Multiple myeloma (MM) is the second most common hematological malignancy of plasma cells, characterized by osteolytic bone lesions, anemia, hypercalcemia, renal failure, and the accumulation of malignant plasma cells. The pathogenesis of MM involves the interaction between MM cells and the bone marrow microenvironment through soluble cytokines and cell adhesion molecules, which activate various signaling pathways such as PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, and NF-κB pathways. Aberrant activation of these pathways contributes to the proliferation, survival, migration, and drug resistance of myeloma cells, making them attractive targets for therapeutic intervention. Currently, approved drugs targeting these signaling pathways in MM are limited, with many inhibitors and inducers still in preclinical or clinical research stages. Therapeutic options for MM include non-targeted drugs like alkylating agents, corticosteroids, immunomodulatory drugs, proteasome inhibitors, and histone deacetylase inhibitors. Additionally, targeted drugs such as monoclonal antibodies, chimeric antigen receptor T cells, bispecific T-cell engagers, and bispecific antibodies are being used in MM treatment. Despite significant advancements in MM treatment, the disease remains incurable, emphasizing the need for the development of novel or combined targeted therapies based on emerging theoretical knowledge, technologies, and platforms. In this review, we highlight the key role of signaling pathways in the malignant progression and treatment of MM, exploring advances in targeted therapy and potential treatments to offer further insights for improving MM management and outcomes.
多发性骨髓瘤(MM)是浆细胞恶性肿瘤中第二常见的血液恶性肿瘤,以溶骨性骨病变、贫血、高钙血症、肾功能衰竭和恶性浆细胞聚集为特征。MM 的发病机制涉及 MM 细胞与骨髓微环境之间通过可溶性细胞因子和细胞粘附分子的相互作用,从而激活各种信号通路,如 PI3K/AKT/mTOR、RAS/MAPK、JAK/STAT、Wnt/β-catenin 和 NF-κB 通路。这些通路的异常激活导致骨髓瘤细胞的增殖、存活、迁移和耐药性,使它们成为有吸引力的治疗干预靶点。目前,针对 MM 这些信号通路的获批药物非常有限,许多抑制剂和诱导剂仍处于临床前或临床研究阶段。MM 的治疗选择包括非靶向药物,如烷化剂、皮质类固醇、免疫调节药物、蛋白酶体抑制剂和组蛋白去乙酰化酶抑制剂。此外,单克隆抗体、嵌合抗原受体T细胞、双特异性T细胞啮合剂和双特异性抗体等靶向药物也被用于MM的治疗。尽管 MM 的治疗取得了重大进展,但这种疾病仍然无法治愈,这就强调了基于新兴理论知识、技术和平台开发新型或联合靶向疗法的必要性。在这篇综述中,我们强调了信号通路在 MM 恶性进展和治疗中的关键作用,探讨了靶向治疗和潜在治疗的进展,为改善 MM 的管理和预后提供了进一步的见解。
{"title":"Multiple myeloma: signaling pathways and targeted therapy.","authors":"Qizhong Lu, Donghui Yang, Hexian Li, Ting Niu, Aiping Tong","doi":"10.1186/s43556-024-00188-w","DOIUrl":"10.1186/s43556-024-00188-w","url":null,"abstract":"<p><p>Multiple myeloma (MM) is the second most common hematological malignancy of plasma cells, characterized by osteolytic bone lesions, anemia, hypercalcemia, renal failure, and the accumulation of malignant plasma cells. The pathogenesis of MM involves the interaction between MM cells and the bone marrow microenvironment through soluble cytokines and cell adhesion molecules, which activate various signaling pathways such as PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, and NF-κB pathways. Aberrant activation of these pathways contributes to the proliferation, survival, migration, and drug resistance of myeloma cells, making them attractive targets for therapeutic intervention. Currently, approved drugs targeting these signaling pathways in MM are limited, with many inhibitors and inducers still in preclinical or clinical research stages. Therapeutic options for MM include non-targeted drugs like alkylating agents, corticosteroids, immunomodulatory drugs, proteasome inhibitors, and histone deacetylase inhibitors. Additionally, targeted drugs such as monoclonal antibodies, chimeric antigen receptor T cells, bispecific T-cell engagers, and bispecific antibodies are being used in MM treatment. Despite significant advancements in MM treatment, the disease remains incurable, emphasizing the need for the development of novel or combined targeted therapies based on emerging theoretical knowledge, technologies, and platforms. In this review, we highlight the key role of signaling pathways in the malignant progression and treatment of MM, exploring advances in targeted therapy and potential treatments to offer further insights for improving MM management and outcomes.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11222366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-28DOI: 10.1186/s43556-024-00187-x
Shuai Guo, Yi Dong, Ran Du, Yu-Xing Liu, Shu Liu, Qin Wang, Ji-Shi Liu, Hui Xu, Yu-Jie Jiang, Huang Hao, Liang-Liang Fan, Rong Xiang
Chronic kidney disease (CKD) poses a significant global health dilemma, emerging from complex causes. Although our prior research has indicated that a deficiency in Reticulon-3 (RTN3) accelerates renal disease progression, a thorough examination of RTN3 on kidney function and pathology remains underexplored. To address this critical need, we generated Rtn3-null mice to study the consequences of RTN3 protein deficiency on CKD. Single-cell transcriptomic analyses were performed on 47,885 cells from the renal cortex of both healthy and Rtn3-null mice, enabling us to compare spatial architectures and expression profiles across 14 distinct cell types. Our analysis revealed that RTN3 deficiency leads to significant alterations in the spatial organization and gene expression profiles of renal cells, reflecting CKD pathology. Specifically, RTN3 deficiency was associated with Lars2 overexpression, which in turn caused mitochondrial dysfunction and increased reactive oxygen species levels. This shift induced a transition in renal epithelial cells from a functional state to a fibrogenic state, thus promoting renal fibrosis. Additionally, RTN3 deficiency was found to drive the endothelial-to-mesenchymal transition process and disrupt cell-cell communication, further exacerbating renal fibrosis. Immunohistochemistry and Western-Blot techniques were used to validate these observations, reinforcing the critical role of RTN3 in CKD pathogenesis. The deficiency of RTN3 protein in CKD leads to profound changes in cellular architecture and molecular profiles. Our work seeks to elevate the understanding of RTN3's role in CKD's narrative and position it as a promising therapeutic contender.
{"title":"Single-cell transcriptomic profiling reveals decreased ER protein Reticulon3 drives the progression of renal fibrosis.","authors":"Shuai Guo, Yi Dong, Ran Du, Yu-Xing Liu, Shu Liu, Qin Wang, Ji-Shi Liu, Hui Xu, Yu-Jie Jiang, Huang Hao, Liang-Liang Fan, Rong Xiang","doi":"10.1186/s43556-024-00187-x","DOIUrl":"10.1186/s43556-024-00187-x","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) poses a significant global health dilemma, emerging from complex causes. Although our prior research has indicated that a deficiency in Reticulon-3 (RTN3) accelerates renal disease progression, a thorough examination of RTN3 on kidney function and pathology remains underexplored. To address this critical need, we generated Rtn3-null mice to study the consequences of RTN3 protein deficiency on CKD. Single-cell transcriptomic analyses were performed on 47,885 cells from the renal cortex of both healthy and Rtn3-null mice, enabling us to compare spatial architectures and expression profiles across 14 distinct cell types. Our analysis revealed that RTN3 deficiency leads to significant alterations in the spatial organization and gene expression profiles of renal cells, reflecting CKD pathology. Specifically, RTN3 deficiency was associated with Lars2 overexpression, which in turn caused mitochondrial dysfunction and increased reactive oxygen species levels. This shift induced a transition in renal epithelial cells from a functional state to a fibrogenic state, thus promoting renal fibrosis. Additionally, RTN3 deficiency was found to drive the endothelial-to-mesenchymal transition process and disrupt cell-cell communication, further exacerbating renal fibrosis. Immunohistochemistry and Western-Blot techniques were used to validate these observations, reinforcing the critical role of RTN3 in CKD pathogenesis. The deficiency of RTN3 protein in CKD leads to profound changes in cellular architecture and molecular profiles. Our work seeks to elevate the understanding of RTN3's role in CKD's narrative and position it as a promising therapeutic contender.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11211315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141473295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-21DOI: 10.1186/s43556-024-00185-z
Zhoucheng Wang, Wenwen Ge, Xinyang Zhong, Shizheng Tong, Shusen Zheng, Xiao Xu, Kai Wang
Hepatic ischemia-reperfusion injury (HIRI) is a critical pathophysiological process during liver transplantation (LT). Multiple genes and signal pathways are dysregulated during HIRI. This study aims to identify genes as potential therapeutic targets for ameliorating HIRI. Datasets containing samples from the human donor liver (GSE151648) and mouse HIRI model (GSE117066) were analyzed to determine differentially expressed genes (DEGs). The selected DEGs were confirmed by real-time PCR and western blot in the hepatocyte hypoxia-reoxygenation (HR) model, mouse HIRI model, and human liver samples after transplantation. Genetic inhibition was used to further clarify the underlying mechanism of the gene in vitro and in vivo. Among the DEGs, CSRNP1 was significantly upregulated (|log FC|= 2.08, P < 0.001), and was positively correlated with the MAPK signal pathway (R = 0.67, P < 0.001). CSRNP1 inhibition by siRNA significantly suppressed apoptosis in the AML-12 cell line after HR (mean Annexin+ ratio = 60.62% vs 42.47%, P = 0.0019), but the protective effect was eliminated with an additional MAPK activator. Knocking down CSRNP1 gene expression by intravenous injection of AAV-shRNA markedly reduced liver injury in mouse HIRI model (ALT: AAV-NC vs AAV-shCsrnp1 = 26,673.5 ± 2761.2 vs 3839.7 ± 1432.8, P < 0.001; AST: AAV-NC vs AAV-shCsrnp1 = 8640.5 ± 1450.3 vs 1786.8 ± 518.3, P < 0.001). Liver-targeted delivery of siRNA by nanoparticles effectively inhibited intra-hepatic genetic expression of Csrnp1 and alleviated IRI by reducing tissue inflammation and hepatocyte apoptosis. Furthermore, CSRNP1 inhibition was associated with reduced activation of the MAPK pathway both in vitro and in vivo. In conclusion, our results demonstrated that CSRNP1 could be a potential therapeutic target to ameliorate HIRI in an MAPK-dependent manner.
肝脏缺血再灌注损伤(HIRI)是肝移植(LT)过程中的一个关键病理生理过程。在肝缺血再灌注损伤过程中,多种基因和信号通路失调。本研究旨在确定作为潜在治疗靶点的基因,以改善 HIRI。研究人员分析了包含人类供体肝脏样本(GSE151648)和小鼠 HIRI 模型样本(GSE117066)的数据集,以确定差异表达基因(DEGs)。在肝细胞缺氧-复氧(HR)模型、小鼠 HIRI 模型和移植后的人类肝脏样本中,通过实时 PCR 和 Western 印迹证实了所选的 DEGs。通过基因抑制进一步阐明了该基因在体外和体内的潜在机制。在 DEGs 中,CSRNP1 明显上调(|log FC|= 2.08,P + ratio = 60.62% vs 42.47%,P = 0.0019),但使用额外的 MAPK 激活剂后,保护作用被消除。在小鼠 HIRI 模型中,通过静脉注射 AAV-shRNA 敲低 CSRNP1 基因表达明显减轻了肝损伤(ALT:AAV-NC vs AAV-shCsrnp1 = 26,673.5 ± 2761.2 vs 3839.7 ± 1432.8,P||=2.08)。
{"title":"Inhibition of cysteine-serine-rich nuclear protein 1 ameliorates ischemia-reperfusion injury during liver transplantation in an MAPK-dependent manner.","authors":"Zhoucheng Wang, Wenwen Ge, Xinyang Zhong, Shizheng Tong, Shusen Zheng, Xiao Xu, Kai Wang","doi":"10.1186/s43556-024-00185-z","DOIUrl":"10.1186/s43556-024-00185-z","url":null,"abstract":"<p><p>Hepatic ischemia-reperfusion injury (HIRI) is a critical pathophysiological process during liver transplantation (LT). Multiple genes and signal pathways are dysregulated during HIRI. This study aims to identify genes as potential therapeutic targets for ameliorating HIRI. Datasets containing samples from the human donor liver (GSE151648) and mouse HIRI model (GSE117066) were analyzed to determine differentially expressed genes (DEGs). The selected DEGs were confirmed by real-time PCR and western blot in the hepatocyte hypoxia-reoxygenation (HR) model, mouse HIRI model, and human liver samples after transplantation. Genetic inhibition was used to further clarify the underlying mechanism of the gene in vitro and in vivo. Among the DEGs, CSRNP1 was significantly upregulated (|log FC|= 2.08, P < 0.001), and was positively correlated with the MAPK signal pathway (R = 0.67, P < 0.001). CSRNP1 inhibition by siRNA significantly suppressed apoptosis in the AML-12 cell line after HR (mean Annexin<sup>+</sup> ratio = 60.62% vs 42.47%, P = 0.0019), but the protective effect was eliminated with an additional MAPK activator. Knocking down CSRNP1 gene expression by intravenous injection of AAV-shRNA markedly reduced liver injury in mouse HIRI model (ALT: AAV-NC vs AAV-shCsrnp1 = 26,673.5 ± 2761.2 vs 3839.7 ± 1432.8, P < 0.001; AST: AAV-NC vs AAV-shCsrnp1 = 8640.5 ± 1450.3 vs 1786.8 ± 518.3, P < 0.001). Liver-targeted delivery of siRNA by nanoparticles effectively inhibited intra-hepatic genetic expression of Csrnp1 and alleviated IRI by reducing tissue inflammation and hepatocyte apoptosis. Furthermore, CSRNP1 inhibition was associated with reduced activation of the MAPK pathway both in vitro and in vivo. In conclusion, our results demonstrated that CSRNP1 could be a potential therapeutic target to ameliorate HIRI in an MAPK-dependent manner.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11189853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141433533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sleep deprivation (SD) has emerged as a critical concern impacting human health, leading to significant damage to the cardiovascular system. However, the underlying mechanisms are still unclear, and the development of targeted drugs is lagging. Here, we used mice to explore the effects of prolonged SD on cardiac structure and function. Echocardiography analysis revealed that cardiac function was significantly decreased in mice after five weeks of SD. Real-time quantitative PCR (RT-q-PCR) and Masson staining analysis showed that cardiac remodeling marker gene Anp (atrial natriuretic peptide) and fibrosis were increased, Elisa assay of serum showed that the levels of creatine kinase (CK), creatine kinase-MB (CK-MB), ANP, brain natriuretic peptide (BNP) and cardiac troponin T (cTn-T) were increased after SD, suggesting that cardiac remodeling and injury occurred. Transcript sequencing analysis indicated that genes involved in the regulation of calcium signaling pathway, dilated cardiomyopathy, and cardiac muscle contraction were changed after SD. Accordingly, Western blotting analysis demonstrated that the cardiac-contraction associated CaMKK2/AMPK/cTNI pathway was inhibited. Since our preliminary research has confirmed the vital role of Casein Kinase-2 -Interacting Protein-1 (CKIP-1, also known as PLEKHO1) in cardiac remodeling regulation. Here, we found the levels of the 3' untranslated region of Ckip-1 (Ckip-1 3'UTR) decreased, while the coding sequence of Ckip-1 (Ckip-1 CDS) remained unchanged after SD. Significantly, adenovirus-mediated overexpression of Ckip-1 3'UTR alleviated SD-induced cardiac dysfunction and remodeling by activating CaMKK2/AMPK/cTNI pathway, which proposed the therapeutic potential of Ckip-1 3'UTR in treating SD-induced heart disease.
{"title":"Ckip-1 3'UTR alleviates prolonged sleep deprivation induced cardiac dysfunction by activating CaMKK2/AMPK/cTNI pathway.","authors":"Beilei Dong, Rui Xue, Jianwei Li, Shukuan Ling, Wenjuan Xing, Zizhong Liu, Xinxin Yuan, Junjie Pan, Ruikai Du, Xinming Shen, Jingwen Zhang, Youzhi Zhang, Yingxian Li, Guohui Zhong","doi":"10.1186/s43556-024-00186-y","DOIUrl":"10.1186/s43556-024-00186-y","url":null,"abstract":"<p><p>Sleep deprivation (SD) has emerged as a critical concern impacting human health, leading to significant damage to the cardiovascular system. However, the underlying mechanisms are still unclear, and the development of targeted drugs is lagging. Here, we used mice to explore the effects of prolonged SD on cardiac structure and function. Echocardiography analysis revealed that cardiac function was significantly decreased in mice after five weeks of SD. Real-time quantitative PCR (RT-q-PCR) and Masson staining analysis showed that cardiac remodeling marker gene Anp (atrial natriuretic peptide) and fibrosis were increased, Elisa assay of serum showed that the levels of creatine kinase (CK), creatine kinase-MB (CK-MB), ANP, brain natriuretic peptide (BNP) and cardiac troponin T (cTn-T) were increased after SD, suggesting that cardiac remodeling and injury occurred. Transcript sequencing analysis indicated that genes involved in the regulation of calcium signaling pathway, dilated cardiomyopathy, and cardiac muscle contraction were changed after SD. Accordingly, Western blotting analysis demonstrated that the cardiac-contraction associated CaMKK2/AMPK/cTNI pathway was inhibited. Since our preliminary research has confirmed the vital role of Casein Kinase-2 -Interacting Protein-1 (CKIP-1, also known as PLEKHO1) in cardiac remodeling regulation. Here, we found the levels of the 3' untranslated region of Ckip-1 (Ckip-1 3'UTR) decreased, while the coding sequence of Ckip-1 (Ckip-1 CDS) remained unchanged after SD. Significantly, adenovirus-mediated overexpression of Ckip-1 3'UTR alleviated SD-induced cardiac dysfunction and remodeling by activating CaMKK2/AMPK/cTNI pathway, which proposed the therapeutic potential of Ckip-1 3'UTR in treating SD-induced heart disease.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11176284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141319180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-07DOI: 10.1186/s43556-024-00178-y
Yanlin Song, Ming Chen, Yuhao Wei, Xuelei Ma, Huashan Shi
Colorectal carcinoma (CRC) stands as a pressing global health issue, marked by the unbridled proliferation of immature cells influenced by multifaceted internal and external factors. Numerous studies have explored the intricate mechanisms of tumorigenesis in CRC, with a primary emphasis on signaling pathways, particularly those associated with growth factors and chemokines. However, the sheer diversity of molecular targets introduces complexity into the selection of targeted therapies, posing a significant challenge in achieving treatment precision. The quest for an effective CRC treatment is further complicated by the absence of pathological insights into the mutations or alterations occurring in tumor cells. This study reveals the transfer of signaling from the cell membrane to the nucleus, unveiling recent advancements in this crucial cellular process. By shedding light on this novel dimension, the research enhances our understanding of the molecular intricacies underlying CRC, providing a potential avenue for breakthroughs in targeted therapeutic strategies. In addition, the study comprehensively outlines the potential immune responses incited by the aberrant activation of signaling pathways, with a specific focus on immune cells, cytokines, and their collective impact on the dynamic landscape of drug development. This research not only contributes significantly to advancing CRC treatment and molecular medicine but also lays the groundwork for future breakthroughs and clinical trials, fostering optimism for improved outcomes and refined approaches in combating colorectal carcinoma.
{"title":"Signaling pathways in colorectal cancer implications for the target therapies.","authors":"Yanlin Song, Ming Chen, Yuhao Wei, Xuelei Ma, Huashan Shi","doi":"10.1186/s43556-024-00178-y","DOIUrl":"10.1186/s43556-024-00178-y","url":null,"abstract":"<p><p>Colorectal carcinoma (CRC) stands as a pressing global health issue, marked by the unbridled proliferation of immature cells influenced by multifaceted internal and external factors. Numerous studies have explored the intricate mechanisms of tumorigenesis in CRC, with a primary emphasis on signaling pathways, particularly those associated with growth factors and chemokines. However, the sheer diversity of molecular targets introduces complexity into the selection of targeted therapies, posing a significant challenge in achieving treatment precision. The quest for an effective CRC treatment is further complicated by the absence of pathological insights into the mutations or alterations occurring in tumor cells. This study reveals the transfer of signaling from the cell membrane to the nucleus, unveiling recent advancements in this crucial cellular process. By shedding light on this novel dimension, the research enhances our understanding of the molecular intricacies underlying CRC, providing a potential avenue for breakthroughs in targeted therapeutic strategies. In addition, the study comprehensively outlines the potential immune responses incited by the aberrant activation of signaling pathways, with a specific focus on immune cells, cytokines, and their collective impact on the dynamic landscape of drug development. This research not only contributes significantly to advancing CRC treatment and molecular medicine but also lays the groundwork for future breakthroughs and clinical trials, fostering optimism for improved outcomes and refined approaches in combating colorectal carcinoma.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11156834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141285576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liver cancer remains one of the most prevalent malignancies worldwide with high incidence and mortality rates. Due to its subtle onset, liver cancer is commonly diagnosed at a late stage when surgical interventions are no longer feasible. This situation highlights the critical role of systemic treatments, including targeted therapies, in bettering patient outcomes. Despite numerous studies on the mechanisms underlying liver cancer, tyrosine kinase inhibitors (TKIs) are the only widely used clinical inhibitors, represented by sorafenib, whose clinical application is greatly limited by the phenomenon of drug resistance. Here we show an in-depth discussion of the signaling pathways frequently implicated in liver cancer pathogenesis and the inhibitors targeting these pathways under investigation or already in use in the management of advanced liver cancer. We elucidate the oncogenic roles of these pathways in liver cancer especially hepatocellular carcinoma (HCC), as well as the current state of research on inhibitors respectively. Given that TKIs represent the sole class of targeted therapeutics for liver cancer employed in clinical practice, we have particularly focused on TKIs and the mechanisms of the commonly encountered phenomena of its resistance during HCC treatment. This necessitates the imperative development of innovative targeted strategies and the urgency of overcoming the existing limitations. This review endeavors to shed light on the utilization of targeted therapy in advanced liver cancer, with a vision to improve the unsatisfactory prognostic outlook for those patients.
{"title":"Signaling pathways in liver cancer: pathogenesis and targeted therapy.","authors":"Yangtao Xue, Yeling Ruan, Yali Wang, Peng Xiao, Junjie Xu","doi":"10.1186/s43556-024-00184-0","DOIUrl":"10.1186/s43556-024-00184-0","url":null,"abstract":"<p><p>Liver cancer remains one of the most prevalent malignancies worldwide with high incidence and mortality rates. Due to its subtle onset, liver cancer is commonly diagnosed at a late stage when surgical interventions are no longer feasible. This situation highlights the critical role of systemic treatments, including targeted therapies, in bettering patient outcomes. Despite numerous studies on the mechanisms underlying liver cancer, tyrosine kinase inhibitors (TKIs) are the only widely used clinical inhibitors, represented by sorafenib, whose clinical application is greatly limited by the phenomenon of drug resistance. Here we show an in-depth discussion of the signaling pathways frequently implicated in liver cancer pathogenesis and the inhibitors targeting these pathways under investigation or already in use in the management of advanced liver cancer. We elucidate the oncogenic roles of these pathways in liver cancer especially hepatocellular carcinoma (HCC), as well as the current state of research on inhibitors respectively. Given that TKIs represent the sole class of targeted therapeutics for liver cancer employed in clinical practice, we have particularly focused on TKIs and the mechanisms of the commonly encountered phenomena of its resistance during HCC treatment. This necessitates the imperative development of innovative targeted strategies and the urgency of overcoming the existing limitations. This review endeavors to shed light on the utilization of targeted therapy in advanced liver cancer, with a vision to improve the unsatisfactory prognostic outlook for those patients.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-24DOI: 10.1186/s43556-024-00181-3
Juan Lei, Lei Wu, Nan Zhang, Xudong Liu, Jiangang Zhang, Liwen Kuang, Jiongming Chen, Yijiao Chen, Dairong Li, Yongsheng Li
Carcinoembryonic antigen (CEA) is a tumor-associated antigen primarily produced by tumor cells. It has been implicated in various biological processes such as cell adhesion, proliferation, differentiation, and metastasis. Despite this, the precise molecular mechanisms through which CEA enhances tumor cell proliferation remain largely unclear. Our study demonstrates that CEA enhances the proliferation and migration of non-small cell lung cancer (NSCLC) while also inhibiting cisplatin-induced apoptosis in NSCLC cells. Treatment with CEA led to an increase in mitochondrial numbers and accumulation of lipid droplets in A549 and H1299 cells. Additionally, our findings indicate that CEA plays a role in regulating the fatty acid metabolism of NSCLC cells. Inhibiting fatty acid metabolism significantly reduced the CEA-mediated proliferation and migration of NSCLC cells. CEA influences fatty acid metabolism and the proliferation of NSCLC cells by activating the PGC-1α signaling pathway. This regulatory mechanism involves CEA increasing intracellular cAMP levels, which in turn activates PKA and upregulates PGC-1α. In NSCLC, inhibiting the PKA-PGC-1α signaling pathway reduces both fatty acid metabolism and the proliferation and migration induced by CEA, both in vitro and in vivo. These results suggest that CEA contributes to the promotion of proliferation and migration by modulating fatty acid metabolism. Targeting CEA or the PKA-PGC-1ɑ signaling pathway may offer a promising therapeutic approach for treating NSCLC.
癌胚抗原(CEA)是一种肿瘤相关抗原,主要由肿瘤细胞产生。它与细胞粘附、增殖、分化和转移等多种生物过程有关。尽管如此,CEA 增强肿瘤细胞增殖的确切分子机制在很大程度上仍不清楚。我们的研究表明,CEA能增强非小细胞肺癌(NSCLC)的增殖和迁移,同时还能抑制顺铂诱导的NSCLC细胞凋亡。用 CEA 处理 A549 和 H1299 细胞会导致线粒体数量增加和脂滴积累。此外,我们的研究结果表明,CEA 在调节 NSCLC 细胞的脂肪酸代谢中发挥作用。抑制脂肪酸代谢可显著减少 CEA 介导的 NSCLC 细胞增殖和迁移。CEA通过激活PGC-1α信号通路影响NSCLC细胞的脂肪酸代谢和增殖。这一调节机制包括 CEA 增加细胞内 cAMP 水平,进而激活 PKA 并上调 PGC-1α。在 NSCLC 中,抑制 PKA-PGC-1α 信号通路可减少脂肪酸代谢以及 CEA 在体外和体内诱导的增殖和迁移。这些结果表明,CEA 通过调节脂肪酸代谢促进增殖和迁移。靶向CEA或PKA-PGC-1ɑ信号通路可能是治疗NSCLC的一种有前景的治疗方法。
{"title":"Carcinoembryonic antigen potentiates non-small cell lung cancer progression via PKA-PGC-1ɑ axis.","authors":"Juan Lei, Lei Wu, Nan Zhang, Xudong Liu, Jiangang Zhang, Liwen Kuang, Jiongming Chen, Yijiao Chen, Dairong Li, Yongsheng Li","doi":"10.1186/s43556-024-00181-3","DOIUrl":"10.1186/s43556-024-00181-3","url":null,"abstract":"<p><p>Carcinoembryonic antigen (CEA) is a tumor-associated antigen primarily produced by tumor cells. It has been implicated in various biological processes such as cell adhesion, proliferation, differentiation, and metastasis. Despite this, the precise molecular mechanisms through which CEA enhances tumor cell proliferation remain largely unclear. Our study demonstrates that CEA enhances the proliferation and migration of non-small cell lung cancer (NSCLC) while also inhibiting cisplatin-induced apoptosis in NSCLC cells. Treatment with CEA led to an increase in mitochondrial numbers and accumulation of lipid droplets in A549 and H1299 cells. Additionally, our findings indicate that CEA plays a role in regulating the fatty acid metabolism of NSCLC cells. Inhibiting fatty acid metabolism significantly reduced the CEA-mediated proliferation and migration of NSCLC cells. CEA influences fatty acid metabolism and the proliferation of NSCLC cells by activating the PGC-1α signaling pathway. This regulatory mechanism involves CEA increasing intracellular cAMP levels, which in turn activates PKA and upregulates PGC-1α. In NSCLC, inhibiting the PKA-PGC-1α signaling pathway reduces both fatty acid metabolism and the proliferation and migration induced by CEA, both in vitro and in vivo. These results suggest that CEA contributes to the promotion of proliferation and migration by modulating fatty acid metabolism. Targeting CEA or the PKA-PGC-1ɑ signaling pathway may offer a promising therapeutic approach for treating NSCLC.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11116303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-17DOI: 10.1186/s43556-024-00183-1
Ke Xu, Wu He, Bo Yu, Kaineng Zhong, Da Zhou, Dao Wen Wang
{"title":"Effects of different treatments for type 2 diabetes mellitus on mortality of coronavirus disease from 2019 to 2021 in China: a multi-institutional retrospective study","authors":"Ke Xu, Wu He, Bo Yu, Kaineng Zhong, Da Zhou, Dao Wen Wang","doi":"10.1186/s43556-024-00183-1","DOIUrl":"https://doi.org/10.1186/s43556-024-00183-1","url":null,"abstract":"","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140962095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-17DOI: 10.1186/s43556-024-00183-1
Ke Xu, Wu He, Bo Yu, Kaineng Zhong, Da Zhou, Dao Wen Wang
The coronavirus disease (COVID-19) pandemic has continued for 5 years. Sporadic cases continue to occur in different locations. Type 2 diabetes mellitus (T2DM) is associated with a high risk of a poor prognosis in patients with COVID-19. Successful control of blood glucose levels can effectively decrease the risks of severe infections and mortality. However, the effects of different treatments were reported differently and even adversely. This retrospective study included 4,922 patients who have been diagnosed as COVID-19 and T2DM from 138 Hubei hospitals. The clinical characteristics and outcomes were compared and calculated their risk for death using multivariate Cox regression and Kaplan-Meier curves. After adjustment of age, sex, comorbidities, and in-hospital medications, metformin and alpha-glucosidase inhibitor (AGI) use performed lower all-cause mortality (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI]: 0.24-0.71; p = 0.001 for metformin; 0.53, 0.35-0.80, p = 0.002 for AGIs), while insulin use was associated with increased all-cause mortality (adjusted HR, 2.07, 95% CI, 1.61-2.67, p < 0.001). After propensity score-matched (PSM) analysis, adjusted HRs for insulin, metformin, and AGIs associated with all-cause mortality were 1.32 (95% CI, 1.03-1.81; p = 0.012), 0.48 (95% CI, 0.23-0.83, p = 0.014), and 0.59 (95% CI, 0.35-0.98, p = 0.05). Therefore, metformin and AGIs might be more suitable for patients with COVID-19 and T2DM while insulin might be used with caution.
{"title":"Effects of different treatments for type 2 diabetes mellitus on mortality of coronavirus disease from 2019 to 2021 in China: a multi-institutional retrospective study.","authors":"Ke Xu, Wu He, Bo Yu, Kaineng Zhong, Da Zhou, Dao Wen Wang","doi":"10.1186/s43556-024-00183-1","DOIUrl":"10.1186/s43556-024-00183-1","url":null,"abstract":"<p><p>The coronavirus disease (COVID-19) pandemic has continued for 5 years. Sporadic cases continue to occur in different locations. Type 2 diabetes mellitus (T2DM) is associated with a high risk of a poor prognosis in patients with COVID-19. Successful control of blood glucose levels can effectively decrease the risks of severe infections and mortality. However, the effects of different treatments were reported differently and even adversely. This retrospective study included 4,922 patients who have been diagnosed as COVID-19 and T2DM from 138 Hubei hospitals. The clinical characteristics and outcomes were compared and calculated their risk for death using multivariate Cox regression and Kaplan-Meier curves. After adjustment of age, sex, comorbidities, and in-hospital medications, metformin and alpha-glucosidase inhibitor (AGI) use performed lower all-cause mortality (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI]: 0.24-0.71; p = 0.001 for metformin; 0.53, 0.35-0.80, p = 0.002 for AGIs), while insulin use was associated with increased all-cause mortality (adjusted HR, 2.07, 95% CI, 1.61-2.67, p < 0.001). After propensity score-matched (PSM) analysis, adjusted HRs for insulin, metformin, and AGIs associated with all-cause mortality were 1.32 (95% CI, 1.03-1.81; p = 0.012), 0.48 (95% CI, 0.23-0.83, p = 0.014), and 0.59 (95% CI, 0.35-0.98, p = 0.05). Therefore, metformin and AGIs might be more suitable for patients with COVID-19 and T2DM while insulin might be used with caution.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11099001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140961078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}