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Ye Z, Wu X, Wei Z, Sun Q, Wang Y, Li T, Yuan Y, Jing J. Microsatellite-Stable Gastric Cancer Can be Classified into 2 Molecular Subtypes with Different Immunotherapy Response and Prognosis Based on Gene Sequencing and Computational Pathology. J Transl Med 2025; 105:104101. [PMID: 39894411 DOI: 10.1016/j.labinv.2025.104101] [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: 08/01/2024] [Revised: 01/07/2025] [Accepted: 01/27/2025] [Indexed: 02/04/2025] Open
Abstract
Most patients with gastric cancer (GC) exhibit microsatellite stability, yet comprehensive subtyping for prognostic prediction and clinical treatment decisions for microsatellite-stable GC is lacking. In this work, RNA-sequencing gene expression data and clinical information of patients with microsatellite-stable GC were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. We employed several machine learning methods to develop and validate a signature based on immune-related genes (IRGs) for subtyping patients with microsatellite-stable GC. Moreover, 2 deep learning models based on the Vision Transformer (ViT) architecture were developed to predict GC tumor tiles and identify microsatellite-stable GC subtypes from digital pathology slides. Microsatellite status was evaluated by immunohistochemistry, and prognostic data as well as hematoxylin and eosin whole-slide images were collected from 105 patients with microsatellite-stable GC to serve as an independent validation cohort. A signature comprising 5 IRGs was established and validated, stratifying patients with microsatellite-stable GC into high-risk (microsatellite-stable-HR) and low-risk (microsatellite-stable-LR) groups. This signature demonstrated consistent performance, with areas under the receiver operating characteristic curve (AUC) of 0.65, 0.70, and 0.70 at 1, 3, and 5 years in the TCGA cohort, and 0.70, 0.60, and 0.62 in the GEO cohort, respectively. The microsatellite-stable-HR subtype exhibited higher levels of tumor immune dysfunction and exclusion, suggesting a greater potential for immune escape compared with the microsatellite-stable-LR subtype. Moreover, the microsatellite-stable-HR/LR subtypes showed differential sensitivities to various therapeutic drugs. Leveraging morphologic differences, the tumor recognition segmentation model achieved an impressive AUC of 0.97, whereas the microsatellite-stable-HR/LR identification model effectively classified microsatellite-stable-HR/LR subtypes with an AUC of 0.94. Both models demonstrated promising results in classifying patients with microsatellite-stable GC in the external validation cohort, highlighting the strong ability to accurately differentiate between microsatellite-stable GC subtypes. The IRG-related microsatellite-stable-HR/LR subtypes had the potential to enhance outcome prediction accuracy and guide treatment strategies. This research may optimize precision treatment and improve the prognosis for patients with microsatellite-stable GC.
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Affiliation(s)
- Zhiyi Ye
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - Xiaoyang Wu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - Zheng Wei
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - Qiuyan Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - Yanli Wang
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang, China
| | - Tan Li
- Department of Cardiovascular Ultrasound, the First Hospital of China Medical University, Shenyang, China.
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang, China.
| | - Jingjing Jing
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, the First Hospital of China Medical University, Shenyang, China.
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Jiang Y, Li W, Zhang J, Liu K, Wu Y, Wang Z. NFS1 as a Candidate Prognostic Biomarker for Gastric Cancer Correlated with Immune Infiltrates. Int J Gen Med 2024; 17:3855-3868. [PMID: 39253726 PMCID: PMC11382660 DOI: 10.2147/ijgm.s444443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 09/01/2024] [Indexed: 09/11/2024] Open
Abstract
Background Cysteine desulfurase (NFS1) is closely associated with the occurrence and development of human tumors, but its relationship with the prognosis and immunity of gastric cancer (GC) patients remains unclear. Methods To study the relationship between NFS1 and GC, GC-related data of TCGA were downloaded and analyzed. At the same time, Tumor Immune Estimation Resource (TIMER) and Kaplan‒Meier Plotter were used for relevant online analysis. Clinical samples were collected for immunohistochemical testing to validate the results. Results The mRNA and protein levels of NFS1 in GC tissues were significantly higher than those in normal tissues. In terms of the operating characteristic curve (ROC), the area under the curve (AUC) was 0.793, indicating that NFS1 had a high diagnostic value for GC. Further analysis showed that NFS1 expression was highly correlated with the depth of tumor invasion, lymph node metastasis, and tumor stage. Survival analysis showed that patients with high expression of NFS1 had a poorer prognosis, and NFS1 was an independent risk factor. Enrichment analysis by GO, KEGG, and GSEA showed that NFS1 was enriched in immune-related pathways. The expression of NFS1 was significantly positively correlated with the proportion of macrophages M0 and plasma cells but negatively correlated with the proportion of B cells memory, monocytes, and mast cells resting. In addition, NFS1 expression was significantly correlated with TMB levels and responses to immunotherapy. Conclusion Our results suggest that NFS1 may be a potential biomarker for the diagnosis and prediction of prognosis and immunotherapy efficacy in GC.
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Affiliation(s)
- You Jiang
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230011, People's Republic of China
- Department of General Surgery, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, 230011, People's Republic of China
| | - Wenbo Li
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230011, People's Republic of China
- Department of General Surgery, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, Anhui, 230011, People's Republic of China
| | - Jun Zhang
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230011, People's Republic of China
| | - Kun Liu
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230011, People's Republic of China
| | - Yuee Wu
- Department of Electrocardiogram Diagnosis, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230060, People's Republic of China
| | - Zhengguang Wang
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230011, People's Republic of China
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Mensah‐Bonsu M, Doss C, Gloster C, Muganda P. Gene expression analysis identifies hub genes and pathways distinguishing fatal from survivor outcomes of Ebola virus disease. FASEB Bioadv 2024; 6:298-310. [PMID: 39399477 PMCID: PMC11467745 DOI: 10.1096/fba.2024-00055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/06/2024] [Accepted: 07/02/2024] [Indexed: 10/15/2024] Open
Abstract
The Ebola virus poses a severe public health threat, yet understanding factors influencing disease outcomes remains incomplete. Our study aimed to identify critical pathways and hub genes associated with fatal and survivor Ebola disease outcomes. We analyzed differentially expressed hub genes (DEGs) between groups with fatal and survival outcomes, as well as a healthy control group. We conducted additional analysis to determine the functions and pathways associated with these DEGs. We found 13,198 DEGs in the fatal and 12,039 DEGs in the survival group compared to healthy controls, and 1873 DEGs in the acute fatal and survivor groups comparison. Upregulated DEGs in the comparison between the acute fatal and survivor groups were linked to ECM receptor interaction, complement and coagulation cascades, and PI3K-Akt signaling. Upregulated hub genes identified from the acute fatal and survivor comparison (FGB, C1QA, SERPINF2, PLAT, C9, SERPINE1, F3, VWF) were enriched in complement and coagulation cascades; the downregulated hub genes (IL1B, 1L17RE, XCL1, CXCL6, CCL4, CD8A, CD8B, CD3D) were associated with immune cell processes. Hub genes CCL2 and F2 were unique to fatal outcomes, while CXCL1, HIST1H4F, and IL1A were upregulated hub genes unique to survival outcomes compared to healthy controls. Our results demonstrate for the first time the association of EVD outcomes to specific hub genes and their associated pathways and biological processes. The identified hub genes and pathways could help better elucidate Ebola disease pathogenesis and contribute to the development of targeted interventions and personalized treatment for distinct EVD outcomes.
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Affiliation(s)
- Melvin Mensah‐Bonsu
- Applied Science and TechnologyNorth Carolina A&T State UniversityGreensboroNorth CarolinaUSA
| | - Christopher Doss
- Department of Electrical and Computer EngineeringNorth Carolina A&T State UniversityGreensboroNorth CarolinaUSA
| | - Clay Gloster
- Department of Computer Systems TechnologyNorth Carolina A&T State UniversityGreensboroNorth CarolinaUSA
| | - Perpetua Muganda
- Department of BiologyNorth Carolina A&T State UniversityGreensboroNorth CarolinaUSA
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Chen H, Zhang W, Shi J, Tang Y, Chen X, Li J, Yao X. Study on the mechanism of S100A4-mediated cancer oncogenesis in uveal melanoma cells through the integration of bioinformatics and in vitro experiments. Gene 2024; 911:148333. [PMID: 38431233 DOI: 10.1016/j.gene.2024.148333] [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: 12/14/2023] [Revised: 02/13/2024] [Accepted: 02/28/2024] [Indexed: 03/05/2024]
Abstract
BACKGROUND The elevated metastasis rate of uveal melanoma (UM) is intricately correlated with patient prognosis, significantly affecting the quality of life. S100 calcium-binding protein A4 (S100A4) has tumorigenic properties; therefore, the present study investigated the impact of S100A4 on UM cell proliferation, apoptosis, migration, and invasion using bioinformatics and in vitro experiments. METHODS Bioinformatic analysis was used to screen S100A4 as a hub gene and predict its possible mechanism in UM cells, and the S100A4 silencing cell line was constructed. The impact of S100A4 silencing on the proliferative ability of UM cells was detected using the Cell Counting Kit-8 and colony formation assays. Annexin V-FITC/PI double fluorescence and Hoechst 33342 staining were used to observe the effects of apoptosis on UM cells. The effect of S100A4 silencing on the migratory and invasive capabilities of UM cells was assessed using wound healing and Transwell assays. Western blotting was used to detect the expression of related proteins. RESULTS The present study found that S100A4 is a biomarker of UM, and its high expression is related to poor prognosis. After constructing the S100A4 silencing cell line, cell viability, clone number, proliferating cell nuclear antigen, X-linked inhibitor of apoptosis protein, and survivin expression were decreased in UM cells. The cell apoptosis rate and relative fluorescence intensity increased, accompanied by increased levels of Bax and caspase-3 and decreased levels of Bcl-2. Additionally, a decrease in the cell migration index and relative invasion rate was observed with increased E-cadherin expression and decreased N-cadherin and vimentin protein expression. CONCLUSION S100A4 silencing can inhibit the proliferation, migration, and invasion and synchronously induces apoptosis in UM cells.
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Affiliation(s)
- Huimei Chen
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Wenqing Zhang
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Jian Shi
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Yu Tang
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Xiong Chen
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Jiangwei Li
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China
| | - Xiaolei Yao
- The First Clinical College of Chinese Medicine, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China; Hunan Provincial Key Laboratory for the Prevention and Treatment of Ophthalmology and Otolaryngology Diseases with Traditional Chinese Medicine, Changsha, Hunan 410208, China.
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Jin Y, Xia Y, Du H, Xiang T, Lan B, Wei S, Li H, Huang H. Super-enhancer-associated EEPD1 facilitates EMT-mediated metastasis by regulating the PI3K/AKT/mTOR pathway in gastric cancer. Biochem Biophys Res Commun 2023; 689:149188. [PMID: 37976838 DOI: 10.1016/j.bbrc.2023.149188] [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: 10/08/2023] [Revised: 10/23/2023] [Accepted: 10/30/2023] [Indexed: 11/19/2023]
Abstract
This study focused on exploring the mechanism of the EMT mediated by endonuclease/exonuclease/phosphatase family domain-containing 1 (EEPD1) in gastric cancer metastasis. Through bioinformatics analysis, EEPD1 was found to be a target gene of super enhancers (SEs) in gastric cancer tissues. EEPD1 exhibited higher expression levels in tumor tissues and was associated with poor prognosis. In vitro and in vivo studies have demonstrated that silencing EEPD1 significantly suppressed the proliferation, metastasis, and invasion of gastric cancer cells. Furthermore, EEPD1 knockdown was involved in the regulation of the EMT and suppressed expression of AKT, a downstream component of the PI3K pathway, leading to a reduction in the phosphorylation levels of AKT and its downstream molecule, mTOR. These results showed the potential of EEPD1 as a prognostic indicator and therapeutic target in gastric cancer.
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Affiliation(s)
- Yong Jin
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China; Department of Laboratory Medicine, The Second People's Hospital of Guizhou Province, Guiyang, 550004, China
| | - Ying Xia
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China; Department of Clinical Laboratory, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, China; Division of Gastroenterology and Hepatology, Department of Medicine and Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Hong Du
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China; School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, China
| | - Tingting Xiang
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, China
| | - Bingxue Lan
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China; School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, China
| | - Sixi Wei
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Hongyu Li
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China; School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, China
| | - Hai Huang
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China; School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, China.
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Lv J, Yu C, Tian H, Li T, Yu C. Expression of Serpin Family E Member 1 (SERPINE1) Is Associated with Poor Prognosis of Gastric Adenocarcinoma. Biomedicines 2023; 11:3346. [PMID: 38137567 PMCID: PMC10741528 DOI: 10.3390/biomedicines11123346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/09/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND The aberrant expression of serpin family E member 1 (SERPINE1) is associated with carcinogenesis. This study assessed the alteration of SERPINE1 expression for an association with gastric adenocarcinoma prognosis. METHODS The Cancer Genome Atlas (TCGA) dataset was applied to investigate the impact of SERPINE1 expression on the survival of patients afflicted with gastric cancer. Subsequently, 136 samples from the Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University were subjected to qRT-PCR and Western blot to validate the expression level of SERPINE1 between tumor and adjacent normal tissues. The correlation between the expression of SERPINE1 with the clinicopathological features in TCGA patients was analyzed using Wilcoxon signed-rank and logistic regression tests. The potential molecular mechanism associated with SERPINE1 expression in gastric cancer were confirmed using gene set enrichment analysis (GSEA). RESULTS The TCGA data showed that SERPINE1 was overexpressed in tumor tissues compared to normal mucosae and associated with the tumor T stage and pathological grade. SERPINE1 overexpression was associated with the poor overall survival (OS) of patients. The findings were confirmed with 136 patients, that is, SERPINE1 expression was associated with poor OS (hazard ratio (HR): 1.82; 95% confidence interval (CI): 0.84-1.83; p = 0.012)) as an independent predictor (HR: 2.11, 95% CI: 0.81-2.34; p = 0.009). The resulting data were further processed by GSEA showed that SERPINE1 overexpression was associated with the activation of EPITHELIAL_MESENCHYMAL_TRANSITION, TNFA_SIGNALING_VIA_NFKB, INFLAMMATORY_RESPONSE, ANGIOGENESIS, and HYPOXIA. CONCLUSIONS SERPINE1 overexpression is associated with a poor gastric cancer prognosis.
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Affiliation(s)
- Jie Lv
- Department of Radiotherapy, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huanghe West Road, Huaiyin District, Huai’an 223300, China; (J.L.); (H.T.); (T.L.)
| | - Chunyang Yu
- Department of Cardiology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an 223300, China;
| | - Hanhan Tian
- Department of Radiotherapy, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huanghe West Road, Huaiyin District, Huai’an 223300, China; (J.L.); (H.T.); (T.L.)
| | - Tao Li
- Department of Radiotherapy, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huanghe West Road, Huaiyin District, Huai’an 223300, China; (J.L.); (H.T.); (T.L.)
| | - Changhua Yu
- Department of Radiotherapy, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huanghe West Road, Huaiyin District, Huai’an 223300, China; (J.L.); (H.T.); (T.L.)
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Shang F, Wang Y, Shi Z, Deng Z, Ma J. Development of a Signature Based on Eight Metastatic-Related Genes for Prognosis of GC Patients. Mol Biotechnol 2023; 65:1796-1808. [PMID: 36790659 PMCID: PMC10518294 DOI: 10.1007/s12033-023-00671-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 01/14/2023] [Indexed: 02/16/2023]
Abstract
Gastric cancer (GC) has been a common tumor type with high mortality. Distal metastasis is one of the main causes of death in GC patients, which is also related to poor prognosis. The mRNA profiles and clinical information of GC patients were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. Univariate Cox and LASSO Cox analyses were used to screen the optimal metastasis-related genes (MRGs) to establish a prognostic Risk Score model for GC patients. The nomogram was used to visualize the Risk Score and predict the 1-, 3-, 5-year survival rate. The immune cell infiltration was analyzed by CIBERSORT and the ratio of immune-stromal component was calculated by the ESTIMATE algorithm. A total of 142 differentially expressed genes were identified between metastatic and non-metastatic GC samples. The optimal 8 genes, comprising GAMT (guanidinoacetate N-methyltransferase), ABCB5 (ATP-binding cassette subfamily B member 5), ITIH3 (inter-alpha-trypsin inhibitor heavy chain 3), GDF3 (growth differentiation factor 3), VSTM2L (V-set and transmembrane domain-containing 2 like), CIDEA (cell death inducing DFFA like effector a), NPTX1 (neuronal pentraxin-1), and UMOD (uromodulin), were further screened to establish a prognostic Risk Score, which proved to be an independent prognostic factor. Patients in high-risk group had a poor prognosis. There were significant differences in the proportion of 11 tumor-infiltrating immune cells between high-risk and low-risk subgroups. In addition, the StromalScore, ImmuneScore, and ESTIMATEScore in high-risk group were higher than those in low-risk group, indicating that the tumor microenvironment of the high-risk group was more complex. A Risk Score model based on eight metastasis-related genes could clearly distinguish the prognosis of GC patients. The poor prognosis of patients with high-Risk Score might be associated with the complex tumor microenvironments.
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Affiliation(s)
- Fanjing Shang
- Department of General Surgery, People's Hospital of Ningxia Hui Autonomous Region, No. 301 Zhengyuan North Road, Jinfeng District, Yinchuan, 750001, Ningxia, China
| | - Yafei Wang
- Department of General Surgery, People's Hospital of Ningxia Hui Autonomous Region, No. 301 Zhengyuan North Road, Jinfeng District, Yinchuan, 750001, Ningxia, China
| | - Zixu Shi
- Department of General Surgery, People's Hospital of Ningxia Hui Autonomous Region, No. 301 Zhengyuan North Road, Jinfeng District, Yinchuan, 750001, Ningxia, China
| | - Zhidong Deng
- Department of General Surgery, People's Hospital of Ningxia Hui Autonomous Region, No. 301 Zhengyuan North Road, Jinfeng District, Yinchuan, 750001, Ningxia, China
| | - Jianwen Ma
- Department of General Surgery, People's Hospital of Ningxia Hui Autonomous Region, No. 301 Zhengyuan North Road, Jinfeng District, Yinchuan, 750001, Ningxia, China.
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Wang S, Yang X, Liu C, Hu J, Yan M, Ding C, Fu Y. Identification of key genes associated with poor prognosis and neoplasm staging in gastric cancer. Medicine (Baltimore) 2023; 102:e35111. [PMID: 37800754 PMCID: PMC10553055 DOI: 10.1097/md.0000000000035111] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 08/16/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is highly biologically and genetically heterogeneous disease with poor prognosis. Increasing evidence indicates that biomarkers can serve as prediction and clinical intervention. Therefore, it is vital to identify core molecules and pathways participating in the development of GC. METHODS In this study, GSE54129, GSE56807, GSE63089, and GSE118916 were used for identified overlapped 75 DEGs. GO and Kyoto Encyclopedia of Genes and Genomes pathway analysis showed DEGs mainly enriched in biological process about collagen-containing extracellular matrix and collagen metabolic. Next, protein-protein interaction network was built and the hub gene was excavated. Clinicopathological features and prognostic value were also evaluated. RESULTS Hub genes were shown as below, FN1, COL1A2, COL1A1, COL3A1, COL4A1, COL6A3, COL5A2, SPARC, PDGFRB, COL12A1. Those genes were upregulation in GC and related to the poor prognosis (except COL5A2, P = .73). What is more, high expression indicated worse T stage and tumor, node, metastasis stage in GC patients. Later, the results of 25 GC tumor specimens and 34 normal tissues showed that FN1, COL3A1, COL4A1, SPARC, COL5A2, and COL12A1 were significantly upregulated in cancer samples. CONCLUSION Our study systematically explored the core genes and crucial pathways in GC, providing insights into clinical management and individual treatment.
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Affiliation(s)
- Shuoshan Wang
- Department of General Medicine, The First People’s Hospital of Foshan, The Affiliated Foshan Hospital of Sun Yat-Sen University, Guangdong, China
| | - Xiansheng Yang
- Second Department of Gastrointestinal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, GuangZhou, China
| | - Chang Liu
- Guangzhou KingMed Center for Clinical Laboratory Co., Ltd, Guangzhou, China
| | - Jinlun Hu
- Department of General Medicine, The First People’s Hospital of Foshan, The Affiliated Foshan Hospital of Sun Yat-Sen University, Guangdong, China
| | - Mei Yan
- Department of General Medicine, The First People’s Hospital of Foshan, The Affiliated Foshan Hospital of Sun Yat-Sen University, Guangdong, China
| | - Chan Ding
- Department of General Medicine, The First People’s Hospital of Foshan, The Affiliated Foshan Hospital of Sun Yat-Sen University, Guangdong, China
| | - Yue Fu
- Department of General Medicine, The First People’s Hospital of Foshan, The Affiliated Foshan Hospital of Sun Yat-Sen University, Guangdong, China
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Chen J, Li X, Mak TK, Wang X, Ren H, Wang K, Kuo ZC, Wu W, Li M, Hao T, Zhang C, He Y. The predictive effect of immune therapy and chemotherapy under T cell-related gene prognostic index for Gastric cancer. Front Cell Dev Biol 2023; 11:1161778. [PMID: 37274740 PMCID: PMC10232754 DOI: 10.3389/fcell.2023.1161778] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 05/09/2023] [Indexed: 06/06/2023] Open
Abstract
Background: Gastric cancer (GC) is one of the most common malignancies in the human digestive tract. CD4+T cells can eliminate tumor cells directly through the mechanism of cytolysis, they can also indirectly attack tumor cells by regulating the tumor TME. A prognostic model of CD4+T cells is urgently needed to improve treatment strategies and explore the specifics of this interaction between CD4+T cells and gastric cancer cells. Methods: The detailed data of GC samples were downloaded from the Cancer Genome Atlas (TCGA), GSE66229, and GSE84437 datasets. CD4+ T cell-related genes were identified to construct a risk-score model by using the Cox regression method and validated with the Gene Expression Omnibus (GEO) dataset. In addition, postoperative pathological tissues of 139 gastric cancer patients were randomly selected for immunohistochemical staining, and their prognostic information were collected for external verification. Immune and molecular characteristics of these samples and their predictive efficacy in immunotherapy and chemotherapy were analysed. Results: The training set and validation set had consistent results, with GC patients of high PROC and SERPINE1 expression having poorer prognosis. In order to improve their clinical application value, we constructed a risk scoring model and established a high-precision nomogram. Low-risk patients had a better overall survival (OS) than high-risk patients, consistent with the results from the GEO cohort. Furthermore, the risk-score model can predict infiltration of immune cells in the tumor microenvironment of GC, as well as the response of immunotherapy. Correlations between the abundance of immune cells with PROC and SERPINE1 genes were shown in the prognostic model according to the training cohort. Finally, sensitive drugs were identified for patients in different risk subgroup. Conclusion: The risk model not only provides a basis for better prognosis in GC patients, but also is a potential prognostic indicator to distinguish the molecular and immune characteristics of the tumor, and its response to immune checkpoint inhibitor (ICI) therapy and chemotherapy.
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Affiliation(s)
- Jingyao Chen
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Xing Li
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Tsz Kin Mak
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Xiaoqun Wang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Hui Ren
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Kang Wang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Zi Chong Kuo
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Wenhui Wu
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Mingzhe Li
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Tengfei Hao
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Changhua Zhang
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yulong He
- Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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Liu F, Han Z, Lu J, Zhong W. Development and validation of a tobacco smoking-related index for predicting overall survival and immunotherapy response in bladder cancer. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:68701-68715. [PMID: 37129813 DOI: 10.1007/s11356-023-27132-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 04/17/2023] [Indexed: 05/03/2023]
Abstract
Bladder cancer is one of the top five most prevalent cancers in the United States and a major cause of cancer-related mortality worldwide. Meanwhile, tobacco smoking is a well-established modifiable risk factor for bladder cancer, with a population-attributable risk of approximately 50%. But the relationship between the prognosis of bladder cancer and tobacco smoking remains unclear. To further explore the potential relationship between tobacco smoking and bladder cancer prognosis, the bladder cancer dataset from The Cancer Genome Atlas Program was used to build a tobacco smoking-related signature known as the "smoker index" for prognosis prediction. Additionally, we validated the efficacy of the signature with some external datasets. Finally, we preliminarily verified the role of CGB5, the hub gene in the smoker index, through pan-cancer analysis and in vitro assays. The study digs into the underlying connection between tobacco smoking and the prognosis of bladder cancer from a multi-omics perspective.
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Affiliation(s)
- Fengping Liu
- Faculty of Medicine, Macau University of Science and Technology, Taipa, 999078, Macau, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, 999078, Macau, China
| | - Zhaodong Han
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, 999078, Macau, China
| | - Jianming Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, 999078, Macau, China
| | - Weide Zhong
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, 999078, Macau, China.
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Wang B, Gu B, Zhang T, Li X, Wang N, Ma C, Xiang L, Wang Y, Gao L, Yu Y, Song K, He P, Wang Y, Zhu J, Chen H. Good or bad: Paradox of plasminogen activator inhibitor 1 (PAI-1) in digestive system tumors. Cancer Lett 2023; 559:216117. [PMID: 36889376 DOI: 10.1016/j.canlet.2023.216117] [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: 01/27/2023] [Revised: 02/17/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023]
Abstract
The fibrinolytic system is involved in many physiological functions, among which the important members can interact with each other, either synergistically or antagonistically to participate in the pathogenesis of many diseases. Plasminogen activator inhibitor 1 (PAI-1) acts as a crucial element of the fibrinolytic system and functions in an anti-fibrinolytic manner in the normal coagulation process. It inhibits plasminogen activator, and affects the relationship between cells and extracellular matrix. PAI-1 not only involved in blood diseases, inflammation, obesity and metabolic syndrome but also in tumor pathology. Especially PAI-1 plays a different role in different digestive tumors as an oncogene or cancer suppressor, even a dual role for the same cancer. We term this phenomenon "PAI-1 paradox". PAI-1 is acknowledged to have both uPA-dependent and -independent effects, and its different actions can result in both beneficial and adverse consequences. Therefore, this review will elaborate on PAI-1 structure, the dual value of PAI-1 in different digestive system tumors, gene polymorphisms, the uPA-dependent and -independent mechanisms of regulatory networks, and the drugs targeted by PAI-1 to deepen the comprehensive understanding of PAI-1 in digestive system tumors.
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Affiliation(s)
- Bofang Wang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Baohong Gu
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Tao Zhang
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Xuemei Li
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Na Wang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Chenhui Ma
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Lin Xiang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yunpeng Wang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Lei Gao
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yang Yu
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Kewei Song
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Puyi He
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Yueyan Wang
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Jingyu Zhu
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
| | - Hao Chen
- Lanzhou University Second Hospital, Lanzhou, Gansu, China; Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, Gansu, China; Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, Gansu, China.
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Cytokine-Like Protein 1 (CYTL1) as a Key Target of M-Stage Immune Infiltration in Stomach Adenocarcinoma. BIOMED RESEARCH INTERNATIONAL 2023; 2023:2926218. [PMID: 36825034 PMCID: PMC9941682 DOI: 10.1155/2023/2926218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 01/12/2023] [Accepted: 01/16/2023] [Indexed: 02/15/2023]
Abstract
Background Stomach adenocarcinoma (STAD) has an extremely high fatality rate worldwide, and survival after metastasis is extremely poor. Cytokine-like protein 1 (CYTL1) has prognostic significance in various tumors. We aimed to explore the impact and underlying molecular mechanisms of CYTL1 in STAD through bioinformatics analysis. Methods We used R software to analyze CYTL1 expression in STAD samples (n = 375) and normal samples (n = 32) in The Cancer Genome Atlas database. Kaplan-Meier analysis was used to verify the relationship between CYTL1 expression and overall survival (OS) and disease-specific survival (DSS) based on the clinical characteristics and subgroups of patients with STAD. Furthermore, univariate and multivariate Cox regression analyses were used to verify the outcome variables of OS and DSS in patients with STAD. Receiver operating characteristic curves were used to test the predictive power of CYTL1. The biological functions and signaling pathways of CYTL1 were determined using gene set enrichment analysis (GSEA), and the immune infiltration patterns of CYTL1 and correlation of immune-related markers were analyzed using single-sample GSEA (ssGSEA) and an estimate algorithm. Results In our research, low CYTL1 expression (tumor vs. normal) was noted in patients with STAD. High CYTL1 expression was detrimental to OS and DSS and had good diagnostic performance (AUC = 0.731). In the subtype analysis of STAD, T3 and T4 stages, N0 and N1 stages, M0 stage, gender (female), and age (≤65 years) showed different performances between OS and DSS. Univariate and multivariate Cox analyses identified CYTL1 as an independent factor, and logistic regression analysis indicated that CYTL1 was associated with M stage (OR = 3.406) and sex (OR = 1.535). GSEA of the differential genes of CYTL1 showed the possible involvement of immunity. ssGSEA and estimation algorithms were used to further evaluate whether immune cells were closely related to CYTL1 expression, and many markers of immune cells also had statistical significance with the expression of CYTL1. Conclusion CYTL1 may, thus, act as an independent prognostic factor for STAD and regulate STAD progression by affecting the immune microenvironment.
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Kong W, Wang Z, Wang B. Unveiling DNA damage repair-based molecular subtypes, tumor microenvironment and pharmacogenomic landscape in gastric cancer. Front Genet 2023; 14:1118889. [PMID: 37124627 PMCID: PMC10140566 DOI: 10.3389/fgene.2023.1118889] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 03/28/2023] [Indexed: 05/02/2023] Open
Abstract
Objective: The current molecular classification system for gastric cancer covers genomic, molecular, and morphological characteristics. Non-etheless, classification of gastric cancer based upon DNA damage repair is still lacking. Here, we defined DNA damage repair-based subtypes across gastric cancer and identified clinicopathological, tumor microenvironment and pharmacogenomic features. Methods: Unsupervised clustering analysis was executed in the TCGA-STAD cohort based upon the transcriptional expression profiling of DNA damage repair genes. LASSO computational approach was adopted for generating a DNA damage repair-relevant gene signature. The identified subtypes or signature were externally verified in the GSE84426 or GSE84433 cohort. The transcriptional levels of immunomodulators, abundance of immune cells and somatic mutations were measured, respectively. Immunotherapeutic response, and drug sensitivity were investigated. The DNA damage repair-relevant genes were further experimentally verified. Results: Two DNA damage repair-based subtypes were identified, with the notable heterogeneity in prognostic stratification, tumor microenvironment and somatic mutations. The gene signature was generated for risk stratification and prognostic prediction, which was in relation to immunomodulators and immune cells. High-risk cases were more likely to respond to immunotherapy, with distinct pharmacogenomic landscapes between low- and high-risk groups. Higher levels of PAPPA2, MPO, MAGEA11, DEPP1, CPZ, and COLEC12 and lower level of CYTL1 were proven in gastric cancer cells versus controls. Silencing CYTL1 facilitated intracellular ROS accumulation and suppressed migration in gastric cancer cells. Conclusion: Collectively, the DNA damage repair-based classification is a suitable complement to existing molecular classification system, and the quantitative gene signature provides a robust tool in selecting specific therapeutic options.
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Development and validation of a novel immune-related prognostic signature in lung squamous cell carcinoma patients. Sci Rep 2022; 12:20737. [PMID: 36456645 PMCID: PMC9715950 DOI: 10.1038/s41598-022-23140-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 10/25/2022] [Indexed: 12/05/2022] Open
Abstract
Lung Squamous Cell Carcinoma (LUSC) is an aggressive malignancy with limited therapeutic options. The response to immune therapy is a determining factor for the prognosis of LUSC patients. This study aimed to develop a reliable immune-related prognostic signature in LUSC. We extracted gene expression and clinical data of LUSC from The Cancer Genome Atlas (TCGA). A total of 502 patients enrolled and were divided into respond and non-responder groups by the TIDE algorithm. The CIBERSORT algorithm and the LM22 gene signature were used to analyze the distribution of immune cells in LUSC. Efficacy and response strength of immunotherapy are calculated by the tumor mutation burden (TMB) and ESTIMATE Score. Differentially expressed genes (DEGs) between the two groups were analyzed. The differential expression genes related to overall survival were pointed as hub DEGs, and a prognostic signature was constructed with lasso regression analysis. LUSC patients were divided into responder and non-responder groups based on the response to immunotherapy. The distribution of immune cells was significantly different between the two groups. Forty-four DGEs were considered as overall survival-related genes. A prognostic signature was constructed, consisting of 11 hub-DGEs, including MMP20, C18orf26, CASP14, FAM71E2, OPN4, CGB5, DIRC1, C9orf11, SPATA8, C9orf144B, and ZCCHC5. The signature can accurately distinguish LUSC patients into high and low-risk groups. Moreover, the high-risk group had a shorter survival time than the low-risk group. The area under the ROC curve was 0.67. The multivariate Cox regression showed that the risk score calculated by the constructed signature was an independent prognostic predictor for LUSC patients. In short, we established a novel immune-related prognostic signature in LUCS, which has significant sensitivity and accuracy in predicting the prognosis of patients. Our research can guide the evaluation of the prognosis of LUSC patients in clinical, and the discovered immune-related genes can provide a theoretical basis for the discovery of new therapeutic targets.
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15
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Zhou XD, Qu YW, Wang L, Jia FH, Chen P, Wang YP, Liu HF. Identification of potential hub genes of gastric cancer. Medicine (Baltimore) 2022; 101:e30741. [PMID: 36254003 PMCID: PMC9575828 DOI: 10.1097/md.0000000000030741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is a malignant tumor originated from gastric mucosa epithelium. It is the third leading cause of cancer mortality in China. The early symptoms are not obvious. When it is discovered, it has developed to the advanced stage, and the prognosis is poor. In order to screen for potential genes for GC development, this study obtained GSE118916 and GSE109476 from the gene expression omnibus (GEO) database for bioinformatics analysis. METHODS First, GEO2R was used to identify differentially expressed genes (DEG) and the functional annotation of DEGs was performed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The Search Tool for the Retrieval of Interacting Genes (STRING) tool was used to construct protein-protein interaction (PPI) network and the most important modules and hub genes were mined. Real time quantitative polymerase chain reaction assay was performed to verify the expression level of hub genes. RESULTS A total of 139 DEGs were identified. The functional changes of DEGs are mainly concentrated in the cytoskeleton, extracellular matrix and collagen synthesis. Eleven genes were identified as core genes. Bioinformatics analysis shows that the core genes are mainly enriched in many processes related to cell adhesion and collagen. CONCLUSION In summary, the DEGs and hub genes found in this study may be potential diagnostic and therapeutic targets.
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Affiliation(s)
- Xu-Dong Zhou
- The Clinical College of the General Hospital of Chinese People's Armed Police Forces, Anhui Medical University, Hefei, P.R. China
| | - Ya-Wei Qu
- Department of Gastroenterology, Third Medical Center of PLA General Hospital, Beijing, P.R. China
| | - Li Wang
- Department of Gastroenterology, Huamei Hospital of China National University of Science and Technology, Ningbo, P.R. China
| | - Fu-Hua Jia
- Department of Gastroenterology, Huamei Hospital of China National University of Science and Technology, Ningbo, P.R. China
| | - Peng Chen
- Department of Ultrasound, Graduate School of Jinzhou Medical University, Jinzhou, P.R. China
| | - Yin-Pu Wang
- Department of Gastroenterology, Baoji Hospital Affiliated to Xi’an Jiaotong University, Baoji, P.R. China
| | - Hai-Feng Liu
- The Clinical College of the General Hospital of Chinese People's Armed Police Forces, Anhui Medical University, Hefei, P.R. China
- *Correspondence: Hai-Feng Liu, The Clinical College of the General Hospital of Chinese People's Armed Police Forces, Anhui Medical University, Hefei 230032, P.R. China (e-mail: )
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Liu Z, Liu H, Wang Y, Li Z. A 9‑gene expression signature to predict stage development in resectable stomach adenocarcinoma. BMC Gastroenterol 2022; 22:435. [PMID: 36241983 PMCID: PMC9564244 DOI: 10.1186/s12876-022-02510-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/31/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Stomach adenocarcinoma (STAD) is a highly heterogeneous disease and is among the leading causes of cancer-related death worldwide. At present, TNM stage remains the most effective prognostic factor for STAD. Exploring the changes in gene expression levels associated with TNM stage development may help oncologists to better understand the commonalities in the progression of STAD and may provide a new way of identifying early-stage STAD so that optimal treatment approaches can be provided. METHODS The RNA profile retrieving strategy was utilized and RNA expression profiling was performed using two large STAD microarray databases (GSE62254, n = 300; GSE15459, n = 192) from the Gene Expression Omnibus (GEO) and the RNA-seq database within the Cancer Genome Atlas (TCGA, n = 375). All sample expression information was obtained from STAD tissues after radical resection. After excluding data with insufficient staging information and lymph node number, samples were grouped into earlier-stage and later-stage. Samples in GSE62254 were randomly divided into a training group (n = 172) and a validation group (n = 86). Differentially expressed genes (DEGs) were selected based on the expression of mRNAs in the training group and the TCGA group (n = 156), and hub genes were further screened by least absolute shrinkage and selection operator (LASSO) logistic regression. Receiver operating characteristic (ROC) curves were used to evaluate the performance of the hub genes in distinguishing STAD stage in the validation group and the GSE15459 dataset. Univariate and multivariate Cox regressions were performed sequentially. RESULTS 22 DEGs were commonly upregulated (n = 19) or downregulated (n = 3) in the training and TCGA datasets. Nine genes, including MYOCD, GHRL, SCRG1, TYRP1, LYPD6B, THBS4, TNFRSF17, SERPINB2, and NEBL were identified as hub genes by LASSO-logistic regression. The model achieved discrimination in the validation group (AUC = 0.704), training-validation group (AUC = 0.743), and GSE15459 dataset (AUC = 0.658), respectively. Gene Set Enrichment Analysis (GSEA) was used to identify the potential stage-development pathways, including the PI3K-Akt and Calcium signaling pathways. Univariate Cox regression indicated that the nine-gene score was a significant risk factor for overall survival (HR = 1.28, 95% CI 1.08-1.50, P = 0.003). In the multivariate Cox regression, only SCRG1 was an independent prognostic predictor of overall survival after backward stepwise elimination (HR = 1.21, 95% CI 1.11-1.32, P < 0.001). CONCLUSION Through a series of bioinformatics and validation processes, a nine-gene signature that can distinguish STAD stage was identified. This gene signature has potential clinical application and may provide a novel approach to understanding the progression of STAD.
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Affiliation(s)
- Zining Liu
- Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hua Liu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yinkui Wang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Ziyu Li
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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Wang W, Liang Q, Zhao J, Pan H, Gao Z, Fang L, Zhou Y, Shi J. Low expression of the metabolism-related gene SLC25A21 predicts unfavourable prognosis in patients with acute myeloid leukaemia. Front Genet 2022; 13:970316. [PMID: 36246603 PMCID: PMC9562002 DOI: 10.3389/fgene.2022.970316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 09/01/2022] [Indexed: 12/02/2022] Open
Abstract
Acute myeloid leukaemia (AML) is a heterogeneous disease associated with poor outcomes. To identify AML-specific genes with prognostic value, we analysed transcriptome and clinical information from The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) datasets, and Genotype-Tissue Expression (GTEx) project. The metabolism-related gene, SLC25A21 was found to be significantly downregulated in AML, and was associated with high white blood cell (WBC) counts, high pretrial blood (PB) and bone marrow (BM) blast abundance, FLT3 mutation, NPM1 mutation, and death events (all p value <0.05). We validated the expression of SLC25A21 in our clinical cohort, and found that SLC25A21 was downregulated in AML. Moreover, we identified low expression of SLC25A21 as an independent prognostic factor by univariate Cox regression (hazard ratio [HR]: 0.550; 95% Confidence interval [CI]: 0.358–0.845; p value = 0.006) and multivariate Cox regression analysis (HR: 0.341; 95% CI: 0.209–0.557; p value <0.05). A survival prediction nomogram was established with a C-index of 0.735, which indicated reliable prognostic prediction. Subsequently, based on the median SLC25A21 expression level, patients in the TCGA-LAML cohort were divided into low- and high-expression groups. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs highlighted growth factor binding, extracellular structure organization, cytokine‒cytokine receptor interaction, etc. The results of gene set enrichment analysis (GSEA) indicated that the epithelial-mesenchymal transition, KRAS signalling, oxidative phosphorylation, and reactive oxygen species pathways were enriched. Through gene coexpression and protein‒protein interaction (PPI) network analysis, we identified two hub genes, EGFR and COL1A2, which were linked to worse clinical outcomes. Furthermore, we found that lower SLC25A21 expression was closely associated with a significant reduction in the levels of infiltrating immune cells, which might be associated with immune escape of AML cells. A similar trend was observed for the expression of checkpoint genes (CTLA4, LAG3, TIGIT, and HAVCR2). Finally, drug sensitivity testing suggested that the low-expression SLC25A21 group is sensitive to doxorubicin, mitomycin C, linifanib but resistant to JQ1, belinostat, and dasatinib. Hence, our study demonstrated that a low expression level of SLC25A21 predicts an unfavourable prognosis in patients with AML.
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Affiliation(s)
| | | | | | | | | | | | - Yuan Zhou
- *Correspondence: Jun Shi, ; Yuan Zhou,
| | - Jun Shi
- *Correspondence: Jun Shi, ; Yuan Zhou,
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Chen H, Rong Z, Ge L, Yu H, Li C, Xu M, Zhang Z, Lv J, He Y, Li W, Chen L. Leader gene identification for digestive system cancers based on human subcellular location and cancer-related characteristics in protein-protein interaction networks. Front Genet 2022; 13:919210. [PMID: 36226184 PMCID: PMC9548996 DOI: 10.3389/fgene.2022.919210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Stomach, liver, and colon cancers are the most common digestive system cancers leading to mortality. Cancer leader genes were identified in the current study as the genes that contribute to tumor initiation and could shed light on the molecular mechanisms in tumorigenesis. An integrated procedure was proposed to identify cancer leader genes based on subcellular location information and cancer-related characteristics considering the effects of nodes on their neighbors in human protein-protein interaction networks. A total of 69, 43, and 64 leader genes were identified for stomach, liver, and colon cancers, respectively. Furthermore, literature reviews and experimental data including protein expression levels and independent datasets from other databases all verified their association with corresponding cancer types. These final leader genes were expected to be used as diagnostic biomarkers and targets for new treatment strategies. The procedure for identifying cancer leader genes could be expanded to open up a window into the mechanisms, early diagnosis, and treatment of other cancer types.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Wan Li
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Lina Chen
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
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Wang B, Zou D, Wang N, Wang H, Zhang T, Gao L, Ma C, Zheng P, Gu B, Li X, Wang Y, He P, Ma Y, Wang X, Chen H. Construction and validation of a novel coagulation-related 7-gene prognostic signature for gastric cancer. Front Genet 2022; 13:957655. [PMID: 36105100 PMCID: PMC9465170 DOI: 10.3389/fgene.2022.957655] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 07/25/2022] [Indexed: 11/18/2022] Open
Abstract
Background: Gastric cancer (GC) is the most common malignant tumor. Due to the lack of practical molecular markers, the prognosis of patients with advanced gastric cancer is still poor. A number of studies have confirmed that the coagulation system is closely related to tumor progression. Therefore, the purpose of this study was to construct a coagulation-related gene signature and prognostic model for GC by bioinformatics methods. Methods: We downloaded the gene expression and clinical data of GC patients from the TCGA and GEO databases. In total, 216 coagulation-related genes (CRGs) were obtained from AmiGO 2. Weighted gene co-expression network analysis (WGCNA) was used to identify coagulation-related genes associated with the clinical features of GC. Last absolute shrinkage and selection operator (LASSO) Cox regression was utilized to shrink the relevant predictors of the coagulation system, and a Coag-Score prognostic model was constructed based on the coefficients. According to this risk model, GC patients were divided into high-risk and low-risk groups, and overall survival (OS) curves and receiver operating characteristic (ROC) curves were drawn in the training and validation sets, respectively. We also constructed nomograms for predicting 1-, 2-, and 3-year survival in GC patients. Single-sample gene set enrichment analysis (ssGSEA) was exploited to explore immune cells’ underlying mechanisms and correlations. The expression levels of coagulation-related genes were verified by real-time quantitative polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Results: We identified seven CRGs employed to construct a Coag-Score risk model using WGCNA combined with LASSO regression. In both training and validation sets, GC patients in the high-risk group had worse OS than those in the low-risk group, and Coag-Score was identified as an independent predictor of OS, and the nomogram provided a quantitative method to predict the 1-, 2-, and 3-year survival rates of GC patients. Functional analysis showed that Coag-Score was mainly related to the MAPK signaling pathway, complement and coagulation cascades, angiogenesis, epithelial–mesenchymal transition (EMT), and KRAS signaling pathway. In addition, the high-risk group had a significantly higher infiltration enrichment score and was positively associated with immune checkpoint gene expression. Conclusion: Coagulation-related gene models provide new insights and targets for the diagnosis, prognosis prediction, and treatment management of GC patients.
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Affiliation(s)
- Bofang Wang
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Dan Zou
- Chengdu Seventh People’s Hospital, Chengdu, China
| | - Na Wang
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Haotian Wang
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Tao Zhang
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of oncology, First Hospital of Lanzhou University, Lanzhou, China
| | - Lei Gao
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Chenhui Ma
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Peng Zheng
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Baohong Gu
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Xuemei Li
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Yunpeng Wang
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Puyi He
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Yanling Ma
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Xueyan Wang
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Hao Chen
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou, China
- Department of Cancer Center, Lanzhou University Second Hospital, Lanzhou, China
- *Correspondence: Hao Chen,
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20
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Significance of a Tumor Mutation Burden Gene Signature with Prognosis and Immune Feature of Gastric Cancer Patients. Int J Genomics 2022; 2022:7684606. [PMID: 35719415 PMCID: PMC9201710 DOI: 10.1155/2022/7684606] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/25/2022] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC) is a common digestive tumor which ranks the fourth most common malignancy worldwide. Immunotherapy is a promising treatment for GC, especially for advanced gastric cancer (AGC). However, in clinical practice, not all patients are sensitive to immunotherapy. Recent studies showed that tumor mutation burden (TMB) is closely correlated with the response of immunotherapy. The current study identified a TMB-related genes' signature to predict the prognosis and immune feature of GC patients. Firstly, we acquired the TMB data and expression data from The Cancer Genome Atlas (TCGA) and the National Center for Biotechnology Information (NCBI) GEO databases. Then, we extracted TMB-related genes from the expression data of TCGA and two GEO cohorts. By using univariate Cox analysis, we identified that the 429 genes were correlated to GC patients' overall survival. Subsequently, an immune prognostic signature was constructed by using the least absolute shrinkage and selection operator analysis (LASSO) and multivariate Cox regression analysis. The signature could be utilized to predict the prognosis of GC patients. In addition, the signature showed a closed correlation with immune feature of GC patients. In conclusion, our risk signature could offer hints for the prognosis of GC patients and might provide insights to formulate new immunotherapy strategies for GC patients.
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21
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Identification and Validation of Immune Cells and Hub Genes in Gastric Cancer Microenvironment. DISEASE MARKERS 2022; 2022:8639323. [PMID: 35422890 PMCID: PMC9005323 DOI: 10.1155/2022/8639323] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 02/24/2022] [Indexed: 12/30/2022]
Abstract
Gastric cancer (GC) is the most common malignant tumor in the digestive system, traditional radiotherapy and chemotherapy are not effective for some patients. The research progress of immunotherapy seems to provide a new way for treatment. However, it is still urgent to predict immunotherapy biomarkers and determine novel therapeutic targets. In this study, the gene expression profiles and clinical data of 407 stomach adenocarcinoma (STAD) patients were downloaded from The Cancer Genome Atlas (TCGA) portal, and the abundance ratio of immune cells in each sample was obtained via the “Cell Type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT)” algorithm. Five immune cells were obtained as a result of abundance comparison, and 295 immune-related genes were obtained through differential gene analysis. Enrichment, protein interaction, and module analysis were performed on these genes. We identified five immune cells associated with infiltration and 20 hub genes, of which five genes were correlated with overall survival. Finally, we used Real-time PCR (RT-PCR) to detect the expression differences of the five hub genes in 18 pairs of GC and adjacent tissues. This research not only provides cellular and gene targets for immunotherapy of GC but also provides new ideas for researchers to explore immunotherapy for various tumors.
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22
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Intracellular CYTL1, a novel tumor suppressor, stabilizes NDUFV1 to inhibit metabolic reprogramming in breast cancer. Signal Transduct Target Ther 2022; 7:35. [PMID: 35115484 PMCID: PMC8813937 DOI: 10.1038/s41392-021-00856-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 10/23/2021] [Accepted: 12/06/2021] [Indexed: 12/31/2022] Open
Abstract
Loss-of-function mutations frequently occur in tumor suppressor genes, i.e., p53, during the malignant progression of various cancers. Whether any intrinsic suppressor carries a rare mutation is largely unknown. Here, we demonstrate that intracellular cytokine-like protein 1 (CYTL1) plays a key role in preventing the robust glycolytic switching characteristic of breast cancer. A low intracellular CYTL1 level, not its mutation, is required for metabolic reprogramming. Breast cancer cells expressing an intracellular form of CYTL1 lacking a 1-22 aa signal peptide, ΔCYTL1, show significantly attenuated glucose uptake and lactate production, which is linked to the inhibition of cell growth and metastasis in vitro and in vivo. Mechanistically, CYTL1 competitively binds the N-terminal sequence of NDUFV1 to block MDM2-mediated degradation by the proteasome, leading to the stability of the NDUFV1 protein. In addition to inducing increased NAD+ levels, NDUFV1 interacts with Src to attenuate LDHA phosphorylation at tyrosine 10 and reduce lactate production. Our results reveal, for the first time, that CYTL1 is a novel tumor suppressor. Its function in reversing metabolic reprogramming toward glycolysis may be very important for the development of novel antitumor strategies.
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23
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Zhao X, Wu S, Jing J. Identifying Diagnostic and Prognostic Biomarkers and Candidate Therapeutic Drugs of Gastric Cancer Based on Transcriptomics and Single-Cell Sequencing. Pathol Oncol Res 2021; 27:1609955. [PMID: 34899080 PMCID: PMC8654733 DOI: 10.3389/pore.2021.1609955] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 10/28/2021] [Indexed: 12/24/2022]
Abstract
Background and Objective: Gastric cancer (GC) is an important health burden and the prognosis of GC is poor. We aimed to explore new diagnostic and prognostic indicators as well as potential therapeutic targets for GC in the current study. Methods: We screened the overlapped differentially expressed genes (DEGs) from GSE54129 and TCGA STAD datasets. Protein-protein interaction network analysis recognized the hub genes among the DEGs. The roles of these genes in diagnosis, prognosis, and their relationship with immune infiltrates and drug sensitivity of GC were analyzed using R studio. Finally, the clinically significant hub genes were verified using single-cell RNA sequencing (scRNA-seq) data. Results: A total of 222 overlapping genes were screened, which were enriched in extracellular matrix-related pathways. Further, 17 hub genes were identified, and our findings demonstrated that BGN, COMP, COL5A2, and SPARC might be important diagnostic and prognostic indicators of GC, which were also correlated with immune cell infiltration, tumor mutation burden (TMB), microsatellite instability (MSI), and sensitivity of therapeutic drugs. The scRNA-seq results further confirmed that all four hub genes were highly expressed in GC. Conclusion: Based on transcriptomics and single-cell sequencing, we identified four diagnostic and prognostic biomarkers of GC, including BGN, COMP, COL5A2, and SPARC, which can help predict drug sensitivity for GC as well.
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Affiliation(s)
- Xu Zhao
- Mathematical Computer Teaching and Research Office, Liaoning Vocational College of Medicine, Shenyang, China
| | - Shuang Wu
- College of Computer Science and Technology, Changchun Normal University, Changchun, China
| | - Jingjing Jing
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
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24
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Cheng Y, Li F, Zhang WS, Zou GY, Shen YX. Silencing BLNK protects against interleukin-1β-induced chondrocyte injury through the NF-κB signaling pathway. Cytokine 2021; 148:155686. [PMID: 34521030 DOI: 10.1016/j.cyto.2021.155686] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/30/2021] [Accepted: 08/17/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Osteoarthritis (OA) is the most common joint disease in the elderly and is characterized by the progressive degeneration of articular cartilage. It is necessary to study the molecular pathology of OA. This study aimed to explore the role and mechanism of BLNK in regulating interleukin-1β (IL-1β)-induced chondrocyte injury and OA progression. METHODS GSE1919 (5 normal samples and 5 OA samples) was downloaded from the Gene Expression Omnibus (GEO) database. The limma package in R software was used to identify differentially expressed genes (DEGs) between control and OA-affected cartilage. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of the differentially expressed genes were also performed. Apoptosis was assessed by flow cytometry. An OA rat model was established, and the relative expression of BLNK was assessed by real time quantitative PCR (qRT-PCR) and immunohistochemical staining. The expression of collagen II, MMP9, p65 and p-p65 was measured by Western blot analysis. Moreover, inflammatory factors (TNF-α and IL-18) were assessed by ELISA. The NF-κB inhibitor JSH-23 was used to assess the impact of BLNK on the NF-κB signaling pathway. RESULTS In total, 1318 DEGs were identified between normal and OA-affected cartilage according to the criteria (P-value <0.05 and |logFC > 1|). These DEGs were mainly enriched in the NF-κB pathway. BLNK was highly expressed in OA cartilage tissue and injured chondrocytes. Silencing BLNK significantly downregulated the IL-1β-induced apoptosis of chondrocytes. Silencing BLNK partially increased collagen II expression and downregulated MMP13 expression. Moreover, silencing BLNK partially decreased TNF-α and IL-18 expression. BLNK silencing inhibited the activation of NF-κB in OA. Silencing BLNK delayed OA progression through the NF-κB signaling pathway. CONCLUSION Silencing BLNK delayed OA progression and IL-1β-induced chondrocyte injury by regulating the NF-κB pathway.
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Affiliation(s)
- Yi Cheng
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China; Department of Orthopaedics, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yancheng 224005, PR China
| | - Feng Li
- Department of Orthopaedics, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yancheng 224005, PR China
| | - Wen-Sheng Zhang
- Department of Orthopaedics, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yancheng 224005, PR China
| | - Guo-You Zou
- Department of Orthopaedics, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yancheng 224005, PR China
| | - Yi-Xin Shen
- Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, PR China.
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25
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Identification of SLITRK6 as a Novel Biomarker in hepatocellular carcinoma by comprehensive bioinformatic analysis. Biochem Biophys Rep 2021; 28:101157. [PMID: 34754951 PMCID: PMC8564567 DOI: 10.1016/j.bbrep.2021.101157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 10/16/2021] [Accepted: 10/18/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the adult liver and morbidity are increasing in recent years, however, there is still no effective strategy to prevent and diagnose HCC. Therefore, it is urgent to research the effective biomarker to predict clinical outcomes of HCC tumorigenesis. In the current study, differentially expressed genes in HCC and normal tissues were investigated using the Gene Expression Omnibus (GEO) dataset GSE144269 and The Cancer Genome Atlas (TCGA). Gene differential expression analysis and weighted correlation network analysis (WGCNA) methods were used to identify nine and 16 key gene modules from the GEO dataset and TCGA dataset, respectively, in which the green module in the GEO dataset and magenta module in TCGA were significantly correlated with HCC occurrence. Third, the enrichment score of gene function annotation results showed that these two key modules focus on the positive regulation of inflammatory response and cell differentiation, etc. Besides, PPI network analysis, mutation analysis, and survival analysis found that SLITRK6 had high connectivity, and its mutation significantly impacted overall survival. In addition, SLITRK6 was found to be low expressed in tumor cells. To summarize, SLITRK6 mutation was found to significantly affect the occurrence and prognosis of HCC. SLITRK6 was confirmed as a new potential gene target for HCC, which may provide a new theoretical basis for personalized diagnosis and chemotherapy of HCC in the future.
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26
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Discovery and Validation of an Epithelial-Mesenchymal Transition-Based Signature in Gastric Cancer by Genomics and Prognosis Analysis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9026918. [PMID: 34746312 PMCID: PMC8570100 DOI: 10.1155/2021/9026918] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 09/18/2021] [Indexed: 12/23/2022]
Abstract
Objective Epithelial-mesenchymal transition (EMT) exerts a key function in cancer initiation and progression. Herein, we aimed to develop an EMT-based prognostic signature in gastric cancer. Methods The gene expression profiles of gastric cancer were obtained from TCGA dataset as a training set and GSE66229 and GSE84437 datasets as validation sets. By LASSO regression and Cox regression analyses, key prognostic EMT-related genes were screened for developing a risk score (RS) model. Potential small molecular compounds were predicted by the CMap database based on the RS model. GSEA was employed to explore signaling pathways associated with the RS. ESTIMATE and seven algorithms (TIMER, CIBERSORT, CIBERSORT-ABS, QUANTISEQ, MCPCOUNTER, XCELL, and EPIC) were applied to assess the RS and immune microenvironment. Results This study developed an EMT-related gene signature comprised of SERPINE1, PCOLCE2, MATN3, and DKK1. High-RS patients displayed poorer survival outcomes than those with low RS. ROC curves demonstrated the robustness of the model in predicting the prognosis. After external validation, the RS model was an independent risk factor for gastric cancer. Several compounds were predicted for gastric cancer treatment based on the RS model. ECM receptor interaction, focal adhesion, pathway in cancer, TGF-beta, and WNT pathways were distinctly activated in high-RS samples. Also, high RS was significantly associated with increased stromal and immune scores and increased infiltration of CD4+ T cell, CD8+ T cell, cancer-associated fibroblast, and macrophage in gastric cancer tissues. Conclusion Our findings suggested that the EMT-related gene model may robustly predict gastric cancer prognosis, which could improve the efficacy of personalized therapy.
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27
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Wang Z, Hou Y, Yao Z, Zhan Y, Chen W, Liu Y. Expressivity of Interleukin-8 and Gastric Cancer Prognosis Susceptibility: A Systematic Review and Meta-Analysis. Dose Response 2021; 19:15593258211037127. [PMID: 34531708 PMCID: PMC8438942 DOI: 10.1177/15593258211037127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 07/07/2021] [Accepted: 07/09/2021] [Indexed: 12/23/2022] Open
Abstract
Background The relationship between interleukin-8 (IL-8) expression and the prognosis of gastric cancer (GC) patients has been reported, but the results are contradictory. Aim To investigate the effect of IL-8 expression on the prognosis of patients with GC. Method A comprehensive search strategy was used to search the PubMed, Web of Science and Cochrane Library databases. The total survival time was analysed using the RevMan 5.4 software. Through extensive search and meta-analysis of relevant studies, studies examining the relationship between IL-8 expression and prognosis in patients with GC were conducted to obtain more accurate estimates. Findings Eight studies (1843 patients) were included. The combined results of all the studies showed that high expression of IL-8 was a risk factor for poor prognosis in patients with GC (hazard ratio (HR): 2.08; 95% CI: 1.81–2.39). Sensitivity analysis suggested that the pooled HR was stable, and omitting a single study did not change the significance of the pooled HR. Funnel plots revealed no significant publication bias in the meta-analysis. Conclusion High IL-8 expression could be a negative prognostic biomarker for patients with GC.
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Affiliation(s)
- Zhenzhen Wang
- Department of Nuclear Accident Medical Emergency, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuhan Hou
- Department of Nuclear Accident Medical Emergency, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhen Yao
- Department of Nuclear Accident Medical Emergency, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yanyan Zhan
- Department of Nuclear Accident Medical Emergency, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Wenyue Chen
- Department of Nuclear Accident Medical Emergency, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yulong Liu
- Department of Nuclear Accident Medical Emergency, The Second Affiliated Hospital of Soochow University, Suzhou, China.,State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China.,Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Suzhou, China
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28
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Wang S, Chen Z, Gu J, Chen X, Wang Z. The Role of lncRNA PCAT6 in Cancers. Front Oncol 2021; 11:701495. [PMID: 34327141 PMCID: PMC8315724 DOI: 10.3389/fonc.2021.701495] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 06/25/2021] [Indexed: 12/24/2022] Open
Abstract
Long non-coding RNA (lncRNA) PCAT6 is a member of the Prostate Cancer Associated Transcripts family of molecules. In this review, we focus on the latest studies involving PCAT6 in the diagnosis, treatment, and prognosis of malignant tumors of the digestive, respiratory, urinary, reproductive, motion, and nervous systems. PCAT6 was found to be highly expressed in gastric cancer, colon cancer, hepatocellular carcinoma, lung cancer, bladder cancer, ovarian cancer, breast cancer, cervical cancer, osteosarcoma, glioblastoma, and other tumors. PCAT6 can promote the development and progression of different types of malignant tumors through various mechanisms. Overall, these findings suggest that PCAT6 may play an increasingly vital role in the clinical assessment of these malignant tumors. It can function as an oncogene and may be used as a potential new prognostic biomarker of these tumors.
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Affiliation(s)
- Siying Wang
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhenyao Chen
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jingyao Gu
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xin Chen
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zhaoxia Wang
- Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
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29
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Carli ALE, Afshar-Sterle S, Rai A, Fang H, O'Keefe R, Tse J, Ferguson FM, Gray NS, Ernst M, Greening DW, Buchert M. Cancer stem cell marker DCLK1 reprograms small extracellular vesicles toward migratory phenotype in gastric cancer cells. Proteomics 2021; 21:e2000098. [PMID: 33991177 DOI: 10.1002/pmic.202000098] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 04/15/2021] [Accepted: 05/12/2021] [Indexed: 12/15/2022]
Abstract
Doublecortin-like kinase 1 (DCLK1) is a putative cancer stem cell marker, a promising diagnostic and prognostic maker for malignant tumors and a proposed driver gene for gastric cancer (GC). DCLK1 overexpression in a majority of solid cancers correlates with lymph node metastases, advanced disease and overall poor-prognosis. In cancer cells, DCLK1 expression has been shown to promote epithelial-to-mesenchymal transition (EMT), driving disruption of cell-cell adhesion, cell migration and invasion. Here, we report that DCLK1 influences small extracellular vesicle (sEV/exosome) biogenesis in a kinase-dependent manner. sEVs isolated from DCLK1 overexpressing human GC cell line MKN1 (MKN1OE -sEVs), promote the migration of parental (non-transfected) MKN1 cells (MKN1PAR ). Quantitative proteome analysis of MKN1OE -sEVs revealed enrichment in migratory and adhesion regulators (STRAP, CORO1B, BCAM, COL3A, CCN1) in comparison to MKN1PAR -sEVs. Moreover, using DCLK1-IN-1, a specific small molecule inhibitor of DCLK1, we reversed the increase in sEV size and concentration in contrast to other EV subtypes, as well as kinase-dependent cargo selection of proteins involved in EV biogenesis (KTN1, CHMP1A, MYO1G) and migration and adhesion processes (STRAP, CCN1). Our findings highlight a specific role of DCLK1-kinase dependent cargo selection for sEVs and shed new light on its role as a regulator of signaling in gastric tumorigenesis.
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Affiliation(s)
- Annalisa L E Carli
- Cancer Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
| | - Shoukat Afshar-Sterle
- Cancer Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
| | - Alin Rai
- Baker Heart and Diabetes Institute, Molecular Proteomics, Melbourne, Victoria, Australia.,Central Clinical School, Monash University, Melbourne, Victoria, Australia
| | - Haoyun Fang
- Baker Heart and Diabetes Institute, Molecular Proteomics, Melbourne, Victoria, Australia
| | - Ryan O'Keefe
- Cancer Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
| | - Janson Tse
- Cancer Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
| | - Fleur M Ferguson
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA
| | - Nathanael S Gray
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA
| | - Matthias Ernst
- Cancer Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
| | - David W Greening
- Baker Heart and Diabetes Institute, Molecular Proteomics, Melbourne, Victoria, Australia.,Central Clinical School, Monash University, Melbourne, Victoria, Australia.,Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.,Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia
| | - Michael Buchert
- Cancer Inflammation Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia.,School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
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30
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Shi L, Shang X, Nie K, Lin Z, Zheng M, Wang M, Yuan H, Zhu Z. Identification of potential crucial genes associated with the pathogenesis and prognosis of liver hepatocellular carcinoma. J Clin Pathol 2020; 74:504-512. [PMID: 33004423 DOI: 10.1136/jclinpath-2020-206979] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 08/06/2020] [Accepted: 08/06/2020] [Indexed: 12/20/2022]
Abstract
AIMS Liver hepatocellular carcinoma (LIHC) is the main manifestation of primary liver cancer, with low survival rate and poor prognosis. Medical decision-making process of LIHC is so complex that new biomarkers for diagnosis and prognosis have yet to be explored, this study aimed to identify the genes involved in the pathophysiology of LIHC and biomarkers that can be used to predict the prognosis of LIHC. METHODS Six Gene Expression Omnibus (GEO) datasets selected from GEO were screened and integrated to find out the differential expression genes (DEGs) obtained from LIHC and normal hepatic tissues. The Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes pathway enrichment analysis of DEGs was implemented by DAVID. The Protein-protein interaction network was performed via STRING. In addition, Cox regression model was used to construct a gene prognostic signature. RESULTS We ascertained 10 hub genes, nine of them (CDK1, CDC20, CCNB1, Thymidylate synthetase, Nuclear division cycle80, NUF2, MAD2L1, CCNA2 and BIRC5) as biomarkers of progression in LIHC patients. We also build a six gene prognosis signature (SOCS2, GAS2L3, NLRP5, TAF3, UTP11 and GAGE2A), which can be implemented to predict over survival effectively. CONCLUSIONS We revealed promising genes that may participate in the pathophysiology of LIHC, and found available biomarkers for LIHC prognosis prediction, which were significant for researchers to further understand the molecular basis of LIHC and direct the synthesis medicine of LIHC.
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Affiliation(s)
- Laner Shi
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xin Shang
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Kechao Nie
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Zhiqin Lin
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Meisi Zheng
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Miao Wang
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Haoyu Yuan
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Zhangzhi Zhu
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
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Qiu XT, Song YC, Liu J, Wang ZM, Niu X, He J. Identification of an immune-related gene-based signature to predict prognosis of patients with gastric cancer. World J Gastrointest Oncol 2020; 12:857-876. [PMID: 32879664 PMCID: PMC7443845 DOI: 10.4251/wjgo.v12.i8.857] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 04/06/2020] [Accepted: 06/17/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is the most commonly diagnosed malignancy worldwide. Increasing evidence suggests that it is necessary to further explore genetic and immunological characteristics of GC. AIM To construct an immune-related gene (IRG) signature for accurately predicting the prognosis of patients with GC. METHODS Differentially expressed genes (DEGs) between 375 gastric cancer tissues and 32 normal adjacent tissues were obtained from The Cancer Genome Atlas (TCGA) GDC data portal. Then, differentially expressed IRGs from the ImmPort database were identified for GC. Cox univariate survival analysis was used to screen survival-related IRGs. Differentially expressed survival-related IRGs were considered as hub IRGs. Genetic mutations of hub IRGs were analyzed. Then, hub IRGs were selected to conduct a prognostic signature. Receiver operating characteristic (ROC) curve analysis was used to evaluate the prognostic performance of the signature. The correlation of the signature with clinical features and tumor-infiltrating immune cells was analyzed. RESULTS Among all DEGs, 70 hub IRGs were obtained for GC. The deletions and amplifications were the two most common types of genetic mutations of hub IRGs. A prognostic signature was identified, consisting of ten hub IRGs (including S100A12, DEFB126, KAL1, APOH, CGB5, GRP, GLP2R, LGR6, PTGER3, and CTLA4). This prognostic signature could accurately distinguish patients into high- and low- risk groups, and overall survival analysis showed that high risk patients had shortened survival time than low risk patients (P < 0.0001). The area under curve of the ROC of the signature was 0.761, suggesting that the prognostic signature had a high sensitivity and accuracy. Multivariate regression analysis demonstrated that the prognostic signature could become an independent prognostic predictor for GC after adjustment for other clinical features. Furthermore, we found that the prognostic signature was significantly correlated with macrophage infiltration. CONCLUSION Our study proposed an immune-related prognostic signature for GC, which could help develop treatment strategies for patients with GC in the future.
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Affiliation(s)
- Xiang-Ting Qiu
- Department of Clinical Laboratory, Linyi Central Hospital, Linyi 276400, Shandong Province, China
| | - Yu-Cui Song
- Department of Operating Room, Linyi Central Hospital, Linyi 276400, Shandong Province, China
| | - Jian Liu
- Department of Clinical Laboratory, Linyi Central Hospital, Linyi 276400, Shandong Province, China
| | - Zhen-Min Wang
- Department of Clinical Laboratory, Linyi Central Hospital, Linyi 276400, Shandong Province, China
| | - Xing Niu
- Second Clinical College, Shengjing Hospital Affiliated to China Medical University, Shenyang 110004, Liaoning Province, China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong Province, China
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32
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Chen B, Ding P, Hua Z, Qin X, Li Z. Analysis and identification of novel biomarkers involved in neuroblastoma via integrated bioinformatics. Invest New Drugs 2020; 39:52-65. [PMID: 32772341 DOI: 10.1007/s10637-020-00980-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 08/01/2020] [Indexed: 12/16/2022]
Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor in children. Under various treatments, some patients still have a poor prognosis. Hence, it is necessary to find new valid targets for NB therapy. In this study, a comprehensive bioinformatic analysis was used to identify differentially expressed genes (DEGs) between NB and control cells, and to select hub genes associated with NB. GSE66586 and GSE78061 datasets were downloaded from the Gene Expression Omnibus (GEO) database and DEGs were selected. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were applied to the selected DEGs. The STRING database and Cytoscape software were used to construct protein-protein interaction (PPI) networks and perform modular analysis of the DEGs. The R2 database was used for prognostic analysis. We identified a total of 238 DEGs from two microarray databases. GO enrichment analysis shows that these DEGs are mainly concentrated in the regulation of cell growth, cell migration, cell fate determination, and cell maturation. KEGG pathway analysis showed that these DEGs are mainly involved in focal adhesion, the TNF signaling pathway, cancer-related pathways, and signaling pathways regulating stem cell pluripotency. We identified the 15 most closely related DEGs from the PPI network, and performed R2 database prognostic analysis to select five hub genes - CTGF, EDN1, GATA2, LOX, and SERPINE1. This study distinguished hub genes and related signaling pathways that can potentially serve as diagnostic indicators and therapeutic biomarkers for NB, thereby improving understanding of the molecular mechanisms involved in NB.
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Affiliation(s)
- Bo Chen
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.,Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang, 110004, China
| | - Peng Ding
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.,Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang, 110004, China
| | - Zhongyan Hua
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.,Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang, 110004, China
| | - Xiuni Qin
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.,Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang, 110004, China
| | - Zhijie Li
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China. .,Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Shengjing Hospital of China Medical University, #36 Sanhao Street, Heping District, Shenyang, 110004, China.
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33
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Shi LE, Shang X, Nie KC, Xu Q, Chen NB, Zhu ZZ. Identification of potential crucial genes associated with the pathogenesis and prognosis of pancreatic adenocarcinoma. Oncol Lett 2020; 20:60. [PMID: 32793313 PMCID: PMC7418510 DOI: 10.3892/ol.2020.11921] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 06/22/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma (PAAD) is a type of malignant tumor with the highest mortality rate among all neoplasms worldwide, and its exact pathogenesis is still poorly understood. Timely diagnosis and treatment are of great importance in order to decrease the mortality rate of PAAD. Therefore, identifying new biomarkers for diagnosis and prognosis is essential to enable early detection of PAAD and to improve the overall survival (OS) rate. In order to screen and integrate differentially expressed genes (DEGs) between PAAD and normal tissues, a total of seven datasets were downloaded from the Gene Expression Omnibus database and the ‘limma’ and ‘robustrankggreg’ packages in R software were used. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of the DEGs was performed using the Database for Annotation, Visualization and Integrated Discovery website, and the protein-protein interaction network analysis was performed using the Search Tool for the Retrieval of Interacting Genes/Proteins database. A gene prognostic signature was constructed using the Cox regression model. A total of 10 genes (CDK1, CCNB1, CDC20, ASPM, UBE2C, TPX2, TOP2A, NUSAP1, KIF20A and DLGAP5) that may be associated with pancreatic adenocarcinoma were identified. According to the differentially expressed genes in The Cancer Genome Atlas, the present study set up four prognostic signatures (matrix metalloproteinase 12, sodium voltage-gated channel α subunit 11, tetraspanin 1 and SH3 domain and tetratricopeptide repeats-containing 2), which effectively predicted OS. The hub genes that were highly associated with the occurrence, development and prognosis of PAAD were identified, which may be helpful to further understand the molecular basis of pancreatic cancer and guide the synthesis of drugs for PPAD.
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Affiliation(s)
- Lan-Er Shi
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Xin Shang
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Ke-Chao Nie
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Qiang Xu
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Na-Bei Chen
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Zhang-Zhi Zhu
- Department of Endocrinology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
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34
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Shi Y, Zheng C, Jin Y, Bao B, Wang D, Hou K, Feng J, Tang S, Qu X, Liu Y, Che X, Teng Y. Reduced Expression of METTL3 Promotes Metastasis of Triple-Negative Breast Cancer by m6A Methylation-Mediated COL3A1 Up-Regulation. Front Oncol 2020; 10:1126. [PMID: 32766145 PMCID: PMC7381173 DOI: 10.3389/fonc.2020.01126] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/04/2020] [Indexed: 12/15/2022] Open
Abstract
The abnormal m6A modification caused by m6A modulators is a common feature of various tumors; however, little is known about which m6A modulator plays the most important role in triple-negative breast cancer (TNBC). In this study, when analyzing the influence of m6A modulators (METTL3, METTL14, WTAP, FTO, and ALKBH5) on the prognosis of breast cancer, especially in TNBC using several on-line databases, methyltransferase-like 3 (METTL3) was found to have low expression in breast cancer, and was closely associated with short-distance-metastasis-free survival in TNBC. Further investigation showed that knockdown of METTL3 could enhance the ability of migration, invasion, and adhesion by decreasing m6A level in TNBC cell lines. Collagen type III alpha 1 chain (COL3A1) was identified and verified as a target gene of METTL3. METTL3 could down-regulate the expression of COL3A1 by increasing its m6A methylation, ultimately inhibiting the metastasis of TNBC cells. Finally, with immunohistochemistry staining in breast cancer tissues, it was proved that METTL3 expression was negatively correlated with COL3A1 in TNBC, but not in non-TNBC. This study demonstrated the potential mechanism of m6A modification in metastasis and provided potential targets for treatment in TNBC.
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Affiliation(s)
- Yu Shi
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, China Medical University, Shenyang, China
| | - Chunlei Zheng
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, China Medical University, Shenyang, China
| | - Yue Jin
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, China Medical University, Shenyang, China
| | - Bowen Bao
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, China Medical University, Shenyang, China
| | - Duo Wang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, China Medical University, Shenyang, China
| | - Kezuo Hou
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, China Medical University, Shenyang, China
| | - Jing Feng
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, China Medical University, Shenyang, China
| | - Shiying Tang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, China Medical University, Shenyang, China
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, China Medical University, Shenyang, China
| | - Yunpeng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, China Medical University, Shenyang, China
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, China Medical University, Shenyang, China
| | - Yuee Teng
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China
- Liaoning Province Clinical Research Center for Cancer, China Medical University, Shenyang, China
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Qi W, Zhang Q. Gene's co-expression network and experimental validation of molecular markers associated with the drug resistance of gastric cancer. Biomark Med 2020; 14:761-773. [PMID: 32715733 DOI: 10.2217/bmm-2019-0504] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 04/20/2020] [Indexed: 12/28/2022] Open
Abstract
Aim: Chemotherapy can significantly improve the overall survival rate of patients with gastric cancer; however, so far little is known about the molecular mechanism of resistance to chemotherapy. Therefore, this study was proposed to elucidate molecular markers of resistance to chemotherapeutic agent in gastric cancer. Materials & methods: Weighted gene co-expression network analyses were performed in gastric cancer cohort. The most relevant genes modules for gastric cancer resistance were selected. Gene oncology function enrichment of genes was conducted. The biological function of resistant genes were identified in vitro. Results & conclusion: Two resistant hub genes, SPTBN1 and LAMP1, were selected. Experiments showed that downregulation of SPTBN1and LAMP1 proteins significantly enhanced the sensitivity of human gastric cancer cells SGC7901 to 5-FU and cisplatin. Thus, our results provide a baseline about the potential factors of drug resistance in gastric cancer.
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Affiliation(s)
- Wenqian Qi
- Department of Gastroenterology China, Japan Union Hospital, Jilin University Changchun, Jilin Province 130033, China
| | - Qian Zhang
- Department of Gastroenterology China, Japan Union Hospital, Jilin University Changchun, Jilin Province 130033, China
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