potential in a mouse model of CRLM. ResultsOur findings showed that LINC02257 was highly expressed in metastatic CRC tissues and its expression was negatively associated with overall survival. Functionally, LINC02257 promoted CRC cell growth, migration, metastasis, and inhibited cell apoptosis in vitro, and enhanced liver metastasis in vivo. Mechanistically, LINC02257 up-regulated phosphorylated c-Jun N-terminal kinase (JNK) to promote CRLM. ConclusionsOur study revealed that LINC02257 played a key role in the proliferation and metastasis of CRC cells through the LINC02257/JNK axis. Targeting this axis may represent a promising therapeutic strategy for the treatment of liver metastases in patients with CRC.

Fatty Acid Binding to the Human Transport Proteins FABP3, FABP4, and FABP5 from a Ligand’s Perspective

Fatty acid binding proteins (FABPs) are a family of amphiphilic transport proteins with high diversity in terms of their amino acid sequences and binding preferences. Beyond their main biological role as cytosolic fatty acid transporters, many aspects regarding their binding mechanism and functional specializations in human cells remain unclear. In this work, the binding properties and thermodynamics of FABP3, FABP4 and FABP5 were analyzed under various physical conditions. For this purpose, the FABPs were loaded with fatty acids bearing fluorescence or spin probes as model ligands, comparing their binding affinities via microscale thermophoresis (MST) and continuous-wave electron paramagnetic resonance (CW EPR) spectroscopy. The CW EPR spectra of non-covalently bound 5- and 16-DOXYL stearic acid (5/16-DSA) deliver in-depth information about the dynamics and chemical environments of ligands inside the binding pockets of the FABPs. EPR spectral simulations allow the construction of binding curves, revealing two different binding states (‘intermediately’ and ‘strongly’ bound). The proportion of bound 5/16-DSA depends strongly on the FABP concentration and the temperature, but with remarkable differences between the three isoforms. Additionally, the more dynamic state (‘intermediately bound’) seems to dominate at body temperature with thermodynamic preference. The ligand binding studies were supplemented by aggregation studies via dynamic light scattering (DLS) and bioinformatic analyses. Beyond the remarkably fine-tuned binding properties exhibited by each FABP, which were discernible with our EPR-centered approach, the results of this work attest the power of simple spectroscopic experiments to provide new insights into the ligand binding mechanisms of proteins in general on a molecular level.

Chromone-based fluorescent probe for peroxynitrite imaging in Arabidopsis thaliana

As a typical reactive nitrogen species, peroxynitrite (ONOO−) plays an important role in cells and organisms. But in plants, information on the role of endogenous ONOO− remains limited. In order to explore its functions, it is necessary to probe ONOO− in biological systems, especially in plants. In this paper, we report RAW-A, a chromone-based fluorescence probe, exhibits a highly selective and sensitive response to ONOO−. It is worth noting that RAW-A has good water solubility, which is beneficial for the application of biological systems. RAW-A can respond to ONOO− even at low concentrations of ONOO−, indicating that the probe is expected to monitor ONOO− in real-time in living systems. In addition, confocal imaging experiments show that RAW-A can image endogenous and exogenous ONOO− in Arabidopsis thaliana root besides HeLa cell. It shows that RAW-A has the potential to be an imaging tool for studying the biological roles of ONOO− in plants. To our knowledge, RAW-A is the first fluorescent probe with highly selective and sensitive response to ONOO− in plants.

Computational Analysis and NGS for Human LDHC Complexed with NAD+ and Ethylamino Acetic Acid (Lung Cancer)

Abstract: This study presents a multidimensional exploration of the structural and functional characteristics of the human Lactate Dehydrogenase C (LDHC) complexed with NAD+ and ethylamino acetic acid (EAA), focusing on its implications in lung cancer. Leveraging data from the Protein Data Bank (PDB) and Molecular Modeling Database (MMDB), a comprehensive analysis was conducted using various computational tools and resources. Structural insights were gained through PDBsum and RasMol, elucidating molecular interactions and identifying potential drug-target sites. Sequence analysis via BLAST and Multiple Sequence Alignment provided further understanding of conserved sequences and structural motifs. Visualization and manipulation of molecular structures were facilitated by PyMOL, enabling the identification of active drug-target sites. Proteinligand docking studies using the CB-Dock2 server assessed the efficiency of LDHC complexation with NAD+. Structural validation through the SAVES server ensured the reliability of the complex structure. Additionally, biological network analysis using the STRING database revealed associations with gene ontology and structural classification of the protein, offering insights into targeted interventions in the ancestry of the protein. This comprehensive approach provides valuable insights into LDHC's role in cancer biology and offers promising avenues for therapeutic development in lung cancer.

Caffeine improves mitochondrial dysfunction in the white matter of neonatal rats with hypoxia-ischemia through deacetylation: a proteomic analysis of lysine acetylation.

White matter damage (WMD) is linked to both cerebral palsy and cognitive deficits in infants born prematurely. The focus of this study was to examine how caffeine influences the acetylation of proteins within the neonatal white matter and to evaluate its effectiveness in treating white matter damage caused by hypoxia-ischemia. We employed a method combining affinity enrichment with advanced liquid chromatography and mass spectrometry to profile acetylation in proteins from the white matter of neonatal rats grouped into control (Sham), hypoxic-ischemic (HI), and caffeine-treated (Caffeine) groups. Our findings included 1,999 sites of lysine acetylation across 1,123 proteins, with quantifiable changes noted in 1,342 sites within 689 proteins. Analysis of these patterns identified recurring sequences adjacent to the acetylation sites, notably YKacN, FkacN, and G * * * GkacS. Investigation into the biological roles of these proteins through Gene Ontology analysis indicated their involvement in a variety of cellular processes, predominantly within mitochondrial locations. Further analysis indicated that the acetylation of tau (Mapt), a protein associated with microtubules, was elevated in the HI condition; however, caffeine treatment appeared to mitigate this over-modification, thus potentially aiding in reducing oxidative stress, inflammation in the nervous system, and improving mitochondrial health. Caffeine inhibited acetylated Mapt through sirtuin 2 (SITR2), promoted Mapt nuclear translocation, and improved mitochondrial dysfunction, which was subsequently weakened by the SIRT2 inhibitor, AK-7. Caffeine-induced changes in lysine acetylation may play a key role in improving mitochondrial dysfunction and inhibiting oxidative stress and neuroinflammation.

MEN1 deficiency stabilizes PD-L1 and promotes tumor immune evasion of lung cancer.

Multiple Endocrine Neoplasia 1 gene (MEN1), which is known to be a tumor suppressor gene in lung tissues, encodes a 610 amino acid protein menin. Previous research has proven that MEN1 deficiency promotes the malignant progression of lung cancer. However, the biological role of this gene in the immune microenvironment of lung cancer remains unclear. In this study, we found that programmed cell death-ligand 1 (PD-L1) is upregulated in lung-specific KrasG12D mutation-induced lung adenocarcinoma in mice, after Men1 deficiency. Simultaneously, CD8+ and CD3+ T cells are depleted, and their cytotoxic effects are suppressed. Invitro, PD-L1 is inhibited by the overexpression of menin. Mechanistically, we found that MEN1 inactivation promotes the deubiquitinating activity of COP9 signalosome subunit 5 (CSN5) and subsequently increases the level of PD-L1.

Genome-wide analysis of bZIP transcription factors and their expression patterns in response to methyl jasmonate and low-temperature stresses in Platycodon grandiflorus.

Platycodon grandiflorus belongs to the genus Platycodon and has many pharmacological effects, such as expectorant, antitussive, and anti-tumor properties. Among transcription factor families peculiar to eukaryotes, the basic leucine zipper (bZIP) family is one of the most important, which exists widely in plants and participates in many biological processes, such as plant growth, development, and stress responses. However, genomic analysis of the bZIP gene family and related stress response genes has not yet been reported in P. grandiflorus. P. grandiflorus bZIP (PgbZIP) genes were first identified here, and the phylogenetic relationships and conserved motifs in the PgbZIPs were also performed. Meanwhile, gene structures, conserved domains, and the possible protein subcellular localizations of these PgbZIPs were characterized. Most importantly, the cis-regulatory elements and expression patterns of selected genes exposed to two different stresses were analyzed to provide further information on PgbZIPs potential biological roles in P. grandiflorus upon exposure to environmental stresses. Forty-six PgbZIPs were identified in P. grandiflorus and divided into nine groups, as displayed in the phylogenetic tree. The results of the chromosomal location and the collinearity analysis showed that forty-six PgbZIP genes were distributed on eight chromosomes, with one tandem duplication event and eleven segmental duplication events identified. Most PgbZIPs in the same phylogenetic group have similar conserved motifs, domains, and gene structures. There are cis-regulatory elements related to the methyl jasmonate (MeJA) response, low-temperature response, abscisic acid response, auxin response, and gibberellin response. Ten PgbZIP genes were selected to study their expression patterns upon exposure to low-temperature and MeJA treatments, and all ten genes responded to these stresses. The real-time quantitative polymerase chain reaction (RT-qPCR) results suggest that the expression levels of most PgbZIPs decreased significantly within 6 h and then gradually increased to normal or above normal levels over the 90 h following MeJA treatment. The expression levels of all PgbZIPs were significantly reduced after 3 h of the low-temperature treatment. These results reveal the characteristics of the PgbZIP family genes and provide valuable information for improving P. grandiflorus's ability to cope with environmental stresses during growth and development.

Stable Ga2O3 soft x-ray detector with ultrahigh responsivity

Soft x-ray detectors play crucial roles in biology, chemistry, and lithography. Current soft x-ray detectors suffer from insufficient responsivity (R), excessively large cell area, and limited stability. Here, the β-Ga2O3 soft x-ray detector is constructed, and the effects of varying the sensitive layer thickness and voltage on the soft x-ray detection characteristics of the device are explored. Meanwhile, the mechanism of the multiplication ionization process from soft x-ray and the photoconductivity gain on the photoresponse performance of the device are analyzed. The device obtains the R up to 3.05 × 103 A/W under 300 eV soft x-ray irradiation at the synchrotron beamline, which is about 1.19 × 104 times higher than that of the conventional device. The Ga2O3 device also maintains stable operation under long-term irradiation and multicycle switching. These results indicate that Ga2O3 is an ideal candidate material for soft x-ray detection, which has great potential for applications such as imaging of biological cells.

Controlled Supramolecular Polymerization via Bioinspired, Liquid-Liquid Phase Separation of Monomers.

Dynamic supramolecular assemblies, driven by noncovalent interactions, pervade the biological realm. In the synthetic domain, their counterparts, supramolecular polymers, endowed with remarkable self-repair and adaptive traits, are often realized through bioinspired designs. Recently, controlled supramolecular polymerization strategies have emerged, drawing inspiration from protein self-assembly. A burgeoning area of research involves mimicking the liquid-liquid phase separation (LLPS) observed in proteins to create coacervate droplets and recognizing their significance in cellular organization and diverse functions. Herein, we introduce a novel perspective on synthetic coacervates, extending beyond their established role in synthetic biology as dynamic, membraneless phases to enable structural control in synthetic supramolecular polymers. Drawing parallels with the cooperative growth of amyloid fibrils through LLPS, we present metastable coacervate droplets as dormant monomer phases for controlled supramolecular polymerization. This is achieved via a π-conjugated monomer design that combines structural characteristics for both coacervation through its terminal ionic groups and one-dimensional growth via a π-conjugated core. This design leads to a unique temporal LLPS, resulting in a metastable coacervate phase, which subsequently undergoes one-dimensional growth via nucleation within the droplets. In-depth spectroscopic and microscopic characterization provides insights into the temporal evolution of disordered and ordered phases. Furthermore, to modulate the kinetics of liquid-to-solid transformation and to achieve precise control over the structural characteristics of the resulting supramolecular polymers, we invoke seeding in the droplets, showcasing living growth characteristics. Our work thus opens up new avenues in the exciting field of supramolecular polymerization, offering general design principles and controlled synthesis of precision self-assembled structures in confined environments.

Circular RNA PRKCI (hsa_circ_0067934): a potential target in the pathogenesis of human malignancies.

Circular RNAs (circRNAs) are a new type of endogenous non-coding RNA formed by a covalent closed loop. CircRNAs are characterized by specificity, universality, conservation, and stability. They are abundant in eukaryotic cells and have biological regulatory roles at various transcriptional and post-transcriptional levels. The upregulation of circPRKCI has been observed in a variety of tumors and is directly related to the clinicopathological characteristics of tumors and prognosis. More importantly, circPRKCI can participate in the tumorigenesis, progression, recurrence, and metastasis of various tumors through many functional mechanisms, including the activation of signaling pathways, such as the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, and sponging of many microRNAs (miRNAs). This review summarizes the progress achieved in understanding the biological functions of circRNA PRKCI in various tumors. The goal is to inform the discovery of more functional mechanisms and new anticancer molecular targets.

The Biological Role of Macrophage in Lung and Its Implications in Lung Cancer Immunotherapy.

The lungs are the largest surface of the body and the most important organ in the respiratory system, which are constantly exposed to the external environment. Tissue Resident Macrophages in lung constitutes the important defense against external pathogens. Macrophages connects the innate and adaptive immune system, and also plays important roles in carcinogenesis and cancer immunotherapy. Lung cancer is the leading cause of cancer-related death worldwide, with an overall five-year survival rate of only 21%. Macrophages that infiltrate or aggregate in lung tumor microenvironment are defined as tumor-associated macrophages (TAMs). TAMs are the main components of immune cells in the lung tumor microenvironment. The differentiation and maturation process of TAMs can be roughly divided into two different types: classical activation pathway produces M1 tumor-associated macrophages, and bypass activation pathway produces M2 tumor-associated macrophages. Studies have found that TAMs are related to tumor invasion, metastasis, and treatment resistance, and show potential as a new target for tumor immunotherapy. Therefore, the biological function of macrophages in lung and the role of TAMs in the occurrence, development, and treatment of lung cancer are discussed in this paper.

SCPL acyltransferases catalyze the metabolism of chlorogenic acid during purple coneflower seed germination.

The metabolism of massively accumulated chlorogenic acid is crucial for the successful germination of purple coneflower (Echinacea purpurea (L.) Menoch). A serine carboxypeptidase-like (SCPL) acyltransferase (chicoric acid synthase, CAS) utilizes chlorogenic acid to produce chicoric acid during germination. However, it seems that the generation of chicoric acid lags behind the decrease in chlorogenic acid, suggesting an earlier route of chlorogenic acid metabolism. We discovered another chlorogenic acid metabolic product, 3,5-dicaffeoylquinic acid, which is produced before chicoric acid, filling the lag phase. Then, we identified two additional typical clade IA SCPL acyltransferases, named chlorogenic acid condensing enzymes (CCEs), that catalyze the biosynthesis of 3,5-dicaffeoylquinic acid from chlorogenic acid with different kinetic characteristics. Chlorogenic acid inhibits radicle elongation in a dose-dependent manner, explaining the potential biological role of SCPL acyltransferases-mediated continuous chlorogenic acid metabolism during germination. Both CCE1 and CCE2 are highly conserved among Echinacea species, supporting the observed metabolism of chlorogenic acid to 3,5-dicaffeoylquinic acid in two Echinacea species without chicoric acid accumulation. The discovery of SCPL acyltransferase involved in the biosynthesis of 3,5-dicaffeoylquinic acid suggests convergent evolution. Our research clarifies the metabolism strategy of chlorogenic acid in Echinacea species and provides more insight into plant metabolism.

A Comprehensive Analysis of HOXB13 Expression in Hepatocellular Carcinoma

Background and objectives: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and is caused by multiple factors. To explore novel targets for HCC treatment, we comprehensively analyzed the expression of HomeoboxB13 (HOXB13) and its role in HCC. Materials and Methods: The clinical significance of HCC was investigated using open gene expression databases, such as TIMER, UALCAN, KM, OSlihc, and LinkedOmics, and immunohistochemistry analysis. We also analyzed cell invasion and migration in HCC cell lines transfected with HOXB13-siRNA and their association with MMP9, E2F1, and MEIS1. Results: HOXB13 expression was higher in fibrolamellar carcinoma than in other histological subtypes. Its expression was associated with lymph node metastasis, histological stage, and tumor grade. It was positively correlated with immune cell infiltration of B cells (R = 0.246), macrophages (R = 0.182), myeloid dendritic cells (R = 0.247), neutrophils (R = 0.117), and CD4+ T cells (R = 0.258) and negatively correlated with immune cell infiltration of CD8+ T cells (R = −0.107). A positive correlation was observed between HOXB13, MMP9 (R = 0.176), E2F1 (R = 0.241), and MEIS1 (R = 0.189) expression (p < 0.001). The expression level of HOXB13 was significantly downregulated in both HepG2 and PLC/PFR/5 cell lines transfected with HOXB13-siRNA compared to that in cells transfected with NC siRNA (p < 0.05). Additionally, HOXB13 significantly affected cell viability and wound healing. Conclusions: HOXB13 overexpression may lead to poor prognosis in patients with HCC. Additional in vivo studies are required to improve our understanding of the biological role and the exact mechanism of action of HOXB13 in HCC.

Molecular Mechanisms Regulating GRF Activity in Plant Growth, Development, and Environmental Responses.

Plants rely on complex regulatory mechanisms to ensure proper growth and development. As sessile organisms, these mechanisms must be flexible enough to adapt to changes in the environment. The GROWTH-REGULATING FACTORs (GRFs) are plant-specific transcription factors that act as a central hub controlling plant growth and development, offering promising biotechnological applications to enhance plant performance. Here, we analyze the complex molecular mechanisms that regulate GRF activity, and how their natural and synthetic variants can impact on plant growth and development. We describe the biological roles of the GRFs and examine how they regulate gene expression and contribute to the control of organ growth and the plant's response to a changing environment. This review focuses on the premise that unlocking their full biotechnological potential requires a thorough understanding of the various regulatory layers governing GRF activity, the functional divergence among GRF family members and the gene networks that they regulate.

Exosomal noncoding RNAs in gynecological cancers: implications for therapy resistance and biomarkers.

Gynecologic cancers, including ovarian cancer (OC), cervical cancer (CC), and endometrial cancer (EC), pose a serious threat to women's health and quality of life due to their high incidence and lethality. Therapeutic resistance in tumors refers to reduced sensitivity of tumor cells to therapeutic drugs or radiation, which compromises the efficacy of treatment or renders it ineffective. Therapeutic resistance significantly contributes to treatment failure in gynecologic tumors, although the specific molecular mechanisms remain unclear. Exosomes are nanoscale vesicles released and received by distinct kinds of cells. Exosomes contain proteins, lipids, and RNAs closely linked to their origins and functions. Recent studies have demonstrated that exosomal ncRNAs may be involved in intercellular communication and can modulate the progression of tumorigenesis, aggravation and metastasis, tumor microenvironment (TME), and drug resistance. Besides, exosomal ncRNAs also have the potential to become significant diagnostic and prognostic biomarkers in various of diseases. In this paper, we reviewed the biological roles and mechanisms of exosomal ncRNAs in the drug resistance of gynecologic tumors, as well as explored the potential of exosomal ncRNAs acting as the liquid biopsy molecular markers in gynecologic cancers.

PKIB, a Novel Target for Cancer Therapy.

The serine-threonine kinase protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent intracellular protein with multiple roles in cellular biology including metabolic and transcription regulation functions. The cAMP-dependent protein kinase inhibitor β (PKIB) is one of three known endogenous protein kinase inhibitors of PKA. The role of PKIB is not yet fully understood. Hormonal signaling is correlated with increased PKIB expression through genetic regulation, and increasing PKIB expression is associated with decreased cancer patient prognosis. Additionally, PKIB impacts cancer cell behavior through two mechanisms; the first is the nuclear modulation of transcriptional activation and the second is the regulation of oncogenic AKT signaling. The limited research into PKIB indicates the oncogenic potential of PKIB in various cancers. However, some studies suggest a role of PKIB in non-cancerous disease states. This review aims to summarize the current literature and background of PKIB regarding cancer and related issues. In particular, we will focus on cancer development and therapeutic possibilities, which are of paramount interest in PKIB oncology research.

Identification of genes related to ribosomal proteins in colorectal cancer: exploring their potential as biomarkers, prognostic indicators, and therapeutic targets.

Colorectal cancer (CRC) ranks as the third most commonly diagnosed cancer in both females and males, underscoring the need for the identification of effective biomarkers. We assessed the expression levels of ribosomal proteins (RPs) at both mRNA and protein levels. Subsequently, leveraging the STRING database, we constructed a protein-protein interaction network and identified hub genes. The co-expression network of differentially expressed genes associated with CRC and their target hub RPs was constructed using the weighted gene co-expression network analysis algorithm. Gene ontology and molecular signatures database were conducted to gain insights into the biological roles of genes associated with the identified module. To confirm the results, the expression level of the candidate genes in the CRC samples compared to the adjacent healthy was evaluated by the RT-qPCR method. Our findings indicated that the genes related to RPs were predominantly enriched in biological processes associated with Myc Targets, Oxidative Phosphorylation, and cell proliferation. Also, results demonstrated that elevated levels of GRWD1, MCM5, IMP4, and RABEPK that related to RPs were associated with poor prognostic outcomes for CRC patients. Notably, IMP4 and RABEPK exhibited higher diagnostic value. Moreover, the expression of IMP4 and RABEPK showed a significant association with drug resistance using cancer cell line encyclopedia and genomics of drug sensitivity in cancer databases. Also, the results showed that the expression level of IMP4 and RABEPK in cancerous samples was significantly higher compared to the adjacent healthy ones. The general results of this study have shown that many genes related to RPs are increased in cancer and could be associated with the death rate of patients. We also highlighted the therapeutic and prognostic potentials of RPs genes in CRC.

S1PR3 suppresses the inflammatory response and extracellular matrix degradation in human nucleus pulposus cells.

Sphingosine 1-phosphate receptor 3 (S1PR3) participates in the inflammatory response in multiple types of diseases. However, the biological role of S1PR3 in intervertebral disc degeneration and the underlying mechanism are unclear. The aim of the present study was to investigate the functional role and the mechanism of S1PR3 in lipopolysaccharide (LPS)-induced human nucleus pulposus cells. The expression of S1PR3 and Toll-like receptor (TLR) 2 in LPS-induced nucleus pulposus (NP) cells was investigated using western blotting. The Cell Counting Kit-8 assay was used to detect cell proliferation, and the levels of inflammatory factors were detected using ELISA. Flow cytometry and western blotting were used for the assessment of apoptosis. The deposition of extracellular matrix (ECM) proteins was investigated using reverse transcription-quantitative PCR and western blotting. In addition, western blotting was used to investigate the protein expression levels of phosphorylated (p)-STAT3, STAT3, p-JNK, JNK, p-ERK, ERK, p-p38 and p38associated with STAT3 and MAPK signaling. S1PR3 expression was reduced, while TLR2 expression was elevated in LPS-induced human nucleus pulposus cells (HNPC). S1PR3 overexpression increased HNPC viability, inhibited the inflammatory response and suppressed apoptosis. Meanwhile, S1PR3 overexpression regulated the expression of ECM-related proteins. Additionally, overexpression of S1PR3 inhibited the expression of the TLR2-regulated STAT3 and MAPK pathways in LPS-induced HNPCs. Furthermore, TLR2 overexpression partially offset the impacts of S1PR3 overexpression on HNPC viability, apoptosis level, inflammation and as ECM degradation. In conclusion, STAT3 overexpression suppressed viability injury, the inflammatory response and the level of apoptosis and alleviated ECM protein deposition in HNPCs through the TLR2/STAT3 and TLR2/MAPK pathways, which may offer a promising candidate for the amelioration of intervertebral disc degeneration.