Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"FBXW8-mediated degradation of PPT1 suppresses epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma","authors":"Jingliang He ,&nbsp;Xun Zou ,&nbsp;Dan Wang ,&nbsp;Lili Zhou ,&nbsp;Xiuming Li ,&nbsp;Shaojie Ma ,&nbsp;Xiaozhu Shen ,&nbsp;Shunfang Liu ,&nbsp;Bin Liu","doi":"10.1016/j.bbadis.2025.167985","DOIUrl":"10.1016/j.bbadis.2025.167985","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, characterized by its aggressive growth, high metastatic potential, and resistance to therapeutic interventions. Dysregulation of the ubiquitin-proteasome system (UPS) is recognized as a hallmark of cancer; however, its precise functional contributions to HCC pathogenesis remain incompletely elucidated. In the present study, we identify F-box and WD repeat domain-containing 8 (FBXW8), an F-box protein component of the Cullin-RING ligase (CRL) complex, as a pivotal tumor suppressor in HCC. Through a combination of in vitro and in vivo models, we demonstrate that FBXW8 depletion facilitates HCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), whereas FBXW8 overexpression exerts inhibitory effects on these malignant phenotypes. Proteomic and mechanistic analyses reveal that FBXW8 targets palmitoyl-protein thioesterase 1 (PPT1), a lysosomal hydrolase, for ubiquitination and subsequent proteasomal degradation. Elevated PPT1 expression correlates with poor clinical prognosis in HCC patients and is positively associated with the activation of EMT and oncogenic signaling pathways. Our data further reveal that PPT1 promotes EMT in part by enhancing the expression of critical EMT transcription factors, notably Snail Family Transcriptional Repressor 1 (SNAIL) and Zinc Finger E-box Binding Homeobox 1 (ZEB1), with a more pronounced effect on SNAIL. Mechanistically, FBXW8-mediated degradation of PPT1 inhibits EMT, reducing metastatic potential, whereas PPT1 silencing reverses the tumor-promoting effects of FBXW8 loss. These findings establish the FBXW8-PPT1 axis as a pivotal regulatory pathway linking UPS-mediated proteostasis to HCC progression and metastasis. Our study highlights the therapeutic potential of targeting PPT1 or restoring FBXW8 activity to disrupt oncogenic signaling and improve outcomes in HCC patients.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167985"},"PeriodicalIF":4.2,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144634001","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":"MicroRNA-126: A key regulator of angiogenesis, inflammation, and tumorigenesis — Exploring its multifaceted functions in vascular health and cancer","authors":"Oliwia Woźniak ,&nbsp;Bartosz Mierzejewski ,&nbsp;Edyta Brzoska","doi":"10.1016/j.bbadis.2025.167984","DOIUrl":"10.1016/j.bbadis.2025.167984","url":null,"abstract":"<div><div>MicroRNAs (miRNAs) are small, noncoding RNA molecules (20 to 24 nucleotides) that serve as essential regulators of gene expression through post-transcriptional mechanisms. Among these miRNAs, microRNA-126 (miR-126) has emerged as a key player in angiogenesis, vascular biology, inflammation, and fibrosis. Encoded in the intron of the epidermal growth factor-like domain 7 <em>(EGFL7</em>) gene, miR-126 undergoes canonical biogenesis and forms complexes that repress target messenger RNAs (mRNAs) by binding to complementary sequences in their 3′-untranslated regions (UTRs). MiR-126 have two distinct mature subtypes, namely miR-126-3p and miR-126-5p. The key miR-126 targets include factors such as <em>SPRED1, PIK3R2, PTEN, VEGF, EGFL7, CXCL12,</em> and others. Importantly, changes in miR-126 expression are associated with numerous diseases affecting vascular functions, which highlights its therapeutic potential to improve neovascularisation and underlines its importance as a biomarker for assessing disease risk. This review integrates the current understanding of miR-126 mechanisms of action, its implications in vascular pathologies, and therapeutic strategies, highlighting its importance in cardiovascular health and cancer biology.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 8","pages":"Article 167984"},"PeriodicalIF":4.2,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621460","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":"Ras association domain family member 1 (RASSF1): Molecular characteristics, clinical relevance and therapeutic interventions in cancer","authors":"Muhammad Omer Iqbal ,&nbsp;Qianqian Wang ,&nbsp;Imran Ahmad Khan ,&nbsp;Yuchao Gu ,&nbsp;Jin Chen ,&nbsp;Xiao Wu","doi":"10.1016/j.bbadis.2025.167977","DOIUrl":"10.1016/j.bbadis.2025.167977","url":null,"abstract":"<div><div>Ras Association Domain Family 1 (RASSF1) proteins are key modulators of tumor suppression, apoptosis, and cell cycle regulation. Among its isoforms, RASSF1A is the most extensively studied due to its crucial role in maintaining cellular homeostasis and preventing cancer progression. It primarily functions as a scaffold protein, orchestrating critical signaling pathways such as Ras, Hippo, and p53 to regulate cell proliferation and apoptosis. Epigenetic silencing of RASSF1A, predominantly through promoter hypermethylation, is a hallmark of numerous human cancers, including those of the lung, breast, and liver. Structural studies have identified conserved domains within RASSF1A, such as the Ras-association (RA) and SARAH domains, which mediate interactions with Ras-GTP and MST kinases to modulate tumor suppressor pathways. Additionally, post-translational modifications (PTMs), such as phosphorylation, influence RASSF1A stability and activity. Dysregulation of RASSF1A impairs several cellular processes, leading to unchecked cell proliferation and tumorigenesis. Understanding the molecular mechanisms regulating RASSF1A—both epigenetically and post-translationally—provides critical insights into potential therapeutic strategies aimed at restoring its tumor-suppressive functions. This review highlights current knowledge of RASSF1A's role in tumorigenesis and explores emerging approaches to target its dysregulation in cancer therapy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167977"},"PeriodicalIF":4.2,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621461","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":"Distinct systemic metabolic features in limb-girdle muscular dystrophy type R1 mouse models as a potential early pathogenic signature","authors":"Fumiko Shinkai-Ouchi ,&nbsp;Yoshiki Itoh ,&nbsp;Mayumi Shindo ,&nbsp;Kyohei Mikami ,&nbsp;Yoshinobu Iguchi ,&nbsp;Shoji Hata ,&nbsp;Rie Tsutsumi ,&nbsp;Yuna Izumi-Mishima ,&nbsp;Kyoka Machida ,&nbsp;Yuki Suzuki ,&nbsp;Hiroshi Sakaue ,&nbsp;Yasuko Ono","doi":"10.1016/j.bbadis.2025.167983","DOIUrl":"10.1016/j.bbadis.2025.167983","url":null,"abstract":"<div><div>Limb-girdle muscular dystrophy type R1 (LGMDR1, formerly LGMD2A) is a genetic disorder caused by mutations in <em>CAPN3</em> and is characterized by progressive proximal limb muscle weakness. The <em>CAPN3</em> gene product, calpain-3/CAPN3/p94, is a member of the intracellular cysteine protease superfamily predominantly expressed in the skeletal muscle. LGMDR1 pathogenesis has been investigated separately using mouse models: CAPN3:C129S [knock-in (KI)] mice, which express a proteolytically inactive variant, and CAPN3 knockout (KO) mice. These studies propose that CAPN3 bears both proteolytic activity-dependent and -independent functions and that the loss of either or both affects phenotypes.</div><div>Here, we report a side-by-side, long-term analysis of KI and KO mice to comprehensively understand the LGMDR1 pathology in terms of CAPN3 function. Their physiques were comparable to those of wild-type animals, but age-dependent LGMDR1 symptoms were observed by histochemical analysis, with more severe symptoms observed in KO mice. Quantitative muscle proteomics and gene ontology analyses revealed more diverse changes in the KO mice than in the KI mice. Of the associated terms, “metabolic process” was the most affected across the genotype and age groups. Metabolomic analysis suggested that the skeletal muscles of these mice had an imbalance in the branched-chain amino acid catabolic pathway. Furthermore, a reduction in lipids and glycogen was observed in the liver of KO mice, suggesting that a systemic energy deficit occurs during CAPN3 deficiency.</div><div>Altogether, our results suggest that muscular dysfunction in LGMDR1 models is associated with compromised systemic energy balance and that the extent of perturbation is implicated in disease severity.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167983"},"PeriodicalIF":4.2,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621458","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":"Finerenone ameliorates high-fat-induced myocardial lipotoxicity by suppressing ferroptosis through augmenting the system Xc−/GSH synthesis pathway","authors":"Zhixin Xu ,&nbsp;Xunjia Li ,&nbsp;Yang Long ,&nbsp;An He ,&nbsp;Zhao Zou ,&nbsp;Gan Wang ,&nbsp;Yong Xia ,&nbsp;Suxin Luo","doi":"10.1016/j.bbadis.2025.167968","DOIUrl":"10.1016/j.bbadis.2025.167968","url":null,"abstract":"<div><div>Obesity cardiomyopathy (OCM) is a distinct clinical entity in cardiovascular disease, yet targeted therapeutic options are scarce. Finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, has shown cardioprotective effects, but its role in mitigating OCM lipotoxicity is unclear. To elucidate the underlying functions and mechanisms, rats were fed on an HFD for 16 weeks to establish the OCM model. At the 12th week of HFD, the OCM rats were administered 10 mg/kg finerenone for 4 weeks. Cardiac ultrasound, glycolipid metabolism, lipid deposition, histopathology, and oxidative stress were evaluated in rats to elucidate the effects of finerenone on myocardial lipotoxic injury phenotype in relation to cardiac function and structure. Additionally, we identified potential mechanisms by which finerenone ameliorates lipotoxicity using cardiac tissue's RNA sequencing technology and bioinformatics analyses. Furthermore, the efficacy and underlying mechanisms of finerenone were validated using an in vitro cardiomyocyte model of lipotoxic injury induced by high palmitate stimulation in H9C2 cells. Finerenone treatment did not affect body weight or insulin resistance but significantly ameliorated cardiac hypertrophy, diastolic dysfunction, and myocardial lipotoxicity in HFD-induced obese rats. Transcriptome analyses revealed that finerenone significantly suppressed the ferroptosis pathway in the hearts of HFD-treated rats. Further studies demonstrated that finerenone attenuated ferroptosis by activating the System Xc⁻ transporter, enhancing cellular cystine uptake, promoting intracellular glutathione (GSH) synthesis, and thus restoring redox balance in cardiomyocytes. Finerenone alleviates myocardial lipotoxicity in HFD-induced obese rats by inhibiting ferroptosis through the regulation of the System Xc⁻/GSH axis. Finerenone may prove an effective treatment for OCM.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167968"},"PeriodicalIF":4.2,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144596617","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":"Mechanism of ruxolitinib enhancing mitophagy against renal fibrosis via PINK1/Parkin pathway","authors":"He Li ,&nbsp;Peipei Meng ,&nbsp;Yuhang Meng ,&nbsp;Yige Yang ,&nbsp;Wensheng Zheng ,&nbsp;Hongdong Huang ,&nbsp;Zhigang Zhao","doi":"10.1016/j.bbadis.2025.167978","DOIUrl":"10.1016/j.bbadis.2025.167978","url":null,"abstract":"<div><div>Renal fibrosis represents a critical pathological hallmark in progressive chronic kidney disease (CKD), yet effective therapeutic strategies remain elusive. Emerging evidence suggests that impaired mitophagy contributes to its pathogenesis. This study investigated whether ruxolitinib alleviates renal fibrosis by enhancing PINK1/Parkin-mediated mitophagy. Network pharmacology was employed to explore the potential regulatory mechanisms of ruxolitinib in renal fibrosis treatment, revealing that ruxolitinib might exert therapeutic effects through modulation of inflammation, oxidative stress and mitophagy. Subsequent <em>in vivo</em> and <em>in vitro</em> studies demonstrated that ruxolitinib treatment not only attenuated renal fibrosis progression but also reduced inflammatory responses and oxidative stress while enhancing mitophagic activity. Mechanistically, the enhancement of mitochondrial autophagy and the amelioration of renal fibrosis by ruxolitinib might be mediated <em>via</em> the PINK1/Parkin pathway. These results suggest that ruxolitinib may ameliorate renal fibrosis by activating PINK1/Parkin-mediated mitophagy, providing new perspectives for CKD therapeutic development.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167978"},"PeriodicalIF":4.2,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621459","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":"The Wnt/β-catenin signaling pathway mediates renal fibrosis in glycogen storage disease type Ib nephropathy","authors":"Kunal Pratap,&nbsp;Cheol Lee,&nbsp;Lisa Zhang,&nbsp;Hung Dar Chen,&nbsp;Irina Arnaoutova,&nbsp;Brian C. Mansfield,&nbsp;Janice Y. Chou","doi":"10.1016/j.bbadis.2025.167979","DOIUrl":"10.1016/j.bbadis.2025.167979","url":null,"abstract":"<div><div>Glycogen storage disease type Ib (GSD-Ib) results from a deficiency in the ubiquitously expressed glucose-6-phosphate transporter (G6PT), which partners with either the liver/kidney-specific glucose-6-phosphatase-α (G6Pase-α, G6PC1) or the ubiquitously expressed G6Pase-β (G6PC3) to produce glucose from G6P. A deficiency in G6Pase-α causes GSD-Ia. Since G6Pase-α is more active than G6Pase-β, glucose homeostasis is mainly maintained by the G6PT/G6Pase-α complex, and both GSD-Ia and GSD-Ib share metabolic defects and renal disease. GSD-Ia nephropathy is characterized by glomerulosclerosis and fibrosis, partly driven by Wnt/β-catenin signaling. In this study, we show that <em>G6pt</em>−/− (GSD-Ib) mice exhibit similar features, including Wnt/β-catenin-mediated fibrosis, but with significantly higher renal triglyceride levels compared to age-matched GSD-Ia mice during weeks 1 to 3 postnatal development, leading to an early onset of more severe kidney disease. G6Pase-β is highly expressed in the kidney but minimally in the liver, distinguishing the GSD-I subtypes. In GSD-Ia, G6PT/G6Pase-α activity is absent in both the liver and kidney, while G6PT/G6Pase-β is functionally active in the kidney. In GSD-Ib, both G6PT complexes are absent in the kidney and liver. Our results suggest that the less active G6PT/G6Pase-β complex plays a protective role in GSD-Ia kidney.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167979"},"PeriodicalIF":4.2,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610598","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":"Maternal inflammation disrupts neurogenesis and neocortical organization, affecting social and stress-related behavior","authors":"Niina Kiriyama ,&nbsp;Takuma Shikata ,&nbsp;Rei Sugiyama ,&nbsp;Myozen Yoshisaka ,&nbsp;Munekazu Komada","doi":"10.1016/j.bbadis.2025.167980","DOIUrl":"10.1016/j.bbadis.2025.167980","url":null,"abstract":"<div><div>It is imperative to acknowledge the potential impact of various environmental factors on the development of developmental disorders. Among these factors, the maternal immune response induced by the onset of infectious diseases during pregnancy emerges as a notable consideration. The study elucidates the behavioral and morphological abnormalities of the cerebral cortex caused by maternal immune response during pregnancy, emphasizing the significance of maternal immunity in this context. To this end, a mouse model of prenatal infection was established, inducing a congenital immune response analogous to viral infection using polyinosinic-polycytidylic acid (poly(I:C)). Pregnant C57BL/6 N mice were administered poly(I:C) (20 mg/kg, intraperitoneally) on gestational day 12.5. This exposure led to specific abnormalities in neural stem cell differentiation and neurogenesis, which manifested as irregularities in the distribution and layering of neurons in the cerebral cortex. Furthermore, an analysis of spontaneous locomotion, social interaction, and social proximity during the developmental and maturation stages of brain function revealed abnormalities in various environments, including novel and familiar environments, as well as single and group-reared environments. Notably, these mice exhibited a heightened sensitivity to stress post-maturation, underscoring the intricate consequences of maternal immune activation (MIA) on neurodevelopment as an environmental factor. These findings underscore the enduring consequences of MIA on brain development, substantiate the association between intrauterine inflammation and neurodevelopmental disorders, and accentuate the potential implications of intrauterine inflammation in modulating stress responses after maturation.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167980"},"PeriodicalIF":4.2,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610580","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":"Mutation profiling of KRAS and BRAF in primary tumours and circulating tumour cells of colorectal cancer patients using PNA-LNA molecular switch","authors":"Md Sajedul Islam ,&nbsp;Eliza Ranjit ,&nbsp;Sharmin Aktar ,&nbsp;Neda Moetamedirad ,&nbsp;Cu Tai Lu ,&nbsp;Muhammad J.A. Shiddiky ,&nbsp;Vinod Gopalan ,&nbsp;Alfred K. Lam","doi":"10.1016/j.bbadis.2025.167982","DOIUrl":"10.1016/j.bbadis.2025.167982","url":null,"abstract":"<div><div>Identifying <em>KRAS</em> and <em>BRAF</em> mutation status is essential for guiding targeted therapies and enhancing treatment outcomes in colorectal cancer (CRC). This study employs the “PNA-LNA molecular switch” to detect mutations in <em>KRAS</em> codon 12 (c.35G&gt;T/G12V) and <em>BRAF</em> codon 600 (c.1799T&gt;A/V600E) from primary tumours and circulating tumour cells (CTCs) in CRC patients, correlating mutation status with clinicopathological parameters. DNA was isolated from 71 primary tumours and 37 CTC samples. Mutation profiles were generated using the PNA-LNA molecular switch. <em>KRAS</em> mutations were detected in 26 primary tumours (36.6 %) and 13 CTCs (26.8 %), while <em>BRAF</em> mutations were observed in 19 primary tumours (26.8 %) and 7 CTCs (19 %). No significant correlation was observed between mutation status and clinicopathological parameters in primary tumours. However, <em>KRAS</em> G12V mutations in CTCs significantly correlated with lymph node metastasis (<em>p</em> = 0.002), overall pathological stage (<em>p</em> = 0.005), and lymphovascular invasion (<em>p</em> = 0.034). <em>BRAF</em> V600E mutation status showed no significant clinicopathological associations. Validation of the PNA-LNA molecular switch against Next-Generation Sequencing (NGS) showed 89 % concordance with <em>p</em>-values &lt;0.001 for both genes. This method is highly comparable to NGS for detecting <em>KRAS</em> and <em>BRAF</em> mutations and shows promise as a point-of-care diagnostic tool. Larger patient cohorts are required to confirm its clinical utility.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167982"},"PeriodicalIF":4.2,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144596719","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":"ETV4 and ETV1-mediated downregulation of the secretory leukocyte protease inhibitor contributes to the indolent phenotype of early-stage prostate cancer","authors":"Irene Cosi ,&nbsp;Annalisa Moccia ,&nbsp;Caterina Nannelli ,&nbsp;Dario Rosini ,&nbsp;Marta Iozzo ,&nbsp;Michela Sica ,&nbsp;Cristina Luceri ,&nbsp;Rosario Notaro ,&nbsp;Maria De Angioletti","doi":"10.1016/j.bbadis.2025.167975","DOIUrl":"10.1016/j.bbadis.2025.167975","url":null,"abstract":"<div><div>The Secretory Leukocyte Peptidase Inhibitor (SLPI) protects tissues from inflammation but it is overexpressed in various cancers. In prostate cancer (PC) SLPI exhibits a unique biphasic expression pattern: reduced levels in patients with early-stage disease and increased levels in those with advanced disease. Reduced SLPI levels, as in early-stage PC patients, were found in the prostate of a mouse model of early-stage PC, which overexpresses ETV4 into prostate. These reduced SLPI levels were modeled in normal human immortalized prostate RWPE cells by SLPI silencing that resulted, paradoxically, in increase of apoptosis and in decrease of cell migration, invasion, and epithelial-to-mesenchymal transition. Moreover, overexpression and silencing of the members of ETS PEA3-subfamily—ETV4 and ETV1—in human prostate cells (RWPE, PC3, LNCaP) showed that both genes mediate SLPI downregulation. Thus, the reduced levels of SLPI, resulting from ETV4- or ETV1-mediated downregulation, could curb the migratory, invasive, and anti-apoptotic capabilities of prostate cells partially counteracting ETV4 and ETV1 oncogenic effects, thereby contributing to the indolent phenotype of early-stage PC. Furthermore, in the androgen-competent LNCaP cells, androgens upregulate SLPI as well as ETV1, which in turn exerts a negative regulation on SLPI, resulting in a regulatory loop that modulates SLPI levels and explains the biphasic pattern of SLPI expression observed in PC patients. In conclusion, both reduced and increased SLPI levels appear to influence the biological and, possibly, the clinical phenotype of PC. These results uncover a relationship between genetic and microenvironment factors that together shape the evolution and progression of PC.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 7","pages":"Article 167975"},"PeriodicalIF":4.2,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602458","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}