Experimental cell research最新文献_第3页

KRM2 promotes renal cell carcinoma progression and inhibits ferroptosis by interacting with ATF2

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-03-07 DOI: 10.1016/j.yexcr.2025.114497

Fang Liu , Mengtong Wang , Gao Li , Sha Cheng , Jia Yu , Heng Luo , Xuhui Zhu

The role of kringle-containing transmembrane protein 2 (KRM2) in renal cell carcinoma (RCC) remains unknown. This study aimed to explore KRM2's mechanistic role in regulating RCC progression. Tissue microarrays were used to map KRM2 expression in tumor tissues and analyze its relationship with RCC clinical features. Cell models were constructed by transfecting RCC cell lines with KRM2 knockdown, KRM2 overexpression, or ATF2 knockdown lentiviral vectors. Tumor xenografts were generated in nude mice to observe the effects of KRM2 on tumor formation. A gene expression microarray was used to identify the regulatory genes downstream of KRM2 and their binding relationships were verified by co-immunoprecipitation and cycloheximide pulse-chase assay. Through a series of in vitro experiments, effects of altering KRM2 and ATF2 expression on cell function and ferroptosis indicators were observed. Following these, we found that KRM2 expression significantly increased in RCC tumor tissues and was associated with tumor size, grade, stage, infiltration, and patient age. In vivo experiments confirmed that inhibition of KRM2 expression slowed the tumor growth. Silencing of KRM2 in RCC cells also significantly inhibited cell proliferation and migration and facilitated apoptosis and ferroptosis. ATF2 is predicted to be downstream of KRM2. Its expression is positively regulated by KRM2 and there was targeted binding between proteins. In vitro experiments further suggested that ATF2 knockdown reversed the cancer-promoting and ferroptosis-inhibiting effects of KRM2 in RCC. In conclusion, KRM2 plays an oncogenic role in RCC by promoting tumor progression and ferroptosis via regulation of its downstream target, ATF2.

{"title":"KRM2 promotes renal cell carcinoma progression and inhibits ferroptosis by interacting with ATF2","authors":"Fang Liu , Mengtong Wang , Gao Li , Sha Cheng , Jia Yu , Heng Luo , Xuhui Zhu","doi":"10.1016/j.yexcr.2025.114497","DOIUrl":"10.1016/j.yexcr.2025.114497","url":null,"abstract":"<div><div>The role of kringle-containing transmembrane protein 2 (KRM2) in renal cell carcinoma (RCC) remains unknown. This study aimed to explore KRM2's mechanistic role in regulating RCC progression. Tissue microarrays were used to map KRM2 expression in tumor tissues and analyze its relationship with RCC clinical features. Cell models were constructed by transfecting RCC cell lines with <em>KRM2</em> knockdown, <em>KRM2</em> overexpression, or <em>ATF2</em> knockdown lentiviral vectors. Tumor xenografts were generated in nude mice to observe the effects of KRM2 on tumor formation. A gene expression microarray was used to identify the regulatory genes downstream of KRM2 and their binding relationships were verified by co-immunoprecipitation and cycloheximide pulse-chase assay. Through a series of <em>in vitro</em> experiments, effects of altering KRM2 and ATF2 expression on cell function and ferroptosis indicators were observed. Following these, we found that KRM2 expression significantly increased in RCC tumor tissues and was associated with tumor size, grade, stage, infiltration, and patient age. <em>In vivo</em> experiments confirmed that inhibition of KRM2 expression slowed the tumor growth. Silencing of <em>KRM2</em> in RCC cells also significantly inhibited cell proliferation and migration and facilitated apoptosis and ferroptosis. <em>ATF2</em> is predicted to be downstream of KRM2. Its expression is positively regulated by KRM2 and there was targeted binding between proteins. <em>In vitro</em> experiments further suggested that ATF2 knockdown reversed the cancer-promoting and ferroptosis-inhibiting effects of KRM2 in RCC. In conclusion, KRM2 plays an oncogenic role in RCC by promoting tumor progression and ferroptosis via regulation of its downstream target, <em>ATF2</em>.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"447 1","pages":"Article 114497"},"PeriodicalIF":3.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Crosstalk between microRNA and inflammation; critical regulator of diabetes

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-03-07 DOI: 10.1016/j.yexcr.2025.114507

Amr Ali Mohamed Abdelgawwad El-Sehrawy , Mohammed Hashim Mohammed , Omar dheyauldeen salahldin , Subasini Uthirapathy , Suhas Ballal , Rishiv Kalia , Renu Arya , Kamal Kant Joshi , Arshed Shakir Kadim , Abed J. Kadhim

A growing body of evidence indicates that microRNAs (miRNAs may be used as biomarkers for the diagnosis, prognosis, and treatment of diabetes, given their changed expression profile as the disease progresses. There is growing interest in using individual miRNAs or whole miRNA clusters linked to diabetes as therapeutic targets because of their abnormal expression and functioning. In diabetes, miRNAs are also involved in inflammatory and immunological responses. Additionally, the inflammatory response controls the generation, processing, and stability of pre- or mature miRNAs and miRNA biogenesis. With a comprehensive grasp of molecular biological activities and the signaling axis, this review emphasizes the critical functions of miRNAs in inflammatory and immunological processes in diabetes. We further emphasized the potential role of these miRNAs in controlling inflammation associated with diabetes. This assessment will direct the shift from many studies to practical applications for tailored diabetes treatment and assist in identifying new therapeutic targets and approaches.

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引用次数: 0

Farnesoid X receptor induction decreases invasion and tumor progression by JAK2/occludin signaling in human glioblastoma cells

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-03-07 DOI: 10.1016/j.yexcr.2025.114500

TzuMin Chen , JenFu Yang , YiHsuan Lin , YuLing Tsai , ChienRui Lai , WenChiuan Tsai , Ying Chen

Glioblastoma multiforme (GBM) is a brain cancer characterized by low survival and high recurrence rates. Farnesoid X receptor (FXR), a nuclear receptor for bile acids, is expressed at low levels in GBM. This study explores the impact of FXR regulation on GBM cell migration and invasion. Higher FXR expression correlated with increased survival in GBM patients, based on TCGA data. FXR overexpression inhibited cell viability, migration and invasion as well as matrix metalloproteinase 2 (MMP2) activity, while knockdown of FXR exerted the opposite effects. The expression of the tight junction proteins occludin and ZO-1 was enhanced after FXR overexpression. Moreover, a JAK2 activator reversed the migration and invasion of FXR-overexpressing GBM cells. In an animal study, FXR overexpression combined with temozolomide treatment decreased tumor mass, and MMP2 expression and elevated occludin expression in mice. In conclusion, FXR overexpression inhibits the progression of GBM, which may be mediated by inhibiting JAK2 and enhancing tight junction protein expression.

{"title":"Farnesoid X receptor induction decreases invasion and tumor progression by JAK2/occludin signaling in human glioblastoma cells","authors":"TzuMin Chen , JenFu Yang , YiHsuan Lin , YuLing Tsai , ChienRui Lai , WenChiuan Tsai , Ying Chen","doi":"10.1016/j.yexcr.2025.114500","DOIUrl":"10.1016/j.yexcr.2025.114500","url":null,"abstract":"<div><div>Glioblastoma multiforme (GBM) is a brain cancer characterized by low survival and high recurrence rates. Farnesoid X receptor (FXR), a nuclear receptor for bile acids, is expressed at low levels in GBM. This study explores the impact of FXR regulation on GBM cell migration and invasion. Higher FXR expression correlated with increased survival in GBM patients, based on TCGA data. FXR overexpression inhibited cell viability, migration and invasion as well as matrix metalloproteinase 2 (MMP2) activity, while knockdown of FXR exerted the opposite effects. The expression of the tight junction proteins occludin and ZO-1 was enhanced after FXR overexpression. Moreover, a JAK2 activator reversed the migration and invasion of FXR-overexpressing GBM cells. In an animal study, FXR overexpression combined with temozolomide treatment decreased tumor mass, and MMP2 expression and elevated occludin expression in mice. In conclusion, FXR overexpression inhibits the progression of GBM, which may be mediated by inhibiting JAK2 and enhancing tight junction protein expression.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"447 1","pages":"Article 114500"},"PeriodicalIF":3.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Carbon monoxide inhibits human bronchial epithelial CCL5 and IL-6 secretion induced by SARS-CoV-2 spike RBD protein

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-03-07 DOI: 10.1016/j.yexcr.2025.114499

Xiao-Min Fang, Xing-Jian Liu, Rui-Gang Zhang

Carbon monoxide (CO) is a novel anti-inflammatory molecule, but the effects of CO on SARS-CoV-2 spike RBD (S-RBD)-induced human bronchial epithelial cytokines release remains unclear. CO was delivered using CO-releasing molecule 3 (CORM-3). The effects of S-RBD, ATPγS and CO on cytokines secretion were determined by enzyme-linked immunosorbent assay (ELISA) in 16HBE14o-human bronchial epithelial cell line. The inhibitory effect of CO on S-RBD-induced ERK phosphorylation was assessed by Western blot analysis. The regulatory effect of CO on extracellular nucleotide-induced ion transport was quantified by short-circuit current (I_SC). S-RBD evoked CCL5 and IL-6 release and this effect could be suppressed by CO. However, CO failed to inhibit ATP release induced by S-RBD while decreased ATP-induced CCL5 and IL-6 secretion as well as ion transport. Furthermore, CO significantly inhibited ERK phosphorylation induced by S-RBD. These findings suggest an anti-inflammatory role of CO during inflammation induced by S-RBD and extracellular nucleotide in human bronchiol epithelial cells.

一氧化碳（CO）是一种新型抗炎分子，但一氧化碳对 SARS-CoV-2 穗状 RBD（S-RBD）诱导的人类支气管上皮细胞因子释放的影响仍不清楚。CO释放分子3（CORM-3）可释放CO。在 16HBE14o- 人支气管上皮细胞系中，通过酶联免疫吸附试验（ELISA）测定了 S-RBD、ATPγS 和 CO 对细胞因子分泌的影响。通过 Western 印迹分析评估了 CO 对 S-RBD 诱导的 ERK 磷酸化的抑制作用。通过短路电流（ISC）量化了 CO 对细胞外 nuleotide 诱导的离子转运的调节作用。S-RBD 可诱导 CCL5 和 IL-6 的释放，CO 可抑制这种效应。然而，CO 未能抑制 S-RBD 诱导的 ATP 释放，但却降低了 ATP 诱导的 CCL5 和 IL-6 分泌以及离子转运。此外，CO 还能明显抑制 S-RBD 诱导的 ERK 磷酸化。这些研究结果表明，CO 在 S-RBD 和细胞外核苷酸诱导的人支气管上皮细胞炎症过程中具有抗炎作用。

{"title":"Carbon monoxide inhibits human bronchial epithelial CCL5 and IL-6 secretion induced by SARS-CoV-2 spike RBD protein","authors":"Xiao-Min Fang, Xing-Jian Liu, Rui-Gang Zhang","doi":"10.1016/j.yexcr.2025.114499","DOIUrl":"10.1016/j.yexcr.2025.114499","url":null,"abstract":"<div><div>Carbon monoxide (CO) is a novel anti-inflammatory molecule, but the effects of CO on SARS-CoV-2 spike RBD (S-RBD)-induced human bronchial epithelial cytokines release remains unclear. CO was delivered using CO-releasing molecule 3 (CORM-3). The effects of S-RBD, ATPγS and CO on cytokines secretion were determined by enzyme-linked immunosorbent assay (ELISA) in 16HBE14o-human bronchial epithelial cell line. The inhibitory effect of CO on S-RBD-induced ERK phosphorylation was assessed by Western blot analysis. The regulatory effect of CO on extracellular nucleotide-induced ion transport was quantified by short-circuit current (<em>I</em><sub><em>SC</em></sub>). S-RBD evoked CCL5 and IL-6 release and this effect could be suppressed by CO. However, CO failed to inhibit ATP release induced by S-RBD while decreased ATP-induced CCL5 and IL-6 secretion as well as ion transport. Furthermore, CO significantly inhibited ERK phosphorylation induced by S-RBD. These findings suggest an anti-inflammatory role of CO during inflammation induced by S-RBD and extracellular nucleotide in human bronchiol epithelial cells.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"447 1","pages":"Article 114499"},"PeriodicalIF":3.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TGF-β-induced acetylation of KLF5 drives TNFAIP2 transcription and EMT in nasopharyngeal carcinoma: Unveiling a novel regulatory mechanism

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-03-05 DOI: 10.1016/j.yexcr.2025.114498

Yi Qian , Xuxu Zhao , Feiyang Wu , Xiaoqiang Wang , Tao Chen

Epithelial-mesenchymal transition (EMT) is one of the critical mechanisms underlying migration, invasion, and metastasis of nasopharyngeal carcinoma (NPC) cells. The transcription factor KLF5 plays a pivotal role in various cancers, however, its precise functions in NPC remain incompletely understood. This study aims to explore the detailed mechanisms by which TGF-β enhances TNFAIP2 transcription by acetylating KLF5, thereby inducing EMT in NPC. KLF5 was significantly overexpressed in NPC tissues and closely associated with adverse clinicopathological features of the patients. Further studies revealed that TGF-β markedly increased the expression of KLF5 and its acetylated form, Ac-KLF5, in NPC cells, with the acetylation status of KLF5 being crucial for its function. KLF5 induced EMT in NPC cells by directly binding to the TNFAIP2 promoter and promoting its transcription. The pro-migratory and pro-invasive effects of acetylated KLF5 on NPC cells depended on TNFAIP2. Additionally, in vivo experiments confirmed that TGF-β treatment induced tumors in NPC mouse models to exhibit apparent EMT characteristics. These results collectively support the central role of the TGF-β-KLF5-TNFAIP2 axis in EMT of NPC. This study elucidates the specific mechanisms by which TGF-β promotes TNFAIP2 transcription by acetylating KLF5, thereby inducing EMT in NPC. This discovery not only provides new insights into the pathogenesis of NPC but also identifies potential therapeutic targets for NPC treatment.

{"title":"TGF-β-induced acetylation of KLF5 drives TNFAIP2 transcription and EMT in nasopharyngeal carcinoma: Unveiling a novel regulatory mechanism","authors":"Yi Qian , Xuxu Zhao , Feiyang Wu , Xiaoqiang Wang , Tao Chen","doi":"10.1016/j.yexcr.2025.114498","DOIUrl":"10.1016/j.yexcr.2025.114498","url":null,"abstract":"<div><div>Epithelial-mesenchymal transition (EMT) is one of the critical mechanisms underlying migration, invasion, and metastasis of nasopharyngeal carcinoma (NPC) cells. The transcription factor KLF5 plays a pivotal role in various cancers, however, its precise functions in NPC remain incompletely understood. This study aims to explore the detailed mechanisms by which TGF-β enhances TNFAIP2 transcription by acetylating KLF5, thereby inducing EMT in NPC. KLF5 was significantly overexpressed in NPC tissues and closely associated with adverse clinicopathological features of the patients. Further studies revealed that TGF-β markedly increased the expression of KLF5 and its acetylated form, Ac-KLF5, in NPC cells, with the acetylation status of KLF5 being crucial for its function. KLF5 induced EMT in NPC cells by directly binding to the TNFAIP2 promoter and promoting its transcription. The pro-migratory and pro-invasive effects of acetylated KLF5 on NPC cells depended on TNFAIP2. Additionally, in vivo experiments confirmed that TGF-β treatment induced tumors in NPC mouse models to exhibit apparent EMT characteristics. These results collectively support the central role of the TGF-β-KLF5-TNFAIP2 axis in EMT of NPC. This study elucidates the specific mechanisms by which TGF-β promotes TNFAIP2 transcription by acetylating KLF5, thereby inducing EMT in NPC. This discovery not only provides new insights into the pathogenesis of NPC but also identifies potential therapeutic targets for NPC treatment.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"447 1","pages":"Article 114498"},"PeriodicalIF":3.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ano5 deficiency disturbed bone formation by inducing osteoclast apoptosis in Gnathodiaphyseal dysplasia

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-03-04 DOI: 10.1016/j.yexcr.2025.114493

Xiu Liu , Shengnan Wang , Chao Liang , Shuai Zhang , Sirui Liu , Ying Hu

Gnathodiaphyseal dysplasia (GDD) is a rare genetic syndrome characterized by cemento-ossifying fibroma lesions in the mandible and sclerosis of tubular bones. Currently, the clinical treatment of GDD is limited to surgical resection; therefore, novel treatment strategies developed through exploration of the related mechanisms are needed. Mutations in the TMEM16E/ANO5 gene are considered the main pathogenic factor of GDD, and the Ano5 knockout mouse model (Ano5^−/−) established previously, which presented GDD-like characteristics, exhibited decreased osteoclastogenesis. ANO5, a calcium-activated chloride channel (CaCC), plays an important role in the maintenance of intracellular calcium homeostasis, which is crucial for osteoclast differentiation. In this study, our data indicated that the intracellular calcium concentration ([Ca²⁺]_i) and calcium transients were significantly decreased in Ano5^−/− osteoclasts accompanied by abnormally altered expression of calcium transporters, resulting in calcium dyshomeostasis. In addition, the endoplasmic reticulum stress (ERS) response was significantly enhanced in Ano5^−/− osteoclasts, possibly because of calcium dyshomeostasis, which leading to the increased proportion of apoptotic osteoclasts via the activation of the C/EBP homologous protein (CHOP) signalling pathway, accompanied by abnormal changes in the expression of apoptosis-related factors. In summary, Ano5 deficiency impairs the function of osteoclasts by increasing osteoclast apoptosis, which is induced by an overactivated ERS response via calcium dyshomeostasis.

{"title":"Ano5 deficiency disturbed bone formation by inducing osteoclast apoptosis in Gnathodiaphyseal dysplasia","authors":"Xiu Liu , Shengnan Wang , Chao Liang , Shuai Zhang , Sirui Liu , Ying Hu","doi":"10.1016/j.yexcr.2025.114493","DOIUrl":"10.1016/j.yexcr.2025.114493","url":null,"abstract":"<div><div>Gnathodiaphyseal dysplasia (GDD) is a rare genetic syndrome characterized by cemento-ossifying fibroma lesions in the mandible and sclerosis of tubular bones. Currently, the clinical treatment of GDD is limited to surgical resection; therefore, novel treatment strategies developed through exploration of the related mechanisms are needed. Mutations in the TMEM16E/ANO5 gene are considered the main pathogenic factor of GDD, and the <em>Ano5</em> knockout mouse model (<em>Ano5</em><sup><em>−/−</em></sup>) established previously, which presented GDD-like characteristics, exhibited decreased osteoclastogenesis. <em>ANO5</em>, a calcium-activated chloride channel (CaCC), plays an important role in the maintenance of intracellular calcium homeostasis, which is crucial for osteoclast differentiation. In this study, our data indicated that the intracellular calcium concentration ([Ca<sup>2+</sup>]<sub>i</sub>) and calcium transients were significantly decreased in <em>Ano5</em><sup><em>−/−</em></sup> osteoclasts accompanied by abnormally altered expression of calcium transporters, resulting in calcium dyshomeostasis. In addition, the endoplasmic reticulum stress (ERS) response was significantly enhanced in <em>Ano5</em><sup><em>−/−</em></sup> osteoclasts, possibly because of calcium dyshomeostasis, which leading to the increased proportion of apoptotic osteoclasts via the activation of the C/EBP homologous protein (CHOP) signalling pathway, accompanied by abnormal changes in the expression of apoptosis-related factors. In summary, <em>Ano5</em> deficiency impairs the function of osteoclasts by increasing osteoclast apoptosis, which is induced by an overactivated ERS response via calcium dyshomeostasis.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"447 1","pages":"Article 114493"},"PeriodicalIF":3.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143550256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Protocadherin 17 weakens the lenvatinib resistance of liver cancer through inducing ferroptosis

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-03-04 DOI: 10.1016/j.yexcr.2025.114495

Jun Yang , Bin Hu , Guowei Zhang , Kai Wu , Xue Zhang , Mengxuan Ji , Bin Zhang , Hengliang Shi , Dechun Li

Lenvatinib has been employed in the treatment of advanced liver cancer; however, its clinical application is significantly impeded by frequent drug resistance. Recent studies have revealed that lenvatinib treatment triggers ferroptosis in liver cancer cells, providing a novel approach to addressing lenvatinib resistance. In this study, we initially validated the induction of ferroptosis by lenvatinib in liver cancer cells. Remarkably, protocadherin 17 (PCDH17), an adhesion-related protein, was found to be down-regulated in liver cancer, and overexpression of PCDH17 could induce ferroptosis in liver cancer cells. Importantly, silencing PCDH17 inhibited the impact of lenvatinib on liver cancer cell ferroptosis, while overexpression of PCDH17 had the opposite effect. These findings were further confirmed using a xenograft tumor model in BALB/c nude mice. Additionally, lenvatinib-resistant (LR) liver cancer cells were generated for additional validation purposes. It was observed that LR-liver cancer cells lost their susceptibility to ferroptosis induction by lenvatinib; however, overexpression of PCDH17 reactivated their sensitivity to ferroptosis. Corresponding results were also verified in BALB/c nude mice models. In conclusion, these results suggest that as a novel regulator of ferroptosis, PCDH17 can alleviate lenvatinib resistance and potentially enhance the therapeutic efficacy of lenvatinib in treating liver cancer.

{"title":"Protocadherin 17 weakens the lenvatinib resistance of liver cancer through inducing ferroptosis","authors":"Jun Yang , Bin Hu , Guowei Zhang , Kai Wu , Xue Zhang , Mengxuan Ji , Bin Zhang , Hengliang Shi , Dechun Li","doi":"10.1016/j.yexcr.2025.114495","DOIUrl":"10.1016/j.yexcr.2025.114495","url":null,"abstract":"<div><div>Lenvatinib has been employed in the treatment of advanced liver cancer; however, its clinical application is significantly impeded by frequent drug resistance. Recent studies have revealed that lenvatinib treatment triggers ferroptosis in liver cancer cells, providing a novel approach to addressing lenvatinib resistance. In this study, we initially validated the induction of ferroptosis by lenvatinib in liver cancer cells. Remarkably, protocadherin 17 (PCDH17), an adhesion-related protein, was found to be down-regulated in liver cancer, and overexpression of PCDH17 could induce ferroptosis in liver cancer cells. Importantly, silencing PCDH17 inhibited the impact of lenvatinib on liver cancer cell ferroptosis, while overexpression of PCDH17 had the opposite effect. These findings were further confirmed using a xenograft tumor model in BALB/c nude mice. Additionally, lenvatinib-resistant (LR) liver cancer cells were generated for additional validation purposes. It was observed that LR-liver cancer cells lost their susceptibility to ferroptosis induction by lenvatinib; however, overexpression of PCDH17 reactivated their sensitivity to ferroptosis. Corresponding results were also verified in BALB/c nude mice models. In conclusion, these results suggest that as a novel regulator of ferroptosis, PCDH17 can alleviate lenvatinib resistance and potentially enhance the therapeutic efficacy of lenvatinib in treating liver cancer.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"447 1","pages":"Article 114495"},"PeriodicalIF":3.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143561765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Btbd8 deficiency exacerbates bleomycin-induced pulmonary fibrosis in mice by enhancing myofibroblast accumulation and inflammatory responses

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-03-04 DOI: 10.1016/j.yexcr.2025.114494

Xiaoqiong Yang , Qiman Dong , Xingyuan Tong , Xiaoling Du , Lingyi Chen

BTBD8 contributes to the pathogenesis of inflammatory bowel disease through regulating intestinal barrier integrity and inflammation. However, its role in idiopathic pulmonary fibrosis (IPF) remains unknown. Here we investigated whether BTBD8 plays a role in bleomycin-induced pulmonary fibrosis. Pulmonary fibrosis was induced in wild-type (WT) and Btbd8 knockout (KO) mice by intratracheal instillation of bleomycin. The mice were sacrificed on day 7 or 12. Subsequently, the progression of bleomycin-induced pulmonary fibrosis was assessed. We found that Btbd8 KO mice are more susceptible to bleomycin-induced pulmonary fibrosis, with more severe body weight loss and pulmonary injury, increased collagen deposition and myofibroblast accumulation. We further demonstrated that BTBD8 functions in pulmonary fibroblasts to suppress the conversion of fibroblasts to myofibroblasts. Moreover, Btbd8 deficiency promotes the infiltration of inflammatory cells and the secretion of pro-inflammatory cytokines in IPF mouse model. These results highlight the critical role of BTBD8 in the pathogenesis of bleomycin-induced pulmonary fibrosis in mice, and suggest that BTBD8 may alleviate bleomycin-induced fibrosis by suppressing the differentiation of fibroblasts to myofibroblast, as well as inflammatory responses.

{"title":"Btbd8 deficiency exacerbates bleomycin-induced pulmonary fibrosis in mice by enhancing myofibroblast accumulation and inflammatory responses","authors":"Xiaoqiong Yang , Qiman Dong , Xingyuan Tong , Xiaoling Du , Lingyi Chen","doi":"10.1016/j.yexcr.2025.114494","DOIUrl":"10.1016/j.yexcr.2025.114494","url":null,"abstract":"<div><div>BTBD8 contributes to the pathogenesis of inflammatory bowel disease through regulating intestinal barrier integrity and inflammation. However, its role in idiopathic pulmonary fibrosis (IPF) remains unknown. Here we investigated whether BTBD8 plays a role in bleomycin-induced pulmonary fibrosis. Pulmonary fibrosis was induced in wild-type (WT) and <em>Btbd8</em> knockout (KO) mice by intratracheal instillation of bleomycin. The mice were sacrificed on day 7 or 12. Subsequently, the progression of bleomycin-induced pulmonary fibrosis was assessed. We found that <em>Btbd8</em> KO mice are more susceptible to bleomycin-induced pulmonary fibrosis, with more severe body weight loss and pulmonary injury, increased collagen deposition and myofibroblast accumulation. We further demonstrated that BTBD8 functions in pulmonary fibroblasts to suppress the conversion of fibroblasts to myofibroblasts. Moreover, <em>Btbd8</em> deficiency promotes the infiltration of inflammatory cells and the secretion of pro-inflammatory cytokines in IPF mouse model. These results highlight the critical role of BTBD8 in the pathogenesis of bleomycin-induced pulmonary fibrosis in mice, and suggest that BTBD8 may alleviate bleomycin-induced fibrosis by suppressing the differentiation of fibroblasts to myofibroblast, as well as inflammatory responses.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"447 1","pages":"Article 114494"},"PeriodicalIF":3.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Low extracellular pH enhances TRAIL-induced apoptosis by downregulating Mcl-1 expression

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-02-28 DOI: 10.1016/j.yexcr.2025.114481

Farzaneh Vafaeinik , Lin Zhang , Yong J. Lee

We previously reported that low extracellular pH promotes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through the mitochondria-mediated caspase signal transduction pathway. In this study, we further investigated the mechanism of low extracellular pH on TRAIL-induced apoptosis. When human colorectal carcinoma HCT116 cells were treated with TRAIL for 4 h, significant cytotoxicity was observed at pH 6.3, while cytotoxic effects were notably reduced at pH 7.2. These findings suggest that TRAIL's cytotoxic effects on human colorectal cancer cells are enhanced in low pH environments following TRAIL treatment. Similar results were observed in human pancreatic adenocarcinoma BxPC-3 cells. Interestingly, TRAIL was found to downregulate the levels of anti-apoptotic proteins, such as Mcl-1. This was confirmed by the knock-in (KI) of an Mcl-1 phosphorylation site mutant in HCT116 cells, which blocked TRAIL-induced Mcl-1 downregulation and the subsequent apoptotic response. These results indicate that Mcl-1 mediates TRAIL resistance in the Mcl-1 KI cells. Additionally, our results revealed that TRAIL significantly induced JNK phosphorylation in HCT116 cells, suggesting the involvement of JNK in TRAIL-induced cell death in colorectal cancer cells. Our findings demonstrate that low extracellular pH enhances TRAIL-induced cytotoxicity, particularly at pH 6.3 and 6.6. Moreover, the anti-apoptotic Bcl-2 family member Mcl-1 is an important target of TRAIL in colorectal carcinoma HCT116 cells under different low pH conditions. TRAIL triggered a rapid decline in Mcl-1, suggesting that Mcl-1 downregulation is crucial for TRAIL-induced apoptosis.

{"title":"Low extracellular pH enhances TRAIL-induced apoptosis by downregulating Mcl-1 expression","authors":"Farzaneh Vafaeinik , Lin Zhang , Yong J. Lee","doi":"10.1016/j.yexcr.2025.114481","DOIUrl":"10.1016/j.yexcr.2025.114481","url":null,"abstract":"<div><div>We previously reported that low extracellular pH promotes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through the mitochondria-mediated caspase signal transduction pathway. In this study, we further investigated the mechanism of low extracellular pH on TRAIL-induced apoptosis. When human colorectal carcinoma HCT116 cells were treated with TRAIL for 4 h, significant cytotoxicity was observed at pH 6.3, while cytotoxic effects were notably reduced at pH 7.2. These findings suggest that TRAIL's cytotoxic effects on human colorectal cancer cells are enhanced in low pH environments following TRAIL treatment. Similar results were observed in human pancreatic adenocarcinoma BxPC-3 cells. Interestingly, TRAIL was found to downregulate the levels of anti-apoptotic proteins, such as Mcl-1. This was confirmed by the knock-in (KI) of an Mcl-1 phosphorylation site mutant in HCT116 cells, which blocked TRAIL-induced Mcl-1 downregulation and the subsequent apoptotic response. These results indicate that Mcl-1 mediates TRAIL resistance in the Mcl-1 KI cells. Additionally, our results revealed that TRAIL significantly induced JNK phosphorylation in HCT116 cells, suggesting the involvement of JNK in TRAIL-induced cell death in colorectal cancer cells. Our findings demonstrate that low extracellular pH enhances TRAIL-induced cytotoxicity, particularly at pH 6.3 and 6.6. Moreover, the anti-apoptotic Bcl-2 family member Mcl-1 is an important target of TRAIL in colorectal carcinoma HCT116 cells under different low pH conditions. TRAIL triggered a rapid decline in Mcl-1, suggesting that Mcl-1 downregulation is crucial for TRAIL-induced apoptosis.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"447 1","pages":"Article 114481"},"PeriodicalIF":3.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Glycolysis-related gene signatures and the functional role of P4HA1 in osteosarcoma prognosis

IF 3.3 3区生物学 Q3 CELL BIOLOGY

Experimental cell research

Pub Date : 2025-02-27 DOI: 10.1016/j.yexcr.2025.114492

Haoran Gui , Shuai Wang , Bo Li

Osteosarcoma, a primary malignant bone tumor predominantly affecting children and adolescents, is characterized by aerobic glycolysis, which is intricately linked to tumor progression and metastasis, yet its prognostic implications remain underexplored. This study aimed to develop a prognostic model utilizing glycolysis-related genes and to elucidate the functional role of P4HA1, a key gene within this model, in osteosarcoma prognosis and immune cell infiltration. We collected clinical and transcriptomic data from osteosarcoma patients in the UCSC Xena and GEO databases. Through univariate Cox and LASSO regression analyses, we identified 12 glycolysis-related genes that significantly influence osteosarcoma prognosis. These genes were employed to construct a risk score model, which accurately predicted patient outcomes as demonstrated by survival analysis and ROC curves, with an AUC of 0.899, 0.881, and 0.878 for 1-year, 3-year, and 5-year survival predictions, respectively. The model was particularly effective across different clinical subgroups. Immune cell infiltration analysis revealed that CD8⁺ T cells, naïve CD4⁺ T cells, resting dendritic cells, and activated mast cells significantly contributed to the model's predictive power. The model also showed significant enrichment of immune-related signaling pathways, indicating a robust association between immune status and glycolytic-related risk scores in osteosarcoma prognosis. Notably, P4HA1 was upregulated in osteosarcoma tissues and promoted cell proliferation in a glycolysis-dependent manner, as evidenced by increased intracellular ATP levels, inhibited glucose absorption, and elevated lactate levels in P4HA1-overexpressing osteosarcoma cells. The promotion of proliferation by P4HA1 could be significantly attenuated by the glycolysis inhibitor 2-DG, highlighting the glycolysis dependency of P4HA1's action. In conclusion, we developed a prognostic model for osteosarcoma by integrating glycolysis-related genes, with a particular emphasis on the functional role of P4HA1. Our findings highlight the interplay between glycolysis and immune cell infiltration in disease prognosis. This model provides insights for targeted therapies and a foundation for further research into osteosarcoma treatment.

{"title":"Glycolysis-related gene signatures and the functional role of P4HA1 in osteosarcoma prognosis","authors":"Haoran Gui , Shuai Wang , Bo Li","doi":"10.1016/j.yexcr.2025.114492","DOIUrl":"10.1016/j.yexcr.2025.114492","url":null,"abstract":"<div><div>Osteosarcoma, a primary malignant bone tumor predominantly affecting children and adolescents, is characterized by aerobic glycolysis, which is intricately linked to tumor progression and metastasis, yet its prognostic implications remain underexplored. This study aimed to develop a prognostic model utilizing glycolysis-related genes and to elucidate the functional role of P4HA1, a key gene within this model, in osteosarcoma prognosis and immune cell infiltration. We collected clinical and transcriptomic data from osteosarcoma patients in the UCSC Xena and GEO databases. Through univariate Cox and LASSO regression analyses, we identified 12 glycolysis-related genes that significantly influence osteosarcoma prognosis. These genes were employed to construct a risk score model, which accurately predicted patient outcomes as demonstrated by survival analysis and ROC curves, with an AUC of 0.899, 0.881, and 0.878 for 1-year, 3-year, and 5-year survival predictions, respectively. The model was particularly effective across different clinical subgroups. Immune cell infiltration analysis revealed that CD8<sup>+</sup> T cells, naïve CD4<sup>+</sup> T cells, resting dendritic cells, and activated mast cells significantly contributed to the model's predictive power. The model also showed significant enrichment of immune-related signaling pathways, indicating a robust association between immune status and glycolytic-related risk scores in osteosarcoma prognosis. Notably, P4HA1 was upregulated in osteosarcoma tissues and promoted cell proliferation in a glycolysis-dependent manner, as evidenced by increased intracellular ATP levels, inhibited glucose absorption, and elevated lactate levels in P4HA1-overexpressing osteosarcoma cells. The promotion of proliferation by P4HA1 could be significantly attenuated by the glycolysis inhibitor 2-DG, highlighting the glycolysis dependency of P4HA1's action. In conclusion, we developed a prognostic model for osteosarcoma by integrating glycolysis-related genes, with a particular emphasis on the functional role of P4HA1. Our findings highlight the interplay between glycolysis and immune cell infiltration in disease prognosis. This model provides insights for targeted therapies and a foundation for further research into osteosarcoma treatment.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"447 1","pages":"Article 114492"},"PeriodicalIF":3.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0