International Journal of Molecular Sciences最新文献

{"title":"Characterising a Novel Therapeutic Target for Psoriasis, TYK2, Using Functional Genomics.","authors":"Shraddha S Rane, Sarah Elyoussfi, Elan Shellard, Steve Eyre, Richard B Warren","doi":"10.3390/ijms252313229","DOIUrl":"https://doi.org/10.3390/ijms252313229","url":null,"abstract":"<p><p>Psoriasis (Ps) is a debilitating immune-mediated chronic skin condition. It affects about 1-3% of the world population, with an 8-11% prevalence in Northern European populations. Tyrosine kinase 2 (TYK2) is a newly identified target for Ps. An independent non-coding genetic association with Ps has been identified ~400 kb upstream of TYK2. The variants making up the credible Ps Single-Nucleotide Polymorphism (SNP) set were identified in their genomic context with the potential to influence TYK2 expression by interacting with regulatory elements involved in gene regulation. Previous evidence from our laboratory has suggested that credible SNP sets in intronic regions can be distal regulators of the genes of interest through long-range chromatin interactions. We hypothesise that SNPs at ILF3 are distal regulators of TYK2 expression via long-range chromatin interactions and Ps risk. The dysregulation of the TYK2 pathway in Ps may be mediated by a combination of GWAS risk SNPs at ILF3 and TYK2 and downstream genes. We investigated this by employing functional genomics and molecular biology methods. We developed a CD4 T cell model system with Jurkat-dCAS9-VP64 and Jurkat-dCAS9-KRAB cells using CRISPR activation and CRISPR inhibition of the risk variants rs892086 and rs7248205, selected from the latest Ps GWAS SNP set for their long-range interaction and light Linkage Disequilibrium (R² > 0.8), respectively. Using CRISPR activation, we demonstrate here that these risk SNPs, although distal to TYK2, do indeed regulate the TYK2 gene. Investigations into annotating the TYK2 pathway using RNA-seq analysis revealed differentially regulated genes, including VEGFA, C1R, ADORA1, GLUD2, NDUFB8, and FCGR2C, which are thought to be implicated in Ps. These genes were observed to be associated with conditions such as psoriatic arthritis, atopic dermatitis, and systemic sclerosis when compared using published databases, which confirms their relevance and importance in inflammatory conditions. With the developed cell model systems using CRISPR technology and differential gene regulation, we demonstrate here that these genes have the potential to define the TYK2/Ps pathway and our understanding of the disease biology.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142835901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carotenoid Cleavage Dioxygenase Gene <i>CCD4</i> Enhances Tanshinone Accumulation and Drought Resistance in <i>Salvia miltiorrhiza</i>.","authors":"Qian Tian, Wei Han, Shuai Zhou, Liu Yang, Donghao Wang, Wen Zhou, Zhezhi Wang","doi":"10.3390/ijms252313223","DOIUrl":"https://doi.org/10.3390/ijms252313223","url":null,"abstract":"<p><p>Danshen (<i>Salvia miltiorrhiza</i> Bunge) is a perennial herbaceous plant of the Salvia genus in the family Lamiaceae. Its dry root is one of the important traditional Chinese herbal medicines with a long officinal history. The yield and quality of <i>S. miltiorrhiza</i> are influenced by various factors, among which drought is one of the most significant types of abiotic stress. Based on the transcriptome database of <i>S. miltiorrhiza</i>, our research group discovered a carotenoid cleavage dioxygenase gene, <i>SmCCD4</i>, belonging to the carotenoid cleavage oxygenase (CCO) gene family which is highly responsive to drought stress on the basis of our preceding work. Here, we identified 26 CCO genes according to the whole-genome database of <i>S. miltiorrhiza</i>. The expression pattern of <i>SmCCD4</i> showed that this gene is strongly overexpressed in the aboveground tissue of <i>S. miltiorrhiza</i>. And by constructing <i>SmCCD4</i> overexpression strains, it was shown that the overexpression of <i>SmCCD4</i> not only promotes the synthesis of abscisic acid and increases plant antioxidant activity but also regulates the synthesis of the secondary metabolites tanshinone and phenolic acids in <i>S. miltiorrhiza</i>. In summary, this study is the first in-depth and systematic identification and investigation of the CCO gene family in <i>S. miltiorrhiza</i>. The results provide useful information for further systematic research on the function of CCO genes and provide a theoretical basis for improving the yield and quality of <i>S. miltiorrhiza</i>.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142835810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sugar Transport and Signaling in Shoot Branching.","authors":"Joan Doidy, Yuhui Wang, Léo Gouaille, Ingrid Goma-Louamba, Zhengrong Jiang, Nathalie Pourtau, José Le Gourrierec, Soulaiman Sakr","doi":"10.3390/ijms252313214","DOIUrl":"https://doi.org/10.3390/ijms252313214","url":null,"abstract":"<p><p>The source-sink relationship is critical for proper plant growth and development, particularly for vegetative axillary buds, whose activity shapes the branching pattern and ultimately the plant architecture. Once formed from axillary meristems, axillary buds remain dormant or become active to grow into new branches. This transition is notably driven by the regulation of the bud sink strength, which is reflected in the ability to unload, metabolize and store photoassimilates. Plants have so far developed two main mechanisms for unloading sugars (sucrose) towards sink organs, a symplasmic pathway and an apoplasmic pathway, but so far limited investigations have been reported about the modes of sugar uptake during the transition from the dormant to the active outgrowth state of the bud. The available data indicate that the switch from dormant bud to active outgrowing state, requires sugar and is shortly preceded by an increase in bud metabolic activity and a remobilization of the stem starch reserves in favor of growing buds. This activation of the bud sink strength is accompanied by an up-regulation of the main markers of apoplasmic unloading, such as sugar transporters (sucrose transporters-SUTs; sugar will eventually be exported transporters-SWEETs), sucrose hydrolyzing enzymes (cell wall invertase-CWINV) and sugar metabolic pathways (glycolysis/tricarboxylic cycle-TCA; oxidative pentose phosphate pathway-OPPP). As these results are limited to a few species, they are not sufficient to provide a complete and accurate picture of the mode(s) of sugar unloading toward axillary buds and deserve to be complemented by additional studies in a wide variety of plants using systems integration, combining genetic, molecular and immunolocalization approaches. Altogether, we discuss here how sugar is a systemic regulator of shoot branching, acting both as an energy-rich molecule and a signaling entity in the establishment of the bud sink strength.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network Pharmacology, Molecular Docking, and In Vitro Insights into the Potential of <i>Mitragyna speciosa</i> for Alzheimer's Disease.","authors":"Rahni Hossain, Kunwadee Noonong, Manit Nuinoon, Hideyuki J Majima, Komgrit Eawsakul, Pradoldej Sompol, Md Atiar Rahman, Jitbanjong Tangpong","doi":"10.3390/ijms252313201","DOIUrl":"https://doi.org/10.3390/ijms252313201","url":null,"abstract":"<p><p><i>Mitragyna speciosa</i> Korth. Havil (MS) has a traditional use in relieving pain, managing hypertension, treating cough, and diarrhea, and as a morphine substitute in addiction recovery. Its potential in addressing Alzheimer's disease (AD), a neurodegenerative condition with no effective treatments, is under investigation. This study aims to explore MS mechanisms in treating AD through network pharmacology, molecular docking, and in vitro studies. Using network pharmacology, we identified 19 MS components that may affect 60 AD-related targets. The compound-target network highlighted significant interactions among 60 nodes and 470 edges, with an average node degree of 15.7. The KEGG enrichment analysis revealed Alzheimer's disease (hsa05010) as a relevant pathway. We connected 20 targets to tau and β-amyloid proteins through gene expression data from the AlzData database. Docking studies demonstrated high binding affinities of MS compounds like acetylursolic acid, beta-sitosterol, isomitraphylline, and speciophylline to AD-related proteins, such as AKT1, GSK3B, NFκB1, and BACE1. In vitro studies showed that ethanolic (EE), distilled water (DWE), and pressurized hot water (PHWE) extracts of MS-treated 100 μM H₂O₂-induced SH-SY5Y cells significantly reduced oxidative damage. This research underscores the multi-component, multi-target, and multi-pathway effects of MS on AD, providing insights for future research and potential clinical applications.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142835859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Meropenem on Conjugative Plasmid Transfer in <i>Klebsiella pneumoniae</i>.","authors":"Daria A Kondratieva, Julia R Savelieva, Maria V Golikova","doi":"10.3390/ijms252313193","DOIUrl":"https://doi.org/10.3390/ijms252313193","url":null,"abstract":"<p><p>Plasmid-mediated resistance is a major mechanism that contributes to the gradual decline in the effectiveness of antibiotics from different classes, including carbapenems. Antibiotics can significantly contribute to the efficiency of plasmid transfer between bacterial strains. To investigate the potential effect of an antibiotic on the efficacy of conjugative plasmid transfer, we conducted mating experiments with <i>Klebsiella pneumoniae</i> strains. Donor strains of <i>K. pneumoniae</i> that carry plasmids with <i>bla</i>_KPC or <i>bla</i>_OXA-48 carbapenemase genes and recipient plasmid-free <i>K. pneumoniae</i> strains were used in matings. Matings were conducted on the agar with or without meropenem at 1/8×, 1/4×, or 1/2×MIC against the respective recipients. In the second part of our study, we investigated the pharmacodynamic properties of meropenem against transconjugant strains of <i>K. pneumoniae</i>, which were obtained in the first part of this study. As a result, at a concentration equivalent to 1/8×MIC, meropenem primarily inhibited conjugation among <i>K. pneumoniae</i> strains, while at a concentration equal to 1/2×MIC, it facilitated conjugation. Transconjugants derived from <i>K. pneumoniae</i> with intermediate MICs failed to respond to simulated treatment with meropenem using prolonged infusion and a high-dose regimen. This finding suggests that such transconjugants may potentially pose a risk if involved in an infectious process.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"StUBC13, a Ubiquitin-Conjugating Enzyme, Positively Regulates Salt and Osmotic Stresses in Potato.","authors":"Xue Fu, Xun Tang, Ning Zhang, Huaijun Si","doi":"10.3390/ijms252313197","DOIUrl":"https://doi.org/10.3390/ijms252313197","url":null,"abstract":"<p><p>Protein ubiquitination is an important regulatory mechanism for biological growth and development against environmental influences, and can affect several biological processes, including the growth, development, and stress responses of plants. However, the function of potato-related ubiquitin-conjugating enzymes in abiotic stress tolerance is poorly understood. In this study, a <i>StUBC13</i> with a UBC conserved structural domain was identified in potato and its function was investigated under osmotic stress and salt stress conditions. The observation of plant phenotypes under stress conditions revealed that overexpressed plants grew better than wild-type plants. In line with the above results, the determination of stress-related physiological indices revealed that the overexpression transgenic plants had better stress tolerance and stronger adaptation to environmental stress, and the transgenic plants were found to tolerate better drought and salt stress by decreasing their malondialdehyde (MDA) content and increasing their superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) contents under stress conditions. Based on these results, StUBC13 has an important regulatory role in the response of plants to abiotic stresses (osmotic stress and salt stress), and overexpression of this gene can improve the tolerance of potatoes to osmotic and salt stresses.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Multiplex RT-qPCR Method for the Identification and Lineage Typing of Porcine Reproductive and Respiratory Syndrome Virus.","authors":"Chunhao Tao, Xizhou Zhu, Ying Huang, Weifeng Yuan, Zhen Wang, Hongfei Zhu, Hong Jia","doi":"10.3390/ijms252313203","DOIUrl":"https://doi.org/10.3390/ijms252313203","url":null,"abstract":"<p><p>Porcine reproductive and respiratory syndrome virus (PRRSV) is the pathogen that causes porcine reproductive and respiratory syndrome (PRRS), leading to abortion of sows and the manifestation of respiratory diseases in piglets. PRRSV strains are categorized into two distinct genotypes: PRRSV-1 and PRRSV-2. PRRSV-2 can be further classified into several lineages, including sub-lineage 1.8 (NADC30-like), sub-lineage 1.5 (NADC34-like), lineage 8 (HP-PRRSV-like), lineage 5 (VR-2332-like), and lineage 3 (QYYZ-like), all of which are prevalent in China. In order to identify PRRSV-1 and PRRSV-2, two primer-probe combinations were designed, targeting the M gene. In order to further differentiate the five lineages of PRRSV-2, another five primer-probe combinations were designed, targeting the Nsp2 gene. A TaqMan-based multiplex RT-qPCR assay was subsequently developed, integrating the aforementioned seven sets into two primer pools. Following the optimization of primer concentration and annealing temperature, a comprehensive evaluation was conducted to assess the assay's amplification efficiency, specificity, repeatability, and sensitivity. The developed multiplex RT-qPCR method exhibited excellent repeatability, with coefficients of variation (CVs) less than 2.12%. The detection limits for all seven targets were found to be less than 5 copies/μL. Ultimately, the method was utilized for the detection of a total of 1009 clinical samples, with a PRRSV-positive rate of 7.63% (77/1009). Specifically, the reference method was utilized to further confirm the status of the 77 PRRSV-positive samples and another 27 samples suspected of PRRSV infection. The sensitivity of the method was 97.40% (75/77), and the specificity was 96.30% (26/27), resulting in an overall coincidence rate of 97.12% (101/104). All the PRRSV-positive samples were typed as NADC30-like strains, and the accuracy of this typing was further confirmed by Sanger sequencing. In conclusion, A one-step multiplex RT-qPCR method was successfully constructed, evaluated, and applied to detect clinical samples. The assay provides an easy-to-operate, time-saving, and highly efficient way for the quick identification of PRRSV and simultaneous detection of five PRRSV-2 lineages prevalent in China. The method could offer guidance for PRRSV prevention and control measures.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142835236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of a Screen-Printed Ion-Selective Electrode Based on Hydrophobic Ti₃C₂/AuNPs for K⁺ Determination Across Variable Temperatures.","authors":"Zhixue Yu, Hui Wang, Yue He, Dongfei Chen, Ruipeng Chen, Xiangfang Tang, Mengting Zhou, Junhu Yao, Benhai Xiong","doi":"10.3390/ijms252313204","DOIUrl":"https://doi.org/10.3390/ijms252313204","url":null,"abstract":"<p><p>Monitoring potassium ion (K⁺) concentration is essential in veterinary medicine, particularly for preventing hypokalemia in dairy cows, which can severely impact their health and productivity. While traditional laboratory methods like atomic absorption spectrometry are accurate, they are also time-consuming and require complex sample preparation. Ion-selective electrodes (ISEs) provide an alternative that is faster and more suitable for field measurements, but their performance is often compromised under variable temperature conditions, leading to inaccuracies. To address this, we developed a novel screen-printed ion-selective electrode (SPE) with hydrophobic Ti₃C₂ Mxene and gold nanoparticles (AuNPs), integrated with a temperature sensor. This design improves stability and accuracy across fluctuating temperatures by preventing water layer formation and enhancing conductivity. The sensor was validated across temperatures from 5 °C to 45 °C, achieving a linear detection range of 10^-⁵ to 10^-1 M and a response time of approximately 15 s. It also demonstrated excellent repeatability, selectivity, and stability, making it a robust tool for K⁺ monitoring in complex environments. This advancement could lead to broader applications in other temperature-sensitive analytical fields.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142835930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-Specific HLA Alleles Contribute to the Modulation of COVID-19 Severity.","authors":"Serena Spartano, Maria Vittoria Faggiano, Giovanna Guidi, Pino D'Ambrosio, Alessandro Vaisfeld, Agnese Novelli, Salvatore Falqui, Antonella Cingolani, Lorenza Lambertenghi, Alessandro Visentin, Annamaria Azzini, Elda Righi, Enrico Maria Trecarichi, Maria Mazzitelli, Silvano Coletti, Jan Mous, Thomas W Rademacher, Carlo Torti, Evelina Tacconelli, Massimo Fantoni, Roberto Cauda, Francesco Danilo Tiziano","doi":"10.3390/ijms252313198","DOIUrl":"https://doi.org/10.3390/ijms252313198","url":null,"abstract":"<p><p>Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, responsible for Coronavirus Disease 2019 (COVID-19), exhibits a spectrum of clinical manifestations, ranging from asymptomatic to severe pulmonary dysfunction or death. The variability in COVID-19 severity has largely been attributed to the host's genetic characteristics, suggesting a polygenic genetic architecture, without significant strong evidence of sex-related genetic differences. In this Italian retrospective case-control study, we investigated the association between COVID-19 severity (severe vs. asymptomatic/oligosymptomatic healed individuals) and HLA gene variants, analyzed by next-generation sequencing (NGS). We identified significant HLA alleles (according to the conventional nomenclature), SNPs and haplotypes in the <i>HLA-B</i>, <i>-C</i>, <i>-F</i>, <i>-DQA1</i>, <i>-DRB1</i>, and <i>-DRB5</i> genes associated with COVID-19 severity. Interestingly, these variants showed biological sex-related effects. Also, we identified specific haplotypes associated with COVID-19 severity that are shared by different conventional HLA alleles, indicated here as \"super-haplotypes\". These haplotypes had a biological sex-specific impact on disease severity and markedly increased the risk of severe COVID-19 compared to the conventional HLA alleles (odds ratio of up to 15). Our data suggest that the revision of the current HLA nomenclature may help to identify variants with a stronger effect on disease susceptibility and that association studies could benefit from the stratification of patients by biological sex. If replicated in other disease models, these findings could help to define the functional diversity in immune response between sexes, also based on the HLA system. Finally, due to the global pandemic's mortality rate, we hypothesize here that SARS-CoV-2 may have acted as a natural selection trigger, leading to a drift in HLA allelic frequencies in the general population.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142836267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Role for Periostin Pathological Variants and Their Interaction with HSP70-1a in Promoting Pancreatic Cancer Progression and Chemoresistance.","authors":"Yasuo Tsunetoshi, Fumihiro Sanada, Yuko Kanemoto, Kana Shibata, Atsushi Masamune, Yoshiaki Taniyama, Koichi Yamamoto, Ryuichi Morishita","doi":"10.3390/ijms252313205","DOIUrl":"https://doi.org/10.3390/ijms252313205","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) characterized by an abundant cancer stroma is an aggressive malignancy with a poor prognosis. Periostin (Pn) is a key extracellular matrix (ECM) protein in various tumor progression. Previously, we described the role of Pn alternative splicing variants (ASVs) with specific functional features in breast cancer. Pn is known to associate with a chemoresistance of PDAC, but the functions of the Pn-ASVs remain largely unknown. In this study, we focused on physiological and pathological Pn-ASVs, and examined the characteristics of Pn-expressing cells and the difference in function of each ASV. We found that cancer-associated fibroblasts (CAFs) are a main source of Pn synthesis, which selectively secrete pathological Pn-ASVs with exon 21 both in mouse and human samples. RNA sequencing identified a gene signature of Pn-positive CAFs associated with ECM-related genes and chemokines, factors that shape the chemoresistance tumor microenvironment (TME). Additionally, only pathological Pn-ASVs interacted with heat shock protein 70-1a (HSP70-1a), leading to significant rescue of gemcitabine-induced PDAC apoptosis. In silico analysis revealed that the presence or absence of exon 21 changes the tertiary structure of Pn and the binding sites for HSP70-1a. Altogether, Pn-ASVs with exon 21 secreted from CAFs play a key role in supporting tumor growth by interacting with cancer cell-derived HSP70-1a, indicating that Pn-ASVs with exon 21 might be a potential therapeutic and diagnostic target in PDAC patients with rich stroma.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"25 23","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}