Pub Date : 2025-02-01DOI: 10.1016/j.neo.2024.101101
Fang Yuan , Juan Xu , Lingmei Xuan , Chan Deng , Wei Wang , Rong Yang
<div><h3>Background</h3><div>Radiotherapy is a major modality for esophageal cancer (ESCA) treatment, yet radioresistance severely hampers its therapeutic efficacy. Ubiquitin-specific peptidase 14 (USP14) is a novel deubiquitinase and can mediate cancer cells’ response to irradiation, although the underlying mechanism remains unclear, including in ESCA.</div></div><div><h3>Methods</h3><div>To evaluate the expression of USP14 in ESCA tissues or cells, we used RNA-Seq, immunoblotting, co-immunoprecipitation (Co-IP), ubiquitination, quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence assays in this investigation. Additionally, we used CCK8, cloning, and migration tests to examine the proliferation and migration of ESCA cells. We also used transplantation tumor mouse model to investigate the course of the cancer cell growth. Finally, we looked into the biological processes linked to USP14 using gene set enrichment analysis (GSEA), which was later verified.</div></div><div><h3>Results</h3><div>We observed a significant upregulation of USP14 in human ESCA tissues and cell lines, especially in those with radioresistance. Moreover, USP14 knockdown significantly restrained the proliferation and inhibited the radiation tolerance of ESCC cells. Here, we identified a potential inhibitor of USP14, Degrasyn (DGS), and investigated its regulatory effects on ESCA radioresistance and progression. We found that DGS had marked antiproliferative effects in radiosensitive ESCA cell lines. Notably, a low dose of DGS significantly enhanced the sensitivity of radioresistant ESCA cells to irradiation, as shown by the significantly reduced cell proliferation, migration, and invasion. Furthermore, the combination of DGS and X-ray irradiation strongly induced DNA damage in radioresistant ESCA cell lines by increasing the phosphorylation levels of H2AX (γ-H2AX) and checkpoint kinase 1/ataxia-telangiectasia-mutated-and-Rad3-related kinase (CHK1/ATR) signaling. Animal experiments confirmed the effective role of the DGS and X-ray combined treatment in reducing tumor growth and irradiation tolerance of ESCA <em>in vivo</em> with undetectable toxicity. Importantly, the promotive and malignant biological behaviors of ESCA cells suppressed by the DGS/X-ray combination treatment were almost eliminated by USP14 overexpression, along with the abolished DNA damage process. Mechanistically, we found that USP14 could interact with Yes-associated protein 1 (YAP1) and induce its deubiquitination in radioresistant ESCA cells. Interestingly, we discovered that DGS/X-ray co-therapy significantly reduced the stability of YAP1 and induced its ubiquitination in radioresistant ESCA cells. More importantly, the proliferation, epithelial-mesenchymal tansition (EMT) process, and DNA damage regulated by DGS/X-ray and USP14 knockdown were significantly eliminated when YAP1 was overexpressed in radioresistant ESCA cells.</div></div><div><h3>Conclusions</h3><div>These data
{"title":"USP14 inhibition by degrasyn induces YAP1 degradation and suppresses the progression of radioresistant esophageal cancer","authors":"Fang Yuan , Juan Xu , Lingmei Xuan , Chan Deng , Wei Wang , Rong Yang","doi":"10.1016/j.neo.2024.101101","DOIUrl":"10.1016/j.neo.2024.101101","url":null,"abstract":"<div><h3>Background</h3><div>Radiotherapy is a major modality for esophageal cancer (ESCA) treatment, yet radioresistance severely hampers its therapeutic efficacy. Ubiquitin-specific peptidase 14 (USP14) is a novel deubiquitinase and can mediate cancer cells’ response to irradiation, although the underlying mechanism remains unclear, including in ESCA.</div></div><div><h3>Methods</h3><div>To evaluate the expression of USP14 in ESCA tissues or cells, we used RNA-Seq, immunoblotting, co-immunoprecipitation (Co-IP), ubiquitination, quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence assays in this investigation. Additionally, we used CCK8, cloning, and migration tests to examine the proliferation and migration of ESCA cells. We also used transplantation tumor mouse model to investigate the course of the cancer cell growth. Finally, we looked into the biological processes linked to USP14 using gene set enrichment analysis (GSEA), which was later verified.</div></div><div><h3>Results</h3><div>We observed a significant upregulation of USP14 in human ESCA tissues and cell lines, especially in those with radioresistance. Moreover, USP14 knockdown significantly restrained the proliferation and inhibited the radiation tolerance of ESCC cells. Here, we identified a potential inhibitor of USP14, Degrasyn (DGS), and investigated its regulatory effects on ESCA radioresistance and progression. We found that DGS had marked antiproliferative effects in radiosensitive ESCA cell lines. Notably, a low dose of DGS significantly enhanced the sensitivity of radioresistant ESCA cells to irradiation, as shown by the significantly reduced cell proliferation, migration, and invasion. Furthermore, the combination of DGS and X-ray irradiation strongly induced DNA damage in radioresistant ESCA cell lines by increasing the phosphorylation levels of H2AX (γ-H2AX) and checkpoint kinase 1/ataxia-telangiectasia-mutated-and-Rad3-related kinase (CHK1/ATR) signaling. Animal experiments confirmed the effective role of the DGS and X-ray combined treatment in reducing tumor growth and irradiation tolerance of ESCA <em>in vivo</em> with undetectable toxicity. Importantly, the promotive and malignant biological behaviors of ESCA cells suppressed by the DGS/X-ray combination treatment were almost eliminated by USP14 overexpression, along with the abolished DNA damage process. Mechanistically, we found that USP14 could interact with Yes-associated protein 1 (YAP1) and induce its deubiquitination in radioresistant ESCA cells. Interestingly, we discovered that DGS/X-ray co-therapy significantly reduced the stability of YAP1 and induced its ubiquitination in radioresistant ESCA cells. More importantly, the proliferation, epithelial-mesenchymal tansition (EMT) process, and DNA damage regulated by DGS/X-ray and USP14 knockdown were significantly eliminated when YAP1 was overexpressed in radioresistant ESCA cells.</div></div><div><h3>Conclusions</h3><div>These data","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101101"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Triple-negative breast cancer (TNBC) is an aggressive subtype that accounts for 10-15 % of breast cancer. Current treatment of high-risk early-stage TNBC includes neoadjuvant chemo-immune therapy. However, the substantial variation in immune response prompts an urgent need for new immune-targeting agents. This requires a comprehensive understanding of TNBC's tumor microenvironment. We recently demonstrated that Galectin-3 (Gal-3) binding protein/Gal-3 complex secreted by TNBC cells induces immunosuppression, through inhibiting CD45 signaling in T cells. Here, we further investigated the interaction between secreted Gal-3 and T cells in TNBC.
Using CRISPR/Cas9 gene editing of the TNBC MDA-MB-231 cell-line, we obtained Gal-3 negative(neg) clones. We studied these in an in-vitro model, co-cultured with peripheral blood mononuclear cells (PBMC) to imitate immune-tumor interaction, and in an in-vivo model, when implanted in mice.
Gal-3neg tumors in mice had decelerated tumor growth after PBMC inoculation. In contrast, the Gal-3 positive(pos) tumors continued growing despite PBMC inoculation, and tumor T regulatory cell (CD4/FoxP3+) infiltration increased. RNA sequencing of T cells from women with TNBC with elevated plasma levels of Gal-3 revealed significantly lower expression of oxidative phosphorylation genes than in T cells from healthy women. Similarly, in our in-vitro model, the decreased expression of oxidative phosphorylation genes and mitochondrial dysfunction resulted in a significant increase in CD8 intracellular reactive oxygen species. Consequently, T exhausted cells (CD8/PD1/Tim3/Lag3+) significantly increased in PBMC co-cultured with Gal-3pos TNBCs.
To conclude, we revealed a novel TNBC-related Gal-3 suppressor mechanism that involved upregulation of CD4 T regulatory and of CD8 T exhausted cells.
{"title":"Galectin-3 secreted by triple-negative breast cancer cells regulates T cell function","authors":"Annat Raiter , Yael Barhum , Julia Lipovetsky , Chen Menachem , Sharona Elgavish , Shmuel Ruppo , Yehudit Birger , Shai Izraeli , Orna Steinberg-Shemer , Rinat Yerushalmi","doi":"10.1016/j.neo.2024.101117","DOIUrl":"10.1016/j.neo.2024.101117","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is an aggressive subtype that accounts for 10-15 % of breast cancer. Current treatment of high-risk early-stage TNBC includes neoadjuvant chemo-immune therapy. However, the substantial variation in immune response prompts an urgent need for new immune-targeting agents. This requires a comprehensive understanding of TNBC's tumor microenvironment. We recently demonstrated that Galectin-3 (Gal-3) binding protein/Gal-3 complex secreted by TNBC cells induces immunosuppression, through inhibiting CD45 signaling in T cells. Here, we further investigated the interaction between secreted Gal-3 and T cells in TNBC.</div><div>Using CRISPR/Cas9 gene editing of the TNBC MDA-MB-231 cell-line, we obtained Gal-3 negative<sup>(neg)</sup> clones. We studied these in an <em>in-vitro</em> model, co-cultured with peripheral blood mononuclear cells (PBMC) to imitate immune-tumor interaction, and in an <em>in-vivo</em> model, when implanted in mice.</div><div>Gal-3<sup>neg</sup> tumors in mice had decelerated tumor growth after PBMC inoculation. In contrast, the Gal-3 positive<sup>(pos)</sup> tumors continued growing despite PBMC inoculation, and tumor T regulatory cell (CD4/FoxP3+) infiltration increased. RNA sequencing of T cells from women with TNBC with elevated plasma levels of Gal-3 revealed significantly lower expression of oxidative phosphorylation genes than in T cells from healthy women. Similarly, in our <em>in-vitro</em> model, the decreased expression of oxidative phosphorylation genes and mitochondrial dysfunction resulted in a significant increase in CD8 intracellular reactive oxygen species. Consequently, T exhausted cells (CD8/PD1/Tim3/Lag3+) significantly increased in PBMC co-cultured with Gal-3<sup>pos</sup> TNBCs.</div><div>To conclude, we revealed a novel TNBC-related Gal-3 suppressor mechanism that involved upregulation of CD4 T regulatory and of CD8 T exhausted cells.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101117"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.neo.2024.101114
Zhen Junhai , Meng Yang , Tan Zongbiao , Yan Wenxuan , Li Tiange , Wu Yanrui , Liu Chuan , Dong Weiguo
Aims
Very early-onset colorectal cancer (EOCRC) was defined as CRC diagnosed before the age of 35 proposed by the latest EOCRC management guideline. Until now, the disease burden of very EOCRC has never been reported. This study aimed to explore the burden of very EOCRC across the past three decades.
Methods
We extracted the data from Global Burden of Disease Study to analyze the disease burden of very EOCRC. Risk factors for the burden of deaths and disability-adjusted life years (DALYs) due to very EOCRC were also explored in this study. Additionally, decomposition analysis and frontier analysis were also conducted.
Results
Despite regional and gender variations, the global very EOCRC incidence cases increased from 21,874 (95 % UI: 20,386-23,470) to 41,545 (95 % UI: 37,978-45,523). Besides, the deaths cases also increased from 11,445 (95 % UI: 10,545-12,374) to 15,486 (95 % UI: 14,289-16,803), and the DALYs cases increased from 718,136 (95 % UI: 659,858-778,283) to 961,460 (95 % UI: 886,807-1,042,734). Decomposition analysis revealed the epidemiological change contributed most to the incidence burden of very EOCRC. Countries or regions with Sociodemographic Index (SDI) between 0.4 and 0.8 had greater disease burden improvement potential through frontier analysis. Diet low in milk, diet low in calcium, alcohol use, and high body-mass index were the main contributors to deaths and DALYs.
Conclusions
The increase in CRC burden among populations younger than 35 years globally requires vigilance from policy makers, physicians, and young individuals themselves, especially those regions experiencing faster growth burden of very EOCRC.
{"title":"Global, regional, and national burden of very early-onset colorectal cancer and its risk factors from 1990 to 2019: A systematic analysis for the global burden of disease study 2019","authors":"Zhen Junhai , Meng Yang , Tan Zongbiao , Yan Wenxuan , Li Tiange , Wu Yanrui , Liu Chuan , Dong Weiguo","doi":"10.1016/j.neo.2024.101114","DOIUrl":"10.1016/j.neo.2024.101114","url":null,"abstract":"<div><h3>Aims</h3><div>Very early-onset colorectal cancer (EOCRC) was defined as CRC diagnosed before the age of 35 proposed by the latest EOCRC management guideline. Until now, the disease burden of very EOCRC has never been reported. This study aimed to explore the burden of very EOCRC across the past three decades.</div></div><div><h3>Methods</h3><div>We extracted the data from Global Burden of Disease Study to analyze the disease burden of very EOCRC. Risk factors for the burden of deaths and disability-adjusted life years (DALYs) due to very EOCRC were also explored in this study. Additionally, decomposition analysis and frontier analysis were also conducted.</div></div><div><h3>Results</h3><div>Despite regional and gender variations, the global very EOCRC incidence cases increased from 21,874 (95 % UI: 20,386-23,470) to 41,545 (95 % UI: 37,978-45,523). Besides, the deaths cases also increased from 11,445 (95 % UI: 10,545-12,374) to 15,486 (95 % UI: 14,289-16,803), and the DALYs cases increased from 718,136 (95 % UI: 659,858-778,283) to 961,460 (95 % UI: 886,807-1,042,734). Decomposition analysis revealed the epidemiological change contributed most to the incidence burden of very EOCRC. Countries or regions with Sociodemographic Index (SDI) between 0.4 and 0.8 had greater disease burden improvement potential through frontier analysis. Diet low in milk, diet low in calcium, alcohol use, and high body-mass index were the main contributors to deaths and DALYs.</div></div><div><h3>Conclusions</h3><div>The increase in CRC burden among populations younger than 35 years globally requires vigilance from policy makers, physicians, and young individuals themselves, especially those regions experiencing faster growth burden of very EOCRC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101114"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.neo.2025.101128
Ryan M. Thomas
Research elucidating the role of the microbiome in carcinogenesis has grown exponentially over the past decade. Initially isolated to associative studies on colon cancer development, the field has expanded to encompass nearly every solid and liquid malignancy that may afflict the human body. Investigations are rapidly progressing from association to causation and one particular area of causal effect relates to microbial metabolites and how they influence cancer development, progression, and treatment response. These metabolites can be produced de novo from individual members of the microbiome, whether that be bacteria, fungi, archaea, or other microbial organisms, or they can be through metabolic processing of dietary compounds or even host-derived molecules. In this review, contemporary research elucidating mechanisms whereby microbial-derived molecules and metabolites impact carcinogenesis and cancer treatment efficacy will be presented. While many of the examples focus on bacterial metabolites in colon carcinogenesis, this simply illustrates the accelerated nature of these investigations that occurred early in microbiome research but provides an opportunity for growth in other cancer areas. Indeed, research into the interaction of microbiome-derived metabolites in other malignancies is growing as well as investigations that involve non-bacterial metabolites. This review will provide the reader a framework to expand their knowledge regarding this complex and exciting field of cancer research.
{"title":"Microbial molecules, metabolites, and malignancy","authors":"Ryan M. Thomas","doi":"10.1016/j.neo.2025.101128","DOIUrl":"10.1016/j.neo.2025.101128","url":null,"abstract":"<div><div>Research elucidating the role of the microbiome in carcinogenesis has grown exponentially over the past decade. Initially isolated to associative studies on colon cancer development, the field has expanded to encompass nearly every solid and liquid malignancy that may afflict the human body. Investigations are rapidly progressing from association to causation and one particular area of causal effect relates to microbial metabolites and how they influence cancer development, progression, and treatment response. These metabolites can be produced <em>de novo</em> from individual members of the microbiome, whether that be bacteria, fungi, archaea, or other microbial organisms, or they can be through metabolic processing of dietary compounds or even host-derived molecules. In this review, contemporary research elucidating mechanisms whereby microbial-derived molecules and metabolites impact carcinogenesis and cancer treatment efficacy will be presented. While many of the examples focus on bacterial metabolites in colon carcinogenesis, this simply illustrates the accelerated nature of these investigations that occurred early in microbiome research but provides an opportunity for growth in other cancer areas. Indeed, research into the interaction of microbiome-derived metabolites in other malignancies is growing as well as investigations that involve non-bacterial metabolites. This review will provide the reader a framework to expand their knowledge regarding this complex and exciting field of cancer research.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101128"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.neo.2025.101122
Chaoyan Yue , Qi Zhang , Fenyong Sun , Qiuhui Pan
Background
Neuroblastoma (NB) is the most common extracranial malignant solid tumor in children, accounting for >15 % of cancer-related deaths in children. We analyzed the epidemiological statistical indicators of neuroblastoma and other peripheral nervous system tumors patients from 1990 to 2021 in Global Burden of Disease (GBD) 2021 database, aiming to provide valuable insights for public health interventions and clinical practices.
Methods
Based on the GBD 2021 database, this study analyzed the incidence, mortality, prevalence, and Disability-Adjusted Life-Years (DALYs) of neuroblastoma and other peripheral nervous system tumors from 1990 to 2021, stratified by sociodemographic development index (SDI) and geographic regions. Cross-country inequalities analysis was conducted to quantify the SDI-related inequality of disease burden across countries. In addition, the average annual percentage change (AAPC) and Age-Period-Cohort (APC) model were used to evaluate the trend of disease burden, while the global burden of disease to 2035 was predicted by Bayesian Age-Period-Cohort (BAPC) model.
Findings
This study reported the disease burden of neuroblastoma and other peripheral nervous system tumors in GBD 2021 database for the first time. Globally, the incidence and mortality of neuroblastoma have increased year by year from 1990 to 2021, especially in regions with low SDI, such as South Asia and sub-Saharan Africa, where the burden of disease has increased significantly. Regions with high SDI, such as North America and Western Europe, have seen a reduction in disease burden due to higher levels of medical care and earlier diagnosis. The age distribution shows that children under 5 years of age are mainly affected, especially in low- and middle-income areas. In addition, the incidence is slightly higher in men than in women. The BAPC model predicts that the global incidence, mortality, and DALYs of neuroblastoma will continue to increase until 2035.
Interpretation
Significant regional and population variation in neuroblastoma and other peripheral nervous system tumors worldwide, with a particularly high disease burden in low SDI areas with limited medical resources. This trend highlights the urgent need for global public health interventions and resource allocation, particularly in low-income countries. Future research should focus on improving early diagnosis, risk stratification and target therapy in order to reduce the global burden of disease and improve patients’ prognosis.
Funding
This study was supported by National Natural Science Foundation of China (No. 82293662, No 82172357 and No 81930066), Key project of Shanghai "Science and Technology Innovation Action Plan (22JC1402304) and Research fund of Shanghai Municipal Health Bureau (No. 2019cxjq03).
{"title":"Global, regional and national burden of neuroblastoma and other peripheral nervous system tumors, 1990 to 2021 and predictions to 2035: visualizing epidemiological characteristics based on GBD 2021","authors":"Chaoyan Yue , Qi Zhang , Fenyong Sun , Qiuhui Pan","doi":"10.1016/j.neo.2025.101122","DOIUrl":"10.1016/j.neo.2025.101122","url":null,"abstract":"<div><h3>Background</h3><div>Neuroblastoma (NB) is the most common extracranial malignant solid tumor in children, accounting for >15 % of cancer-related deaths in children. We analyzed the epidemiological statistical indicators of neuroblastoma and other peripheral nervous system tumors patients from 1990 to 2021 in Global Burden of Disease (GBD) 2021 database, aiming to provide valuable insights for public health interventions and clinical practices.</div></div><div><h3>Methods</h3><div>Based on the GBD 2021 database, this study analyzed the incidence, mortality, prevalence, and Disability-Adjusted Life-Years (DALYs) of neuroblastoma and other peripheral nervous system tumors from 1990 to 2021, stratified by sociodemographic development index (SDI) and geographic regions. Cross-country inequalities analysis was conducted to quantify the SDI-related inequality of disease burden across countries. In addition, the average annual percentage change (AAPC) and Age-Period-Cohort (APC) model were used to evaluate the trend of disease burden, while the global burden of disease to 2035 was predicted by Bayesian Age-Period-Cohort (BAPC) model.</div></div><div><h3>Findings</h3><div>This study reported the disease burden of neuroblastoma and other peripheral nervous system tumors in GBD 2021 database for the first time. Globally, the incidence and mortality of neuroblastoma have increased year by year from 1990 to 2021, especially in regions with low SDI, such as South Asia and sub-Saharan Africa, where the burden of disease has increased significantly. Regions with high SDI, such as North America and Western Europe, have seen a reduction in disease burden due to higher levels of medical care and earlier diagnosis. The age distribution shows that children under 5 years of age are mainly affected, especially in low- and middle-income areas. In addition, the incidence is slightly higher in men than in women. The BAPC model predicts that the global incidence, mortality, and DALYs of neuroblastoma will continue to increase until 2035.</div></div><div><h3>Interpretation</h3><div>Significant regional and population variation in neuroblastoma and other peripheral nervous system tumors worldwide, with a particularly high disease burden in low SDI areas with limited medical resources. This trend highlights the urgent need for global public health interventions and resource allocation, particularly in low-income countries. Future research should focus on improving early diagnosis, risk stratification and target therapy in order to reduce the global burden of disease and improve patients’ prognosis.</div></div><div><h3>Funding</h3><div>This study was supported by <span>National Natural Science Foundation of China</span> (No. 82293662, No 82172357 and No 81930066), Key project of Shanghai \"Science and Technology Innovation Action Plan (22JC1402304) and Research fund of Shanghai Municipal Health Bureau (No. 2019cxjq03).</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101122"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.neo.2025.101124
Lisa Staffeldt , Hanna Maar , Julia Beimdiek , Samuel Chambers , Kristoffer Riecken , Mark von Itzstein , Falk FR Buettner , Arun Everest-Dass , Tobias Lange
{"title":"Corrigendum to “Depletion of ß1,6-N-acetylglucosaminyltransferase reduces E-selectin binding capacity and migratory potential of human gastrointestinal adenocarcinoma cells” [Neoplasia 59 (2024) 10183]","authors":"Lisa Staffeldt , Hanna Maar , Julia Beimdiek , Samuel Chambers , Kristoffer Riecken , Mark von Itzstein , Falk FR Buettner , Arun Everest-Dass , Tobias Lange","doi":"10.1016/j.neo.2025.101124","DOIUrl":"10.1016/j.neo.2025.101124","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101124"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.neo.2024.101119
Shu Wang , Hong Chen , Bo Dai , Kang Zheng , Jiajun Zheng , Yuqi Zhu , Yan Yuan , Tianling Ding , Qian Wang , Liqian Xie , Rui Feng , Fengping Zhu , Jianbin Xiang , Weiqun Ding , Hong Ding , Yuan Li , Xiaodong Gu , Kunpeng Wu , Yifan Yuan , Jianping Song , Tong Chen
Primary central nervous system diffused large B-cell lymphoma (PCNS-DLBCL) is a rare type of non-Hodgkin lymphoma restricted to the central nervous system (CNS). To explore its specific pathogenesis and therapeutic targets, we performed multi-omics sequencing on tumor samples from patients diagnosed with PCNS-DLBCL, secondary CNS-DLBCL or extracranial (ec) DLBCL.By single-cell RNA sequencing, highly proliferated and dark zone (DZ)-related B cell subclusters, MKI67_B1, PTTG1_B2 and BTG1_B3, were predominant significantly in PCNS-DLBCL. Compared to SCNS-DLBCL and ecDLBCL, an immune-suppressive tumor microenvironment was observed in PCNS-DLBCL by analysis of immune-stimulating/inhibitory ligand‒receptor (L-R) pairs. By performing whole-exome sequencing in 93 patients, mutations enriched in BCR-NFkB and TLR pathways and the cooperation of these two pathways were found to be predominant in PCNS-DLBCL comparing to nonGCB-ecDLBCL. In summary, our study provides comprehensive insights into the transcriptomic and genetic characteristics of PCNS-DLBCL in contrast to ecDLBCL and will help dissect the oncogenic mechanism of this disease.
{"title":"Comparison of differences in transcriptional and genetic profiles between intra-central nervous system and extra-central nervous system large B-cell lymphoma","authors":"Shu Wang , Hong Chen , Bo Dai , Kang Zheng , Jiajun Zheng , Yuqi Zhu , Yan Yuan , Tianling Ding , Qian Wang , Liqian Xie , Rui Feng , Fengping Zhu , Jianbin Xiang , Weiqun Ding , Hong Ding , Yuan Li , Xiaodong Gu , Kunpeng Wu , Yifan Yuan , Jianping Song , Tong Chen","doi":"10.1016/j.neo.2024.101119","DOIUrl":"10.1016/j.neo.2024.101119","url":null,"abstract":"<div><div>Primary central nervous system diffused large B-cell lymphoma (PCNS-DLBCL) is a rare type of non-Hodgkin lymphoma restricted to the central nervous system (CNS). To explore its specific pathogenesis and therapeutic targets, we performed multi-omics sequencing on tumor samples from patients diagnosed with PCNS-DLBCL, secondary CNS-DLBCL or extracranial (ec) DLBCL.By single-cell RNA sequencing, highly proliferated and dark zone (DZ)-related B cell subclusters, MKI67_B1, PTTG1_B2 and BTG1_B3, were predominant significantly in PCNS-DLBCL. Compared to SCNS-DLBCL and ecDLBCL, an immune-suppressive tumor microenvironment was observed in PCNS-DLBCL by analysis of immune-stimulating/inhibitory ligand‒receptor (L-R) pairs. By performing whole-exome sequencing in 93 patients, mutations enriched in BCR-NFkB and TLR pathways and the cooperation of these two pathways were found to be predominant in PCNS-DLBCL comparing to nonGCB-ecDLBCL. In summary, our study provides comprehensive insights into the transcriptomic and genetic characteristics of PCNS-DLBCL in contrast to ecDLBCL and will help dissect the oncogenic mechanism of this disease.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"60 ","pages":"Article 101119"},"PeriodicalIF":4.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neo.2024.101091
Sonia A.M. Ferkel, Elizabeth A. Holman, Raoul S. Sojwal, Samuel J.S. Rubin, Stephan Rogalla
Colorectal cancer encompasses a heterogeneous group of malignancies that differ in pathophysiological mechanisms, immune response and infiltration, therapeutic response, and clinical prognosis. Numerous studies have highlighted the clinical relevance of tumor-infiltrating immune cells among different types of colorectal tumors yet vary in cell type definitions and cell identification strategies. The distinction of immune signatures is particularly challenging when several immune subtypes are involved but crucial to identify novel intercellular mechanisms within the tumor microenvironment. In this review, we compile human and non-human studies on tumor-infiltrating immune cells and provide an overview of immune subtypes, their pathophysiological functions, and their prognostic role in colorectal cancer. We discuss how differentiating immune signatures can guide the development of immunotherapeutic targets and personalized treatment regimens. We analyzed comprehensive human protein biomarker profiles across the entire immune spectrum to improve interpretability and application of tumor studies and to ultimately enhance immunotherapy and advance precision medicine for colorectal cancer patients.
{"title":"Tumor-Infiltrating Immune Cells in Colorectal Cancer","authors":"Sonia A.M. Ferkel, Elizabeth A. Holman, Raoul S. Sojwal, Samuel J.S. Rubin, Stephan Rogalla","doi":"10.1016/j.neo.2024.101091","DOIUrl":"10.1016/j.neo.2024.101091","url":null,"abstract":"<div><div>Colorectal cancer encompasses a heterogeneous group of malignancies that differ in pathophysiological mechanisms, immune response and infiltration, therapeutic response, and clinical prognosis. Numerous studies have highlighted the clinical relevance of tumor-infiltrating immune cells among different types of colorectal tumors yet vary in cell type definitions and cell identification strategies. The distinction of immune signatures is particularly challenging when several immune subtypes are involved but crucial to identify novel intercellular mechanisms within the tumor microenvironment. In this review, we compile human and non-human studies on tumor-infiltrating immune cells and provide an overview of immune subtypes, their pathophysiological functions, and their prognostic role in colorectal cancer. We discuss how differentiating immune signatures can guide the development of immunotherapeutic targets and personalized treatment regimens. We analyzed comprehensive human protein biomarker profiles across the entire immune spectrum to improve interpretability and application of tumor studies and to ultimately enhance immunotherapy and advance precision medicine for colorectal cancer patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101091"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11665540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.neo.2024.101062
Xuedong Wang , Xinping Wang , Juan Gu , Yilei Wei , Yueping Wang
Objective
Docetaxel (DTX) represents an effective chemotherapeutic agent for treating triple-negative breast cancer (TNBC), but the efficacy is strongly limited by drug resistance. c-MYC-mediated ribosome biogenesis is considered a feasible strategy to confront chemoresistance in BC. We elucidated the impact of CMTM6 on TNBC DTX chemoresistance by governing c-MYC-mediated ribosome biogenesis, and its upstream ceRNA regulatory pathways.
Methods
DTX-resistant TNBC cells MDA-MB-231R and HCC1937R were generated by exposing sensitive cells MDA-MB-231 and HCC1937 to escalating doses of DTX. The expression patterns of CMTM6 and c-MYC were assessed by Western blot. The relationships between CMTM6 and miR-340-5p, circUBR5 and miR-340-5p were determined using bioinformatics analysis, luciferase assay, RIP, RNA in situ hybridization and biotin-labeled miR co-precipitation assay. Following ectopic expression and depletion experiments in DTX-resistant cells, cell chemoresistance, apoptosis, colony formation and nascent protein synthesis were evaluated.
Results
CMTM6 expression was elevated in DTX-resistant TNBC cells. CMTM6 knockdown enhanced apoptosis of DTX-resistant TNBC cells and increased their sensitivity to DTX by blocking c-MYC-mediated ribosome biogenesis. Mechanistically, miR-340-5p targeted CMTM6 and negatively regulated the expression of CMTM6 in DTX-resistant TNBC cells. Moreover, circUBR5 attenuated the repression on CMTM6 expression as a ceRNA for miR-340-5p. circUBR5 knockdown inactivated c-MYC-mediated ribosome biogenesis, and therefore enhanced DTX efficacy by promoting miR-340-5p binding to CMTM6.
Conclusion
circUBR5 knockdown facilitated miR-340-5p-targeted CMTM6 via a ceRNA mechanism, thereby reducing c-MYC-mediated ribosome biogenesis and accelerating chemosensitization of DTX-resistant TNBC cells, which offered a theoretical guideline for clinical research on the feasibility of inhibiting ribosome biogenesis to reduce TNBC chemoresistance.
{"title":"circUBR5 promotes ribosome biogenesis and induces docetaxel resistance in triple-negative breast cancer cell lines via the miR-340-5p/CMTM6/c-MYC axis","authors":"Xuedong Wang , Xinping Wang , Juan Gu , Yilei Wei , Yueping Wang","doi":"10.1016/j.neo.2024.101062","DOIUrl":"10.1016/j.neo.2024.101062","url":null,"abstract":"<div><h3>Objective</h3><div>Docetaxel (DTX) represents an effective chemotherapeutic agent for treating triple-negative breast cancer (TNBC), but the efficacy is strongly limited by drug resistance. c-MYC-mediated ribosome biogenesis is considered a feasible strategy to confront chemoresistance in BC. We elucidated the impact of CMTM6 on TNBC DTX chemoresistance by governing c-MYC-mediated ribosome biogenesis, and its upstream ceRNA regulatory pathways.</div></div><div><h3>Methods</h3><div>DTX-resistant TNBC cells MDA-MB-231R and HCC1937R were generated by exposing sensitive cells MDA-MB-231 and HCC1937 to escalating doses of DTX. The expression patterns of CMTM6 and c-MYC were assessed by Western blot. The relationships between CMTM6 and miR-340-5p, circUBR5 and miR-340-5p were determined using bioinformatics analysis, luciferase assay, RIP, RNA in situ hybridization and biotin-labeled miR co-precipitation assay. Following ectopic expression and depletion experiments in DTX-resistant cells, cell chemoresistance, apoptosis, colony formation and nascent protein synthesis were evaluated.</div></div><div><h3>Results</h3><div>CMTM6 expression was elevated in DTX-resistant TNBC cells. CMTM6 knockdown enhanced apoptosis of DTX-resistant TNBC cells and increased their sensitivity to DTX by blocking c-MYC-mediated ribosome biogenesis. Mechanistically, miR-340-5p targeted CMTM6 and negatively regulated the expression of CMTM6 in DTX-resistant TNBC cells. Moreover, circUBR5 attenuated the repression on CMTM6 expression as a ceRNA for miR-340-5p. circUBR5 knockdown inactivated c-MYC-mediated ribosome biogenesis, and therefore enhanced DTX efficacy by promoting miR-340-5p binding to CMTM6.</div></div><div><h3>Conclusion</h3><div>circUBR5 knockdown facilitated miR-340-5p-targeted CMTM6 via a ceRNA mechanism, thereby reducing c-MYC-mediated ribosome biogenesis and accelerating chemosensitization of DTX-resistant TNBC cells, which offered a theoretical guideline for clinical research on the feasibility of inhibiting ribosome biogenesis to reduce TNBC chemoresistance.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101062"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Epidemiological studies have implicated ovulation as a risk factor for ovarian high-grade serous carcinoma (HGSC) at the initiation stage. Precancerous lesions of HGSC commonly exhibit TP53 mutations attributed to DNA deamination and are frequently localized in the fallopian tube epithelium (FTE), a site regularly exposed to ovulatory follicular fluid (FF). This study aimed to assess the mutagenic potential of FF and investigate the expression levels and functional role of activation-induced cytidine deaminase (AID) following ovulation, along with the resulting TP53 DNA deamination.
Methods
The mutagenic activity of FF toward premalignant and malignant FTE cells was determined using the hypoxanthine phosphoribosyl transferase (HPRT) mutation assay with or without AID knockdown. The sequential activation of AID, including expressional induction, nuclear localization, DNA binding, and deamination, was determined. AID inducers in FF were identified, and the times of action and signaling pathways were determined.
Results
FF induced AID activation and de novo FTE cell mutagenesis in two waves of activity in accordance with post-ovulation FF exposure. The ERK-mediated early activity started at 2 min and peaked at 45 min, and the NF-κB-mediated late activity started at 6 h and peaked at 8.5 h after exposure. ROS, TNF-α, and estradiol, which are abundant in FF, all induced the two activities, while all activities were abolished by antioxidant cotreatment. AID physically bound to and biochemically deaminated the TP53 gene, regardless of known mutational hotspots. It did not act on other prevalent tumor-suppressor genes of HGSC.
Conclusion
This study revealed the ROS-dependent AID-mediated mutagenic activity of the ovulatory FF. The results filled up the missing link between ovulation and the initial TP53 mutation and invited a strategy of antioxidation in prevention of HGSC.
{"title":"Ovulation sources ROS to confer mutagenic activities on the TP53 gene in the fallopian tube epithelium","authors":"Kanchana Subramani , Hsuan-Shun Huang , Pao-Chu Chen , Dah-Ching Ding , Tang-Yuan Chu","doi":"10.1016/j.neo.2024.101085","DOIUrl":"10.1016/j.neo.2024.101085","url":null,"abstract":"<div><h3>Introduction</h3><div>Epidemiological studies have implicated ovulation as a risk factor for ovarian high-grade serous carcinoma (HGSC) at the initiation stage. Precancerous lesions of HGSC commonly exhibit TP53 mutations attributed to DNA deamination and are frequently localized in the fallopian tube epithelium (FTE), a site regularly exposed to ovulatory follicular fluid (FF). This study aimed to assess the mutagenic potential of FF and investigate the expression levels and functional role of activation-induced cytidine deaminase (AID) following ovulation, along with the resulting TP53 DNA deamination.</div></div><div><h3>Methods</h3><div>The mutagenic activity of FF toward premalignant and malignant FTE cells was determined using the hypoxanthine phosphoribosyl transferase (HPRT) mutation assay with or without AID knockdown. The sequential activation of AID, including expressional induction, nuclear localization, DNA binding, and deamination, was determined. AID inducers in FF were identified, and the times of action and signaling pathways were determined.</div></div><div><h3>Results</h3><div>FF induced AID activation and <em>de novo</em> FTE cell mutagenesis in two waves of activity in accordance with post-ovulation FF exposure. The ERK-mediated early activity started at 2 min and peaked at 45 min, and the NF-κB-mediated late activity started at 6 h and peaked at 8.5 h after exposure. ROS, TNF-α, and estradiol, which are abundant in FF, all induced the two activities, while all activities were abolished by antioxidant cotreatment. AID physically bound to and biochemically deaminated the <em>TP53</em> gene, regardless of known mutational hotspots. It did not act on other prevalent tumor-suppressor genes of HGSC.</div></div><div><h3>Conclusion</h3><div>This study revealed the ROS-dependent AID-mediated mutagenic activity of the ovulatory FF. The results filled up the missing link between ovulation and the initial <em>TP53</em> mutation and invited a strategy of antioxidation in prevention of HGSC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101085"},"PeriodicalIF":4.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142787442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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