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Middha P, Kachuri L, Nierenberg JL, Graff RE, Cavazos TB, Hoffmann TJ, Zhang J, Alexeeff S, Habel L, Corley DA, Van Den Eeden S, Kushi LH, Ziv E, Sakoda LC, Witte JS. Unraveling the genetic landscape of susceptibility to multiple primary cancers. HGG ADVANCES 2025; 6:100413. [PMID: 39910817 PMCID: PMC11910107 DOI: 10.1016/j.xhgg.2025.100413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/29/2025] [Accepted: 01/29/2025] [Indexed: 02/07/2025] Open
Abstract
With advances in cancer screening and treatment, there is a growing population of cancer survivors who may develop subsequent primary cancers. While hereditary cancer syndromes account for only a portion of multiple cancer cases, we sought to explore the role of common genetic variation in susceptibility to multiple primary tumors. We conducted a cross-ancestry genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) of 10,983 individuals with multiple primary cancers, 84,475 individuals with single cancer, and 420,944 cancer-free controls from two large-scale studies. Our GWAS identified six lead variants across five genomic regions that were significantly associated (p < 5 × 10-8) with the risk of developing multiple primary tumors (overall and invasive) relative to cancer-free controls (at 3q26, 8q24, 10q24, 11q13.3, and 17p13). We also found one variant significantly associated with multiple cancers when compared with single cancer cases (at 22q13.1). Multi-tissue TWAS detected associations with genes involved in telomere maintenance in two of these regions (ACTRT3 in 3q26 and SLK and STN1 in 10q24) and the development of multiple cancers. Additionally, the TWAS also identified several novel genes associated with multiple cancers, including two immune-related genes, IRF4 and TNFRSF6B. Telomere maintenance and immune dysregulation emerge as central, common pathways influencing susceptibility to multiple cancers. These findings underscore the importance of exploring shared mechanisms in carcinogenesis, offering insights for targeted prevention and intervention strategies.
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Affiliation(s)
- Pooja Middha
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Linda Kachuri
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA
| | - Jovia L Nierenberg
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Rebecca E Graff
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Taylor B Cavazos
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Thomas J Hoffmann
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
| | - Jie Zhang
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Stacey Alexeeff
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Laurel Habel
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Douglas A Corley
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | | | - Lawrence H Kushi
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Elad Ziv
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA
| | - Lori C Sakoda
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA; Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA
| | - John S Witte
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA; Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA.
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Middha P, Kachuri L, Nierenberg JL, Graff RE, Cavazos TB, Hoffmann TJ, Zhang J, Alexeeff S, Habel L, Corley DA, Van Den Eeden S, Kushi LH, Ziv E, Sakoda LC, Witte JS. Unraveling the genetic landscape of susceptibility to multiple primary cancers. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.10.29.24316326. [PMID: 39574869 PMCID: PMC11581075 DOI: 10.1101/2024.10.29.24316326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/01/2024]
Abstract
With advances in cancer screening and treatment, there is a growing population of cancer survivors who may develop subsequent primary cancers. While hereditary cancer syndromes account for only a portion of multiple cancer cases, we sought to explore the role of common genetic variation in susceptibility to multiple primary tumors. We conducted a cross-ancestry genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) of 10,983 individuals with multiple primary cancers, 84,475 individuals with single cancer, and 420,944 cancer-free controls from two large-scale studies. Our GWAS identified six lead variants across five genomic regions that were significantly associated (P<5×10-8) with the risk of developing multiple primary tumors (overall and invasive) relative to cancer-free controls (at 3q26, 8q24, 10q24, 11q13.3, and 17p13). We also found one variant significantly associated with multiple cancers when comparing to single cancer cases (at 22q13.1). Multi-tissue TWAS detected associations with genes involved in telomere maintenance in two of these regions (ACTRT3 in 3q26 and SLK and STN1 in 10q24) and the development of multiple cancers. Additionally, the TWAS also identified several novel genes associated with multiple cancers, including two immune-related genes, IRF4 and TNFRSF6B. Telomere maintenance and immune dysregulation emerge as central, common pathways influencing susceptibility to multiple cancers. These findings underscore the importance of exploring shared mechanisms in carcinogenesis, offering insights for targeted prevention and intervention strategies.
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Affiliation(s)
- Pooja Middha
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - Linda Kachuri
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
| | - Jovia L Nierenberg
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Rebecca E Graff
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Taylor B Cavazos
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Thomas J Hoffmann
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Jie Zhang
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Stacey Alexeeff
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Laurel Habel
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Douglas A Corley
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
- Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
| | - Stephen Van Den Eeden
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Lawrence H Kushi
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Elad Ziv
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
| | - Lori C Sakoda
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
- Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, USA
| | - John S Witte
- Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University, Stanford, CA, USA
- Department of Biomedical Data Sciences, Stanford University, Stanford, CA, USA
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Zhang A, Ji Q, Sheng X, Wu H. mRNA vaccine in gastrointestinal tumors: Immunomodulatory effects and immunotherapy. Biomed Pharmacother 2023; 166:115361. [PMID: 37660645 DOI: 10.1016/j.biopha.2023.115361] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/04/2023] [Accepted: 08/22/2023] [Indexed: 09/05/2023] Open
Abstract
Gastrointestinal tumors remain a significant healthcare burden worldwide, necessitating the development of innovative therapeutic strategies. mRNA vaccines have emerged as a promising approach in cancer immunotherapy, harnessing the immune system's potential to recognize and eliminate tumor cells. mRNA vaccines offer several advantages, including their ability to elicit both innate and adaptive immune responses, ease of production, and adaptability to different tumor types. In the context of gastrointestinal tumors, mRNA vaccines hold great potential as a therapeutic strategy. In this review, we will delve into the immunomodulatory mechanisms and immunotherapy strategies of mRNA vaccines in gastrointestinal tumors. Additionally, we will discuss the challenges and ongoing research efforts in optimizing mRNA vaccine development, delivery, and stability. By understanding the potential of mRNA vaccines in addressing the unmet medical need of gastrointestinal tumors, we aim to pave the way for improved treatment strategies and better patient outcomes.
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Affiliation(s)
- Ao Zhang
- Department of Neurology, The First Hospital of Jilin University, Changchun 130012, China
| | - Qingming Ji
- Department of Intensive Care Medicine, The First Hospital of Jilin University, Changchun 130012, China
| | - Xia Sheng
- Department of Cadre Ward, The First Hospital of Jilin University, Changchun 130012, China
| | - Hui Wu
- Department of Ophthalmology, The First Hospital of Jilin University, Changchun 130012, China.
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The Role of the Key Differentially Mutated Gene FGFR3 in the Immune Microenvironment of Bladder Cancer. J Immunol Res 2022; 2022:7952706. [PMID: 35991125 PMCID: PMC9391163 DOI: 10.1155/2022/7952706] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/17/2022] [Accepted: 07/29/2022] [Indexed: 11/17/2022] Open
Abstract
The tumor microenvironment (TME) has been a major focus of research in recent years as a crucial factor in the development and progression of bladder cancer. Unfortunately, the precise composition of TME, particularly the immunological and stromal components, remains unknown. In this work, we downloaded the RNA-seq expression profiles and somatic mutation data of 433 bladder cancer cases from The Cancer Genome Atlas (TCGA) and then employed a comprehensive bioinformatics approach to evaluate them. Firstly, the expression profiles were used to predict the scores and then the content of immune and stromal cells via the estimate package in R software. We then identified differentially expressed genes (DEGs) and differentially mutated genes (DMGs) according to the high-stromal score cohort and low-stromal score cohort. Finally, fibroblast growth factor receptor 3 (FGFR3) was the main differentially mutated gene in bladder carcinoma that we discovered after conducting a cross-study on DEGs and DMGs. Follow-up investigation revealed that FGFR3, whose expression correlated inversely with cancer progression stage, appeared to be a protective factor in bladder cancer. The method of Gene Set Enrichment Analysis (GSEA) was employed to, respectively, interpret the expression data of FGFR3 in high and low expression lists. We observed that the genes in the low FGFR3 expression list were strongly enriched in the biological processes associated with transplantation and cell adhesion, suggesting the possible role of FGFR3 in predicting TME metastasis status in bladder cancer. Therefore, this study is aimed at investigating whether FGFR3 is promising as a biomarker of TME remodeling to explain underlying mechanisms involved in tumorigenesis and metastasis, which may help to make decisions on treatments for bladder cancer.
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Gu W, Shen H, Xie L, Zhang X, Yang J. The Role of Feedback Loops in Targeted Therapy for Pancreatic Cancer. Front Oncol 2022; 12:800140. [PMID: 35651786 PMCID: PMC9148955 DOI: 10.3389/fonc.2022.800140] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 04/11/2022] [Indexed: 11/17/2022] Open
Abstract
Pancreatic cancer is the leading cause of cancer-related deaths worldwide, with limited treatment options and low long-term survival rates. The complex and variable signal regulation networks are one of the important reasons why it is difficult for pancreatic cancer to develop precise targeted therapy drugs. Numerous studies have associated feedback loop regulation with the development and therapeutic response of cancers including pancreatic cancer. Therefore, we review researches on the role of feedback loops in the progression of pancreatic cancer, and summarize the connection between feedback loops and several signaling pathways in pancreatic cancer, as well as recent advances in the intervention of feedback loops in pancreatic cancer treatment, highlighting the potential of capitalizing on feedback loops modulation in targeted therapy for pancreatic cancer.
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Affiliation(s)
- Weigang Gu
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - HongZhang Shen
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lu Xie
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaofeng Zhang
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- *Correspondence: Xiaofeng Zhang, ; Jianfeng Yang,
| | - Jianfeng Yang
- Department of Gastroenterology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Xiaofeng Zhang, ; Jianfeng Yang,
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Zhang C, Li H, Huang Y, Tang Y, Wang J, Cheng Y, Wei Y, Zhu D, Cao Z, Zhou J. Integrative analysis of TNFRSF6B as a potential therapeutic target for pancreatic cancer. J Gastrointest Oncol 2021; 12:1673-1690. [PMID: 34532119 PMCID: PMC8421915 DOI: 10.21037/jgo-21-303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 06/23/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Pancreatic cancer is one of the most lethal malignant tumors worldwide with poor outcomes. Previous studies have shown that tumor necrosis factor receptor superfamily member 6b (TNFRSF6B) plays an important role in cancer progression and immunosuppression. However, the mechanisms by which TNFRSF6B influence pancreatic cancer, and the regulatory networks involved remain to be further studied. METHODS This study analyzed the mRNA information and clinical data of patients from The Cancer Genome Atlas (TCGA) and the ONCOMINE databases. The gene co-expression data regarding TNFRSF6B was obtained from the c-BioPortal and used to explore the functional network of TNFRSF6B in pancreatic cancer, as well as its function in tumor immunity. Short hairpin (sh) RNA knock-down experiments were performed to examine the functional roles of TNFRSF6B in pancreatic cancer cell lines. RESULTS The expression of TNFRSF6B was elevated in pancreatic cancer tissues compared to normal pancreatic tissues, and its high expression was associated with poor prognosis of patients with pancreatic cancer. TNFRSF6B was found to be widely involved in cell cycle processes, apoptosis, apoptosis signaling pathways, immune responses, and responses to interferon. Knock-down of TNFRSF6B expression inhibited pancreatic cancer cell proliferation and invasion in vitro. Moreover, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) was found to be co-expressed with TNFRSF6B, and there was a positive correlation between these molecules in pancreatic cancer cells. CONCLUSIONS This report suggested that TNFRSF6B has a critical role in the progression and metastasis of pancreatic cancer. These findings provide novel insights into the role of TNFRSF6B in the functional network of pancreatic cancer, and suggest that TNFRSF6B may be a potential therapeutic target.
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Affiliation(s)
- Chen Zhang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Haoran Li
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yujie Huang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuchen Tang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jie Wang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yinxiang Cheng
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yijun Wei
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Dongming Zhu
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhifei Cao
- Department of Pathology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jian Zhou
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
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Zhang Y, Fu Y. Comprehensive Analysis and Identification of an Immune-Related Gene Signature with Prognostic Value for Prostate Cancer. Int J Gen Med 2021; 14:2931-2942. [PMID: 34234523 PMCID: PMC8254424 DOI: 10.2147/ijgm.s321319] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 06/14/2021] [Indexed: 12/27/2022] Open
Abstract
Background The tumor microenvironment (TME) has recently been proven to play a crucial role in the development and prognosis of tumors. However, the current knowledge on the potential of the TME in prostate cancer (PCa) remains scarce. Purpose This study aims to elucidate the value of TME-related genes for PCa prognosis by integrative bioinformatics analysis. Materials and Methods We downloaded the immune and stromal scores of PCa samples via the ESTIMATE and correlated these scores to clinicopathological characteristics and recurrence-free survival (RFS) of patients. Based on these scores, the TME-related differentially expressed genes were identified for functional enrichment analysis. Cox regression analyses were performed to identify prognostic genes and establish a predictive risk model. Moreover, gene set enrichment analysis (GSEA) was performed to evaluate the relationship between risk score and immune pathway. Results The stromal and immune scores were associated with clinicopathological characteristics and RFS in PCa patients. In total, 238 intersecting differentially expressed genes were identified. Functional enrichment analysis further revealed that these genes dramatically participated in the immune-related pathways. The immune-related risk model was built with C-type lectin domain containing 7A (CLEC7A) and collagen type XI alpha 1 chain (COL11A1) using Cox regression analyses. Kaplan–Meier survival analysis showed that the expression levels of CLEC7A and COL11A1 were significantly associated with the RFS. Further, the RFS time in high-risk group was significantly shorter than that in low-risk group. The areas under the curve for the risk model in predicting 3- and 5-year RFS rates were 0.694 and 0.731, respectively. GSEA suggested that immunosuppression existed in high-risk PCa patients. Conclusion CLEC7A and COL11A1 were selected to build a predictive risk model, which may help clinicians to assess the prognosis of PCa patients and select appropriate targets for immunotherapy.
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Affiliation(s)
- Yongrui Zhang
- Department of Urology, The First Hospital of Jilin University, Changchun, 130021, Jilin, People's Republic of China
| | - Yaowen Fu
- Department of Urology, The First Hospital of Jilin University, Changchun, 130021, Jilin, People's Republic of China
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Reclassification of Kidney Clear Cell Carcinoma Based on Immune Cell Gene-Related DNA CpG Pairs. Biomedicines 2021; 9:biomedicines9020215. [PMID: 33672457 PMCID: PMC7923436 DOI: 10.3390/biomedicines9020215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/11/2021] [Accepted: 02/15/2021] [Indexed: 12/18/2022] Open
Abstract
Background: A new method was developed based on the relative ranking of gene expression level, overcoming the flaw of the batch effect, and having reliable results in various studies. In the current study, we defined the two methylation sites as a pair. The methylation level in a specific sample was subject to pairwise comparison to calculate a score for each CpGs-pair. The score was defined as a CpGs-pair score. If the first immune-related CpG value was higher than the second one in a specific CpGs-pair, the output score of this immune-related CpGs-pair was 1; otherwise, the output score was 0. This study aimed to construct a new classification of Kidney Clear Cell Carcinoma (KIRC) based on DNA CpGs (methylation sites) pairs. Methods: In this study, the biomarkers of 28 kinds of immune infiltration cells and corresponding methylation sites were acquired. The methylation data were compared between KIRC and normal tissue samples, and differentially methylated sites (DMSs) were obtained. Then, DNA CpGs-pairs were obtained according to the pairs of DMSs. In total, 441 DNA CpGs-pairs were utilized to construct a classification using unsupervised clustering analysis. We also analyzed the potential mechanism and therapy of different subtypes, and validated them in a testing set. Results: The classification of KIRC contained three subgroups. The clinicopathological features were different across three subgroups. The distribution of immune cells, immune checkpoints and immune-related mechanisms were significantly different across the three clusters. The mutation and copy number variation (CNV) were also different. The clinicopathological features and potential mechanism in the testing dataset were consistent with those in the training set. Conclusions: Our findings provide a new accurate and stable classification for developing personalized treatments for the new specific subtypes.
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A Methylation-Based Reclassification of Bladder Cancer Based on Immune Cell Genes. Cancers (Basel) 2020; 12:cancers12103054. [PMID: 33092083 PMCID: PMC7593922 DOI: 10.3390/cancers12103054] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 10/13/2020] [Accepted: 10/16/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Bladder cancer (BC) development is highly related to immune cell infiltration. In this study, we aimed to construct a new classification of bladder cancer molecular subtypes based on immune-cell-associated CpG(Methylation) sites. The classification was accurate and stable. BC patients were successfully divided into three subtypes based on the immune-cell-associated CpG sites. The clinicopathologic features, distribution of immune cells, level of expression of checkpoints, stromal score, immune score, ESTIMATEScore, tumor purity, APC co_inhibition, APC co_stimulation, HLA, MHC class_I, Type I IFN_respons, Type II IFN response, and DNA stemness score (DNAss) presented significant differences among the three subgroups. The specific genomic alteration was also different across subgroups. High-level immune infiltration showed a correlation with high-level methylation. A lower RNA stemness score (RNAss) was associated with higher immune infiltration. Cluster 2 demonstrated a better response to chemotherapy. The anti-cancer targeted drug therapy results are different among the three subgroups. Abstract Background: Bladder cancer is highly related to immune cell infiltration. This study aimed to develop a new classification of BC molecular subtypes based on immune-cell-associated CpG sites. Methods: The genes of 28 types of immune cells were obtained from previous studies. Then, methylation sites corresponding to immune-cell-associated genes were acquired. Differentially methylated sites (DMSs) were identified between normal samples and bladder cancer samples. Unsupervised clustering analysis of differentially methylated sites was performed to divide the sites into several subtypes. Then, the potential mechanism of different subtypes was explored. Results: Bladder cancer patients were divided into three groups. The cluster 3 subtype had the best prognosis. Cluster 1 had the poorest prognosis. The distribution of immune cells, level of expression of checkpoints, stromal score, immune score, ESTIMATEScore, tumor purity, APC co_inhibition, APC co_stimulation, HLA, MHC class_I, Type I IFN Response, Type II IFN Response, and DNAss presented significant differences among the three subgroups. The distribution of genomic alterations was also different. Conclusions: The proposed classification was accurate and stable. BC patients could be divided into three subtypes based on the immune-cell-associated CpG sites. Specific biological signaling pathways, immune mechanisms, and genomic alterations were varied among the three subgroups. High-level immune infiltration was correlated with high-level methylation. The lower RNAss was associated with higher immune infiltration. The study of the intratumoral immune microenvironment may provide a new perspective for BC therapy.
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Li F, Teng H, Liu M, Liu B, Zhang D, Xu Z, Wang Y, Zhou H. Prognostic Value of Immune-Related Genes in the Tumor Microenvironment of Bladder Cancer. Front Oncol 2020; 10:1302. [PMID: 32850407 PMCID: PMC7399341 DOI: 10.3389/fonc.2020.01302] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 06/23/2020] [Indexed: 12/12/2022] Open
Abstract
The tumor microenvironment (TME) is a complex system that plays an important role in tumor development and progression, but the current knowledge about its effect on bladder cancer (BC) is scarce. In this study, we performed a comprehensive analysis of the relationship between the TME and gene expression profiles to identify prognostic biomarkers for BC. The ESTIMATE algorithm was used to calculate immune and stromal scores of BC patients who were obtained from the Gene Expression Omnibus database. We found that the immune and stromal scores were associated with clinical characteristics and the prognosis of BC patients. Based on these scores, 104 immune-related differentially expressed genes were identified. Further, functional enrichment analysis revealed that these genes were mainly involved in the immune-related biological processes and signaling pathways. Three prognostic genes were then identified and used to establish a risk prediction model using Cox regression analyses. Kaplan–Meier survival analysis showed that the expression levels of COL1A1, COMP, and SERPINE2 significantly correlated with cancer-specific survival and overall survival of BC patients. Additionally, we validated the prognostic values of these genes using two independent cohorts from The Cancer Genome Atlas and Gene Expression Omnibus databases. Finally, the relationships between the three prognostic genes and several immune cells were evaluated using Tumor Immune Estimation Resource, indicating that the expression levels of COL1A1, COMP, and SERPINE2 correlated positively with the tumor infiltration levels of CD4+ T cells and macrophages. In conclusion, the current study comprehensively analyzed the TME and presented immune-related prognostic genes for BC, providing new insights into immunotherapeutic strategies for BC patients.
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Affiliation(s)
- Faping Li
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Haolin Teng
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Mingdi Liu
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Bin Liu
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Difei Zhang
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Zhixiang Xu
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Honglan Zhou
- Department of Urology, The First Hospital of Jilin University, Changchun, China
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Vascular Endothelial Growth Factor Protects CD200-Rich and CD34-Positive Hair Follicle Stem Cells Against Androgen-Induced Apoptosis Through the Phosphoinositide 3-Kinase/Akt Pathway in Patients With Androgenic Alopecia. Dermatol Surg 2020; 46:358-368. [PMID: 31478937 DOI: 10.1097/dss.0000000000002091] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND 5α-DHT can decrease the cell viability of the hair follicle stem cells (HFSCs) with CD34-positive and CD200-rich in bald scalp area of androgenic alopecia (AGA) patients and the apoptosis of HFSCs may be involved in the pathogenesis of AGA. The expression of Vascular endothelial growth factor (VEGF) turns to be weakened or disappeared in hair follicles of AGA patients. OBJECTIVE To investigate whether VEGF is involved in the apoptosis of HFSCs induced by 5α-DHT in the patients of AGA. METHODS By 5α-DHT, apoptosis of CD200-rich and CD34-positive HFSCs was induced and apoptotic rates up to 24 hours were assessed using flow cytometry. The expression grades of Bcl-2, Akt, caspase-3 and Bax were observed through Western blot analysis. RESULTS Vascular endothelial growth factor could cut 5α-DHT induced apoptosis down substantially in a concentration-dependent manner. The 5α-DHT induced decline in the rise of Bcl-2/Bax proportion and the increase in caspase-3 degrees were mostly reversed by using VEGF and the VEGF's anti-apoptotic actions were impeded through preventing the activation of phosphoinositide 3-kinase (PI3K)/Akt. CONCLUSION Vascular endothelial growth factor can protect CD200-rich and CD34-positive HFSCs from androgen induced apoptosis by means of the PI3K/Akt pathway.
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Wei Y, Chen X, Yang J, Yao J, Yin N, Zhang Z, Li D, Zhu D, Zhou J. DcR3 promotes proliferation and invasion of pancreatic cancer via a DcR3/STAT1/IRF1 feedback loop. Am J Cancer Res 2019; 9:2618-2633. [PMID: 31911850 PMCID: PMC6943350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 11/21/2019] [Indexed: 06/10/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most common gastrointestinal malignancies that are highly aggressive with a low 5-year survival rate. Accumulated evidence has indicated that decoy receptor 3 (DcR3) is involved in several pathologic processes and various cancers. However, the mechanisms underlying dysregulated DcR3 expression and activation in PC remain to be fully established. In this study, we investigate the function and regulatory network of DcR3 in PC. We found that DcR3 was upregulated in PC tissues and serum. High DcR3 expression was associated with aggressive clinicopathological features and poor prognosis. Functionally, DcR3 not only increased cell migration and invasion in vitro but also promoted tumour growth both in vitro and in vivo by loss-of-function and gain-of-function experiments. Mechanistically, DcR3 promoted the phosphorylation of signal transducers and activators of transcription 1 (STAT1), leading to a dramatic increase in interferon regulatory factor 1 (IRF1). IRF1 then increased the transcriptional activity of DcR3, forming a positive feedback loop to reinforce DcR3 expression. In addition, DcR3 promoted carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expression through activated IRF1. In conclusion, our findings provided novel insights into the function and mechanism of DcR3 in the pathogenesis of PC, which may be a potential therapeutic target for PC.
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Affiliation(s)
- Yijun Wei
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
- Department of General Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
| | - Xingyu Chen
- Taizhou Fourth People’s HospitalTaizhou 225300, Jiangsu, China
| | - Jian Yang
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
- Department of General Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
| | - Jun Yao
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
- Department of General Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
| | - Ni Yin
- Department of Oncology, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
| | - Zixiang Zhang
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
- Department of General Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
| | - Dechun Li
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
- Department of General Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
| | - Dongming Zhu
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
- Department of General Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
| | - Jian Zhou
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
- Department of General Surgery, The First Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu, China
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Chen J, Li HY, Wang D, Guo XZ. Delphinidin protects β2m-/Thy1+ bone marrow-derived hepatocyte stem cells against TGF-β1-induced oxidative stress and apoptosis through the PI3K/Akt pathway in vitro. Chem Biol Interact 2018; 297:109-118. [PMID: 30365941 DOI: 10.1016/j.cbi.2018.10.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 08/15/2018] [Accepted: 10/22/2018] [Indexed: 12/12/2022]
Abstract
β2m-/Thy1+ bone marrow-derived hepatocyte stem cells (BDHSCs) have a potential to be applied for cellular treatment in liver cirrhosis. However, the resultant tissue regeneration is restricted by transplanted cells' death. The accumulation of transforming growth factor beta 1 (TGF-β1) in liver fibrosis local microenvironment may play an essential role in the rapid cell death of implanted β2m-/Thy1+ BDHSCs. The main mechanism of poor survival of the target stem cells is still unknown. Delphinidin, an anthocyanidin, has potent antioxidant and anti-inflammatory activities. However, whether this bio-active ingredient can substantially contribute to β2m-/Thy1+ BDHSCs' protection from TGF-β1 induced apoptosis in vitro remains to be elucidated. In the present research, we determined whether delphinidin pretreatment can improve the survival of β2m-/Thy1+ BDHSCs during exposure to TGF-β1 and elucidated its underlying mechanisms. By using TGF-β1, we induced the apoptosis of β2m-/Thy1+ BDHSCs and assessed the apoptotic rates up to 24 h by flow cytometry. β2m-/Thy1+ BDHSC proliferation was gauged using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl- 2H-tetrazolium bromide (MTT) assay. The expression grades of Bcl-2, Akt, caspase-3, and Bax were observed through Western blot analysis. We found that delphinidin can significantly impede TGF-β1-induced apoptosis dose-dependently, scavenge reactive oxygen species (ROS), and inhibit the discharge of caspase-3 in β2m-/Thy1+ BDHSCs. We also demonstrated that delphinidin can activate the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway. The suppression of ROS and succeeding apoptosis was achieved by pretreatment with LY294002, a PI3K/Akt pathway inhibitor. In summary, our findings revealed that delphinidin can protect β2m-/Thy1+ BDHSCs from apoptosis and ROS-dependent oxidative stress induced by the TGF-β1 via PI3K/Akt signaling pathway. On the basis of these data, delphinidin can be regarded as a promising anti-apoptotic agent for enhancing β2m-/Thy1+ BDHSC survival during cell transplantation in liver cirrhosis patients.
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Affiliation(s)
- Jiang Chen
- Department of Gastroenterology, Shenyang General Hospital of PLA, No. 83 Wenhua Road Shenyang City, 110016, Liaoning, PR China
| | - Hong-Yu Li
- Department of Gastroenterology, Shenyang General Hospital of PLA, No. 83 Wenhua Road Shenyang City, 110016, Liaoning, PR China
| | - Di Wang
- Department of Gastroenterology, Shenyang General Hospital of PLA, No. 83 Wenhua Road Shenyang City, 110016, Liaoning, PR China
| | - Xiao-Zhong Guo
- Department of Gastroenterology, Shenyang General Hospital of PLA, No. 83 Wenhua Road Shenyang City, 110016, Liaoning, PR China.
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