Biochimica et biophysica acta. Molecular cell research最新文献

{"title":"Ion channel expression in intrinsic cardiac neurons: new players in cardiac channelopathies?","authors":"J. Bescond ,&nbsp;J.-F. Faivre ,&nbsp;A. Jean ,&nbsp;P. Bois ,&nbsp;A. Chatelier","doi":"10.1016/j.bbamcr.2025.119983","DOIUrl":"10.1016/j.bbamcr.2025.119983","url":null,"abstract":"<div><div>The autonomic nervous system is an important modulator of electrical disorders observed in cardiac pathologies through changes in the balance between sympathetic and parasympathetic tone. The final common pathway for cardiac neuronal autonomic control resides in the intrinsic cardiac nervous system (ICNS), composed of intracardiac neurons (ICN), and which allows sympathetic-parasympathetic efferent neuronal interactions at intracardiac sites. The ICNS is a complex system that plays a crucial role in the regulation of cardiac physiological parameters and has been shown to contribute to cardiac diseases, in particular cardiac arrhythmias. It is therefore crucial to understand the molecular determinants, such as ion channels, that control the excitability of the ICNS and their potential modulation in pathological conditions.</div><div>This review discusses several ion channels expressed by ICN, including potassium channels (e.g., inward rectifier, calcium-dependent, voltage-activated, muscarinic-sensitive), voltage-gated sodium channels (VGSC), voltage-gated calcium channels (VGCC), hyperpolarization-activated cyclic nucleotide–gated (HCN) channels and Transient Receptor Potential (TRP) Channels, and their potential involvement in cardiac pathologies. We highlight the need for further research on ICN ion channels, particularly under pathological conditions, to develop therapies for cardiac arrhythmias.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119983"},"PeriodicalIF":4.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917585","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":"Proprotein convertase subtilisin/kexin type 9 contributes to cisplatin-induced acute kidney injury by interacting with cyclase-associated protein 1 to promote megalin lysosomal degradation","authors":"Zihan Wang ,&nbsp;Xinying Yu ,&nbsp;Huimin Ma ,&nbsp;Shuang Yao ,&nbsp;Zongda Li ,&nbsp;Rui Zhang ,&nbsp;Haihai Liang ,&nbsp;Jundong Jiao","doi":"10.1016/j.bbamcr.2025.119984","DOIUrl":"10.1016/j.bbamcr.2025.119984","url":null,"abstract":"<div><div>Cisplatin-induced acute kidney injury (AKI) is associated with a considerable risk of mortality, highlighting the critical need for effective preventive and therapeutic strategies to mitigate its impact on patients' outcomes. Mounting evidence suggests that administration of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab significantly reduces the risk of AKI, however, the underlying mechanisms remain poorly understood. Megalin is an endocytic receptor that plays a crucial role in tubular cells. In this study, elevated PCSK9 expression, accompanied by decreased megalin expression, was observed in cellular and murine models of cisplatin-induced AKI. Further experiments revealed that PCSK9 overexpression downregulated megalin expression and promoted tubular injury. Additionally, the PCSK9 inhibitor evolocumab inhibited megalin loss and protected against increases in urinary protein levels, blood urea nitrogen, serum creatinine, and the kidney injury markers neutrophil gelatinase-associated lipocalin and kidney injury molecule 1. Mechanistically, PCSK9 binds to megalin and facilitates its lysosomal degradation through the coordinated actions of cyclase-associated protein 1 (CAP1) and human leukocyte antigen C (HLA-C). Similar to evolocumab, CAP1 deletion significantly protected against megalin loss and mitigated tubular injury both in vitro and in vivo. Collectively, these findings suggest that PCSK9 and CAP1 are potential therapeutic targets for patients with cisplatin-induced AKI.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119984"},"PeriodicalIF":4.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143922455","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":"Ion channel expression and function in glioblastoma multiforme (GBM): pathophysiological mechanisms and therapeutic potential","authors":"Gauri C. Kulkarni,&nbsp;Rayna Saha,&nbsp;Christian J. Peters","doi":"10.1016/j.bbamcr.2025.119982","DOIUrl":"10.1016/j.bbamcr.2025.119982","url":null,"abstract":"<div><div>Glioblastoma Multiforme (GBM) is a highly malignant and diffusely invasive WHO Grade IV brain tumor arising from glial and neural stem cells. GBM is characterized by rapid proliferation and migration, aggressive invasion of local brain parenchyma, a hypoxic microenvironment, resistance to apoptosis and high vascular remodeling and angiogenesis. These hallmarks contribute to a near universal tumor recurrence after treatment or resection and poor patient prognosis. Ion channels, a superfamily of proteins responsible for permitting ion flux across otherwise impermeant membranes, show extensive remodeling in GBM with aberrant function mechanistically linked to manipulation of each of these hallmarks. In this review, we will discuss the known links between ion channel expression and activity and cellular processes that are enhanced or perturbed during GBM formation or progression. We will also discuss the extent to which basic or translational findings on ion channels in GBM samples or cell lines have shown preclinical promise towards the development of improved therapeutics against GBMs.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119982"},"PeriodicalIF":4.6,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906645","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":"m6A-mediated regulation of ECA39 promotes renal fibrosis in chronic kidney disease by enhancing glycolysis and epithelial-mesenchymal transition","authors":"Ziyuan TONG ,&nbsp;Hainan ZHAO ,&nbsp;Changwan CUI ,&nbsp;Mengqi HONG ,&nbsp;Yutong MA ,&nbsp;Lu SUI ,&nbsp;Jingyu WANG ,&nbsp;Quan YUAN ,&nbsp;Li SUN","doi":"10.1016/j.bbamcr.2025.119981","DOIUrl":"10.1016/j.bbamcr.2025.119981","url":null,"abstract":"<div><div>Renal fibrosis is a vital pathological manifestation of chronic kidney disease (CKD). ECA39 is a conserved gene in the regulation of cell behavior; however, its function in renal fibrosis remains unclarified. A murine model of renal fibrosis was established by unilateral ureteral obstruction (UUO) operation. ECA39 expression was significantly upregulated in the kidneys of UUO mice. Prior to UUO operation (14 days), mice were administrated adeno-associated virus serotype 9 (AAV9, 1 × 10¹¹ vector genomes) expressing ECA39 shRNA via tail vein injection. At postoperative day 7, AAV9-mediated inhibition of ECA39 was found to mitigate UUO-induced kidney damage, as manifested by reduced NGAL expression in kidneys, along with reduced serum creatinine and blood urea nitrogen (BUN) levels. Inhibition of ECA39 decreased collagen I, α-SMA and vimentin expression, but increased E-cadherin in kidney tissues. ECA39 inhibition reduced serum lactic acid level, increased ATP production, and suppressed glycolysis-related indicators HK2, PFKM, PKM2, PDK1, and LDHA expression. In parallel, human proximal tubular epithelial cells (HK−2) were treated with TGF-β1 (5 ng/ml, 48 h) to induce a cellular model of injury. ECA39 knockdown inhibit epithelial-mesenchymal transition (EMT) and glycolysis in HK-2 cells. Mechanistically, TGF-β1 treatment increased m⁶A modification of ECA39 mRNA, and the m⁶A “reader” IGF2BP2 knockdown reduced ECA39 mRNA stability. IGF2BP2 knockdown reduced lactic acid content and inhibited EMT in HK-2 cells, whereas ECA39 overexpression reversed these effects. Collectively, our studies demonstrated that inhibition of ECA39 suppresses glycolysis and EMT processes, thereby alleviating renal fibrosis in CKD.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119981"},"PeriodicalIF":4.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917586","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":"Characterization of 3D human pulmonary epithelial model morphology and oxygen status under normoxia and hypoxia","authors":"Maura Lynch-Miller ,&nbsp;Sandra Lockow ,&nbsp;Katrin Dümmer ,&nbsp;Timo Henneck ,&nbsp;Ruth Olmer ,&nbsp;Mark-Christian Jaboreck ,&nbsp;AhmedElmontaser O. Mergani ,&nbsp;Madita Wandrey ,&nbsp;Katja Branitzki-Heinemann ,&nbsp;Graham Brogden ,&nbsp;Hassan Y. Naim ,&nbsp;Ulrich Martin ,&nbsp;Claudia Schulz ,&nbsp;Steven R. Talbot ,&nbsp;Marita Meurer ,&nbsp;Wolfgang Baumgärtner ,&nbsp;Maren von Köckritz-Blickwede","doi":"10.1016/j.bbamcr.2025.119980","DOIUrl":"10.1016/j.bbamcr.2025.119980","url":null,"abstract":"<div><div>Infection generates localized hypoxia in affected tissue, inducing cellular survival responses and modulating inflammatory processes. Consideration of oxygen status as a parameter in <em>in vitro</em> infection research is therefore vital to the generation of physiologically relevant data within the 3R context. In this study, we characterize the culture morphology and oxygenation of liquid-liquid interface (LLI) permanent bronchial epithelial (Calu-3), classical air-liquid interface (cALI) Calu-3, and cALI human primary bronchial epithelial cell (hBEC) models under the normoxic conditions within standard incubators, commonly employed in <em>in vitro</em> work. We compare the normoxic state of these models to their hypoxic state to assess changes in the airway epithelial environment in response to oxygen deprivation, and the extent to which select hypoxia responses can be observed at the molecular level. Additional juxtapositions are drawn between Calu-3 LLI and cALI models and Calu-3 conventional monolayer (CM) and inverted air-liquid interface (iALI) models, due to their relevance for basic and specialized research, respectively. Epithelial complexity was observed to vary amongst the filter-based models, and all models were found to exhibit characteristic extracellular oxygen depletion patterns under normoxia. Importantly, the extracellular oxygen contents of Calu-3 LLI, cALI, and CM models significantly decreased during normoxic incubation. Specific hypoxia responses through stabilization of HIF-1α, HIF-2α, and/or HIF-3α and alteration of ACE2 protein levels differed in response to both culture format and cell type. Therefore, while all models examined provide valuable opportunities for <em>in vitro</em> exploration, variation in their morphological, physiological, and molecular characteristics necessitates careful consideration during experimental design.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119980"},"PeriodicalIF":4.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931385","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":"High fat and high cholesterol diet induced cognitive impairment in GSDMD knockout mice via the compensatory activation of apoptosis pathway","authors":"Ruitong Liu ,&nbsp;Guiping Wang ,&nbsp;Kuiying Gu ,&nbsp;Tongtong Ma ,&nbsp;Zhilong He ,&nbsp;Li-Qiang Qin ,&nbsp;Zhongxiao Wan","doi":"10.1016/j.bbamcr.2025.119978","DOIUrl":"10.1016/j.bbamcr.2025.119978","url":null,"abstract":"<div><div>Via the GSDMD knockout (KO) mice as model, we aimed to determine the roles of GSDMD-mediated pyroptosis and its crosstalk with apoptosis in regulating high fat high cholesterol (HFHC) diet associated cognitive dysfunction. Wild type (WT) and GSDMD KO mice were divided into 4 groups, i.e. WT control (WTCON), WT fed with HFHC (WTHFHC), GSDMD KO control (KOCON), GSDMD KO HFHC (KOHFHC). Compared to the KOCON group, mice from the KOHFHC group demonstrated the worst learning and memory disabilities. In the hippocampus, p-Tau ser404, RIPK1/RIP, cleaved caspase-3 and apoptosis rate were increased, while BDNF and p-CREB were reduced from the KOHFHC group. In the cortex, p-Tau ser404, p-Tau ser396, RIPK1/RIP, cleaved caspase-8 and cleaved caspase-3 were significantly increased, while BDNF, synaptophysin were reduced from KOHFHC group. RNA sequencing analysis showed that 2 pathways closely related to apoptosis were significantly upregulated from KOHFHC group compared to KOCON group, including apoptosis and positive regulation of execution phase of apoptosis. The combination of palmitic acid with LDC7559 further increased the number of apoptotic cells and cleaved caspase-3 protein expression compared to vehicle in BV2 cells and HT22 cells. In conclusion, knocking out GSDMD gene in mice had no notable effects on learning and memory abilities under normal diet, but notably led to cognitive dysfunction when stimulated by a high-fat and high-cholesterol diet. The inhibition of pyroptosis may unexpectedly compensate for the activation of exogenous apoptotic pathways, this might be associated with worsening of tau phosphorylation, synaptic plasticity, and neuroinflammation.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119978"},"PeriodicalIF":4.6,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902390","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":"Deletion of Nrf1α exacerbates oxidative stress-induced cellular senescence by disrupting cell homeostasis","authors":"Da Lyu ,&nbsp;Meng Wang ,&nbsp;Lu Qiu ,&nbsp;Rongzhen Deng ,&nbsp;Shaofan Hu ,&nbsp;Yiguo Zhang","doi":"10.1016/j.bbamcr.2025.119970","DOIUrl":"10.1016/j.bbamcr.2025.119970","url":null,"abstract":"<div><div>Cellular senescence is recognized as a fundamental hallmark contributing to ageing and various age-related diseases, with oxidative stress playing a critical initiating role in their pathological processes. However, the anti-senescence potential of the antioxidant nuclear factor erythroid-derived 2-like 1 (Nrf1, encoded by <em>Nfe2l1</em>) remains elusive, despite accumulating evidence demonstrating its role as an indispensable redox-determining transcription factor for maintaining cellular homeostasis and organ integrity. This study reveals that deletion of Nrf1α significantly elevates senescence characteristics in <em>Nrf1α</em>^{<em>−/−</em>}-deficient cells, as evidenced by two distinct experimental models. These cells exhibit heightened activity of senescence-associated β-galactosidase and progressive senescence-associated secretory phenotype (SASP), accompanied by decreased cell vitality and intensified cell cycle arrest. Further investigation uncovers that this acceleration of oxidative stress-induced senescence results from increased disturbance in cellular homeostasis. The <em>Nrf1α</em>^{<em>−/−</em>} deficiency leads to STAG2- and SMC3-dependent chromosomal stability disruption and autophagy dysfunction, albeit being accompanied by excessive accumulation of Nrf2 (encoded by <em>Nfe2l2</em>). The aberrantly hyperactive Nrf2 cannot effectively counteract the escalating disturbance of cellular homeostasis caused by <em>Nrf1α</em>^{<em>−/−</em>}. This study provides evidence supporting Nrf1α's essential cytoprotective function against stress-induced cellular senescence, highlighting its indispensable contribution to maintaining robust cell homeostasis during the senescence pathophysiological process.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119970"},"PeriodicalIF":4.6,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887546","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":"Clozapine blunts mitochondrial biogenesis in differentiating adipocytes: The increased ATP demand is met via stimulation of electron transport chain expression and activity in residual mitochondria","authors":"Mara Fiorani ,&nbsp;Gloria Buffi ,&nbsp;Nazanin Bagherlou ,&nbsp;Barbara Canonico ,&nbsp;Rita De Matteis ,&nbsp;Andrea Guidarelli ,&nbsp;Mariele Montanari ,&nbsp;Michela Battistelli ,&nbsp;Stefano Papa ,&nbsp;Lucia Coppo ,&nbsp;Liana Cerioni ,&nbsp;Andrea Spina ,&nbsp;Orazio Cantoni","doi":"10.1016/j.bbamcr.2025.119967","DOIUrl":"10.1016/j.bbamcr.2025.119967","url":null,"abstract":"<div><div>Clozapine (CLZ), a second-generation antipsychotic, is associated with an elevated risk of metabolic syndrome, the underlying mechanism of which remains poorly understood. We recently showed that CLZ inhibits lipid accumulation and CAAT/enhancer-binding protein β and peroxisome proliferator-activated receptor γ expression in early differentiating SW872 liposarcoma cells. Additionally, while not affecting viability, CLZ disrupts the cellular redox state of these cells by inhibiting NADPH oxidase-dependent ROS formation, thereby leading to nuclear factor (erythroid-derived2)-like 2 downregulation, reduced antioxidant defence and increased mitochondrial ROS emission.</div><div>We confirmed and extended these results by showing that, under the same conditions, CLZ reduces the size of the lipid droplets, inhibits the otherwise increased expression of transcription factors regulating mitochondrial biogenesis, as peroxisome proliferator-activated receptor γ coactivator 1-α, and prevents the increase in mitochondrial DNA and mass. Consistently, decreased expression of mitochondrial proteins as thioredoxin 2, 2-oxoglutarate/malate carrier, and translocase of outer mitochondrial membrane 20 was also observed. However, the expression of various components of the electron transport chain was unexpectedly increased, and this event was accompanied by enhanced mitochondrial dehydrogenase activity, coupled oxygen consumption, mitochondrial membrane potential, ATP synthesis and ROS production. Moreover, residual mitochondria appeared remarkably enlarged and functional, with dense and organized cristae and uniform electron density.</div><div>Thus, early adipocytes differentiated with or without CLZ meet the increased ATP demand by switching from glycolysis to oxidative phosphorylation, respectively <em>via</em> enhanced mitochondrial biogenesis, and increased activity of residual mitochondria.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119967"},"PeriodicalIF":4.6,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869645","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":"RBM22-depletion delays progression through all steps of cell cycle and increases ploidy in myeloid cells","authors":"Eloïse Le Hir-Reynaud ,&nbsp;Benoît Soubise ,&nbsp;Abrahan Molina Mendoza ,&nbsp;Cassandra Konan ,&nbsp;Séverine Commet ,&nbsp;Nadia Gueganic ,&nbsp;Corinne Tous ,&nbsp;Laurent Corcos ,&nbsp;Nathalie Douet-Guilbert ,&nbsp;Marie-Bérengère Troadec","doi":"10.1016/j.bbamcr.2025.119965","DOIUrl":"10.1016/j.bbamcr.2025.119965","url":null,"abstract":"<div><div>RNA-Binding Motif 22 (<em>RBM22</em>) is a splicing factor and a transcription regulator that plays important roles in cancer. Our goal was to document further the implication of RBM22 in cell cycle progression. Using normal human haematopoietic stem and progenitor cells and myeloid cell lines (MDS-L, HL-60), we demonstrated that <em>RBM22</em> depletion reduces proliferation by delaying the progression of the G1-phase, S-phase and G2/M phase. <em>RBM22</em> depletion alters mitosis, generating endomitosis and alters megakaryocyte differentiation. Altogether, we propose, for the first time, <em>RBM22</em> as an essential actor of the cell cycle regulation in human haematopoietic stem and progenitor cells and myeloid cells. We demonstrated that <em>RBM22</em> alteration is partially responsible for the phenotype of cytopenia of myeloid cell lineages observed in myelodysplastic syndromes (MDS) with a partial deletion of chromosome 5 (MDS with del(5q)) where one allele of <em>RBM22</em> is lost. We hypothesise that the impact of <em>RBM22</em> on cell cycle progression could explain some phenotypic features of other cancers.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119965"},"PeriodicalIF":4.6,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883010","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":"Non-canonical Wnt co-receptors ROR1/ROR2 are differentially regulated by hypoxia in colon cancer cells","authors":"Eduardo Alvarado-Ortiz ,&nbsp;María Cristina Castañeda-Patlán ,&nbsp;Angela Patricia Moreno-Londoño ,&nbsp;José Manuel Tinajero-Rodríguez ,&nbsp;Paola Briseño-Díaz ,&nbsp;Miguel Angel Sarabia-Sánchez ,&nbsp;Miguel Vargas ,&nbsp;Elizabeth Ortiz-Sánchez ,&nbsp;Martha Robles-Flores","doi":"10.1016/j.bbamcr.2025.119968","DOIUrl":"10.1016/j.bbamcr.2025.119968","url":null,"abstract":"<div><div>ROR1 and ROR2 co-receptors are transducers of non-canonical Wnt responses that promote an aggressive phenotype in several cancer types, including colon cancer. It has been demonstrated that hypoxia promotes tumor progression through the action of Hypoxia Inducible Factors (HIFs). An in silico analysis revealed that ROR2 is overexpressed in the advanced clinical stages of colon cancer. In line with this, ROR1 and ROR2 were found to be only expressed in malignant colon cells compared to non-malignant ones. The blockade of either ROR1 or ROR2 impaired colon cancer cells' colony formation abilities and the migration capacity of them. Additionally, the silencing of the ROR2 co-receptor blocked the metastatic ability of colon cancer cells in a xenografted mice model. We found that while silencing HIF-1α did not significantly reduce ROR1 or ROR2 expression, inhibiting HIF-2α and HIF-3α expression greatly decreased the protein levels of both co-receptors in colon cancer cells. The HIF-1α subunit expression is induced in acute hypoxia, whereas HIF-2α and HIF-3α show higher activity in chronic hypoxia, which may be functionally relevant since hypoxia induced a decrease in the constitutive active β-catenin transcriptional activity in SW480 cells. While both ROR1 and ROR2 stimulate proliferation and migration under normoxic conditions, the exposure of cells to hypoxia increased the expression of ROR1 or ROR2, depending on the Wnt cellular context, Thus, our results indicate that hypoxia partially represses β-catenin transcriptional activity and activates non-canonical Wnt signaling by regulating ROR1/ROR2 expression to induce an aggressive migrating and metastatic phenotype in colon cancer cells.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 5","pages":"Article 119968"},"PeriodicalIF":4.6,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863862","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}