Experimental Cell Research[JOURNAL]
Sun
200 papers
MiR-181c-5p-SIRT1 axis-driven Pink1/Parkin-mediated mitophagy prevents ferroptosis and vascular calcification in chronic kidney disease.
Chen R, He J, An N … +3 more , Xu M, Wang L, Bai Y
Exp Cell Res · 2026 Mar · PMID 41512994 · Publisher ↗
BACKGROUND: Vascular calcification (VC) is a severe cardiovascular complication of chronic kidney disease (CKD), driven by vascular smooth muscle cell (VSMC) osteogenic trans-differentiation and exacerbated by oxidative...
BACKGROUND: Vascular calcification (VC) is a severe cardiovascular complication of chronic kidney disease (CKD), driven by vascular smooth muscle cell (VSMC) osteogenic trans-differentiation and exacerbated by oxidative stress and cellular dysfunction. Despite its clinical relevance, the molecular mechanisms underlying CKD-associated VC remain incompletely understood. This study investigates the role of Sirtuin 1 (SIRT1) in modulating VC through ferroptosis inhibition and mitophagy activation and examines whether microRNA-181c-5p (miR-181c-5p) contributes to SIRT1 dysregulation in this context. METHODS: A CKD-associated VC model was induced in rats by 5/6 nephrectomy followed by high calcium/phosphate and calcitriol loading, and an in vitro calcification model was established in primary rat VSMCs. SIRT1 was manipulated using AAV9-mediated overexpression in vivo and plasmid overexpression or inhibition in vitro. Upstream regulation of SIRT1 by miR-181c-5p was predicted bioinformatically and validated by RNA pull-down and dual-luciferase assays. Ferroptosis was assessed by redox and Fe indices, and mitophagy by Pink1/Parkin, LC3-II and p62 expression. Rescue experiments employed erastin, Mdivi-1 and Parkin knockdown. RESULTS: SIRT1 expression was markedly reduced in calcified aortic tissues and VSMCs. SIRT1 overexpression suppressed VC by reducing calcium deposition, downregulating osteogenic markers, and increasing fetuin-A levels. SIRT1 also suppressed ferroptosis by restoring the GSH/GPX4/SLC7A11 axis and limiting ROS and lipid peroxidation, whereas erastin abolished these effects. Mechanistically, miR-181c-5p was found to directly target SIRT1 and promote VSMC calcification by repressing SIRT1. Moreover, SIRT1 promoted mitophagy via the Pink1/Parkin pathway activation. Furthermore, inhibition of mitophagy reversed the anti-ferroptotic effects of SIRT1, confirming their functional interplay. CONCLUSIONS: SIRT1, negatively regulated by miR-181c-5p, mitigates CKD-associated VC by suppressing ferroptosis and activating Pink1/Parkin-dependent mitophagy in VSMCs, highlighting a potential therapeutic axis for vascular protection in CKD. CLINICAL TRIAL REGISTRATION NUMBER: Not applicable.
Fetuin B drives metabolism-associated steatohepatitis by promoting hepatocyte pyroptosis via NLRP3/GSDMD pathway.
Chen S, Wang Y, Gao J … +8 more , Lin J, Liu L, Zhu S, Liu L, Xu C, Liu X, Zhu M, Zhu J
Exp Cell Res · 2026 Mar · PMID 41506566 · Publisher ↗
Hepatocyte pyroptosis critically contributes to metabolism-associated fatty liver disease (MAFLD) progression. Fetuin-B (FETUB), a hepatocytokine, promotes pyroptosis by downregulating adiponectin receptor 1 (AdipoR1), t...
Hepatocyte pyroptosis critically contributes to metabolism-associated fatty liver disease (MAFLD) progression. Fetuin-B (FETUB), a hepatocytokine, promotes pyroptosis by downregulating adiponectin receptor 1 (AdipoR1), thereby activating the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome/GSDMD pathway. This study investigated the role of FETUB in metabolic dysfunction-associated steatohepatitis (MASH) and the therapeutic efficacy of FETUB inhibition. In primary mouse hepatocytes, free fatty acid (FFA) stimulation upregulated FETUB transcription, expression, and secretion, which suppressed membrane AdipoR1 and triggered NLRP3/GSDMD-mediated pyroptosis, exacerbating steatosis. In high-fat diet (HFD)-induced MASH mice, hepatic FETUB expression increased concordantly with AdipoR1 downregulation. FETUB blockade ameliorated hepatic steatosis, inflammation, ballooning, and fibrosis by disrupting this pathway. These findings establish FETUB as a key regulator of NLRP3/GSDMD-driven pyroptosis in MASH and identify it as a promising therapeutic target.
The circ-GLG1/miR-346/KCNJ9 axis drives malignant progression of bladder cancer by modulating KCNJ9 expression.
He K, Lin C, Wang H … +4 more , Wu H, Yin S, Tao C, Yan X
Exp Cell Res · 2026 Feb · PMID 41490595 · Publisher ↗
Bladder cancer is a common malignant tumor of the urinary system, with its malignant progression mechanisms remaining unclear. In this study, a circular RNA (hsa_circ_0040457, hereinafter referred to as "circ-GLG1″), whi...
Bladder cancer is a common malignant tumor of the urinary system, with its malignant progression mechanisms remaining unclear. In this study, a circular RNA (hsa_circ_0040457, hereinafter referred to as "circ-GLG1″), which has been less characterized in bladder cancer, was identified. It is significantly overexpressed in bladder cancer tissues and cells, and closely associated with patients' pTNM stage and poor prognosis. Circ-GLG1 is formed by back-splicing of exons 23-26 of the GLG1 gene, with circular stability and IRES-dependent translational potential. Functional studies confirmed that silencing circ-GLG1 inhibits cellular malignant phenotypes and tumor formation in nude mice, while overexpression promotes progression by activating TGF-β, PI3K-AKT, and MAPK pathways. Mechanistically, transcriptome sequencing identified 555 differentially expressed genes, with GO/KEGG enrichment in cancer-related pathways. Combined with database prediction, KCNJ9 was identified as a key target. Luciferase assays confirmed that circ-GLG1 may sponge miR-346, relieving its inhibitory effect on KCNJ9's 3'UTR. Functional rescue experiments showed that KCNJ9 overexpression reversed the phenotypic and pathway inactivation induced by circ-GLG1 silencing, verifying the "circ-GLG1/miR-346/KCNJ9″ regulatory axis. This study reveals that circ-GLG1 acts as a ceRNA to target KCNJ9, relieving miR-346-mediated post-transcriptional inhibition, with concurrent activation of TGF-β, PI3K-AKT, and MAPK pathways via KCNJ9 that are associated with bladder cancer progression.
GLRX5 is a prognostic marker in bladder cancer and correlates with activation of cancer-associated fibroblasts in the tumor microenvironment.
Wang Y, Liu H, Wang T … +3 more , Yang Y, Ma X, Wu J
Exp Cell Res · 2026 Feb · PMID 41485701 · Publisher ↗
OBJECTIVE: Investigate the function of glutathione reductase-associated protein 5 (GLRX5) and its prognostic significance, as well as its association with CAFs and the TME. METHODS: Based on data from TCGA and the GEO da...
OBJECTIVE: Investigate the function of glutathione reductase-associated protein 5 (GLRX5) and its prognostic significance, as well as its association with CAFs and the TME. METHODS: Based on data from TCGA and the GEO databases, this study investigates the expression of GLRX5 in BLCA and its association with clinical outcomes. Using the ssGSEA algorithm, we explored the association between functional features of GLRX5 and BLCA. We validated our findings using in vitro cellular functional assays. We explored the regulatory mechanisms associated with GLRX5 using GO, KEGG, and GSEA. Furthermore, based on single-cell and spatial transcriptomics data from bladder cancer, we analyzed the expression patterns and potential functions of GLRX5 in bladder cancer. The results of the above analyses were experimentally explored and validated. RESULTS: High expression of GLRX5 in BLCA correlates with malignant biological behavior and poor prognosis. Enrichment analysis indicates that GLRX5 is primarily associated with malignant functional characteristics in bladder cancer, and its expression levels are also linked to EMT, OXPHOS, and FAM. The above analyses have all been validated through in vitro experiments. Single-cell and spatial transcriptomics analyses indicate that GLRX5 is also expressed in CAFs and participates in metabolic pathways. Experiments demonstrated that GLRX5 promotes the activation of CAFs and may enhance tumor cell migration by influencing pathways within the TME. CONCLUSION: High expression of GLRX5 in tumor cells promotes malignant biological behavior and predicts poor prognosis. At the same time, high expression of GLRX5 in CAFs promotes tumor cell migration by affecting the TME.
Corrigendum to "ISG15 promotes esophageal squamous cell carcinoma tumorigenesis via c-MET/Fyn/β-catenin signaling pathway" [Exp. Cell Res. 367 (2018) 47-55].
Yuan H, Zhou W, Yang Y … +3 more , Xue L, Liu L, Song Y
Exp Cell Res · 2026 Feb · PMID 41484007 · Publisher ↗
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MICA/B-driven NK cell dysfunction promotes cervical cancer via Toll signaling.
Tuerxun H, Li J, Liu Q … +4 more , Tursun M, BaoXiao J, Wang C, Hasim A
Exp Cell Res · 2026 Feb · PMID 41475523 · Publisher ↗
The immune status is of crucial importance in the development of cervical cancer (CC). MICA/B, as a major histocompatibility complex Class I associated protein, mediates anti-tumor immunity by activating NK cell receptor...
The immune status is of crucial importance in the development of cervical cancer (CC). MICA/B, as a major histocompatibility complex Class I associated protein, mediates anti-tumor immunity by activating NK cell receptors. However, the precise mechanisms underlying MICA/B-mediated regulation of CC progression remain poorly understood. This study combined spatial transcriptome sequencing and bioinformatics analysis and found that MICA/B was significantly highly expressed in CC tissues and cells, accompanied by more NK cell infiltration. Flow cytometry and Cell Functional assays, Knockdown of MICA/MICB weakens the activation receptor efficacy of NK cells, enhances the inhibitory signal, leads to a decrease in cytotoxicity, and simultaneously upregulates Cyclin expression in CC cells while downregulating BCL-2/BAX. Tumor xenograft models indicated that tumors with MICA knockdown exhibited a growth tendency in the presence of natural killer (NK) cells. Mechanistically, MICA/B regulates inflammatory factors such as IL-6 and CXCL10/11 through the Toll-like signaling pathway, affecting the function of NK cells. Thus, MICA/B expression on cervical cancer cells plays a pivotal role in eliciting NK cell-mediated antitumor immunity. Their downregulation attenuates NK cell function, promoting cervical cancer cell proliferation and survival via the Toll signaling pathway. These findings highlight the potential of targeting MICA/B-NK cell interactions as a therapeutic strategy for cervical cancer.
Integrin β1 contributes to acute pancreatitis by mediating macrophage adhesion and inflammatory cascades.
Xu Y, Sun Y, Yin C … +2 more , Xie F, Li H
Exp Cell Res · 2026 Feb · PMID 41461235 · Publisher ↗
Acute pancreatitis (AP) exhibits marked clinical heterogeneity. To investigate the molecular mechanisms involved in AP, we integrated bioinformatics analysis of public sequencing datasets, which identified differentially...
Acute pancreatitis (AP) exhibits marked clinical heterogeneity. To investigate the molecular mechanisms involved in AP, we integrated bioinformatics analysis of public sequencing datasets, which identified differentially expressed genes (DEGs) significantly associated with AP. Subsequently, GO/KEGG enrichment analyses revealed robust involvement of these DEGs in cellular adhesion and MAPK signaling pathways. Protein-protein interaction (PPI) network analysis pinpointed integrin β1 (ITGB1) as the central hub gene, while single-gene gene set enrichment analysis (GSEA) across ontological databases confirmed its significant enrichment in pathways associated with adhesion and inflammation. These findings establish ITGB1 as a pivotal regulator coordinating cell adhesion and inflammatory responses in AP. In murine AP models, ITGB1 protein was significantly upregulated in the pancreas and co-localized specifically with macrophages. In vitro studies using bone marrow-derived macrophages (BMDMs) revealed that ITGB1 upregulation enhanced macrophage-endothelial adhesion and inflammatory cascades through p38 MAPK phosphorylation. Critically, clinical translation studies established the dual diagnostic value of ITGB1. The receiver operating characteristic (ROC) curve exhibited significant discriminatory power for distinguishing patients with AP from healthy controls, along with robust efficacy in stratifying disease severity. In conclusion, ITGB1 orchestrates macrophage-mediated inflammation through p38 MAPK-dependent mechanisms and can function as a biomarker for diagnosis and severity stratification in AP.
Neutrophil extracellular traps promote epithelial-mesenchymal transition in COPD via the RAGE/PI3K/AKT pathway.
Zou J, Chen L, Yang Y … +6 more , Huo Z, Liu Y, Luo Z, Ou S, Xu C, Bai J
Exp Cell Res · 2026 Feb · PMID 41453711 · Publisher ↗
Neutrophil extracellular traps (NETs) play a critical role in smoking-related chronic airway inflammation. However, it remains unknown whether NETs promote COPD progression by affecting epithelial-mesenchymal transition...
Neutrophil extracellular traps (NETs) play a critical role in smoking-related chronic airway inflammation. However, it remains unknown whether NETs promote COPD progression by affecting epithelial-mesenchymal transition (EMT). This study aimed to investigate the correlation between serum biomarker profiles and pulmonary function in COPD patients, elucidate the relationship between NETs formation and EMT in COPD lung tissue, and explore the effect of cigarette smoke extract (CSE)-induced NETs on EMT in bronchial epithelial cells and its molecular mechanisms. We found that COPD patients showed decreased serum DNase-I and elevated IL-6, TNF-α, dsDNA, and MPO-DNA levels. COPD lung tissues exhibited increased NETs accumulation and altered EMT-related protein expression. In vitro, CSE-NETs treatment altered the gene expression profile of BEAS-2B cells, activating the RAGE/PI3K/AKT signaling pathway and promoting EMT. Inhibition of RAGE or PI3K attenuated CSE-NETs-induced EMT. In vivo, DNase-I and CI-amidine Attenuate Emphysema and EMT in Cigarette Smoke-Induced COPD Mice by Reducing NETs. This study reveals the critical role of CSE-induced-NETs in the pathogenesis of COPD and identifies the RAGE/PI3K/AKT signaling pathway as a potential therapeutic target, providing new insights for COPD treatment.
GNA15 as a potential prognostic and immunological biomarker in ccRCC based on bioinformatics analysis and experimental verification.
Xu X, Zuo Z, Zhu J … +2 more , Wu J, Zhang T
Exp Cell Res · 2026 Feb · PMID 41453710 · Publisher ↗
As the most common and aggressive subtype of renal cancer, clear cell renal cell carcinoma (ccRCC) often shows poor responsiveness to current therapeutic strategies. Although GNA15, a G protein alpha subunit, has been as...
As the most common and aggressive subtype of renal cancer, clear cell renal cell carcinoma (ccRCC) often shows poor responsiveness to current therapeutic strategies. Although GNA15, a G protein alpha subunit, has been associated with the progression of multiple tumor types, its functional significance in ccRCC remains largely undefined. Public datasets were used to profile GNA15 expression across cancers, and its links to prognosis, genomic diversity, stemness, and immune infiltration were analyzed with multiple computational tools. In ccRCC, transcriptomic and protein expression levels were validated using immunofluorescence and western blotting. Functional assays, including colony formation, transwell migration, tumor spheroid formation, and GSEA, were used to investigate the biological role of GNA15. The effects of GNA15 knockdown were assessed in renal cancer cell lines. GNA15 was aberrantly upregulated in multiple cancers and significantly elevated in ccRCC tissues and cell lines. High GNA15 expression correlated with poor overall survival and advanced clinical stage. It was also positively associated with tumor heterogeneity, stemness, and immunosuppressive microenvironment characteristics, particularly M2 macrophage and neutrophil infiltration. GSEA identified enrichment in oncogenic pathways, including JAK-STAT, Wnt, and Notch signaling. In vitro knockdown of GNA15 reduced tumor cell proliferation, migration, spheroid formation, and expression of stemness markers and PD-L1. Our results highlight GNA15 as a novel oncogenic and immune-related contributor to ccRCC progression, supporting its potential as a prognostic biomarker and therapeutic target.
Targeting the Gas6-TAM-SOCS1/3 axis: CP-25 attenuates macrophage dysfunction in primary Sjögren's syndrome.
Chen Y, Tian Q, Yang M … +10 more , Zhang Y, Kuang F, Sun L, Xi Q, Xu W, Cai H, Mao Y, Wang T, Wei W, Wu H
Exp Cell Res · 2026 Feb · PMID 41448264 · Publisher ↗
The etiology of primary Sjögren's syndrome (pSS) remains largely unexplained to date, and there is a relative lack of effective clinical treatment options.This study aimed to explore the potential therapeutic mechanism o...
The etiology of primary Sjögren's syndrome (pSS) remains largely unexplained to date, and there is a relative lack of effective clinical treatment options.This study aimed to explore the potential therapeutic mechanism of paeoniflorin-6'-O-benzenesulfonate (CP-25) for pSS, especially regarding whether it exerts its effect by regulating the Gas6/TAM signaling axis. The study assessed the expression of the Gas6/TAM axis and its association with macrophage polarization using labial gland tissues, peripheral blood samples from patients with primary Sjögren's syndrome (pSS), and an experimental Sjögren's syndrome mouse model. In vitro, RAW264.7 cells and submandibular gland epithelial cells were employed to analyze changes in the TAM-SOCS1/3 axis, JAK1-STAT1 pathway, and polarization markers (iNOS, Arg1). ELISA was used to detect Gas6 secretion by SGECs, while flow cytometry and confocal microscopy evaluated macrophage function.Both primary Sjögren's syndrome patients and experimental Sjögren's syndrome mice showed dysregulation of the Gas6/TAM signaling pathway, which was closely linked to macrophage polarization imbalance.CP-25 alleviated ESS mouse symptoms by activating the TAM-SOCS1/3 axis, inhibiting the JAK1-STAT1 pathway, and promoting M2 macrophage polarization. In vitro experiments confirmed that CP-25 stimulated salivary gland epithelial cells (SGECs) to secrete Gas6 and reduced matrix metalloproteinase-9 (MMP-9) expression. Moreover, exogenous Gas6 promoted M2 polarization via TAM receptor activation; knockdown of the Mer receptor impaired macrophage phagocytic function. The study also indicated that MMP-9 may be involved in regulating TAM receptors on macrophages.In conclusion, CP-25 treats pSS by regulating SGEC Gas6/MMP-9 secretion, targeting macrophage TAM-SOCS1/3, modulating JAK1-STAT1, and restoring macrophage function.
Corrigendum to "m6A-mediated upregulation of miRNA-193a aggravates cardiomyocyte apoptosis and inflammatory response in sepsis-induced cardiomyopathy via the METTL3/ miRNA-193a/BCL2L2 pathway" [Exp Cell Res. 2023 Sep 1; 430(1): 113712].
Liang L, Liu S, Wu Q … +3 more , Chen R, Jiang S, Yang Z
Exp Cell Res · 2026 Feb · PMID 41444057 · Publisher ↗
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FBXL6 drives tumorigenesis in lung adenocarcinoma through ubiquitination and proteasomal degradation of CDKN1C.
Dong G, Zhang N, Yang D … +2 more , Zhu Z, He Y
Exp Cell Res · 2026 Feb · PMID 41443404 · Publisher ↗
Lung adenocarcinoma (LUAD) is a highly prevalent and lethal malignancy. Although F-box and leucine-rich repeat protein 6 (FBXL6), an E3 ubiquitin ligase, has been implicated in tumor progression across certain cancers, i...
Lung adenocarcinoma (LUAD) is a highly prevalent and lethal malignancy. Although F-box and leucine-rich repeat protein 6 (FBXL6), an E3 ubiquitin ligase, has been implicated in tumor progression across certain cancers, its functional role in LUAD remains unclear. In this study, we investigated the oncogenic potential of FBXL6 in LUAD pathogenesis. Bioinformatics analysis of GEO, TCGA, and TNM datasets revealed significant upregulation of FBXL6 in LUAD tissues. Functional studies using FBXL6-knockdown (via shRNA in PC-9 cells) and FBXL6-overexpressing (via plasmid transfection in A549 cells) demonstrated that FBXL6 depletion suppressed cell proliferation, migration, and invasion, whereas its overexpression reversed these effects. In vivo experiments further confirmed that FBXL6 knockdown in PC-9 cells inhibited tumor growth and liver metastasis in BALB/c nude mice following subcutaneous or tail vein injection. Mechanistically, FBXL6 was found to physically interact with cyclin-dependent kinase inhibitor 1C (CDKN1C/p57Kip2) and promote its polyubiquitination and proteasomal degradation, thereby destabilizing this tumor suppressor. Rescue assays validated that CDKN1C mediates the pro-tumorigenic effects of FBXL6 on LUAD cell proliferation and metastasis. Collectively, our findings reveal that FBXL6 drives LUAD progression by ubiquitinating and degrading CDKN1C, highlighting its potential as a therapeutic target for LUAD.
p38 MAPK-mediated suppression of Nrf2-MPC2 axis drives metabolic reprogramming which confers imatinib resistance in blast crisis phase of chronic myeloid leukemia.
Bhat M, Narasimhan M, Shelar A … +3 more , Patwardhan R, Sandur SK, Govekar R
Exp Cell Res · 2026 Feb · PMID 41423144 · Publisher ↗
BACKGROUND: Metabolic reprogramming is a hallmark of cancer and its role in tumour drug resistance is emerging. This study explored its role in resistance to tyrosine kinase inhibitors (TKIs) in the blast crisis (BC) pha...
BACKGROUND: Metabolic reprogramming is a hallmark of cancer and its role in tumour drug resistance is emerging. This study explored its role in resistance to tyrosine kinase inhibitors (TKIs) in the blast crisis (BC) phase of chronic myeloid leukemia (CML), which occurs despite inactivation of the oncogenic Bcr-Abl by TKIs. We previously reported that this Bcr-Abl-independent resistance is mimicked in TKI-resistant CML-BC cell line and is causally associated with p38MAPK, a known modulator of metabolism. Thus, we investigated whether p38MAPK-mediated metabolic rewiring caused resistance in CML-BC. METHODS: Imatinib sensitive and resistant CML-BC cell lines K562 and KU812 were analysed for metabolic proteins by Western blotting, metabolome by mass spectrometry, and apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) by flow cytometry. Sequence of alterations was established by inhibition and knockdown studies. RESULTS: TKI-resistant cells exhibited enhanced glucose uptake, increased levels of GLUT1, glycolytic enzymes, and those of pyruvate and ATP which reduced upon inhibition of GLUT1, indicative of enhanced glycolysis as contributor of energy. In contrast, the cells displayed reduced NADH/NAD ratio, MMP, mitochondrial ROS which resulted in reduction in apoptotic population. Inhibition studies revealed that suppression of hyperphosphorylated p38MAPK-mediated activation of Nrf2, caused reduced mitochondrial pyruvate carrier (MPC2) expression. MPC2 inhibition in sensitive cells recapitulated the resistant phenotype with reduced MMP and ROS levels. CONCLUSION: p38MAPK-mediated suppression of Nrf2/MPC2 axis abrogates mitochondrial function and ROS-mediated cell death while enhanced glycolysis generates ATP to sustain growth. The resultant pro-survival conditions allow leukemic cell survival under drug pressure causing resistance.
Mechanistic insights into hypoxia-induced TCF7L2 upregulation and its oncogenic effects on colorectal cancer.
Tang K, Cheng Y, Gong J … +1 more , Li Y
Exp Cell Res · 2026 Feb · PMID 41418870 · Publisher ↗
Hypoxia plays a crucial role in the advancement of colorectal cancer (CRC); however, the downstream mechanisms facilitated by hypoxia-inducible factor 1α (HIF-1α) remain incompletely understood. This study employed in vi...
Hypoxia plays a crucial role in the advancement of colorectal cancer (CRC); however, the downstream mechanisms facilitated by hypoxia-inducible factor 1α (HIF-1α) remain incompletely understood. This study employed in vitro and in vivo models to investigate the role of transcription factor 7-like 2 (TCF7L2) under hypoxic conditions in CRC. Utilizing reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis, we observed an upregulation of TCF7L2 mRNA and protein expression in Caco-2 and HCT-116 CRC cell lines under hypoxia. Functional assays, including CCK-8, colony and sphere formation, Transwell, flow cytometry, and xenograft tumor models, provided evidence that the knockdown of TCF7L2 leads to the suppression of CRC cell proliferation, the induction of apoptosis, cell cycle arrest at the G0/G1 phase, and a decrease in migration and invasion capabilities. Furthermore, it inhibited epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) characteristics in vitro, while also reducing tumor growth in vivo. Mechanistically, chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (co-IP) assays have elucidated that the expression of TCF7L2 induced by hypoxia is dependent on HIF-1α, which directly binds to hypoxia response elements (HREs) within the TCF7L2 promoter. Additionally, Western blot and experiments employing the PI3K inhibitor LY294002 have demonstrated that TCF7L2 activates the PI3K/AKT signaling pathway, thereby facilitating the proliferation of CRC cells. A clinical analysis of 104 CRC specimens, utilizing immunohistochemistry (IHC) and RT-qPCR, revealed that elevated expression levels of TCF7L2 were significantly associated with advanced T stage, metastasis, and unfavorable prognosis. Spearman correlation analysis confirmed a positive relationship between the expressions of TCF7L2 and HIF-1α, while Kaplan-Meier survival analysis demonstrated that their co-expression was predictive of reduced overall survival. Collectively, these findings position TCF7L2 as a critical downstream effector of HIF-1α in hypoxic CRC, and its mechanistic role in promoting malignancy and correlation with poor prognosis provide a theoretical basis for exploring TCF7L2 as a potential therapeutic target in future studies.
Metabolic adaptation in colorectal cancer microenvironment: Focus on cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs).
Hsu CY, El-Sehrawy AAMA, Baig MR … +7 more , Khudhair Z, Murtazaev S, Patel PN, Ganesan S, Arora V, Shukla SK, Nayak PP
Exp Cell Res · 2026 Feb · PMID 41407008 · Publisher ↗
Metabolic reprogramming within the tumor microenvironment (TME) is a critical driver of colorectal cancer (CRC) progression, influencing tumor growth, immune evasion, and metastatic dissemination. Cancer-associated fibro...
Metabolic reprogramming within the tumor microenvironment (TME) is a critical driver of colorectal cancer (CRC) progression, influencing tumor growth, immune evasion, and metastatic dissemination. Cancer-associated fibroblasts (CAFs) undergo adaptive shifts toward aerobic glycolysis, a process often termed the "reverse Warburg effect," producing high levels of lactate and pyruvate that are shuttled to adjacent CRC cells to fuel oxidative phosphorylation and anabolic biosynthesis. CAFs additionally secrete cytokines and growth factors, including TGF-β, IL-6, and VEGF, which integrate metabolic and signaling networks to stimulate epithelial-mesenchymal transition (EMT), angiogenesis, and metastatic potential. Similarly, tumor-associated macrophages (TAMs) exhibit remarkable metabolic plasticity that correlates with their functional heterogeneity. Beyond the classical M1/M2 dichotomy, TAM subsets display differential reliance on oxidative phosphorylation, fatty acid oxidation, or glycolysis depending on local oxygen and nutrient availability. M2-like TAMs, for example, preferentially use oxidative phosphorylation and fatty acid metabolism to sustain survival in hypoxic niches while secreting immunosuppressive metabolites such as arginase, polyamines, and lactate, which inhibit cytotoxic T-cell function. Crosstalk between CAFs and TAMs amplifies these metabolic adaptations: CAF-derived lactate promotes M2 polarization, while TAMs enhance glycolysis and biosynthetic activity in tumor cells. This study aims to systematically investigate the metabolic reprogramming of CAFs and TAMs within the CRC tumor microenvironment. Specifically, we seek to characterize the metabolic adaptations and heterogeneity of these stromal populations, elucidate their reciprocal interactions with tumor cells, and identify potential metabolic vulnerabilities that can be therapeutically targeted to disrupt tumor growth, immune evasion, and metastatic progression.
Tumor cell exosome circ-0023919 promotes EMT through the miR-197-5p/ICAM5 axis and enhances the drug resistance of colorectal cancer to 5-fu.
Zhang J, Wu Y, Wang Y … +1 more , Zeng H
Exp Cell Res · 2026 Feb · PMID 41397666 · Publisher ↗
5-Fluorouracil (5-Fu) is a cornerstone chemotherapeutic agent in the treatment of colorectal cancer (CRC). However, its clinical efficacy is frequently hampered by the development of drug resistance, which remains a majo...
5-Fluorouracil (5-Fu) is a cornerstone chemotherapeutic agent in the treatment of colorectal cancer (CRC). However, its clinical efficacy is frequently hampered by the development of drug resistance, which remains a major obstacle to successful treatment. The aim of this study is to gain a comprehensive understanding of the role and mechanism of the tumor cell-derived exosomal circ-0023919 in 5-Fu resistance. High-throughput microarray technology was employed to identify differentially expressed circRNAs in 5-Fu resistance CRC cells and their derived exosomes. A CRC/5-Fu drug-resistant cell line was successfully established using the drug gradient induction method, and its resistance index was subsequently determined. We employed transmission electron microscopy, nanoparticle tracking analysis (NTA) and Western blot to characterize exosomes by detecting the exosomal markers CD63 and TSG101. The circular structure, stability, and subcellular localization of circ-0023919 were confirmed using a combination of approaches, including actinomycin D treatment, RNase R digestion, specific primer PCR amplification, Sanger sequencing and FISH. Furthermore, we systematically evaluated the regulatory role of circ-0023919 in multiple biological functions of CRC cells by assessing cell proliferation, migration, invasion, drug resistance, stemness and EMT-related markers. Our findings demonstrate that circ-0023919 promotes the migration and invasion of CRC/5-Fu cells both in vitro and in vivo, while also enhancing resistance to 5-Fu chemotherapy. Mechanistically, circ-0023919 acts as a molecular sponge for miR-197-5p, thereby upregulating the expression of ICAM5. In this scientific study, circ-0023919 is shown to enhance the resistance of CRC cells to 5-Fu by promoting EMT. Thus, circ-0023919 is considered a potential therapeutic target for CRC treatment.
Phospholipase C δ1 affects integrin-mediated cell adhesion and migration by altering available phosphatidylinositol 4,5-bisphosphate levels.
Yoneda A, Fujinaka R, Tsuchiya N … +6 more , Yaita S, Suzuki S, Kishi Y, Nakamura Y, Satow R, Fukami K
Exp Cell Res · 2026 Feb · PMID 41391593 · Publisher ↗
Integrins are primary extracellular matrix receptors that play essential roles in homeostasis and development. Integrin activity is tightly regulated and is associated with conformational states. Although phosphatidylino...
Integrins are primary extracellular matrix receptors that play essential roles in homeostasis and development. Integrin activity is tightly regulated and is associated with conformational states. Although phosphatidylinositol 4,5-bisphosphate (PIP), produced by phosphatidylinositol 4-phosphate 5-kinases, is involved in integrin activation, it is unclear whether PIP-reducing enzymes affect integrin conformation and integrin-mediated cell behavior by altering PIP levels. Herein, we showed that phospholipase C (PLC) δ1, a PIP-hydrolyzing enzyme, affected integrin-mediated cell adhesion and migration. In PLCδ1 null murine fibroblasts and PLCδ1 knockdown-human melanoma cells, integrin-mediated cell behavior and basal PIP levels in the plasma membrane increased compared with those in control cells. PLCδ1 reduction led to increases in the extended conformation of integrin β1 ectodomain and the interaction between integrin and its activator/stabilizer talin in the absence of ligands. Overexpression of full-length-PLCδ1 or its pleckstrin homology domain but not their PIP-binding incompetent mutants inhibited the integrin-mediated cell behavior. To understand how altering plasma membrane PIP levels affects integrin-mediated cell behavior, the catalytic domain of PIP phosphatase was used. It reduced the basal levels of plasma membrane PIP, inhibited integrin-mediated cell migration, increased the closed conformation of the integrin β1 headpiece, and decreased integrin-talin interaction. These data suggested that the effects of PLCδ1 reduction were due to a PIP increase and that the plasma membrane PIP levels affected integrin conformation in the absence of ligands. Our results revealed that PLCδ1 finely tunes integrin-mediated cell adhesion and migration and integrin conformation by altering available PIP levels in the plasma membrane.
Migrasomes in the tumor microenvironment: Functional roles and therapeutic potential.
Li X, Yang J, Xie H … +4 more , Guo J, Cha J, Wang J, Lin C
Exp Cell Res · 2026 Feb · PMID 41391592 · Publisher ↗
Migrasomes are large extracellular vesicles (0.5-3 μm in diameter) with a distinctive pomegranate-like structure, formed along retraction fibers during cell migration and released their content through migracytosis. Unli...
Migrasomes are large extracellular vesicles (0.5-3 μm in diameter) with a distinctive pomegranate-like structure, formed along retraction fibers during cell migration and released their content through migracytosis. Unlike other extracellular vesicles, migrasomes play unique roles in intercellular communication by transferring proteins, RNAs, and signaling molecules within the tumor microenvironment. This review summarizes recent advances in understanding migrasome biogenesis, composition, and functional roles in cancer progression. We highlight their contributions to tumor angiogenesis, extracellular matrix remodeling, and most notably immune escape, through the regulation of tumor-associated macrophages, T cells, and other immune and stromal cells. Pan-cancer evidence supports a strong correlation between migrasome abundance and immunosuppressive gene signatures, including immune checkpoint expression and tumor immune dysfunction and exclusion (TIDE) scores. We also highlight the promising diagnostic and therapeutic potential of migrasomes as novel biomarkers and targets for cancer therapy. Finally, we discuss current research challenges and outline future directions for advancing migrasome research toward clinical translation.
Extracellular vesicles from tumor-associated macrophages: implications for tumor progression and emerging therapeutic strategies.
Amorim CS, Moraes JA, Renovato-Martins M … +1 more , Motta JM
Exp Cell Res · 2026 Feb · PMID 41389906 · Publisher ↗
Extracellular vesicles (EVs) derived from tumor cells have been extensively explored over the past decades, as they represent a powerful means of communication that promotes tumor progression, including the formation of...
Extracellular vesicles (EVs) derived from tumor cells have been extensively explored over the past decades, as they represent a powerful means of communication that promotes tumor progression, including the formation of pre-metastatic niches and the consequent facilitation of successful metastatic dissemination. However, macrophages comprise a substantial population of non-tumoral cells within the tumor microenvironment and can either facilitate or inhibit tumor progression through the messages carried by their EVs. In this paper, we reviewed the literature on macrophage-derived EVs and their role in modulating tumor behavior, including development, metastasis, immune evasion, and chemoresistance. We begin by outlining the main categories of EVs and the subtypes of macrophage polarization, followed by a discussion of key aspects of macrophage-derived EVs across various tumor types. Finally, we examine emerging therapeutic strategies that utilize these EVs as potential tools in anticancer therapy.
Overcoming multidrug resistance in cancer cells targeting ABC transporter ABCB1 with tyrosine kinase inhibitor: Olverembatinib.
Zhang B, Chen X, Dong X … +6 more , Li Y, Bo L, Patel H, Chou B, Wang S, Chen ZS
Exp Cell Res · 2026 Feb · PMID 41386459 · Publisher ↗
The overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) remains a primary challenge in overcoming multidrug resistance (MDR) in cancer cells. This study investigates the potential of olverembatinib, a thi...
The overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) remains a primary challenge in overcoming multidrug resistance (MDR) in cancer cells. This study investigates the potential of olverembatinib, a third-generation tyrosine kinase inhibitor (TKI), to reverse ABCB1-mediated MDR and enhance the efficacy of chemotherapeutic drugs. Non-cytotoxic concentrations of olverembatinib significantly increased the sensitivity of ABCB1-overexpressing cells to paclitaxel and vincristine. Mechanistic analyses revealed that olverembatinib did not alter the expression or localization of ABCB1 but inhibited its drug efflux function, resulting in increased intracellular drug retention. Additionally, olverembatinib activated the ATPase activity of ABCB1 in a concentration-dependent manner and exhibited potent binding affinity to ABCB1 in docking simulations. These findings suggest that olverembatinib holds promise as a potent reversal agent for MDR, paving the way for its integration into novel combination chemotherapy regimens to improve cancer treatment outcomes.
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