It has been reported that human embryonic stem cells (hESCs) treated with BMP4 and inhibitors of TGFβ signaling (A83-01) and FGF signaling (PD173074), called BAP, can efficiently differentiate to extraembryonic (ExE) cells in vitro. Due to restricted access to human embryos, it is ethically impossible to test the developmental potential of ExE cells in vivo. Here, we demonstrate that most ExE cells expressed molecular markers for both trophoblasts (TBs) and amniotic cells (ACs). Following intra-uterine transplantation, ExE cells contributed to the mouse placenta. More interestingly, ExE cells could chimerize with the mouse blastocyst as, after injection into the blastocyst, they penetrated its trophectoderm. After implantation of the injected blastocysts into surrogate mice, human cells were found at E14 in placental labyrinth, junction zones, and even near the uterine decidua, expressed placental markers, and secreted human chorionic gonadotropin. Surprisingly, ExE cells also contributed to cartilages of the chimeric embryo with some expressing the chondrogenic marker SOX9, consistent with the mesodermal potential of TBs and ACs in the placenta. Deleting MSX2, a mesodermal determinant, restricted the contribution of ExE cells to the placenta. Thus, we conclude that hESC-derived ExE cells can chimerize with the mouse blastocyst and contribute to both the placenta and cartilages of the chimera consistent with their heteogenious nature. Intra-uterus and intra-blastocyst injections are novel and sensitive methods to study the developmental potential of ExE cells.
{"title":"Chimerization of human ESC-derived extraembryonic cells with the mouse blastocyst.","authors":"Siyi Fu, Borong Huang, Enqin Li, Xiaoling Xu, Ren-He Xu","doi":"10.7150/ijbs.99519","DOIUrl":"10.7150/ijbs.99519","url":null,"abstract":"<p><p>It has been reported that human embryonic stem cells (hESCs) treated with BMP4 and inhibitors of TGFβ signaling (A83-01) and FGF signaling (PD173074), called BAP, can efficiently differentiate to extraembryonic (ExE) cells <i>in vitro</i>. Due to restricted access to human embryos, it is ethically impossible to test the developmental potential of ExE cells <i>in vivo</i>. Here, we demonstrate that most ExE cells expressed molecular markers for both trophoblasts (TBs) and amniotic cells (ACs). Following intra-uterine transplantation, ExE cells contributed to the mouse placenta. More interestingly, ExE cells could chimerize with the mouse blastocyst as, after injection into the blastocyst, they penetrated its trophectoderm. After implantation of the injected blastocysts into surrogate mice, human cells were found at E14 in placental labyrinth, junction zones, and even near the uterine decidua, expressed placental markers, and secreted human chorionic gonadotropin. Surprisingly, ExE cells also contributed to cartilages of the chimeric embryo with some expressing the chondrogenic marker SOX9, consistent with the mesodermal potential of TBs and ACs in the placenta. Deleting <i>MSX2</i>, a mesodermal determinant, restricted the contribution of ExE cells to the placenta. Thus, we conclude that hESC-derived ExE cells can chimerize with the mouse blastocyst and contribute to both the placenta and cartilages of the chimera consistent with their heteogenious nature. Intra-uterus and intra-blastocyst injections are novel and sensitive methods to study the developmental potential of ExE cells.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 13","pages":"5056-5069"},"PeriodicalIF":8.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464515","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 : 2024-09-23eCollection Date: 2024-01-01DOI: 10.7150/ijbs.96748
Junyan Wang, Haowen Zhuang, Xiaocui Yang, Zhijiang Guo, Kainan Zhou, Nanyang Liu, Yang An, Ye Chen, Zhongzheng Zhang, Mengyuan Wang, Jinhong Chen, Chun Li, Xing Chang
Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, encompasses squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Compared to small cell lung cancer, NSCLC cells grow and divide more slowly, and their metastasis occurs at a later stage. Currently, chemotherapy is the primary treatment for this disease. Sappanone A (SA) is a flavonoid compound extracted from the plant Caesalpinia sappan, known for its antitumor, redox-regulating, and anti-inflammatory properties. Recent studies have investigated the interaction of SA with mitochondrial pathways in regulating cell death through the Nrf-2/GPX-4/xCT axis. This study specifically explores the mechanism by which SA affects mitochondrial morphology and structure through the regulation of mitophagy and mitochondrial biogenesis in tumor cells. The study primarily utilizes second-generation transcriptomic sequencing data and molecular docking techniques to elucidate the role of SA in regulating programmed cell death in tumor cells. The omics results indicate that SA treatment significantly targets genes involved in oxidative phosphorylation, mitophagy, mitochondrial dynamics, and oxidative stress. Further findings confirmed that the Nrf-2/GPX4/xCT pathway serves as a crucial target of SA in the treatment of NSCLC. Knockdown of Nrf-2 (si-Nrf-2) and Nrf-2 overexpression (ad-Nrf-2) were shown to modulate the therapeutic efficacy of SA to varying degrees. Additionally, modifications to the GPX4/xCT genes significantly affected the regulatory effects of SA on mitochondrial autophagy, biogenesis, and energy metabolism. These regulatory mechanisms may be mediated through the caspase pathway and ferroptosis-related signaling. Molecular biology experiments have demonstrated that SA intervention further inhibits the phosphorylation of FUNDC1 at Tyr18 and downregulates TOM20 expression. SA treatment was found to reduce the expression of PGC1α, Nrf-1, and Tfam, resulting in a decrease in mitochondrial respiration and energy metabolism. Overexpression of Nrf-2 was shown to counteract the regulatory effects of SA on mitophagy and mitochondrial biogenesis. Confocal microscopy experiments further revealed that SA treatment increases mitochondrial fragmentation, subsequently inducing mitochondrial pathway-mediated programmed cell death. However, genetic modification of the Nrf-2/GPX4/xCT pathway significantly altered the regulatory effects of SA on tumor cells. In conclusion, SA has been identified as a promising therapeutic agent for NSCLC. The mitochondrial pathway-mediated apoptosis and ferroptosis may represent key mechanisms in regulating tumor cell death. Targeting the Nrf-2/GPX-4/xCT axis offers a novel therapeutic approach for maintaining mitochondrial homeostasis within the cellular microenvironment.
{"title":"Exploring the Mechanism of Ferroptosis Induction by Sappanone A in Cancer: Insights into the Mitochondrial Dysfunction Mediated by NRF2/xCT/GPX4 Axis.","authors":"Junyan Wang, Haowen Zhuang, Xiaocui Yang, Zhijiang Guo, Kainan Zhou, Nanyang Liu, Yang An, Ye Chen, Zhongzheng Zhang, Mengyuan Wang, Jinhong Chen, Chun Li, Xing Chang","doi":"10.7150/ijbs.96748","DOIUrl":"10.7150/ijbs.96748","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC), a major subtype of lung cancer, encompasses squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Compared to small cell lung cancer, NSCLC cells grow and divide more slowly, and their metastasis occurs at a later stage. Currently, chemotherapy is the primary treatment for this disease. Sappanone A (SA) is a flavonoid compound extracted from the plant Caesalpinia sappan, known for its antitumor, redox-regulating, and anti-inflammatory properties. Recent studies have investigated the interaction of SA with mitochondrial pathways in regulating cell death through the Nrf-2/GPX-4/xCT axis. This study specifically explores the mechanism by which SA affects mitochondrial morphology and structure through the regulation of mitophagy and mitochondrial biogenesis in tumor cells. The study primarily utilizes second-generation transcriptomic sequencing data and molecular docking techniques to elucidate the role of SA in regulating programmed cell death in tumor cells. The omics results indicate that SA treatment significantly targets genes involved in oxidative phosphorylation, mitophagy, mitochondrial dynamics, and oxidative stress. Further findings confirmed that the Nrf-2/GPX4/xCT pathway serves as a crucial target of SA in the treatment of NSCLC. Knockdown of Nrf-2 (si-Nrf-2) and Nrf-2 overexpression (ad-Nrf-2) were shown to modulate the therapeutic efficacy of SA to varying degrees. Additionally, modifications to the GPX4/xCT genes significantly affected the regulatory effects of SA on mitochondrial autophagy, biogenesis, and energy metabolism. These regulatory mechanisms may be mediated through the caspase pathway and ferroptosis-related signaling. Molecular biology experiments have demonstrated that SA intervention further inhibits the phosphorylation of FUNDC1 at Tyr18 and downregulates TOM20 expression. SA treatment was found to reduce the expression of PGC1α, Nrf-1, and Tfam, resulting in a decrease in mitochondrial respiration and energy metabolism. Overexpression of Nrf-2 was shown to counteract the regulatory effects of SA on mitophagy and mitochondrial biogenesis. Confocal microscopy experiments further revealed that SA treatment increases mitochondrial fragmentation, subsequently inducing mitochondrial pathway-mediated programmed cell death. However, genetic modification of the Nrf-2/GPX4/xCT pathway significantly altered the regulatory effects of SA on tumor cells. In conclusion, SA has been identified as a promising therapeutic agent for NSCLC. The mitochondrial pathway-mediated apoptosis and ferroptosis may represent key mechanisms in regulating tumor cell death. Targeting the Nrf-2/GPX-4/xCT axis offers a novel therapeutic approach for maintaining mitochondrial homeostasis within the cellular microenvironment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 13","pages":"5145-5161"},"PeriodicalIF":8.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464417","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 : 2024-09-23eCollection Date: 2024-01-01DOI: 10.7150/ijbs.99680
Xuan Zhao, Tong Ren, Sijin Li, Xu Wang, Rui Hou, Zhangchun Guan, Dan Liu, Junnian Zheng, Ming Shi
Tumor-associated macrophages (TAMs) undergo metabolic reprogramming, encompassing glucose, amino acid, fatty acid metabolism, tricarboxylic acid (TCA) cycle, purine metabolism, and autophagy, within the tumor microenvironment (TME). The metabolic interdependencies between TAMs and tumor cells critically influence macrophage recruitment, differentiation, M2 polarization, and secretion of epithelial-mesenchymal transition (EMT)-related factors, thereby activating intratumoral EMT pathways and enhancing tumor cell invasion and metastasis. Tumor cell metabolic alterations, including hypoxia, metabolite secretion, aerobic metabolism, and autophagy, affect the TME's metabolic landscape, driving macrophage recruitment, differentiation, M2 polarization, and metabolic reprogramming, ultimately facilitating EMT, invasion, and metastasis. Additionally, macrophages can induce tumor cell EMT by reprogramming their aerobic glycolysis. Recent experimental and clinical studies have focused on the metabolic interactions between macrophages and tumor cells to control metastasis and inhibit tumor progression. This review highlights the regulatory role of TAM-tumor cell metabolic codependencies in EMT, offering valuable insights for TAM-targeted therapies in highly metastatic tumors. Modulating the metabolic interplay between tumors and TAMs represents a promising therapeutic strategy for treating patients with metastatic cancers.
肿瘤相关巨噬细胞(TAMs)在肿瘤微环境(TME)中进行代谢重编程,包括葡萄糖、氨基酸、脂肪酸代谢、三羧酸(TCA)循环、嘌呤代谢和自噬。TAMs和肿瘤细胞之间的代谢相互依存关系对巨噬细胞的募集、分化、M2极化以及上皮-间质转化(EMT)相关因子的分泌产生了关键影响,从而激活了瘤内EMT通路,增强了肿瘤细胞的侵袭和转移。肿瘤细胞的新陈代谢改变,包括缺氧、代谢物分泌、有氧代谢和自噬,会影响肿瘤组织间质(TME)的新陈代谢格局,推动巨噬细胞的招募、分化、M2 极化和新陈代谢重编程,最终促进 EMT、侵袭和转移。此外,巨噬细胞还能通过对其有氧糖酵解进行重编程来诱导肿瘤细胞的 EMT。最近的实验和临床研究重点关注巨噬细胞和肿瘤细胞之间的代谢相互作用,以控制转移和抑制肿瘤进展。本综述强调了巨噬细胞-肿瘤细胞代谢相互依存关系在 EMT 中的调控作用,为针对高度转移性肿瘤的巨噬细胞-肿瘤细胞靶向疗法提供了宝贵的见解。调节肿瘤和 TAM 之间的代谢相互作用是治疗转移性癌症患者的一种很有前景的治疗策略。
{"title":"A new perspective on the therapeutic potential of tumor metastasis: targeting the metabolic interactions between TAMs and tumor cells.","authors":"Xuan Zhao, Tong Ren, Sijin Li, Xu Wang, Rui Hou, Zhangchun Guan, Dan Liu, Junnian Zheng, Ming Shi","doi":"10.7150/ijbs.99680","DOIUrl":"10.7150/ijbs.99680","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) undergo metabolic reprogramming, encompassing glucose, amino acid, fatty acid metabolism, tricarboxylic acid (TCA) cycle, purine metabolism, and autophagy, within the tumor microenvironment (TME). The metabolic interdependencies between TAMs and tumor cells critically influence macrophage recruitment, differentiation, M2 polarization, and secretion of epithelial-mesenchymal transition (EMT)-related factors, thereby activating intratumoral EMT pathways and enhancing tumor cell invasion and metastasis. Tumor cell metabolic alterations, including hypoxia, metabolite secretion, aerobic metabolism, and autophagy, affect the TME's metabolic landscape, driving macrophage recruitment, differentiation, M2 polarization, and metabolic reprogramming, ultimately facilitating EMT, invasion, and metastasis. Additionally, macrophages can induce tumor cell EMT by reprogramming their aerobic glycolysis. Recent experimental and clinical studies have focused on the metabolic interactions between macrophages and tumor cells to control metastasis and inhibit tumor progression. This review highlights the regulatory role of TAM-tumor cell metabolic codependencies in EMT, offering valuable insights for TAM-targeted therapies in highly metastatic tumors. Modulating the metabolic interplay between tumors and TAMs represents a promising therapeutic strategy for treating patients with metastatic cancers.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 13","pages":"5109-5126"},"PeriodicalIF":8.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11489172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464513","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}
Glioblastoma (GBM) is highly invasive and lethal. The failure to cure GBM highlights the necessity of developing more effective targeted therapeutic strategies. KIF15 is a motor protein to be involved in cell mitosis promotion, cell structure assembly and cell signal transduction. The precise biological function and the potential upstream regulatory mechanisms of KIF15 in GBM remain elusive. Here, we demonstrated that KIF15 was abnormally up-regulated in GBM and predicted poor prognosis of GBM patients. KIF15 promotes GBM cell proliferation, metastasis and cell cycle progression. REST could bind to KIF15 promoter and transactivate KIF15. Furthermore, REST interacts with P300 and depends on its histone acetyltransferase (HAT) activity to co-regulate KIF15 expression. Both REST and P300 were highly expressed in GBM and predicted poor prognosis of GBM patients alone or in combination with KIF15. The tumorigenic function of KIF15 in GBM was regulated by REST in vitro and in vivo and the combinational treatment of cell cycle inhibitor Palbociclib with P300 HAT inhibitor inhibited GBM xenografts survival more significantly. Our findings indicate that KIF15 promotes GBM progression under the synergistic transactivation of REST and P300. P300/REST/KIF15 signaling axis is expected to be served as a cascade of candidate therapeutic targets in anti-GBM.
{"title":"KIF15 promotes human glioblastoma progression under the synergistic transactivation of REST and P300.","authors":"Wendan Yu, Shilong Han, Sheng Hu, Liyuan Ru, Chunyu Hua, Guoqing Xue, Guohui Zhang, Kuan Lv, Hanxiao Ge, Meiyi Wang, Lina Zheng, Jie Zhou, Shuai Hou, Yun Teng, Wuguo Deng, Wei Guo","doi":"10.7150/ijbs.98668","DOIUrl":"10.7150/ijbs.98668","url":null,"abstract":"<p><p>Glioblastoma (GBM) is highly invasive and lethal. The failure to cure GBM highlights the necessity of developing more effective targeted therapeutic strategies. KIF15 is a motor protein to be involved in cell mitosis promotion, cell structure assembly and cell signal transduction. The precise biological function and the potential upstream regulatory mechanisms of KIF15 in GBM remain elusive. Here, we demonstrated that KIF15 was abnormally up-regulated in GBM and predicted poor prognosis of GBM patients. KIF15 promotes GBM cell proliferation, metastasis and cell cycle progression. REST could bind to KIF15 promoter and transactivate KIF15. Furthermore, REST interacts with P300 and depends on its histone acetyltransferase (HAT) activity to co-regulate KIF15 expression. Both REST and P300 were highly expressed in GBM and predicted poor prognosis of GBM patients alone or in combination with KIF15. The tumorigenic function of KIF15 in GBM was regulated by REST <i>in vitro</i> and <i>in vivo</i> and the combinational treatment of cell cycle inhibitor Palbociclib with P300 HAT inhibitor inhibited GBM xenografts survival more significantly. Our findings indicate that KIF15 promotes GBM progression under the synergistic transactivation of REST and P300. P300/REST/KIF15 signaling axis is expected to be served as a cascade of candidate therapeutic targets in anti-GBM.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 13","pages":"5127-5144"},"PeriodicalIF":8.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142485636","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}
Peroxiredoxin 1 (PRDX1) is a potent antioxidant protein that displays a unique molecular chaperone activity. However, the role of overexpression of PRDX1 in colorectal cancer (CRC) was elusive. Herein, we found that the number of AOM/DSS-induced colitis-associated CRC in PRDX1 knockout mice was significantly lower than that in wild-type mice, concomitant with the downregulation of NRF2 and GPX4. Mechanistically, RNA sequencing results indicated that knockdown of PRDX1 resulted in a significant reduction of NRF2, which further triggered ROS-induced mitochondrial dysfunction and lipid peroxidation-induced ferroptosis in CRC cells. Notably, PRDX1 inhibited NRF2 degradation and promoted NRF2 nuclear translocation, thereby triggering the transcription of GPX4. Immunoprecipitation-mass spectrometry (IP-MS) and Co-immunoprecipitation (Co-IP) assays revealed that PRDX1 could act as a molecular chaperone by binding to CUL3 to inhibit NRF2 ubiquitination. Importantly, the binding of PRDX1 to CUL3 was enhanced by conoidin A but abolished by the PRDX1 Cys83Ser mutant. The inhibitory effects of PRDX1 knockdown on CRC could be attenuated by NRF2 activation or ferrostatin-1 administration in vivo. Collectively, these results provide a novel insight into the molecular chaperone activity of PRDX1 in promoting CRC progression through suppression of CUL3-mediated NRF2 degradation, suggesting PRDX1 Cys83 is a potential drug target in inhibiting CRC.
{"title":"PRDX1 inhibits ferroptosis by binding to Cullin-3 as a molecular chaperone in colorectal cancer.","authors":"Yujia Song, Xiaohui Wang, Yuqi Sun, Nianhua Yu, Yajie Tian, Jinli Han, Xianjun Qu, Xinfeng Yu","doi":"10.7150/ijbs.99804","DOIUrl":"10.7150/ijbs.99804","url":null,"abstract":"<p><p>Peroxiredoxin 1 (PRDX1) is a potent antioxidant protein that displays a unique molecular chaperone activity. However, the role of overexpression of PRDX1 in colorectal cancer (CRC) was elusive. Herein, we found that the number of AOM/DSS-induced colitis-associated CRC in PRDX1 knockout mice was significantly lower than that in wild-type mice, concomitant with the downregulation of NRF2 and GPX4. Mechanistically, RNA sequencing results indicated that knockdown of PRDX1 resulted in a significant reduction of NRF2, which further triggered ROS-induced mitochondrial dysfunction and lipid peroxidation-induced ferroptosis in CRC cells. Notably, PRDX1 inhibited NRF2 degradation and promoted NRF2 nuclear translocation, thereby triggering the transcription of GPX4. Immunoprecipitation-mass spectrometry (IP-MS) and Co-immunoprecipitation (Co-IP) assays revealed that PRDX1 could act as a molecular chaperone by binding to CUL3 to inhibit NRF2 ubiquitination. Importantly, the binding of PRDX1 to CUL3 was enhanced by conoidin A but abolished by the PRDX1 Cys83Ser mutant. The inhibitory effects of PRDX1 knockdown on CRC could be attenuated by NRF2 activation or ferrostatin-1 administration <i>in vivo</i>. Collectively, these results provide a novel insight into the molecular chaperone activity of PRDX1 in promoting CRC progression through suppression of CUL3-mediated NRF2 degradation, suggesting PRDX1 Cys83 is a potential drug target in inhibiting CRC.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 13","pages":"5070-5086"},"PeriodicalIF":8.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11489176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464522","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 : 2024-09-23eCollection Date: 2024-01-01DOI: 10.7150/ijbs.99817
Yan Liu, Mengmeng Yuan, Xinxin Xu, Huini Yang, Yao Yao, Peng Hou, Wei Yu, Meiju Ji
Ubiquitin-specific peptidase 44 (USP44) belongs to the ubiquitin-specific protease family and is pivotal in the development and progression of tumors across various human cancers. However, its biological function and the underlying mechanisms in thyroid cancer remain poorly understood. In this study, we observed that USP44 was frequently downregulated by promoter hypermethylation in thyroid cancers and found that its decreased expression was closely associated with poor patient survival. Subsequent in vitro and in vivo functional studies revealed that USP44 substantially suppressed the proliferation of thyroid cancer cells by impeding the G1/S transition in cell cycle. Mechanistically, USP44 directly interacted with p21 and eliminated its K-48-linked polyubiquitination chain, thereby stabilizing p21 proteins in a cell cycle-independent manner. In addition, the rescue of p21 partially alleviated cell cycle advancement and cell proliferation induced by the depletion of USP44. Our findings, taken together, indicate that USP44 is frequently repressed in thyroid cancer due to promoter hypermethylation and functions as a tumor suppressor by stabilizing p21 via deubiquitination.
{"title":"USP44 inactivation accelerates the progression of thyroid cancer by inducing ubiquitylation and degradation of p21.","authors":"Yan Liu, Mengmeng Yuan, Xinxin Xu, Huini Yang, Yao Yao, Peng Hou, Wei Yu, Meiju Ji","doi":"10.7150/ijbs.99817","DOIUrl":"10.7150/ijbs.99817","url":null,"abstract":"<p><p>Ubiquitin-specific peptidase 44 (USP44) belongs to the ubiquitin-specific protease family and is pivotal in the development and progression of tumors across various human cancers. However, its biological function and the underlying mechanisms in thyroid cancer remain poorly understood. In this study, we observed that <i>USP44</i> was frequently downregulated by promoter hypermethylation in thyroid cancers and found that its decreased expression was closely associated with poor patient survival. Subsequent <i>in vitro</i> and <i>in vivo</i> functional studies revealed that USP44 substantially suppressed the proliferation of thyroid cancer cells by impeding the G1/S transition in cell cycle. Mechanistically, USP44 directly interacted with p21 and eliminated its K-48-linked polyubiquitination chain, thereby stabilizing p21 proteins in a cell cycle-independent manner. In addition, the rescue of p21 partially alleviated cell cycle advancement and cell proliferation induced by the depletion of USP44. Our findings, taken together, indicate that USP44 is frequently repressed in thyroid cancer due to promoter hypermethylation and functions as a tumor suppressor by stabilizing p21 via deubiquitination.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 13","pages":"5223-5238"},"PeriodicalIF":8.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11489182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464539","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}
Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor with a poor prognosis. Extensive research has revealed the significant role of long noncoding RNAs (lncRNAs) in the regulation of tumor development. In this study, high-throughput sequencing analysis was used to assess the expression levels of lncRNAs in three pairs of HCC tissues and their corresponding noncancerous tissues. Through quantitative real-time polymerase chain reaction (qRT-PCR) analysis and clinicopathological analysis, it was discovered that HNF4A-AS1 was downregulated in HCC tissues. Furthermore, its expression levels were found to be positively correlated with the prognosis of HCC patients. Subsequent in vitro and in vivo functional studies demonstrated that HNF4A-AS1 inhibits the proliferation, invasion, and stemness of HCC cells. Mechanistically, it was observed that HNF4A-AS1 physically interacts with the KH3 domain of PCBP2 through a specific segment (491-672 nt). This interaction facilitates the recruitment of PCBP2 by AIP4, leading to the ubiquitination and subsequent degradation of PCBP2. Furthermore, HNF4A-AS1 was found to regulate the stability of AGR2 mRNA by modulating PCBP2, thereby influencing the malignant phenotype of HCC. Overall, our study demonstrated a positive association between the decrease in HNF4A-AS1 expression and the prognosis of patients with HCC in a clinical setting. HNF4A-AS1 can suppress the stability of ARG2 mRNA by promoting the ubiquitin-modulated degradation of PCBP2, which suppresses HCC progression. HNF4A-AS1 may serve as a potential therapeutic target for HCC.
{"title":"HNF4A-AS1 inhibits the progression of hepatocellular carcinoma by promoting the ubiquitin-modulated degradation of PCBP2 and suppressing the stability of ARG2 mRNA.","authors":"Wenbo Jia, Liang Yu, Bin Xu, Yanzhi Feng, Jinyi Wang, Deming Zhu, Chao Xu, Litao Liang, Yongping Zhou, Lianbao Kong, Wenzhou Ding","doi":"10.7150/ijbs.95276","DOIUrl":"10.7150/ijbs.95276","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor with a poor prognosis. Extensive research has revealed the significant role of long noncoding RNAs (lncRNAs) in the regulation of tumor development. In this study, high-throughput sequencing analysis was used to assess the expression levels of lncRNAs in three pairs of HCC tissues and their corresponding noncancerous tissues. Through quantitative real-time polymerase chain reaction (qRT-PCR) analysis and clinicopathological analysis, it was discovered that HNF4A-AS1 was downregulated in HCC tissues. Furthermore, its expression levels were found to be positively correlated with the prognosis of HCC patients. Subsequent <i>in vitro</i> and <i>in vivo</i> functional studies demonstrated that HNF4A-AS1 inhibits the proliferation, invasion, and stemness of HCC cells. Mechanistically, it was observed that HNF4A-AS1 physically interacts with the KH3 domain of PCBP2 through a specific segment (491-672 nt). This interaction facilitates the recruitment of PCBP2 by AIP4, leading to the ubiquitination and subsequent degradation of PCBP2. Furthermore, HNF4A-AS1 was found to regulate the stability of AGR2 mRNA by modulating PCBP2, thereby influencing the malignant phenotype of HCC. Overall, our study demonstrated a positive association between the decrease in HNF4A-AS1 expression and the prognosis of patients with HCC in a clinical setting. HNF4A-AS1 can suppress the stability of ARG2 mRNA by promoting the ubiquitin-modulated degradation of PCBP2, which suppresses HCC progression. HNF4A-AS1 may serve as a potential therapeutic target for HCC.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 13","pages":"5087-5108"},"PeriodicalIF":8.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464516","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 : 2024-09-23eCollection Date: 2024-01-01DOI: 10.7150/ijbs.100015
Yiming Zhang, Ruilin Pan, Kun Li, Lek Hang Cheang, Jing Zhao, Zhangfeng Zhong, Shaoping Li, Jinghao Wang, Xiaofang Zhang, Yanmei Cheng, Xiaofei Zheng, Rongrong He, Huajun Wang
Malignant transformation is concomitant with excessive activation of stress response pathways. Heat shock proteins (HSPs) are stress-inducible proteins that play a role in folding and processing proteins, contributing to the non-oncogene addiction of stressed tumor cells. However, the detailed role of the HSP family in osteosarcoma has not been investigated. Bulk and single-cell transcriptomic data from the GEO and TARGET databases were used to identify HSPs associated with prognosis in osteosarcoma patients. The expression level of HSPD1 was markedly increased in osteosarcoma, correlating with a negative prognosis. Through in vitro and in vivo experiments, we systematically identified HSPD1 as an important contributor to the regulation of proliferation, metastasis, and apoptosis in osteosarcoma by promoting the epithelial-mesenchymal transition (EMT) and activating AKT/mTOR signaling. Subsequently, ATP5A1 was determined as a potential target of HSPD1 using immunoprecipitation followed by mass spectrometry. Mechanistically, HSPD1 may interact with ATP5A1 to reduce the K48-linked ubiquitination and degradation of ATP5A1, which ultimately activates the AKT/mTOR pathway to ensure osteosarcoma progression and EMT process. These findings expand the potential mechanisms by which HSPD1 exerts biological effects and provide strong evidence for its inclusion as a potential therapeutic target in osteosarcoma.
{"title":"HSPD1 Supports Osteosarcoma Progression through Stabilizing ATP5A1 and thus Activation of AKT/mTOR Signaling.","authors":"Yiming Zhang, Ruilin Pan, Kun Li, Lek Hang Cheang, Jing Zhao, Zhangfeng Zhong, Shaoping Li, Jinghao Wang, Xiaofang Zhang, Yanmei Cheng, Xiaofei Zheng, Rongrong He, Huajun Wang","doi":"10.7150/ijbs.100015","DOIUrl":"10.7150/ijbs.100015","url":null,"abstract":"<p><p>Malignant transformation is concomitant with excessive activation of stress response pathways. Heat shock proteins (HSPs) are stress-inducible proteins that play a role in folding and processing proteins, contributing to the non-oncogene addiction of stressed tumor cells. However, the detailed role of the HSP family in osteosarcoma has not been investigated. Bulk and single-cell transcriptomic data from the GEO and TARGET databases were used to identify HSPs associated with prognosis in osteosarcoma patients. The expression level of HSPD1 was markedly increased in osteosarcoma, correlating with a negative prognosis. Through <i>in vitro</i> and <i>in vivo</i> experiments, we systematically identified HSPD1 as an important contributor to the regulation of proliferation, metastasis, and apoptosis in osteosarcoma by promoting the epithelial-mesenchymal transition (EMT) and activating AKT/mTOR signaling. Subsequently, ATP5A1 was determined as a potential target of HSPD1 using immunoprecipitation followed by mass spectrometry. Mechanistically, HSPD1 may interact with ATP5A1 to reduce the K48-linked ubiquitination and degradation of ATP5A1, which ultimately activates the AKT/mTOR pathway to ensure osteosarcoma progression and EMT process. These findings expand the potential mechanisms by which HSPD1 exerts biological effects and provide strong evidence for its inclusion as a potential therapeutic target in osteosarcoma.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 13","pages":"5162-5190"},"PeriodicalIF":8.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11489178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464517","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 : 2024-09-23eCollection Date: 2024-01-01DOI: 10.7150/ijbs.99734
Yushan Hou, Yiming Zhang, Kun Zheng, Han Wang, Yingying Zhou, Yuanjun Zhai, Fuchu He, Chunyan Tian, Aihua Sun
The high rate of postoperative recurrence contributes to the poor outcome in hepatocellular carcinoma (HCC), and effective strategies for managing recurrence are currently lacking. Based on seven pairs of tumors and non-tumor adjacent tissues (NATs) proteomic datasets across five cancer types, this study systematically investigates the stratified and therapeutic value of tumors and NATs for tumor recurrence. NATs exhibited stable and irreplaceable independent prognostic capabilities for recurrence, complementing clinical indicators and tumor characteristics. In comparison to tumor tissues, NATs exhibit higher enrichment levels of recurrence-related proteins in pathways such as immunity, extracellular matrix, and angiogenesis. Taking HCC as an example, we identified SERPINH1 as a recurrent biomarker with drug-targeting potential that applied to both tumors and NATs and then validated them through independent immunohistochemistry cohorts and animal experiments. Patients with high SERPINH1 expression in both tumors and NATs have the highest 5-year recurrence rates, even among clinically low recurrence risk groups. Targeting SERPINH1 can effectively delay tumor occurrence and progression. This study highlights the significant importance of NATs in recurrence prediction and postoperative management, proposing a recurrence management strategy that focuses on both tumors and NATs. SERPINH1 emerges as a valuable biomarker and drug target for addressing postoperative recurrence in HCC.
{"title":"Integrated analysis of tumor and adjacent non-tumor proteomic data reveals SERPINH1 as a recurrence biomarker and drug target in hepatocellular carcinoma.","authors":"Yushan Hou, Yiming Zhang, Kun Zheng, Han Wang, Yingying Zhou, Yuanjun Zhai, Fuchu He, Chunyan Tian, Aihua Sun","doi":"10.7150/ijbs.99734","DOIUrl":"10.7150/ijbs.99734","url":null,"abstract":"<p><p>The high rate of postoperative recurrence contributes to the poor outcome in hepatocellular carcinoma (HCC), and effective strategies for managing recurrence are currently lacking. Based on seven pairs of tumors and non-tumor adjacent tissues (NATs) proteomic datasets across five cancer types, this study systematically investigates the stratified and therapeutic value of tumors and NATs for tumor recurrence. NATs exhibited stable and irreplaceable independent prognostic capabilities for recurrence, complementing clinical indicators and tumor characteristics. In comparison to tumor tissues, NATs exhibit higher enrichment levels of recurrence-related proteins in pathways such as immunity, extracellular matrix, and angiogenesis. Taking HCC as an example, we identified SERPINH1 as a recurrent biomarker with drug-targeting potential that applied to both tumors and NATs and then validated them through independent immunohistochemistry cohorts and animal experiments. Patients with high SERPINH1 expression in both tumors and NATs have the highest 5-year recurrence rates, even among clinically low recurrence risk groups. Targeting SERPINH1 can effectively delay tumor occurrence and progression. This study highlights the significant importance of NATs in recurrence prediction and postoperative management, proposing a recurrence management strategy that focuses on both tumors and NATs. SERPINH1 emerges as a valuable biomarker and drug target for addressing postoperative recurrence in HCC.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"20 13","pages":"5191-5207"},"PeriodicalIF":8.2,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11489177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464518","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}
Xinglong Liu, Yimeng Song, Songling Hu, Yang Bai, Jianghong Zhang, Guomei Tai, Chunlin Shao, Yan Pan
Patients who receive thoracic radiotherapy may suffer from radiation-induced lung injury, but the treatment options are limited as the underlying mechanisms are unclear. Using a mouse model of right thorax irradiation with fractionated doses of X-rays for three consecutive days (8 Gy/per day), this study found that the thoracic irradiation (Th-IR) induced tissue injury with aberrant infiltration of macrophages, and it significantly increased the secretion of TNF-α, IL-1β, IL-6, TGF-β1 and serum amyloid A (SAA) in mice. Interestingly, SAA could activate macrophages and then induce epithelial-mesenchymal transition (EMT) of lung epithelial cells and fibrosis progression in lung tissue. Mechanistically, SAA enhanced the transient binding of FPR2 to Rac1 protein and further activated NF-κB signaling pathway in macrophages. Inhibition of FPR2 significantly reduced pulmonary fibrosis induced by SAA administration in mice. In addition, cimetidine could reduce the level of SAA release after irradiation and attenuate the lung injury induced by SAA or Th-IR. In conclusion, our results demonstrated that SAA activated macrophages via FPR2/Rac1/NF-κB pathway and might contribute to the Th-IR induced lung injury, which may provide a new strategy to attenuate radiation-induced adverse effects during radiotherapy.
接受胸部放疗的患者可能会受到辐射诱导的肺损伤,但由于其潜在机制尚不清楚,因此治疗方案有限。本研究利用小鼠模型,连续三天(每天 8 Gy)使用分次剂量的 X 射线照射右胸,发现胸腔照射(Th-IR)会诱发组织损伤,巨噬细胞异常浸润,并显著增加小鼠体内 TNF-α、IL-1β、IL-6、TGF-β1 和血清淀粉样蛋白 A(SAA)的分泌。有趣的是,SAA能激活巨噬细胞,进而诱导肺上皮细胞的上皮-间质转化(EMT)和肺组织的纤维化进展。从机理上讲,SAA 可增强 FPR2 与 Rac1 蛋白的瞬时结合,并进一步激活巨噬细胞中的 NF-κB 信号通路。抑制 FPR2 能显著减轻小鼠因服用 SAA 而诱发的肺纤维化。此外,西咪替丁能降低照射后 SAA 的释放水平,减轻 SAA 或 Th-IR 诱导的肺损伤。总之,我们的研究结果表明,SAA通过FPR2/Rac1/NF-κB途径激活巨噬细胞,并可能导致Th-IR诱导的肺损伤,这可能为减轻放疗期间辐射诱导的不良反应提供了一种新策略。
{"title":"Serum amyloid A contributes to radiation-induced lung injury by activating macrophages through FPR2/Rac1/NF-κB pathway","authors":"Xinglong Liu, Yimeng Song, Songling Hu, Yang Bai, Jianghong Zhang, Guomei Tai, Chunlin Shao, Yan Pan","doi":"10.7150/ijbs.100823","DOIUrl":"https://doi.org/10.7150/ijbs.100823","url":null,"abstract":"Patients who receive thoracic radiotherapy may suffer from radiation-induced lung injury, but the treatment options are limited as the underlying mechanisms are unclear. Using a mouse model of right thorax irradiation with fractionated doses of X-rays for three consecutive days (8 Gy/per day), this study found that the thoracic irradiation (Th-IR) induced tissue injury with aberrant infiltration of macrophages, and it significantly increased the secretion of TNF-α, IL-1β, IL-6, TGF-β1 and serum amyloid A (SAA) in mice. Interestingly, SAA could activate macrophages and then induce epithelial-mesenchymal transition (EMT) of lung epithelial cells and fibrosis progression in lung tissue. Mechanistically, SAA enhanced the transient binding of FPR2 to Rac1 protein and further activated NF-κB signaling pathway in macrophages. Inhibition of FPR2 significantly reduced pulmonary fibrosis induced by SAA administration in mice. In addition, cimetidine could reduce the level of SAA release after irradiation and attenuate the lung injury induced by SAA or Th-IR. In conclusion, our results demonstrated that SAA activated macrophages via FPR2/Rac1/NF-κB pathway and might contribute to the Th-IR induced lung injury, which may provide a new strategy to attenuate radiation-induced adverse effects during radiotherapy.","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"9 1","pages":""},"PeriodicalIF":9.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142258119","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}