Pub Date : 2024-07-31Epub Date: 2024-07-26DOI: 10.21037/tcr-24-151
Hailiang Tang, Wendi Hua, Ying Wang, Ji Xiong, Haixia Cheng, Ming Xu, Jian Xu, Ping Zhong
Background: Angioleiomyoma is a benign lesion of mesenchymal origin, which always occurs in the uterine system. Pathologically, angioleiomyoma is usually composed of well-differentiated smooth muscle cells with few mitotic features. However, primary intracranial angioleiomyoma represents an exceedingly rare tumor, since the first case reported in 1994.
Case description: Here, we reported a case of primary intracranial angioleiomyoma, which mimicking meningioma in pre-operative images. The patient was a 42-year-old male, presented with dizziness and unsteady walking for about 6 months, without symptoms of cranial nerve deficit. Head computer tomography scan showed a well-defined lesion adjacent to right brain stem with high intensity. Contrast brain magnetic resonance imaging (MRI) scan exhibited an extra-axial mass with homogeneous enhancement located at the right pontine, presented as meningioma features; however, other tumors including lymphoma should be differentiated as well. The patient underwent sub-temporal craniotomy for the tumor resection. Histological analysis confirmed the diagnosis of angioleiomyoma. Follow-up brain MRI scan (6 months after surgery) showed total resection of the lesion without residual.
Conclusions: In summary, primary intracranial angioleiomyoma is rare. Thus, diagnosis and differential diagnosis are important before surgical resection, which was mimicking meningioma in our case. Pathological analysis could reveal spindle shaped cells with few mitotic features, and confirm the diagnosis of angioleiomyoma. Currently, the optimal therapy for primary intracranial angioleiomyoma is surgical resection, and adjuvant radiation therapy for the residual tumor. However, long-term prognosis of the disease should be monitor in the future.
{"title":"Brain stem angioleiomyoma mimicking meningioma: a case report.","authors":"Hailiang Tang, Wendi Hua, Ying Wang, Ji Xiong, Haixia Cheng, Ming Xu, Jian Xu, Ping Zhong","doi":"10.21037/tcr-24-151","DOIUrl":"10.21037/tcr-24-151","url":null,"abstract":"<p><strong>Background: </strong>Angioleiomyoma is a benign lesion of mesenchymal origin, which always occurs in the uterine system. Pathologically, angioleiomyoma is usually composed of well-differentiated smooth muscle cells with few mitotic features. However, primary intracranial angioleiomyoma represents an exceedingly rare tumor, since the first case reported in 1994.</p><p><strong>Case description: </strong>Here, we reported a case of primary intracranial angioleiomyoma, which mimicking meningioma in pre-operative images. The patient was a 42-year-old male, presented with dizziness and unsteady walking for about 6 months, without symptoms of cranial nerve deficit. Head computer tomography scan showed a well-defined lesion adjacent to right brain stem with high intensity. Contrast brain magnetic resonance imaging (MRI) scan exhibited an extra-axial mass with homogeneous enhancement located at the right pontine, presented as meningioma features; however, other tumors including lymphoma should be differentiated as well. The patient underwent sub-temporal craniotomy for the tumor resection. Histological analysis confirmed the diagnosis of angioleiomyoma. Follow-up brain MRI scan (6 months after surgery) showed total resection of the lesion without residual.</p><p><strong>Conclusions: </strong>In summary, primary intracranial angioleiomyoma is rare. Thus, diagnosis and differential diagnosis are important before surgical resection, which was mimicking meningioma in our case. Pathological analysis could reveal spindle shaped cells with few mitotic features, and confirm the diagnosis of angioleiomyoma. Currently, the optimal therapy for primary intracranial angioleiomyoma is surgical resection, and adjuvant radiation therapy for the residual tumor. However, long-term prognosis of the disease should be monitor in the future.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31Epub Date: 2024-07-11DOI: 10.21037/tcr-24-154
Liang Ma, Xue Zhang, Yan Liu, Hui Jin, Dan Li, Hui Zhang, Li Feng, Jing Zuo, Yudong Wang, Jiayin Liu, Jing Han
Background: Despite evidence suggesting a significant role of pyruvate kinase muscle isozyme (PKM) in cancer development, its particular function in colorectal cancer (CRC) remains unclear. This study aimed to elucidate the specific role and mechanism of PKM and its isoforms, PKM1 and PKM2, in the progression of CRC.
Methods: We analyzed PKM, PKM1, and PKM2 expression in CRC tissues and their correlation with clinicopathological features. Plasmids were constructed to modulate these isoforms' expression in CRC cells. Cellular behavior changes, including glucose metabolism alterations, were assessed using the Seahorse Energy Meter, and the Cell Counting Kit-8 (CCK8) assay to determine the inhibitory concentration of 5-fluorouracil (5-FU) on different CRC cell groups.
Results: Our results showed significant PKM overexpression in CRC tissues, which was correlated with negative prognostic factors such as advanced T stages and lymph node metastasis. A lower PKM1/PKM2 ratio was associated with these adverse outcomes. Functionally, PKM1 overexpression decreased cell migration and invasion, increasing 5-FU sensitivity. Conversely, PKM2 overexpression promoted malignant traits and reduced 5-FU sensitivity. Intriguingly, the introduction of glycolysis inhibitors attenuated the impact of PKM on the biological functions of CRC cells, suggesting a glycolysis-dependent mechanism.
Conclusions: This study establishes the PKM1/PKM2 ratio as crucial in CRC progression and 5-FU response. PKM1 overexpression reduces CRC malignancy and increases 5-FU sensitivity, while PKM2 does the opposite. Notably, glycolysis inhibitors lessen PKM's impact on CRC cells, highlighting a glycolysis-dependent mechanism. These insights suggest targeting PKM isoforms and glycolysis pathways as a promising CRC therapeutic strategy, potentially enhancing treatment efficacy.
{"title":"The ratio of PKM1/PKM2 is the key factor affecting the glucose metabolism and biological function of colorectal cancer cells.","authors":"Liang Ma, Xue Zhang, Yan Liu, Hui Jin, Dan Li, Hui Zhang, Li Feng, Jing Zuo, Yudong Wang, Jiayin Liu, Jing Han","doi":"10.21037/tcr-24-154","DOIUrl":"10.21037/tcr-24-154","url":null,"abstract":"<p><strong>Background: </strong>Despite evidence suggesting a significant role of pyruvate kinase muscle isozyme (PKM) in cancer development, its particular function in colorectal cancer (CRC) remains unclear. This study aimed to elucidate the specific role and mechanism of PKM and its isoforms, PKM1 and PKM2, in the progression of CRC.</p><p><strong>Methods: </strong>We analyzed PKM, PKM1, and PKM2 expression in CRC tissues and their correlation with clinicopathological features. Plasmids were constructed to modulate these isoforms' expression in CRC cells. Cellular behavior changes, including glucose metabolism alterations, were assessed using the Seahorse Energy Meter, and the Cell Counting Kit-8 (CCK8) assay to determine the inhibitory concentration of 5-fluorouracil (5-FU) on different CRC cell groups.</p><p><strong>Results: </strong>Our results showed significant PKM overexpression in CRC tissues, which was correlated with negative prognostic factors such as advanced T stages and lymph node metastasis. A lower <i>PKM1/PKM2</i> ratio was associated with these adverse outcomes. Functionally, <i>PKM1</i> overexpression decreased cell migration and invasion, increasing 5-FU sensitivity. Conversely, <i>PKM2</i> overexpression promoted malignant traits and reduced 5-FU sensitivity. Intriguingly, the introduction of glycolysis inhibitors attenuated the impact of <i>PKM</i> on the biological functions of CRC cells, suggesting a glycolysis-dependent mechanism.</p><p><strong>Conclusions: </strong>This study establishes the <i>PKM1/PKM2</i> ratio as crucial in CRC progression and 5-FU response. PKM1 overexpression reduces CRC malignancy and increases 5-FU sensitivity, while <i>PKM2</i> does the opposite. Notably, glycolysis inhibitors lessen <i>PKM</i>'s impact on CRC cells, highlighting a glycolysis-dependent mechanism. These insights suggest targeting <i>PKM</i> isoforms and glycolysis pathways as a promising CRC therapeutic strategy, potentially enhancing treatment efficacy.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31Epub Date: 2024-07-26DOI: 10.21037/tcr-24-695
Xuanyu Lu, Yurui Zhu, Tianyu Qin, Yu Shen
The skin is a complex organ that serves as a critical barrier against external pathogens and environmental impact. Recent advances in immunometabolism have highlighted the intricate link between cellular metabolism and immune function, particularly in the context of skin cancers. This review aims to provide a comprehensive overview of the key metabolic pathways and adaptations that occur in immune cells during homeostasis and activation, and explore how metabolic reprogramming contributes to the pathogenesis of specific skin cancers. We discuss the complex interplay between tumor cells and infiltrating immune cells, which shapes the tumor microenvironment and influences disease outcomes. The review delves into the role of various metabolic pathways, such as glycolysis, oxidative phosphorylation, and lipid metabolism, in the regulation of immune cell function and their impact on the development and progression of skin cancers. Furthermore, we examine the potential of targeting metabolic pathways as a therapeutic strategy in skin cancers and discuss the challenges and future perspectives in this rapidly evolving field. By understanding the metabolic basis of skin immune responses, we can develop novel, personalized therapies for the treatment of skin cancers, ultimately improving patient outcomes and quality of life. The insights gained from this review will contribute to the growing body of knowledge in immunometabolism and its application in the management of skin cancers, paving the way for more effective and targeted interventions in the future.
{"title":"The role of immune metabolism in skin cancers: implications for pathogenesis and therapy.","authors":"Xuanyu Lu, Yurui Zhu, Tianyu Qin, Yu Shen","doi":"10.21037/tcr-24-695","DOIUrl":"10.21037/tcr-24-695","url":null,"abstract":"<p><p>The skin is a complex organ that serves as a critical barrier against external pathogens and environmental impact. Recent advances in immunometabolism have highlighted the intricate link between cellular metabolism and immune function, particularly in the context of skin cancers. This review aims to provide a comprehensive overview of the key metabolic pathways and adaptations that occur in immune cells during homeostasis and activation, and explore how metabolic reprogramming contributes to the pathogenesis of specific skin cancers. We discuss the complex interplay between tumor cells and infiltrating immune cells, which shapes the tumor microenvironment and influences disease outcomes. The review delves into the role of various metabolic pathways, such as glycolysis, oxidative phosphorylation, and lipid metabolism, in the regulation of immune cell function and their impact on the development and progression of skin cancers. Furthermore, we examine the potential of targeting metabolic pathways as a therapeutic strategy in skin cancers and discuss the challenges and future perspectives in this rapidly evolving field. By understanding the metabolic basis of skin immune responses, we can develop novel, personalized therapies for the treatment of skin cancers, ultimately improving patient outcomes and quality of life. The insights gained from this review will contribute to the growing body of knowledge in immunometabolism and its application in the management of skin cancers, paving the way for more effective and targeted interventions in the future.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Ferroptosis-related genes are correlated with the prognosis of patients with neuroblastoma (NB) remains unknown. This study aims to establish a prognostic ferroptosis-related gene model for predicting prognostic value in pediatric NB patients.
Methods: The gene expression array and clinical characteristics of NB were downloaded from a public database. Correlations between ferroptosis-related genes and drug responses were analyzed by Childhood Cancer Therapeutics. The prognostic model was constructed by least absolute shrinkage and selection operator (LASSO) Cox regression and was validated in NB patients from the ICGC cohort. The survival analysis was performed by Cox regression analysis. single-sample gene set enrichment analysis (ssGSEA) was used to quantify the immune cell infiltration correlation.
Results: Overall, 70 genes were identified as ferroptosis-related differentially expressed genes (DEGs) from 247 samples. Then, 13 ferroptosis-related genes were correlated with OS in the univariate Cox regression analysis. Five prognostic ferroptosis-related DEGs (pFR-DEGs) (STEAP3, MAP1LC3A, ULK2, MTOR and TUBE1), which were defined as the intersection of DEGs and prognostic ferroptosis-related genes, were identified and utilized to construct the prognostic signature. The correlation between five pFR-DEGs and drug responses was analyzed, and the box plots indicated that MTOR gene expression was highest, suggesting that MTOR expression is related to progressive NB disease. The receiver operating characteristic (ROC) curve showed that the model had moderate predictive power. The survival analysis indicated that the high-risk group had poor overall survival (OS) (P=2.087×10-06). Univariate and multivariate analyses identified the risk score as a significant prognostic risk factor [P=0.003, hazard ratio (HR) =1.933]. Immune cell infiltration correlation analysis showed that the high-risk group was related to more immune cells.
Conclusions: The present study indicated a difference in ferroptosis-related gene expression between low- and high-risk NB patients. The ferroptosis-related signature could serve as a prognostic prediction tool. Additionally, immune infiltration might play an important role in different risk groups for NB patients.
背景:铁蛋白沉积相关基因与神经母细胞瘤(NB)患者预后的相关性仍然未知。本研究旨在建立一个预后铁蛋白沉积相关基因模型,以预测小儿NB患者的预后价值:方法:从公共数据库下载NB的基因表达阵列和临床特征。方法:从公共数据库下载NB的基因表达阵列和临床特征,通过儿童癌症治疗学分析铁蛋白沉积相关基因与药物反应之间的相关性。预后模型采用最小绝对收缩和选择算子(LASSO)Cox回归法构建,并在ICGC队列的NB患者中进行了验证。单样本基因组富集分析(ssGSEA)用于量化免疫细胞浸润相关性:结果:总体而言,从 247 个样本中发现了 70 个与铁沉积相关的差异表达基因(DEGs)。然后,在单变量考克斯回归分析中,13个与铁沉积相关的基因与OS相关。五个预后铁变态相关 DEGs(pFR-DEGs)(STEAP3、MAP1LC3A、ULK2、MTOR 和 TUBE1)被定义为 DEGs 和预后铁变态相关基因的交叉点,并被用于构建预后特征。分析了五个pFR-DEGs与药物反应的相关性,盒图显示MTOR基因表达量最高,表明MTOR的表达与NB疾病进展有关。接收者操作特征曲线(ROC)显示该模型具有中等预测能力。生存分析表明,高风险组的总生存期(OS)较差(P=2.087×10-06)。单变量和多变量分析表明,风险评分是一个重要的预后风险因素[P=0.003,危险比(HR)=1.933]。免疫细胞浸润相关性分析表明,高风险组与更多的免疫细胞有关:结论:本研究表明,低危和高危 NB 患者的铁蛋白沉积相关基因表达存在差异。结论:本研究表明,低危和高危 NB 患者的铁蛋白沉积相关基因表达存在差异,铁蛋白沉积相关特征可作为预后预测工具。此外,免疫浸润可能在不同风险组别的 NB 患者中发挥重要作用。
{"title":"Identification of a ferroptosis-related gene signature for the prognosis of pediatric neuroblastoma.","authors":"Xijin Lin, Kongfeng Shao, Zhuangbin Lin, Qiandong Liang, Xiaoyan Li, Haiyan Chen, Junxin Wu","doi":"10.21037/tcr-24-269","DOIUrl":"10.21037/tcr-24-269","url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis-related genes are correlated with the prognosis of patients with neuroblastoma (NB) remains unknown. This study aims to establish a prognostic ferroptosis-related gene model for predicting prognostic value in pediatric NB patients.</p><p><strong>Methods: </strong>The gene expression array and clinical characteristics of NB were downloaded from a public database. Correlations between ferroptosis-related genes and drug responses were analyzed by Childhood Cancer Therapeutics. The prognostic model was constructed by least absolute shrinkage and selection operator (LASSO) Cox regression and was validated in NB patients from the ICGC cohort. The survival analysis was performed by Cox regression analysis. single-sample gene set enrichment analysis (ssGSEA) was used to quantify the immune cell infiltration correlation.</p><p><strong>Results: </strong>Overall, 70 genes were identified as ferroptosis-related differentially expressed genes (DEGs) from 247 samples. Then, 13 ferroptosis-related genes were correlated with OS in the univariate Cox regression analysis. Five prognostic ferroptosis-related DEGs (pFR-DEGs) (<i>STEAP3</i>, <i>MAP1LC3A</i>, <i>ULK2</i>, <i>MTOR</i> and <i>TUBE1</i>), which were defined as the intersection of DEGs and prognostic ferroptosis-related genes, were identified and utilized to construct the prognostic signature. The correlation between five pFR-DEGs and drug responses was analyzed, and the box plots indicated that <i>MTOR</i> gene expression was highest, suggesting that <i>MTOR</i> expression is related to progressive NB disease. The receiver operating characteristic (ROC) curve showed that the model had moderate predictive power. The survival analysis indicated that the high-risk group had poor overall survival (OS) (P=2.087×10<sup>-06</sup>). Univariate and multivariate analyses identified the risk score as a significant prognostic risk factor [P=0.003, hazard ratio (HR) =1.933]. Immune cell infiltration correlation analysis showed that the high-risk group was related to more immune cells.</p><p><strong>Conclusions: </strong>The present study indicated a difference in ferroptosis-related gene expression between low- and high-risk NB patients. The ferroptosis-related signature could serve as a prognostic prediction tool. Additionally, immune infiltration might play an important role in different risk groups for NB patients.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31Epub Date: 2024-07-22DOI: 10.21037/tcr-24-14
Bing Gao, Shaochun Yan, Wei Xie, Guo Shao
Background: Neuroblastoma (NB) is a malignant tumor primarily found in children, presenting significant challenges in its development and prognosis. The role of necroptosis in the pathogenesis of NB has been acknowledged as crucial for treatment. This study aimed to investigate the key genes and functional pathways associated with necroptosis, as well as immune infiltration analysis, in NB. Furthermore, we aimed to evaluate the diagnostic significance of these genes for prognostic assessment and explore their potential immunological characteristics.
Methods: The NB dataset (GSE19274, GSE73517, and GSE85047) was obtained from the Gene Expression Omnibus (GEO) database, and genes associated with necroptosis were collected from GeneCards and previous literature. First, we conducted differential expression analysis and performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We employed gene set enrichment analysis (GSEA) to identify overlapping enriched functional pathways from the NB dataset. In addition, we constructed a protein-protein interaction (PPI) network, predicting relevant microRNAs (miRNAs) and transcription factors (TFs), as well as their corresponding drug predictions. Furthermore, the diagnostic value was assessed using receiver operating characteristic (ROC) curves. Finally, an immune infiltration analysis was performed.
Results: We identified six necroptosis-related differentially expressed genes (NRDEGs) closely associated with necroptosis in NB. They were enriched in Tuberculosis, Apoptosis-multiple species, Salmonella infection, legionellosis, and platinum drug resistance. GSEA and PPI network analyses, along with mRNA-drug interaction network, revealed 38 potential drugs corresponding to BIRC2, CAMK2G, CASP3, and IL8. ROC curve analysis showed that in GSE19274, FLOT2 with area under the ROC curve (AUC) of 0.850 and DAPK1 with AUC of 0.789.
Conclusions: Our study elucidates the key genes and functional pathways associated with necroptosis in NB, offering valuable insights to enhance our comprehension of the pathogenesis of NB, and improve prognosis assessment.
背景:神经母细胞瘤(NB)是一种主要见于儿童的恶性肿瘤,在其发展和预后方面面临着巨大挑战。坏死细胞增多症在NB发病机制中的作用已被认为是治疗的关键。本研究旨在研究 NB 中与坏死相关的关键基因和功能通路,以及免疫浸润分析。此外,我们还旨在评估这些基因对预后评估的诊断意义,并探索其潜在的免疫学特征:NB数据集(GSE19274、GSE73517和GSE85047)来自基因表达总库(GEO)数据库,与坏死相关的基因来自GeneCards和以往文献。首先,我们进行了差异表达分析,并执行了基因本体(GO)和京都基因和基因组百科全书(KEGG)。我们采用基因组富集分析(GSEA)从 NB 数据集中找出重叠富集的功能通路。此外,我们还构建了一个蛋白质-蛋白质相互作用(PPI)网络,预测了相关的微RNA(miRNA)和转录因子(TF),以及相应的药物预测。此外,还利用接收者操作特征曲线(ROC)评估了诊断价值。最后,还进行了免疫浸润分析:结果:我们发现了 6 个与 NB 坏死密切相关的坏死相关差异表达基因(NRDEGs)。它们在结核病、多物种凋亡、沙门氏菌感染、军团菌病和铂类药物耐药性中富集。GSEA和PPI网络分析以及mRNA-药物相互作用网络发现了38种潜在的药物,分别对应于BIRC2、CAMK2G、CASP3和IL8。ROC曲线分析表明,在GSE19274中,FLOT2的ROC曲线下面积(AUC)为0.850,DAPK1的AUC为0.789:我们的研究阐明了与 NB 坏死相关的关键基因和功能通路,为我们进一步了解 NB 的发病机制和改善预后评估提供了有价值的见解。
{"title":"Bioinformatics reveals the potential mechanisms and biomarkers of necroptosis in neuroblastoma.","authors":"Bing Gao, Shaochun Yan, Wei Xie, Guo Shao","doi":"10.21037/tcr-24-14","DOIUrl":"10.21037/tcr-24-14","url":null,"abstract":"<p><strong>Background: </strong>Neuroblastoma (NB) is a malignant tumor primarily found in children, presenting significant challenges in its development and prognosis. The role of necroptosis in the pathogenesis of NB has been acknowledged as crucial for treatment. This study aimed to investigate the key genes and functional pathways associated with necroptosis, as well as immune infiltration analysis, in NB. Furthermore, we aimed to evaluate the diagnostic significance of these genes for prognostic assessment and explore their potential immunological characteristics.</p><p><strong>Methods: </strong>The NB dataset (GSE19274, GSE73517, and GSE85047) was obtained from the Gene Expression Omnibus (GEO) database, and genes associated with necroptosis were collected from GeneCards and previous literature. First, we conducted differential expression analysis and performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We employed gene set enrichment analysis (GSEA) to identify overlapping enriched functional pathways from the NB dataset. In addition, we constructed a protein-protein interaction (PPI) network, predicting relevant microRNAs (miRNAs) and transcription factors (TFs), as well as their corresponding drug predictions. Furthermore, the diagnostic value was assessed using receiver operating characteristic (ROC) curves. Finally, an immune infiltration analysis was performed.</p><p><strong>Results: </strong>We identified six necroptosis-related differentially expressed genes (NRDEGs) closely associated with necroptosis in NB. They were enriched in Tuberculosis, Apoptosis-multiple species, Salmonella infection, legionellosis, and platinum drug resistance. GSEA and PPI network analyses, along with mRNA-drug interaction network, revealed 38 potential drugs corresponding to <i>BIRC2</i>, <i>CAMK2G</i>, <i>CASP3</i>, and <i>IL8</i>. ROC curve analysis showed that in GSE19274, <i>FLOT2</i> with area under the ROC curve (AUC) of 0.850 and <i>DAPK1</i> with AUC of 0.789.</p><p><strong>Conclusions: </strong>Our study elucidates the key genes and functional pathways associated with necroptosis in NB, offering valuable insights to enhance our comprehension of the pathogenesis of NB, and improve prognosis assessment.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: In v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant colorectal cancer (CRC), encorafenib-cetuximab has been established as standard second-line therapy, but not all patients respond and the duration of response is relatively short. Overcoming intrinsic or acquired resistance to BRAF/EGFR inhibitors is crucial for enhancing treatment outcomes in metastatic BRAF-mutated CRC. The aim of the study is to investigate the resistance mechanisms in BRAF-mutant CRC patient refractory to BRAF/EGFR targeted therapy.
Methods: We established patient-derived cells (PDCs) from a patient with BRAF/PTEN-mutant metastatic colon cancer who progressed rapidly on encorafenib plus cetuximab. To explore potential treatment options for inherent resistance caused by simultaneous PTEN mutation in BRAF-mutated CRC, we conducted cell viability assays using PDCs treated with encorafenib-cetuximab in combination with a cyclin-dependent kinase-4 and 6 (CDK4/6) inhibitor.
Results: The patient's tumor had concurrent PTEN loss-of-function alteration at diagnosis and PDCs were generated from ascites after resistance to the BRAF/EGFR inhibitor. The PDCs were resistant to the encorafenib-cetuximab combination even at a high concentration of cetuximab (up to 500 µg/mL). Adding the CDK4/6 inhibitor, ribociclib, to encorafenib-cetuximab showed a synergistic effect in a proliferation assay. Ribociclib plus encorafenib-cetuximab represented a significantly lower expression of Ki-67 compared to the dual combination alone. An MTS assay showed that triplet therapy with ribociclib, encorafenib, and cetuximab suppressed cell viability more efficiently than the two-drug combinations. Investigating the combined effect of triplet therapy using the calculated combination index (CI) showed that ribociclib had a synergistic effect with encorafenib-cetuximab when applied to PDCs with a concurrent BRAF/PTEN mutation.
Conclusions: Our results suggest that combining the CDK4/6 inhibitor with the BRAF/EGFR inhibitor might be a novel treatment strategy for concomitant BRAF and PTEN-mutant CRC.
{"title":"CDK4/6 inhibition to resensitize BRAF/EGFR inhibitor in patient-derived BRAF/PTEN-mutant colon cancer cells.","authors":"Sung Hee Lim, Song-Yi Lee, Jung Yong Hong, Jeeyun Lee, Seung Tae Kim","doi":"10.21037/tcr-24-20","DOIUrl":"10.21037/tcr-24-20","url":null,"abstract":"<p><strong>Background: </strong>In v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant colorectal cancer (CRC), encorafenib-cetuximab has been established as standard second-line therapy, but not all patients respond and the duration of response is relatively short. Overcoming intrinsic or acquired resistance to BRAF/EGFR inhibitors is crucial for enhancing treatment outcomes in metastatic BRAF-mutated CRC. The aim of the study is to investigate the resistance mechanisms in BRAF-mutant CRC patient refractory to BRAF/EGFR targeted therapy.</p><p><strong>Methods: </strong>We established patient-derived cells (PDCs) from a patient with BRAF/PTEN-mutant metastatic colon cancer who progressed rapidly on encorafenib plus cetuximab. To explore potential treatment options for inherent resistance caused by simultaneous PTEN mutation in BRAF-mutated CRC, we conducted cell viability assays using PDCs treated with encorafenib-cetuximab in combination with a cyclin-dependent kinase-4 and 6 (CDK4/6) inhibitor.</p><p><strong>Results: </strong>The patient's tumor had concurrent PTEN loss-of-function alteration at diagnosis and PDCs were generated from ascites after resistance to the BRAF/EGFR inhibitor. The PDCs were resistant to the encorafenib-cetuximab combination even at a high concentration of cetuximab (up to 500 µg/mL). Adding the CDK4/6 inhibitor, ribociclib, to encorafenib-cetuximab showed a synergistic effect in a proliferation assay. Ribociclib plus encorafenib-cetuximab represented a significantly lower expression of Ki-67 compared to the dual combination alone. An MTS assay showed that triplet therapy with ribociclib, encorafenib, and cetuximab suppressed cell viability more efficiently than the two-drug combinations. Investigating the combined effect of triplet therapy using the calculated combination index (CI) showed that ribociclib had a synergistic effect with encorafenib-cetuximab when applied to PDCs with a concurrent BRAF/PTEN mutation.</p><p><strong>Conclusions: </strong>Our results suggest that combining the CDK4/6 inhibitor with the BRAF/EGFR inhibitor might be a novel treatment strategy for concomitant BRAF and PTEN-mutant CRC.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31Epub Date: 2024-07-26DOI: 10.21037/tcr-24-1019
Meiyu Zhou, Li Liu, Yonghong Tan, Rui Huang, Zailiang Yang
Background: Taohong Siwu decoction (THSWD) is a classic traditional Chinese medicine (TCM) formula known for its effects in promoting blood circulation, removing blood stasis, and rejuvenating energy. There have been clinical reports of THSWD treating chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel. We conducted a network pharmacology and molecular docking analysis to further clarify the molecular mechanisms by which THSWD exerts its protective effects against CIPN.
Methods: Chemical components of THSWD and their corresponding targets were obtained through the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP), and related targets of CIPN were searched in disease databases including Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), GeneCards, and DrugBank. Common targets between THSWD and CIPN were identified using Venn diagrams. A protein-protein interaction (PPI) network was constructed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), which was followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. AutoDock and PyMOL were used for the molecular docking validation of the key components of THSWD with core targets.
Results: At total of 69 chemical components of THSWD were identified, corresponding to 856 targets; 2,297 targets were associated with CIPN, with an intersection of 105 common targets. PPI analysis identified eight core targets: MYC, TNF, MAPK14, AKT1, ESR1, RELA, TP53, and HSP90AA1; KEGG enrichment analysis implicated signaling pathways such as PI3K-Akt, NF-κB, and HIF-1, etc. Molecular docking results indicated that the selected active components and their corresponding target proteins have good binding activity.
Conclusions: Through network pharmacology, this study found that THSWD has significant advantages in treating CIPN. By analyzing potential core targets, biological functions, and involved signaling pathways, we clarified the potential molecular biological mechanisms involved in THSWD's treatment effect. This study provides a theoretical basis for the clinical application of THSWD in treating CIPN.
{"title":"The mechanism of Taohong Siwu decoction in treating chemotherapy-induced peripheral neuropathy: a network pharmacology and molecular docking study.","authors":"Meiyu Zhou, Li Liu, Yonghong Tan, Rui Huang, Zailiang Yang","doi":"10.21037/tcr-24-1019","DOIUrl":"10.21037/tcr-24-1019","url":null,"abstract":"<p><strong>Background: </strong>Taohong Siwu decoction (THSWD) is a classic traditional Chinese medicine (TCM) formula known for its effects in promoting blood circulation, removing blood stasis, and rejuvenating energy. There have been clinical reports of THSWD treating chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel. We conducted a network pharmacology and molecular docking analysis to further clarify the molecular mechanisms by which THSWD exerts its protective effects against CIPN.</p><p><strong>Methods: </strong>Chemical components of THSWD and their corresponding targets were obtained through the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP), and related targets of CIPN were searched in disease databases including Online Mendelian Inheritance in Man (OMIM), Therapeutic Target Database (TTD), GeneCards, and DrugBank. Common targets between THSWD and CIPN were identified using Venn diagrams. A protein-protein interaction (PPI) network was constructed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), which was followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. AutoDock and PyMOL were used for the molecular docking validation of the key components of THSWD with core targets.</p><p><strong>Results: </strong>At total of 69 chemical components of THSWD were identified, corresponding to 856 targets; 2,297 targets were associated with CIPN, with an intersection of 105 common targets. PPI analysis identified eight core targets: <i>MYC</i>, <i>TNF</i>, <i>MAPK14</i>, <i>AKT1</i>, <i>ESR1</i>, <i>RELA</i>, <i>TP53</i>, and <i>HSP90AA1</i>; KEGG enrichment analysis implicated signaling pathways such as PI3K-Akt, NF-κB, and HIF-1, etc. Molecular docking results indicated that the selected active components and their corresponding target proteins have good binding activity.</p><p><strong>Conclusions: </strong>Through network pharmacology, this study found that THSWD has significant advantages in treating CIPN. By analyzing potential core targets, biological functions, and involved signaling pathways, we clarified the potential molecular biological mechanisms involved in THSWD's treatment effect. This study provides a theoretical basis for the clinical application of THSWD in treating CIPN.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Gliomas are the most prevalent primary brain tumors, and patients typically exhibit poor prognoses. Increasing evidence suggests that telomere maintenance mechanisms play a crucial role in glioma development. However, the prognostic value of telomere-related genes in glioma remains uncertain. This study aimed to construct a prognostic model of telomere-related genes and further elucidate the potential association between the two.
Methods: We acquired RNA-seq data for low-grade glioma (LGG) and glioblastoma (GBM), along with corresponding clinical information from The Cancer Genome Atlas (TCGA) database, and normal brain tissue data from the Genotype-Tissue Expression (GTEX) database for differential analysis. Telomere-related genes were obtained from TelNet. Initially, we conducted a differential analysis on TCGA and GTEX data to identify differentially expressed telomere-related genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on these genes. Subsequently, univariate Cox analysis and log-rank tests were employed to obtain prognosis-related genes. Least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate Cox regression analysis were sequentially utilized to construct prognostic models. The model's robustness was demonstrated using receiver operating characteristic (ROC) curve analysis, and multivariate Cox regression of risk scores for clinical characteristics and prognostic models were calculated to assess independent prognostic factors. The aforementioned results were validated using the Chinese Glioma Genome Atlas (CGGA) dataset. Finally, the CIBERSORT algorithm analyzed differences in immune cell infiltration levels between high- and low-risk groups, and candidate genes were validated in the Human Protein Atlas (HPA) database.
Results: Differential analysis yielded 496 differentially expressed telomere-related genes. GO and KEGG pathway analyses indicated that these genes were primarily involved in telomere-related biological processes and pathways. Subsequently, a prognostic model comprising ten telomere-related genes was constructed through univariate Cox regression analysis, log-rank test, LASSO regression analysis, and multivariate Cox regression analysis. Patients were stratified into high-risk and low-risk groups based on risk scores. Kaplan-Meier (K-M) survival analysis revealed worse outcomes in the high-risk group compared to the low-risk group, and establishing that this prognostic model was a significant independent prognostic factor for glioma patients. Lastly, immune infiltration analysis was conducted, uncovering notable differences in the proportion of multiple immune cell infiltrations between high- and low-risk groups, and eight candidate genes were verified in the HPA database.
Conclusions: This study successfully constructed a prog
{"title":"Development and validation of a glioma prognostic model based on telomere-related genes and immune infiltration analysis.","authors":"Xiaozhuo Liu, Jingjing Wang, Dongpo Su, Qing Wang, Mei Li, Zhengyao Zuo, Qian Han, Xin Li, Fameng Zhen, Mingming Fan, Tong Chen","doi":"10.21037/tcr-23-2294","DOIUrl":"10.21037/tcr-23-2294","url":null,"abstract":"<p><strong>Background: </strong>Gliomas are the most prevalent primary brain tumors, and patients typically exhibit poor prognoses. Increasing evidence suggests that telomere maintenance mechanisms play a crucial role in glioma development. However, the prognostic value of telomere-related genes in glioma remains uncertain. This study aimed to construct a prognostic model of telomere-related genes and further elucidate the potential association between the two.</p><p><strong>Methods: </strong>We acquired RNA-seq data for low-grade glioma (LGG) and glioblastoma (GBM), along with corresponding clinical information from The Cancer Genome Atlas (TCGA) database, and normal brain tissue data from the Genotype-Tissue Expression (GTEX) database for differential analysis. Telomere-related genes were obtained from TelNet. Initially, we conducted a differential analysis on TCGA and GTEX data to identify differentially expressed telomere-related genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses on these genes. Subsequently, univariate Cox analysis and log-rank tests were employed to obtain prognosis-related genes. Least absolute shrinkage and selection operator (LASSO) regression analysis and multivariate Cox regression analysis were sequentially utilized to construct prognostic models. The model's robustness was demonstrated using receiver operating characteristic (ROC) curve analysis, and multivariate Cox regression of risk scores for clinical characteristics and prognostic models were calculated to assess independent prognostic factors. The aforementioned results were validated using the Chinese Glioma Genome Atlas (CGGA) dataset. Finally, the CIBERSORT algorithm analyzed differences in immune cell infiltration levels between high- and low-risk groups, and candidate genes were validated in the Human Protein Atlas (HPA) database.</p><p><strong>Results: </strong>Differential analysis yielded 496 differentially expressed telomere-related genes. GO and KEGG pathway analyses indicated that these genes were primarily involved in telomere-related biological processes and pathways. Subsequently, a prognostic model comprising ten telomere-related genes was constructed through univariate Cox regression analysis, log-rank test, LASSO regression analysis, and multivariate Cox regression analysis. Patients were stratified into high-risk and low-risk groups based on risk scores. Kaplan-Meier (K-M) survival analysis revealed worse outcomes in the high-risk group compared to the low-risk group, and establishing that this prognostic model was a significant independent prognostic factor for glioma patients. Lastly, immune infiltration analysis was conducted, uncovering notable differences in the proportion of multiple immune cell infiltrations between high- and low-risk groups, and eight candidate genes were verified in the HPA database.</p><p><strong>Conclusions: </strong>This study successfully constructed a prog","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31Epub Date: 2024-07-11DOI: 10.21037/tcr-24-136
Fuli Gao, Luojie Liu, Xiaodan Xu
Background: Liver metastases from cancer of unknown primary (CUPL) constitute a rare disease, particularly among individuals younger than 50 years old. This paper aims to investigate the clinical characteristics of patients with CUPL and analyze prognostic differences across distinct age groups.
Methods: Data pertaining to patients with CUPL were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was employed to adjust for clinical variables. Cox regression analysis identified risk factors influencing overall survival (OS), while competing-risk analyses were conducted to determine prognostic factors for cancer-specific survival (CSS). Survival differences were compared using the Kaplan-Meier method and cumulative incidence function (CIF).
Results: The study encompassed 4,691 patients, with 319 (6.8%) in the age <50 years group and 4,372 (93.2%) in the age ≥50 years group. Individuals with unexplained liver metastases exhibited a 1-year OS rate of 14.7% and a 1-year CSS rate of 23%. Following matching, age, histology, brain metastases, and chemotherapy were identified as independent prognostic factors affecting OS. Additionally, race, grade, histology, brain metastases, and chemotherapy were recognized as independent prognostic factors influencing CSS. Notably, the age <50 years group demonstrated superior OS and CSS compared to the age ≥50 years group before and after PSM. Among patients undergoing chemotherapy, the age <50 years group exhibited enhanced OS and CSS compared to their age ≥50 years counterparts. Furthermore, in individuals subjected to radiotherapy, the age <50 years group demonstrated superior OS, although no significant difference in CSS was observed.
Conclusions: The survival prognosis of patients with CUPL was found to be poor. However, both OS and CSS were more favorable in the age <50 years group compared to the age ≥50 years group. Additionally, radiotherapy and chemotherapy were associated with an OS benefit for patients in the age <50 years group.
{"title":"Clinical characteristics and prognosis of liver metastases with unknown primary site.","authors":"Fuli Gao, Luojie Liu, Xiaodan Xu","doi":"10.21037/tcr-24-136","DOIUrl":"10.21037/tcr-24-136","url":null,"abstract":"<p><strong>Background: </strong>Liver metastases from cancer of unknown primary (CUPL) constitute a rare disease, particularly among individuals younger than 50 years old. This paper aims to investigate the clinical characteristics of patients with CUPL and analyze prognostic differences across distinct age groups.</p><p><strong>Methods: </strong>Data pertaining to patients with CUPL were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was employed to adjust for clinical variables. Cox regression analysis identified risk factors influencing overall survival (OS), while competing-risk analyses were conducted to determine prognostic factors for cancer-specific survival (CSS). Survival differences were compared using the Kaplan-Meier method and cumulative incidence function (CIF).</p><p><strong>Results: </strong>The study encompassed 4,691 patients, with 319 (6.8%) in the age <50 years group and 4,372 (93.2%) in the age ≥50 years group. Individuals with unexplained liver metastases exhibited a 1-year OS rate of 14.7% and a 1-year CSS rate of 23%. Following matching, age, histology, brain metastases, and chemotherapy were identified as independent prognostic factors affecting OS. Additionally, race, grade, histology, brain metastases, and chemotherapy were recognized as independent prognostic factors influencing CSS. Notably, the age <50 years group demonstrated superior OS and CSS compared to the age ≥50 years group before and after PSM. Among patients undergoing chemotherapy, the age <50 years group exhibited enhanced OS and CSS compared to their age ≥50 years counterparts. Furthermore, in individuals subjected to radiotherapy, the age <50 years group demonstrated superior OS, although no significant difference in CSS was observed.</p><p><strong>Conclusions: </strong>The survival prognosis of patients with CUPL was found to be poor. However, both OS and CSS were more favorable in the age <50 years group compared to the age ≥50 years group. Additionally, radiotherapy and chemotherapy were associated with an OS benefit for patients in the age <50 years group.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31Epub Date: 2024-07-24DOI: 10.21037/tcr-24-201
Wanting Zheng, Wangjianfei Yu, Ruheng Hua, Jun He, Nuwa Wu, Siyun Tian, Wentao Huang, Lei Qin
Background: Triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane immunoglobulin-superfamily receptor, is expressed primarily on cells such as macrophages and dendritic cells. TREM2 has been shown to be associated with diseases such as neurodegeneration, fatty liver, obesity, and atherosclerosis. Currently, it has become one of the hotspots in oncology research. However, the role of TREM2 in pan-cancer, especially pancreatic cancer, remains unclear.
Methods: We used the Tumor-immune System Interactions Database (TISIDB) to explore TREM2 expression differences, Tumor Immune Single-cell Hub 2 (TISCH2) to explore TREM2 expression distribution, Tumor IMmune Estimation Resource 2.0 (TIMER 2.0) to explore immune infiltration, cBio Cancer Genomics Portal (cBioPortal) to explore genetic variation, Genomics of Drug Sensitivity in Cancer (GDSC) to explore drug resistance, and Kaplan-Meier plotter database to explore the relationship between TREM2 and prognosis in pancreatic cancer. In addition, we used The Cancer Genome Atlas-pancreatic adenocarcinoma (TCGA-PAAD) and normal pancreas samples from the Genotype-Tissue Expression (GTEx) databases to explore the relationship between TREM2 and lymph node metastasis. We verified the protein level of TREM2 in pancreatic cancer by Human Protein Atlas (HPA) and western blotting and detected the colocalization of TREM2 with malignant cell markers by multiplex immunohistochemistry (mIHC). Finally, we identified the tumor-promoting role of TREM2 in pancreatic cancer via in vitro experiments, such as cell cycle assays, colony formation assays, and transwell migration and invasion assays.
Results: Our results showed that TREM2 was differentially expressed in various tumors according to different molecular and immune subtypes of pan-cancer. It was found that TREM2 was mainly expressed in monocytes/macrophages. In addition, our study showed that TREM2 expression was closely associated with macrophages in the tumor microenvironment (TME) of pan-cancer. TREM2 was shown to be related to anti-inflammatory and immunosuppressive effects in most cancers. Furthermore, we found that amplification was the main somatic mutation of TREM2 in pan-cancer. Further correlational analysis revealed a significant negative association of TREM2 expression with sensitivity to AZD8186, which is a selective inhibitor of PI3K, but not gemcitabine and paclitaxel. Finally, through the knockdown and overexpression of TREM2, our findings verified that TREM2 on cancer cells promoted the progression of PAAD.
Conclusions: In conclusion, our comprehensive analysis identified that TREM2 expression level was correlated with the TME and the immunosuppressive effects. In particular, our study indicated that TREM2 was involved in the progression of pancreatic cancer.
背景:髓系细胞上表达的触发受体 2(TREM2)是一种跨膜免疫球蛋白超家族受体,主要在巨噬细胞和树突状细胞等细胞上表达。研究表明,TREM2 与神经变性、脂肪肝、肥胖和动脉粥样硬化等疾病有关。目前,它已成为肿瘤学研究的热点之一。然而,TREM2在泛癌症尤其是胰腺癌中的作用仍不清楚:方法:我们利用肿瘤免疫系统相互作用数据库(TISIDB)探究TREM2的表达差异,利用肿瘤免疫单细胞中心2(TISCH2)探究TREM2的表达分布,利用肿瘤免疫估计资源2.0(TIMER 2.0)来探究免疫浸润;cBio Cancer Genomics Portal(cBioPortal)来探究基因变异;Genomics of Drug Sensitivity in Cancer(GDSC)来探究耐药性;Kaplan-Meier plotter 数据库来探究 TREM2 与胰腺癌预后的关系。此外,我们还利用癌症基因组图谱-胰腺癌(TCGA-PAAD)和基因型-组织表达(GTEx)数据库中的正常胰腺样本来探讨TREM2与淋巴结转移的关系。我们通过人类蛋白质图谱(HPA)和Western印迹验证了TREM2在胰腺癌中的蛋白水平,并通过多重免疫组化(mIHC)检测了TREM2与恶性细胞标记物的共定位。最后,我们通过体外实验,如细胞周期实验、集落形成实验和经孔迁移与侵袭实验,确定了TREM2在胰腺癌中的促瘤作用:结果:我们的研究结果表明,根据泛癌的不同分子亚型和免疫亚型,TREM2在不同肿瘤中的表达存在差异。研究发现,TREM2 主要在单核细胞/巨噬细胞中表达。此外,我们的研究还表明,TREM2 的表达与泛癌症肿瘤微环境(TME)中的巨噬细胞密切相关。在大多数癌症中,TREM2 被证明与抗炎和免疫抑制作用有关。此外,我们还发现扩增是泛癌症中 TREM2 的主要体细胞突变。进一步的相关分析表明,TREM2的表达与PI3K选择性抑制剂AZD8186的敏感性呈显著负相关,但与吉西他滨和紫杉醇的敏感性无关。最后,通过TREM2的敲除和过表达,我们的研究结果验证了癌细胞上的TREM2促进了PAAD的进展:总之,我们的综合分析发现,TREM2的表达水平与TME和免疫抑制效应相关。我们的研究尤其表明,TREM2参与了胰腺癌的进展。
{"title":"Systematic analysis of TREM2 and its carcinogenesis in pancreatic cancer.","authors":"Wanting Zheng, Wangjianfei Yu, Ruheng Hua, Jun He, Nuwa Wu, Siyun Tian, Wentao Huang, Lei Qin","doi":"10.21037/tcr-24-201","DOIUrl":"10.21037/tcr-24-201","url":null,"abstract":"<p><strong>Background: </strong>Triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane immunoglobulin-superfamily receptor, is expressed primarily on cells such as macrophages and dendritic cells. TREM2 has been shown to be associated with diseases such as neurodegeneration, fatty liver, obesity, and atherosclerosis. Currently, it has become one of the hotspots in oncology research. However, the role of TREM2 in pan-cancer, especially pancreatic cancer, remains unclear.</p><p><strong>Methods: </strong>We used the Tumor-immune System Interactions Database (TISIDB) to explore TREM2 expression differences, Tumor Immune Single-cell Hub 2 (TISCH2) to explore TREM2 expression distribution, Tumor IMmune Estimation Resource 2.0 (TIMER 2.0) to explore immune infiltration, cBio Cancer Genomics Portal (cBioPortal) to explore genetic variation, Genomics of Drug Sensitivity in Cancer (GDSC) to explore drug resistance, and Kaplan-Meier plotter database to explore the relationship between TREM2 and prognosis in pancreatic cancer. In addition, we used The Cancer Genome Atlas-pancreatic adenocarcinoma (TCGA-PAAD) and normal pancreas samples from the Genotype-Tissue Expression (GTEx) databases to explore the relationship between TREM2 and lymph node metastasis. We verified the protein level of TREM2 in pancreatic cancer by Human Protein Atlas (HPA) and western blotting and detected the colocalization of TREM2 with malignant cell markers by multiplex immunohistochemistry (mIHC). Finally, we identified the tumor-promoting role of TREM2 in pancreatic cancer via <i>in vitro</i> experiments, such as cell cycle assays, colony formation assays, and transwell migration and invasion assays.</p><p><strong>Results: </strong>Our results showed that TREM2 was differentially expressed in various tumors according to different molecular and immune subtypes of pan-cancer. It was found that TREM2 was mainly expressed in monocytes/macrophages. In addition, our study showed that TREM2 expression was closely associated with macrophages in the tumor microenvironment (TME) of pan-cancer. TREM2 was shown to be related to anti-inflammatory and immunosuppressive effects in most cancers. Furthermore, we found that amplification was the main somatic mutation of TREM2 in pan-cancer. Further correlational analysis revealed a significant negative association of TREM2 expression with sensitivity to AZD8186, which is a selective inhibitor of PI3K, but not gemcitabine and paclitaxel. Finally, through the knockdown and overexpression of TREM2, our findings verified that TREM2 on cancer cells promoted the progression of PAAD.</p><p><strong>Conclusions: </strong>In conclusion, our comprehensive analysis identified that TREM2 expression level was correlated with the TME and the immunosuppressive effects. In particular, our study indicated that TREM2 was involved in the progression of pancreatic cancer.</p>","PeriodicalId":23216,"journal":{"name":"Translational cancer research","volume":null,"pages":null},"PeriodicalIF":1.5,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}