Pub Date : 2024-05-13DOI: 10.1007/s10565-024-09863-8
Jiayu Chen, Lei Li, Yongpu Feng, Yating Zhao, Fengyuan Sun, Xianzhu Zhou, Du Yiqi, Zhaoshen Li, Fanyang Kong, Xiangyu Kong
In pancreatic ductal adenocarcinomas (PDAC), profound hypoxia plays key roles in regulating cancer cell behavior, including proliferation, migration, and resistance to therapies. The initial part of this research highlights the important role played by long noncoding RNA (lncRNA) MKLN1-AS, which is controlled by hypoxia-inducible factor-1 alpha (HIF-1α), in the progression of PDAC. Human samples of PDAC showed a notable increase in MKLN1-AS expression, which was linked to a worse outcome. Forced expression of MKLN1-AS greatly reduced the inhibitory impact on the growth and spread of PDAC cells caused by HIF-1α depletion. Experiments on mechanisms showed that HIF-1α influences the expression of MKLN1-AS by directly attaching to a hypoxia response element in the promoter region of MKLN1-AS.MKLN1-AS acts as a competitive endogenous RNA (ceRNA) by binding to miR-185-5p, resulting in the regulation of TEAD1 expression and promoting cell proliferation, migration, and tumor growth. TEAD1 subsequently enhances the development of PDAC. Our study results suggest that MKLN1-AS could serve as a promising target for treatment and a valuable indicator for predicting outcomes in PDAC. PDAC is associated with low oxygen levels, and the long non-coding RNA MKLN1-AS interacts with TEAD1 in this context.
{"title":"MKLN1-AS promotes pancreatic cancer progression as a crucial downstream mediator of HIF-1α through miR-185-5p/TEAD1 pathway.","authors":"Jiayu Chen, Lei Li, Yongpu Feng, Yating Zhao, Fengyuan Sun, Xianzhu Zhou, Du Yiqi, Zhaoshen Li, Fanyang Kong, Xiangyu Kong","doi":"10.1007/s10565-024-09863-8","DOIUrl":"10.1007/s10565-024-09863-8","url":null,"abstract":"<p><p>In pancreatic ductal adenocarcinomas (PDAC), profound hypoxia plays key roles in regulating cancer cell behavior, including proliferation, migration, and resistance to therapies. The initial part of this research highlights the important role played by long noncoding RNA (lncRNA) MKLN1-AS, which is controlled by hypoxia-inducible factor-1 alpha (HIF-1α), in the progression of PDAC. Human samples of PDAC showed a notable increase in MKLN1-AS expression, which was linked to a worse outcome. Forced expression of MKLN1-AS greatly reduced the inhibitory impact on the growth and spread of PDAC cells caused by HIF-1α depletion. Experiments on mechanisms showed that HIF-1α influences the expression of MKLN1-AS by directly attaching to a hypoxia response element in the promoter region of MKLN1-AS.MKLN1-AS acts as a competitive endogenous RNA (ceRNA) by binding to miR-185-5p, resulting in the regulation of TEAD1 expression and promoting cell proliferation, migration, and tumor growth. TEAD1 subsequently enhances the development of PDAC. Our study results suggest that MKLN1-AS could serve as a promising target for treatment and a valuable indicator for predicting outcomes in PDAC. PDAC is associated with low oxygen levels, and the long non-coding RNA MKLN1-AS interacts with TEAD1 in this context.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11090931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-03DOI: 10.1007/s10565-024-09871-8
Mengxue Zhang, Jie Xing, Shijie Zhao, Minjun Lu, Yueqin Liu, Li Lin, Wujiang Gao, Lu Chen, Wenxin Li, Junyu Shang, Jiamin Zhou, Xinming Yin, Xiaolan Zhu
Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. Mesenchymal stem cells-derived small extracellular vesicles (MSCs-sEVs) are attractive candidates for ovarian function restoration and folliculogenesis for POF due to their safety and efficacy, however, the key mediator in MSCs-sEVs that modulates this response and underlying mechanisms remains elusive. Herein, we reported that YB-1 protein was markedly downregulated in vitro and in vivo models of POF induced with H2O2 and CTX respectively, accompanied by granulosa cells (GCs) senescence phenotype. Notably, BMSCs-sEVs transplantation upregulated YB-1, attenuated oxidative damage-induced cellular senescence in GCs, and significantly improved the ovarian function of POF rats, but that was reversed by YB-1 depletion. Moreover, YB-1 showed an obvious decline in serum and GCs in POF patients. Mechanistically, YB-1 as an RNA-binding protein (RBP) physically interacted with a long non-coding RNA, MALAT1, and increased its stability, further, MALAT1 acted as a competing endogenous RNA (ceRNA) to elevate FOXO3 levels by sequestering miR-211-5p to prevent its degradation, leading to repair of ovarian function. In summary, we demonstrated that BMSCs-sEVs improve ovarian function by releasing YB-1, which mediates MALAT1/miR-211-5p/FOXO3 axis regulation, providing a possible therapeutic target for patients with POF.
{"title":"Exosomal YB-1 facilitates ovarian restoration by MALAT1/miR-211-5p/FOXO<sub>3</sub> axis.","authors":"Mengxue Zhang, Jie Xing, Shijie Zhao, Minjun Lu, Yueqin Liu, Li Lin, Wujiang Gao, Lu Chen, Wenxin Li, Junyu Shang, Jiamin Zhou, Xinming Yin, Xiaolan Zhu","doi":"10.1007/s10565-024-09871-8","DOIUrl":"10.1007/s10565-024-09871-8","url":null,"abstract":"<p><p>Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. Mesenchymal stem cells-derived small extracellular vesicles (MSCs-sEVs) are attractive candidates for ovarian function restoration and folliculogenesis for POF due to their safety and efficacy, however, the key mediator in MSCs-sEVs that modulates this response and underlying mechanisms remains elusive. Herein, we reported that YB-1 protein was markedly downregulated in vitro and in vivo models of POF induced with H<sub>2</sub>O<sub>2</sub> and CTX respectively, accompanied by granulosa cells (GCs) senescence phenotype. Notably, BMSCs-sEVs transplantation upregulated YB-1, attenuated oxidative damage-induced cellular senescence in GCs, and significantly improved the ovarian function of POF rats, but that was reversed by YB-1 depletion. Moreover, YB-1 showed an obvious decline in serum and GCs in POF patients. Mechanistically, YB-1 as an RNA-binding protein (RBP) physically interacted with a long non-coding RNA, MALAT1, and increased its stability, further, MALAT1 acted as a competing endogenous RNA (ceRNA) to elevate FOXO<sub>3</sub> levels by sequestering miR-211-5p to prevent its degradation, leading to repair of ovarian function. In summary, we demonstrated that BMSCs-sEVs improve ovarian function by releasing YB-1, which mediates MALAT1/miR-211-5p/FOXO<sub>3</sub> axis regulation, providing a possible therapeutic target for patients with POF.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11068691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140847390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-02DOI: 10.1007/s10565-024-09866-5
Shouying Xu, Bin Cao, Ge Xuan, Shu Xu, Zihao An, Chongying Zhu, Lin Li, Chao Tang
The Rab small GTPases are characterized by the distinct intracellular localization and modulate various endocytic, transcytic and exocytic transport pathways. Rab proteins function as scaffolds that connect signaling pathways and intracellular membrane trafficking processes through the recruitment of effectors, such as tethering factors, phosphatases, motors and kinases. In different cancers, Rabs play as either an onco-protein or a tumor suppressor role, highly dependending on the context. The molecular mechanistic research has revealed that Rab proteins are involved in cancer progression through influences on migration, invasion, metabolism, exosome secretion, autophagy, and drug resistance of cancer cells. Therefore, targeting Rab GTPases to recover the dysregulated vesicle transport systems may provide potential strategy to restrain cancer progression. In this review, we discuss the regulation of Rab protein level and activity in modulating pathways involved in tumor progression, and propose that Rab proteins may serve as a prognostic factor in different cancers.
{"title":"Function and regulation of Rab GTPases in cancers.","authors":"Shouying Xu, Bin Cao, Ge Xuan, Shu Xu, Zihao An, Chongying Zhu, Lin Li, Chao Tang","doi":"10.1007/s10565-024-09866-5","DOIUrl":"10.1007/s10565-024-09866-5","url":null,"abstract":"<p><p>The Rab small GTPases are characterized by the distinct intracellular localization and modulate various endocytic, transcytic and exocytic transport pathways. Rab proteins function as scaffolds that connect signaling pathways and intracellular membrane trafficking processes through the recruitment of effectors, such as tethering factors, phosphatases, motors and kinases. In different cancers, Rabs play as either an onco-protein or a tumor suppressor role, highly dependending on the context. The molecular mechanistic research has revealed that Rab proteins are involved in cancer progression through influences on migration, invasion, metabolism, exosome secretion, autophagy, and drug resistance of cancer cells. Therefore, targeting Rab GTPases to recover the dysregulated vesicle transport systems may provide potential strategy to restrain cancer progression. In this review, we discuss the regulation of Rab protein level and activity in modulating pathways involved in tumor progression, and propose that Rab proteins may serve as a prognostic factor in different cancers.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11065922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140847577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Small membranes known as exosomes surround them and are released by several cell types both in vitro and in vivo. These membranes are packed with a variety of biomolecules, including proteins, lipids, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and non-coding RNA (ncRNA). As a source of biological nanomaterials, exosomes play a role in information and substance transmission between cells and have been identified as a general method of facilitating communication during interactions between the body, target organs, and toxins.. In order to understand the changes and mechanism of the composition and level of exosomes after biotoxin infection, this review focuses on current findings on the exosomes and highlights their novel uses in the toxicity mechanism. Exosomes are mainly used as a delivery carrier or mediated by receptors, and play an immune role after the toxin enters the body. This review expounds on the importance of exosomes in the toxicological mechanism of biotoxins and provides new insights for further diagnosis of toxic biomarkers, detoxification, and treatment development.
{"title":"Exosomes as mediators of signal transmitters in biotoxins toxicity: a comprehensive review.","authors":"Tongxiao Xu, Bingxin Huangfu, Xiaoyun He, Kunlun Huang","doi":"10.1007/s10565-024-09867-4","DOIUrl":"10.1007/s10565-024-09867-4","url":null,"abstract":"<p><p>Small membranes known as exosomes surround them and are released by several cell types both in vitro and in vivo. These membranes are packed with a variety of biomolecules, including proteins, lipids, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and non-coding RNA (ncRNA). As a source of biological nanomaterials, exosomes play a role in information and substance transmission between cells and have been identified as a general method of facilitating communication during interactions between the body, target organs, and toxins.. In order to understand the changes and mechanism of the composition and level of exosomes after biotoxin infection, this review focuses on current findings on the exosomes and highlights their novel uses in the toxicity mechanism. Exosomes are mainly used as a delivery carrier or mediated by receptors, and play an immune role after the toxin enters the body. This review expounds on the importance of exosomes in the toxicological mechanism of biotoxins and provides new insights for further diagnosis of toxic biomarkers, detoxification, and treatment development.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11062979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140854452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lung cancer is a common malignancy that is frequently associated with systemic metabolic disorders. Early detection is pivotal to survival improvement. Although blood biomarkers have been used in its early diagnosis, missed diagnosis and misdiagnosis still exist due to the heterogeneity of lung cancer. Integration of multiple biomarkers or trans-omics results can improve the accuracy and reliability for lung cancer diagnosis. As metabolic reprogramming is a hallmark of lung cancer, metabolites, specifically lipids might be useful for lung cancer detection, yet systematic characterizations of metabolites in lung cancer are still incipient. The present study profiled the polar metabolome and lipidome in the plasma of lung cancer patients to construct an inclusive metabolomic atlas of lung cancer. A comprehensive analysis of lung cancer was also conducted combining metabolomics with clinical phenotypes. Furthermore, the differences in plasma lipid metabolites were compared and analyzed among different lung cancer subtypes. Alcohols, amides, and peptide metabolites were significantly increased in lung cancer, while carboxylic acids, hydrocarbons, and fatty acids were remarkably decreased. Lipid profiling revealed a significant increase in plasma levels of CER, PE, SM, and TAG in individuals with lung cancer as compared to those in healthy controls. Correlation analysis confirmed the association between a panel of metabolites and TAGs. Clinical trans-omics studies elucidated the complex correlations between lipidomic data and clinical phenotypes. The present study emphasized the clinical importance of lipidomics in lung cancer, which involves the correlation between metabolites and the expressions of other omics, ultimately influencing clinical phenotypes. This novel trans-omics network approach would facilitate the development of precision therapy for lung cancer.
Graphical Abstract
1. Integrating multiple biomarkers or trans-omics results improves diagnostic accuracy and reliability in heterogeneous lung cancer.
2. Metabolomics and lipidomics, along with clinical phenotypes, construct a comprehensive metabolic profile of lung cancer patients.
3. TAG expression shows strong positive correlation with polar metabolites, potentially impacting clinical phenotypic changes in lung cancer patients.