Pub Date : 2025-01-27DOI: 10.1016/j.bbamcr.2025.119912
Zhiyuan Ma , Hu Wang , Zhengxing Zhou , Chengli Lu , Minglin Zhang , Renmin Mu , Chengmin Zhang , Zhiqiang Yi , Zilin Deng , Yingying Zhao , Jiaxing Zhu , Guorong Wen , Hai Jin , Jiaxing An , Biguang Tuo , Peng Yuan , Xuemei Liu , Taolang Li
SLC26A9 is a member of the Slc26a family of multifunctional anion transporters that function as Cl− channels in the stomach. We reported for the first time that SLC26A9 is involved in gastric tumorigenesis. However, the role of SLC26A9 in breast cancer has not yet been investigated. We first demonstrated that the upregulation of SLC26A9 is associated with the clinicopathological progression and poor prognosis of patients with breast cancer and is positively correlated with HER2 amplification. SLC26A9 alters the proliferation, migration, and invasion potential of breast cancer cells by regulating the PI3K/AKT signaling pathway. SLC26A9 acts as an oncogene in the development of breast cancer. These findings provide valuable insights for the development of future diagnostic and therapeutic strategies for BC.
{"title":"SLC26A9 promotes the initiation and progression of breast cancer by activating the PI3K/AKT signaling pathway","authors":"Zhiyuan Ma , Hu Wang , Zhengxing Zhou , Chengli Lu , Minglin Zhang , Renmin Mu , Chengmin Zhang , Zhiqiang Yi , Zilin Deng , Yingying Zhao , Jiaxing Zhu , Guorong Wen , Hai Jin , Jiaxing An , Biguang Tuo , Peng Yuan , Xuemei Liu , Taolang Li","doi":"10.1016/j.bbamcr.2025.119912","DOIUrl":"10.1016/j.bbamcr.2025.119912","url":null,"abstract":"<div><div>SLC26A9 is a member of the Slc26a family of multifunctional anion transporters that function as Cl<sup>−</sup> channels in the stomach. We reported for the first time that SLC26A9 is involved in gastric tumorigenesis. However, the role of SLC26A9 in breast cancer has not yet been investigated. We first demonstrated that the upregulation of SLC26A9 is associated with the clinicopathological progression and poor prognosis of patients with breast cancer and is positively correlated with HER2 amplification. SLC26A9 alters the proliferation, migration, and invasion potential of breast cancer cells by regulating the PI3K/AKT signaling pathway. SLC26A9 acts as an oncogene in the development of breast cancer. These findings provide valuable insights for the development of future diagnostic and therapeutic strategies for BC.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119912"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1016/j.bbamcr.2025.119907
Su-Min Lee , Eunsu Seo , Yang-Hoon Kim , Jiho Min
Senescence significantly contributes to aging in various tissues, influenced by factors such as lysosomal alkalinization, which disrupts autophagic flux and accumulates toxic substances. This disruption leads to oxidative stress, increased lysosomal permeability, cellular senescence, and apoptosis. Similar to mammalian lysosomes, S. cerevisiae-derived vacuoles degrade macromolecules using hydrolytic enzymes and mitigate these aging effects. Our study assessed the anti-aging potential of yeast vacuoles in human lung fibroblasts treated with hydrogen peroxide (H2O2). Pretreatment with vacuoles at concentrations of 1, 5, and 10 μg/ml decreased SA-β-gal-positive cell counts, reduced mRNA levels of senescence markers (p21 and p53), and senescence-associated secretory phenotype (SASP) factors (IL-6 and TNF-α) compared to controls treated with H2O2 alone. Additionally, these vacuoles significantly diminished intracellular reactive oxygen species (ROS) levels, indicating their potential as effective lung anti-senescence agents. This study suggests that yeast vacuoles could be used as a preventive measure against changes associated with lung aging.
{"title":"Inhibition of hydrogen peroxide-induced senescence markers by yeast-derived vacuoles in human lung fibroblasts","authors":"Su-Min Lee , Eunsu Seo , Yang-Hoon Kim , Jiho Min","doi":"10.1016/j.bbamcr.2025.119907","DOIUrl":"10.1016/j.bbamcr.2025.119907","url":null,"abstract":"<div><div>Senescence significantly contributes to aging in various tissues, influenced by factors such as lysosomal alkalinization, which disrupts autophagic flux and accumulates toxic substances. This disruption leads to oxidative stress, increased lysosomal permeability, cellular senescence, and apoptosis. Similar to mammalian lysosomes, <em>S. cerevisiae</em>-derived vacuoles degrade macromolecules using hydrolytic enzymes and mitigate these aging effects. Our study assessed the anti-aging potential of yeast vacuoles in human lung fibroblasts treated with hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>). Pretreatment with vacuoles at concentrations of 1, 5, and 10 μg/ml decreased SA-β-gal-positive cell counts, reduced mRNA levels of senescence markers (p21 and p53), and senescence-associated secretory phenotype (SASP) factors (IL-6 and TNF-α) compared to controls treated with H<sub>2</sub>O<sub>2</sub> alone. Additionally, these vacuoles significantly diminished intracellular reactive oxygen species (ROS) levels, indicating their potential as effective lung anti-senescence agents. This study suggests that yeast vacuoles could be used as a preventive measure against changes associated with lung aging.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119907"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063509","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}
Pub Date : 2025-01-27DOI: 10.1016/j.bbamcr.2025.119909
Joshua MacNeil , Yuehong Wang , Guangdong Yang
Hydrogen sulfide (H2S) is an important gasotransmitter that regulates a wide range of pathophysiological processes. Higher uric acid levels are associated with an increased risk of metabolic diseases. The causal mechanism linking H2S signalling and uric acid metabolism in skeletal muscles has not yet been elucidated. This study aimed to explore the intertwined metabolisms of H2S and uric acid as well as their integrated roles in controlling myoblast cell functions. It was first found that purine overload increased uric acid levels, promoted oxidative stress, mitochondrial damage, and apoptosis in cultured mouse myoblasts, which could be reversed by the exogenously application of H2S at physiologically relevant concentration. In addition, H2S significantly inhibited the expressions of inflammatory genes (encoding IL2, IL4, and TNFα) but had no effect on oxidative stress, mitochondrial damage and cell death induced by excessive uric acid. Mechanistically, H2S inhibited xanthine oxidoreductase (XOR) activity by blocking the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO), thus reducing uric acid levels and improving myoblast functions. In addition, purine and uric acid attenuated the expression of cystathionine gamma-lyase (CSE, an H2S-generating enzyme) and suppressed endogenous H2S production. Blood uric acid levels and skeletal muscle XOR activity were significantly higher in CSE knockout mice than in wild-type mice. This study revealed a mutual interaction between H2S signalling and uric acid metabolism in the regulation myoblast functions. Thus, the CSE/H2S system may be a target for the prevention of hyperuricemia-related metabolic syndromes.
{"title":"H2S inhibition of xanthine dehydrogenase to xanthine oxidase conversion reduces uric acid levels and improves myoblast functions","authors":"Joshua MacNeil , Yuehong Wang , Guangdong Yang","doi":"10.1016/j.bbamcr.2025.119909","DOIUrl":"10.1016/j.bbamcr.2025.119909","url":null,"abstract":"<div><div>Hydrogen sulfide (H<sub>2</sub>S) is an important gasotransmitter that regulates a wide range of pathophysiological processes. Higher uric acid levels are associated with an increased risk of metabolic diseases. The causal mechanism linking H<sub>2</sub>S signalling and uric acid metabolism in skeletal muscles has not yet been elucidated. This study aimed to explore the intertwined metabolisms of H<sub>2</sub>S and uric acid as well as their integrated roles in controlling myoblast cell functions. It was first found that purine overload increased uric acid levels, promoted oxidative stress, mitochondrial damage, and apoptosis in cultured mouse myoblasts, which could be reversed by the exogenously application of H<sub>2</sub>S at physiologically relevant concentration. In addition, H<sub>2</sub>S significantly inhibited the expressions of inflammatory genes (encoding IL2, IL4, and TNFα) but had no effect on oxidative stress, mitochondrial damage and cell death induced by excessive uric acid. Mechanistically, H<sub>2</sub>S inhibited xanthine oxidoreductase (XOR) activity by blocking the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO), thus reducing uric acid levels and improving myoblast functions. In addition, purine and uric acid attenuated the expression of cystathionine gamma-lyase (CSE, an H<sub>2</sub>S-generating enzyme) and suppressed endogenous H<sub>2</sub>S production. Blood uric acid levels and skeletal muscle XOR activity were significantly higher in CSE knockout mice than in wild-type mice. This study revealed a mutual interaction between H<sub>2</sub>S signalling and uric acid metabolism in the regulation myoblast functions. Thus, the CSE/H<sub>2</sub>S system may be a target for the prevention of hyperuricemia-related metabolic syndromes.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119909"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063462","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}
Mitochondrial E3 ubiquitin ligase (MARCH5) as an important regulator in maintaining mitochondrial function. Our aims were to investigate the role and mechanism of MARCH5 in aortic valve calcification.
Methods
Human aortic valves, both calcified and non-calcified, were analyzed for MARCH5 expression using western blotting. Mitochondrial fragmentation was evaluated using transmission electron microscope. Osteogenic differentiation of human aortic valvular interstitial cells (HVICs) was induced with osteoblastic medium (OM), confirmed by western blotting and Alizarin red staining. Mitochondrial morphology and oxidative phosphorylation were assessed using MitoTracker and Seahorse, respectively. MARCH5-knockdown and ApoE-knockout mice fed high-fat diet were used to study aortic valve calcification.
Results
The mitochondrial quality control was impaired in calcified valves, and the level of MARCH5 protein was also decreased in calcified valves. Inhibition of MARCH5 impaired mitochondrial quality control, increased mitochondrial stress and accelerates osteogenic transformation in OM treated HVICs. While, overexpression MARCH5 has the opposite effects. Co-immunoprecipitation, mass spectrometry and molecular docking found MARCH5 interacted Rac GTPase-activating protein 1 (RACGAP1) and promoted its ubiquitination, leading to impaired mitochondrial quality control. Inhibiting RACGAP1 reversed osteogenic transformation induced by MARCH5 silencing in OM treated HVICs. Silencing dynamin-related protein 1 (DRP1) under RACGAP1 inhibition had no additional benefit. In vivo, deficiency of MARCH5 promoted aortic valve calcification, while inhibition RACGAP1 reversed aortic valve calcification in MARCH5 deficiency mice.
Conclusion
Downregulation of MARCH5 promotes RACGAP1 ubiquitination, activating DRP1 and impairing mitochondrial quality control, which contributes to aortic valve calcification. This identifies a potential therapeutic target for aortic valve calcification.
{"title":"MARCH5 ameliorates aortic valve calcification via RACGAP1-DRP1 associated mitochondrial quality control","authors":"Jialiang Zhang , Yaoyu Zhang , Wenhua Lei , Jing Zhou , Yanjiani Xu , Zhou Hao , Yanbiao Liao , Fangyang Huang , Mao Chen","doi":"10.1016/j.bbamcr.2025.119911","DOIUrl":"10.1016/j.bbamcr.2025.119911","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondrial E3 ubiquitin ligase (MARCH5) as an important regulator in maintaining mitochondrial function. Our aims were to investigate the role and mechanism of MARCH5 in aortic valve calcification.</div></div><div><h3>Methods</h3><div>Human aortic valves, both calcified and non-calcified, were analyzed for MARCH5 expression using western blotting. Mitochondrial fragmentation was evaluated using transmission electron microscope. Osteogenic differentiation of human aortic valvular interstitial cells (HVICs) was induced with osteoblastic medium (OM), confirmed by western blotting and Alizarin red staining. Mitochondrial morphology and oxidative phosphorylation were assessed using MitoTracker and Seahorse, respectively. MARCH5-knockdown and ApoE-knockout mice fed high-fat diet were used to study aortic valve calcification.</div></div><div><h3>Results</h3><div>The mitochondrial quality control was impaired in calcified valves, and the level of MARCH5 protein was also decreased in calcified valves. Inhibition of MARCH5 impaired mitochondrial quality control, increased mitochondrial stress and accelerates osteogenic transformation in OM treated HVICs. While, overexpression MARCH5 has the opposite effects. Co-immunoprecipitation, mass spectrometry and molecular docking found MARCH5 interacted Rac GTPase-activating protein 1 (RACGAP1) and promoted its ubiquitination, leading to impaired mitochondrial quality control. Inhibiting RACGAP1 reversed osteogenic transformation induced by MARCH5 silencing in OM treated HVICs. Silencing dynamin-related protein 1 (DRP1) under RACGAP1 inhibition had no additional benefit. In vivo, deficiency of MARCH5 promoted aortic valve calcification, while inhibition RACGAP1 reversed aortic valve calcification in MARCH5 deficiency mice.</div></div><div><h3>Conclusion</h3><div>Downregulation of MARCH5 promotes RACGAP1 ubiquitination, activating DRP1 and impairing mitochondrial quality control, which contributes to aortic valve calcification. This identifies a potential therapeutic target for aortic valve calcification.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119911"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063510","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}
The imbalance of microglial homeostasis is highly associated with age-related neurological diseases, where cytosolic endogenous DNA is also likely to be found. As the main medium for storing biological information, endogenous DNA could be localized to cellular compartments normally free of DNA when cells are stimulated. However, the intracellular trafficking of endogenous DNA remains unidentified. In this study, we demonstrated that nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), as the components of endogenous DNA, undergo different intracellular trafficking under conditions of microglial homeostasis imbalance induced by serum starvation. Upon detecting various components of endogenous DNA in the cytoplasmic and extracellular microglia, we found that cytosolic nDNA primarily exists in a free form and undergoes degradation through the autophagy-lysosome pathway. In contrast, cytosolic mtDNA predominantly exists in a membrane-wrapped form and is trafficked through both exosome and autophagy-lysosome pathways, with the exosome pathway serving as the primary one. When the autophagy-lysosome pathway was inhibited, there was an increase in exosomes. More importantly, the inhibition of the autophagy-lysosome pathway resulted in enhanced trafficking of mtDNA through the exosome pathway. These findings unveiled the crosstalk between these two pathways in the trafficking of microglial cytosolic DNA and thus provide new insights into intervening in age-related neurological diseases.
{"title":"Serum starvation induces cytosolic DNA trafficking via exosome and autophagy-lysosome pathway in microglia","authors":"Liyan Zhou, Zilong Wu, Xiaoqing Yi, Dongxue Xie, Jufen Wang, Wenhe Wu","doi":"10.1016/j.bbamcr.2025.119905","DOIUrl":"10.1016/j.bbamcr.2025.119905","url":null,"abstract":"<div><div>The imbalance of microglial homeostasis is highly associated with age-related neurological diseases, where cytosolic endogenous DNA is also likely to be found. As the main medium for storing biological information, endogenous DNA could be localized to cellular compartments normally free of DNA when cells are stimulated. However, the intracellular trafficking of endogenous DNA remains unidentified. In this study, we demonstrated that nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), as the components of endogenous DNA, undergo different intracellular trafficking under conditions of microglial homeostasis imbalance induced by serum starvation. Upon detecting various components of endogenous DNA in the cytoplasmic and extracellular microglia, we found that cytosolic nDNA primarily exists in a free form and undergoes degradation through the autophagy-lysosome pathway. In contrast, cytosolic mtDNA predominantly exists in a membrane-wrapped form and is trafficked through both exosome and autophagy-lysosome pathways, with the exosome pathway serving as the primary one. When the autophagy-lysosome pathway was inhibited, there was an increase in exosomes. More importantly, the inhibition of the autophagy-lysosome pathway resulted in enhanced trafficking of mtDNA through the exosome pathway. These findings unveiled the crosstalk between these two pathways in the trafficking of microglial cytosolic DNA and thus provide new insights into intervening in age-related neurological diseases.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119905"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063511","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}
Pub Date : 2025-01-27DOI: 10.1016/j.bbamcr.2025.119908
Gouranga Saha , Mrinal K. Ghosh
The MDM2/MDMX-p53 circuitry is essential for controlling the development, apoptosis, immune response, angiogenesis, senescence, cell cycle progression, and proliferation of cancer cells. Research has demonstrated that USP7 exerts strong control over p53, MDM2, and MDMX stability, with multiple mediator proteins influencing the USP7-p53-MDM2/MDMX axis to modify p53 expression level and function. In cases where p53 is of the wild type (Wt-p53) in tumors, inhibiting USP7 promotes the degradation of MDM2/MDMX, leading to the activation of p53 signaling. This, in turn, results in cell cycle arrest and apoptosis. Hence, targeting USP7 presents a promising avenue for cancer therapy. Targeting USP7 in tumors that harbor mutant p53 (Mut-p53) is unlikely and remains largely unexplored due to the existence of numerous USP7 targets that function independently of p53. Considering that Mut-p53 exhibits resistance to degradation by MDM2 and other E3 ligases and also shares the same signaling pathways as Wt-p53, it is reasonable to suggest that USP7 may play a role in stabilizing Mut-p53. However, there is still much to be done in this area. If the hypothesis is correct, USP7 may be a potent target in cancers containing both Wt-p53 and Mut-p53.
{"title":"The key vulnerabilities and therapeutic opportunities in the USP7-p53/MDM2 axis in cancer","authors":"Gouranga Saha , Mrinal K. Ghosh","doi":"10.1016/j.bbamcr.2025.119908","DOIUrl":"10.1016/j.bbamcr.2025.119908","url":null,"abstract":"<div><div>The MDM2/MDMX-p53 circuitry is essential for controlling the development, apoptosis, immune response, angiogenesis, senescence, cell cycle progression, and proliferation of cancer cells. Research has demonstrated that USP7 exerts strong control over p53, MDM2, and MDMX stability, with multiple mediator proteins influencing the USP7-p53-MDM2/MDMX axis to modify p53 expression level and function. In cases where p53 is of the wild type (Wt-p53) in tumors, inhibiting USP7 promotes the degradation of MDM2/MDMX, leading to the activation of p53 signaling. This, in turn, results in cell cycle arrest and apoptosis. Hence, targeting USP7 presents a promising avenue for cancer therapy. Targeting USP7 in tumors that harbor mutant p53 (Mut-p53) is unlikely and remains largely unexplored due to the existence of numerous USP7 targets that function independently of p53. Considering that Mut-p53 exhibits resistance to degradation by MDM2 and other E3 ligases and also shares the same signaling pathways as Wt-p53, it is reasonable to suggest that USP7 may play a role in stabilizing Mut-p53. However, there is still much to be done in this area. If the hypothesis is correct, USP7 may be a potent target in cancers containing both Wt-p53 and Mut-p53.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119908"},"PeriodicalIF":4.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063513","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}
Pub Date : 2025-01-22DOI: 10.1016/j.bbamcr.2025.119903
Lu Wang , Na Li , Yang Chen, Yehua Qiao, Yaolin Song, Xiangyan Zhang, Han Zhao, Wenwen Ran, Guangqi Li, Xiaoming Xing
Among patients with colorectal cancer (CRC), metastasis accounts for the majority of deaths, and epithelial–mesenchymal transition (EMT) is important in the metastatic process. However, the mechanism underlying the correlation between the two in CRC is unknown. Here, we verified that a receptor-independent protein, G-protein signaling modulator 1 (GPSM1), was increased in CRC and had a significant positive correlation with matrix metalloproteinase 19 (MMP19). GPSM1 and MMP19 knockdown or overexpression decreased and increased proliferation, migration and invasion of CRC cells, respectively. In addition, overexpression or knockdown of GPSM1 and MMP19 upregulated and inhibited EMT, respectively. Interfering with MMP19 reversed EMT activation via GPSM1 overexpression. Apoptosis was induced by GPSM1 and MMP19 knockdown and activated the caspase3/Bcl-2/Bax signaling pathway. In conclusion, these results support the role of GPSM1 and MMP19 in CRC progression.
{"title":"GPSM1 interacts and cooperates with MMP19 to promote proliferation and EMT in colorectal cancer cells","authors":"Lu Wang , Na Li , Yang Chen, Yehua Qiao, Yaolin Song, Xiangyan Zhang, Han Zhao, Wenwen Ran, Guangqi Li, Xiaoming Xing","doi":"10.1016/j.bbamcr.2025.119903","DOIUrl":"10.1016/j.bbamcr.2025.119903","url":null,"abstract":"<div><div>Among patients with colorectal cancer (CRC), metastasis accounts for the majority of deaths, and epithelial–mesenchymal transition (EMT) is important in the metastatic process. However, the mechanism underlying the correlation between the two in CRC is unknown. Here, we verified that a receptor-independent protein, G-protein signaling modulator 1 (GPSM1), was increased in CRC and had a significant positive correlation with matrix metalloproteinase 19 (MMP19). GPSM1 and MMP19 knockdown or overexpression decreased and increased proliferation, migration and invasion of CRC cells, respectively. In addition, overexpression or knockdown of GPSM1 and MMP19 upregulated and inhibited EMT, respectively. Interfering with MMP19 reversed EMT activation via GPSM1 overexpression. Apoptosis was induced by GPSM1 and MMP19 knockdown and activated the caspase3/Bcl-2/Bax signaling pathway. In conclusion, these results support the role of GPSM1 and MMP19 in CRC progression.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119903"},"PeriodicalIF":4.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143036156","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}
Pub Date : 2025-01-19DOI: 10.1016/j.bbamcr.2025.119906
Francesca Inferrera , Ylenia Marino , Tiziana Genovese , Salvatore Cuzzocrea , Roberta Fusco , Rosanna Di Paola
Mitochondria play a key role in the regulation of energy homeostasis and ATP production in cardiac cells. Mitochondrial dysfunction can trigger several pathological events that contribute to the development and progression of cardiovascular diseases. These mechanisms include the induction of oxidative stress, dysregulation of intracellular calcium cycling, activation of the apoptotic pathway, and alteration of lipid metabolism. This review focuses on the role of mitochondria in intracellular signaling associated with cardiovascular diseases, emphasizing the contributions of reactive oxygen species production and mitochondrial dynamics. Indeed, mitochondrial dysfunction has been implicated in every aspect of cardiovascular disease and is currently being evaluated as a potential target for therapeutic interventions. To treat cardiovascular diseases and improve overall heart health, it is important to better understand these biochemical systems. These findings allow the achievement of targeted therapies and preventive measures. Therefore, this review investigates different studies that demonstrate how changes in mitochondrial dynamics like fusion, fission, and mitophagy contribute to the development or worsening of disorders related to heart diseases by summarizing current research on their role.
{"title":"Mitochondrial quality control: Biochemical mechanism of cardiovascular disease","authors":"Francesca Inferrera , Ylenia Marino , Tiziana Genovese , Salvatore Cuzzocrea , Roberta Fusco , Rosanna Di Paola","doi":"10.1016/j.bbamcr.2025.119906","DOIUrl":"10.1016/j.bbamcr.2025.119906","url":null,"abstract":"<div><div>Mitochondria play a key role in the regulation of energy homeostasis and ATP production in cardiac cells. Mitochondrial dysfunction can trigger several pathological events that contribute to the development and progression of cardiovascular diseases. These mechanisms include the induction of oxidative stress, dysregulation of intracellular calcium cycling, activation of the apoptotic pathway, and alteration of lipid metabolism. This review focuses on the role of mitochondria in intracellular signaling associated with cardiovascular diseases, emphasizing the contributions of reactive oxygen species production and mitochondrial dynamics. Indeed, mitochondrial dysfunction has been implicated in every aspect of cardiovascular disease and is currently being evaluated as a potential target for therapeutic interventions. To treat cardiovascular diseases and improve overall heart health, it is important to better understand these biochemical systems. These findings allow the achievement of targeted therapies and preventive measures. Therefore, this review investigates different studies that demonstrate how changes in mitochondrial dynamics like fusion, fission, and mitophagy contribute to the development or worsening of disorders related to heart diseases by summarizing current research on their role.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119906"},"PeriodicalIF":4.6,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Colorectal cancer (CRC) ranks second in mortality worldwide while metastasis accounts for most CRC-related deaths. Thus, understanding cell migration, a crucial step in metastasis, is imperative for developing new therapies. Growth Differentiation Factor-15 (GDF15), a member of the Transforming Growth Factor β superfamily, is overexpressed in CRC and promotes metastasis with a so far unknown mechanism. LIMS1 is a cell-matrix adhesion prosurvival protein that is also overexpressed in CRC and localized at the tumor invasive front, while bioinformatics analysis shows that both genes exhibit the same expression pattern in metastatic CRC samples. In the present study, treatment of low-aggressiveness HT29 CRC cells with human recombinant GDF15 (hrGDF15) led to increased LIMS1 expression, increased mRNA level of RhoGTPases RAC1 and RHOA but not CDC42, and increased migration. Conversely, GDF15 or LIMS1-siRNA-mediated silencing in invasive HCT116 cells resulted in downregulation of LIMS1 and GDF15 respectively, decreased RAC1, and RHOA as well as reduced cell migration, which were fully restored by hrGDF15 treatment both in GDF15 and LIMS1-siRNA-treated cells. Our findings indicate that GDF15 and LIMS1 have an interdependent role in the migration process which renders them potent targets for the development of novel therapeutic strategies to inhibit metastatic spread.
{"title":"Interdependent roles for growth differentiation factor-15 (GDF15) and LIMS1 in regulating cell migration: Implications for colorectal cancer metastasis","authors":"Andria Kotsoni , Louiza Valentina Kozaki , Andreas Stylianou , Vasiliki Gkretsi","doi":"10.1016/j.bbamcr.2025.119904","DOIUrl":"10.1016/j.bbamcr.2025.119904","url":null,"abstract":"<div><div>Colorectal cancer (CRC) ranks second in mortality worldwide while metastasis accounts for most CRC-related deaths. Thus, understanding cell migration, a crucial step in metastasis, is imperative for developing new therapies. Growth Differentiation Factor-15 (GDF15), a member of the Transforming Growth Factor β superfamily, is overexpressed in CRC and promotes metastasis with a so far unknown mechanism. LIMS1 is a cell-matrix adhesion prosurvival protein that is also overexpressed in CRC and localized at the tumor invasive front, while bioinformatics analysis shows that both genes exhibit the same expression pattern in metastatic CRC samples. In the present study, treatment of low-aggressiveness HT29 CRC cells with human recombinant GDF15 (hrGDF15) led to increased <em>LIMS1</em> expression, increased mRNA level of RhoGTPases <em>RAC1</em> and <em>RHOA</em> but not <em>CDC42,</em> and increased migration. Conversely, <em>GDF15</em> or <em>LIMS1-</em>siRNA-mediated silencing in invasive HCT116 cells resulted in downregulation of <em>LIMS1</em> and <em>GDF15</em> respectively, decreased <em>RAC1,</em> and <em>RHOA</em> as well as reduced cell migration, which were fully restored by hrGDF15 treatment both in <em>GDF15</em> and <em>LIMS1</em>-siRNA-treated cells<em>.</em> Our findings indicate that GDF15 and LIMS1 have an interdependent role in the migration process which renders them potent targets for the development of novel therapeutic strategies to inhibit metastatic spread.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119904"},"PeriodicalIF":4.6,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999047","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}
Pub Date : 2025-01-13DOI: 10.1016/j.bbamcr.2025.119902
Yongqi Yu , Bohao Zhao , Jiali Li , Jie Yang , Zhiyuan Bao , Jiawei Cai , Yang Chen , Xinsheng Wu
Dermal papilla cells (DPCs) are crucial for the growth and development of hair follicles (HF). (−)-Epigallocatechin-3-gallate (EGCG) is the primary catechin identified in green tea, which has antioxidant effects and regulates cell activity. This study demonstrates that EGCG could promote the proliferation of DPCs. In addition, EGCG treatment significantly upregulated the expression of PCNA, CCND1, HIF-1α, VEGFA, and Bcl-2 mRNAs in DPCs, while significantly reducing the gene expression of Bax. The optimal concentration of EGCG addition was screened. When detecting the antioxidant ability of DPCs, treatment with 0.5 μM EGCG could intensify the relative activity of catalase, superoxide dismutase, and glutathione, promoting the antioxidant ability and migration of DPCs. Subsequently, the differentially expressed genes (DEGs) associated with the EGCG treatment in DPCs were identified by RNA sequencing, revealing 21 DEGs, including VEGFA, POSTN, CLU, SERPINE2, and NPY. As the candidate gene, the role of VEGFA in regulating HF growth and development was investigated. Immunofluorescence staining revealed that EGCG treatment enhanced the fluorescence intensity of VEGFA and CLU in DPCs. After VEGFA overexpression and knockdown in DPCs, it was found to regulate the HF growth and the expression of development-related genes, enhance the expression of proliferating cell nuclear antigen, and promote DPCs proliferation. EGCG could also rescue the siRNA-VEGFA effect in DPCs. Thus, this study demonstrates that EGCG possibly regulates cell viability in DPCs by inducing VEGFA expression level, and provides a reference for exploring the mechanism of HF growth and the treatment of hair-related illnesses.
{"title":"(−)-Epigallocatechin-3-gallate promotes the dermal papilla cell proliferation and migration through the induction of VEGFA","authors":"Yongqi Yu , Bohao Zhao , Jiali Li , Jie Yang , Zhiyuan Bao , Jiawei Cai , Yang Chen , Xinsheng Wu","doi":"10.1016/j.bbamcr.2025.119902","DOIUrl":"10.1016/j.bbamcr.2025.119902","url":null,"abstract":"<div><div>Dermal papilla cells (DPCs) are crucial for the growth and development of hair follicles (HF). (−)-Epigallocatechin-3-gallate (EGCG) is the primary catechin identified in green tea, which has antioxidant effects and regulates cell activity. This study demonstrates that EGCG could promote the proliferation of DPCs. In addition, EGCG treatment significantly upregulated the expression of <em>PCNA</em>, <em>CCND1</em>, <em>HIF-1α</em>, <em>VEGFA</em>, and <em>Bcl-2</em> mRNAs in DPCs, while significantly reducing the gene expression of <em>Bax</em>. The optimal concentration of EGCG addition was screened. When detecting the antioxidant ability of DPCs, treatment with 0.5 μM EGCG could intensify the relative activity of catalase, superoxide dismutase, and glutathione, promoting the antioxidant ability and migration of DPCs. Subsequently, the differentially expressed genes (DEGs) associated with the EGCG treatment in DPCs were identified by RNA sequencing, revealing 21 DEGs, including <em>VEGFA</em>, <em>POSTN</em>, <em>CLU</em>, <em>SERPINE2</em>, and <em>NPY</em>. As the candidate gene, the role of <em>VEGFA</em> in regulating HF growth and development was investigated. Immunofluorescence staining revealed that EGCG treatment enhanced the fluorescence intensity of VEGFA and CLU in DPCs. After <em>VEGFA</em> overexpression and knockdown in DPCs, it was found to regulate the HF growth and the expression of development-related genes, enhance the expression of proliferating cell nuclear antigen, and promote DPCs proliferation. EGCG could also rescue the siRNA-<em>VEGFA</em> effect in DPCs. Thus, this study demonstrates that EGCG possibly regulates cell viability in DPCs by inducing <em>VEGFA</em> expression level, and provides a reference for exploring the mechanism of HF growth and the treatment of hair-related illnesses.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119902"},"PeriodicalIF":4.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998009","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}
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