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Liang X, Zhang J, Yu J, Zhao J, Yang S. Quercetin ameliorates ox-LDL-induced cellular senescence of aortic endothelial cells and macrophages by p16/p21, p53/SERPINE1, and AMPK/mTOR pathways. Eur J Med Res 2025; 30:359. [PMID: 40319296 PMCID: PMC12049051 DOI: 10.1186/s40001-025-02562-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 04/06/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND Atherosclerosis (AS), a chronic inflammatory disease of the arterial wall, remains a dominant cause of death and disability globally. Quercetin has been evidenced to be effective against AS, but the exact mechanisms are still largely unclear. METHODS Oxidized low-density lipoprotein (ox-LDL)-induced human aortic endothelial cells (HAECs) and mouse RAW264.7 macrophages were established, with quercetin treatment or p16, p21 or SERPINE1 siRNA transfection. Cellular senescence was assessed by SA-β-gal staining and detection of cellular senescence markers. Cell cycle, apoptosis and intracellular ROS were detected by flow cytometry, with cell proliferation by CCK-8. Lipid accumulation was assessed utilizing oil red O staining. Through transmission electron microscope, autophagosomes and mitochondria were investigated, with detection of autophagy markers. Finally, AS models of ApoE-/- mice were established through feeding high-fat diet, and the effect of quercetin on alleviating AS progression was investigated. RESULTS Quercetin protected HAECs from ox-LDL-elicited senescent phenotype, growth arrest and apoptosis and promoted cell viability in a concentration-dependent fashion. Furthermore, quercetin alleviated ox-LDL-elicited cellular senescence, ROS and lipid accumulation in macrophages. In ox-LDL-induced HAECs or/and macrophages, quercetin down-regulated the expression of p16, p21, p53 and SERPINE1, elevated p-AMPK/AMPK levels and decreased p-mTOR/mTOR levels, and these effects of quercetin were ameliorated by SERPINE1 knockdown. In AS mouse models, quercetin treatment alleviated AS progression. CONCLUSION Our findings proposed a novel anti-atherosclerotic mechanism of quercetin by mitigating ox-LDL-elicited senescent phenotype of aortic endothelial cells and macrophages by regulating p16/p21, p53/SERPINE1, and AMPK/mTOR pathways.
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Affiliation(s)
- Xiao Liang
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
- Department of Cardiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, 68167, Mannheim, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, 68167, Mannheim, Germany
| | - Jingyuan Zhang
- Department of Cardiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
- First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, 68167, Mannheim, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, 68167, Mannheim, Germany
| | - Jiangbo Yu
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Jiyi Zhao
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Shusen Yang
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
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Liu L, Yu P, Zhao Z, Yang H, Yu R. Pharmacological mechanisms of carvacrol against hepatocellular carcinoma by network pharmacology and molecular docking. Technol Health Care 2025:9287329241306192. [PMID: 39973856 DOI: 10.1177/09287329241306192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
BACKGROUND Preclinical studies have demonstrated that carvacrol possesses various biological and pharmacological properties, including anti-hepatocellular carcinoma (HCC) effects. However, the molecular basis of its therapeutic action on HCC remains unclear. OBJECTIVE The aim of this study was to investigate and further validate the multi-target therapeutic mechanism of carvacrol against HCC. METHODS The chemical structure of carvacrol was obtained from the PubChem database, and its potential targets were identified using SwissTargetPrediction, HERB, and BATMAN-TCM. HCC-specific genes were screened from the TCGA-LIHC cohort. The therapeutic targets of carvacrol against HCC were determined through the intersection of these datasets. Subsequently, a multivariate Cox regression prognostic model was established. Molecular docking was performed to analyze the interactions between carvacrol and its therapeutic targets. Additionally, molecular dynamics simulations were conducted to validate the molecular docking results using Discovery Studio 2019 software. RESULTS A total of 223 carvacrol targets and 882 HCC-specific genes were identified. Fifteen therapeutic targets of carvacrol against HCC were obtained, including CA2, AR, ALB, AURKA, ALPL, EPHX2, BCHE, IL1RN, AGRN, CRP, DMGDH, APOA1, SOX9, HPX, and CHKA. The prognostic model accurately and independently predicted survival outcomes. AGRN and AURKA were significantly associated with HCC overall survival. Molecular docking and molecular dynamics simulations demonstrated that carvacrol exhibited strong potential for stable binding to the therapeutic targets AGRN and AURKA. CONCLUSION Our findings elucidate the multi-target mechanism of action of carvacrol against HCC, providing a foundation for future research on its application in HCC management.
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Affiliation(s)
- Lu Liu
- Cancer Center, Zhejiang University, Lishui Hospital, Lishui City, Zhejiang Province, China
- Cancer Center, The Fifth Affiliated Hospital of Wenzhou Medical College, Lishui City, Zhejiang Province, China
- Cancer Center, Lishui Central Hospital, Lishui City, Zhejiang Province, China
| | - Ping Yu
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing City, Zhejiang Province, China
- Department of Pharmacy, Shaoxing Hospital Affiliated Zhejiang University School of Medicine, Shaoxing City, Zhejiang Province, China
| | - Zhongwei Zhao
- Cancer Center, Zhejiang University, Lishui Hospital, Lishui City, Zhejiang Province, China
- Cancer Center, The Fifth Affiliated Hospital of Wenzhou Medical College, Lishui City, Zhejiang Province, China
- Cancer Center, Lishui Central Hospital, Lishui City, Zhejiang Province, China
| | - Hongyuan Yang
- Cancer Center, Zhejiang University, Lishui Hospital, Lishui City, Zhejiang Province, China
- Cancer Center, The Fifth Affiliated Hospital of Wenzhou Medical College, Lishui City, Zhejiang Province, China
- Cancer Center, Lishui Central Hospital, Lishui City, Zhejiang Province, China
| | - Risheng Yu
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou City, Zhejiang, China
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Chen Y, Yang X, Li Q. PDLIM1 Inhibits Chemoresistance by Blocking DNA Damage Repair in Gastric Cancer. Recent Pat Anticancer Drug Discov 2025; 20:260-273. [PMID: 38779728 DOI: 10.2174/0115748928307544240502064448] [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: 02/21/2024] [Revised: 04/06/2024] [Accepted: 04/18/2024] [Indexed: 05/25/2024]
Abstract
OBJECTIVE Current cisplatin (CDDP) resistance remains a major challenge in the treatment of advanced gastric cancer. To address the issue of drug resistance, we explored the regulatory functions of PDZ and LIM structural domain protein 1 (PDLIM1) in CDDP chemotherapy for gastric cancer. METHODS In this study, we analyzed PDLIM1 expression and prognosis using bioinformatics on publicly available data. PDLIM1 expression in a gastric mucosal epithelial cell line (GSE-1), CDDP- sensitive (SGC7901, BGC823) and CDDP-resistant gastric cancer cells was detected by RTqPCR and Western blotting. Cell proliferative capacity was assessed by knockdown of PDLIM1 and overexpression of PDLIM1 in cells administered in combination with cisplatin, and apoptotic levels were measured by CCK-8 and colony formation assay and by flow cytometry. Expression of breast cancer susceptibility gene 1 (BRCA1) and γH2AX was determined by Western blotting or immunofluorescence staining. RESULTS Downregulation of PDLIM1 was found in tumor tissues and cells, which was associated with poor clinical outcomes. Knockdown of PDLIM1 enhanced proliferation and attenuated apoptosis in gastric cancer cells. In addition, the therapeutic effects of CDDP on proliferation, apoptosis, and DNA damage repair were attenuated by PDLIM1 deletion.PDLIM1 expression was downregulated in CDDP-resistant tumor cells. Overexpression of PDLIM1 overcomes CDDP resistance in tumor cells as BRCA1 expression decreases and γH2AX expression increases. CONCLUSION Our findings demonstrate that PDLIM1 enables to alleviate gastric cancer progression and resistance to cisplatin via impeding DNA damage repair.
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Affiliation(s)
- Yuli Chen
- Health Management Center, The Third People's Hospital of Chengdu, Sichuan, Chengdu, 610014, China
| | - Xin Yang
- School of Clinical Medicine, Chengdu Medical College, Department of Pediatrics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China
| | - Qiang Li
- Department of Emergency, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, 341000, China
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Wang Z, Zhao M, Huang X, Wang Y, Li W, Qiao J, Yang X. Therapeutic types and advantages of functionalized nanoparticles in inducing ferroptosis in cancer therapy. Ann Med 2024; 56:2396568. [PMID: 39276361 PMCID: PMC11404394 DOI: 10.1080/07853890.2024.2396568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 06/24/2024] [Accepted: 07/10/2024] [Indexed: 09/17/2024] Open
Abstract
BACKGROUND The clinical efficacy of cancer treatment protocols remains unsatisfactory; however, the emergence of ferroptosis-driven therapy strategies has renewed hope for tumor treatment, owing to their remarkable tumor suppression effects. Biologically based small-molecule inducers are used in conventional method to induce ferroptosis. Nevertheless, some molecular drugs have limited solubility, poor ability to target cells, and fast metabolism, which hinder their ability to induce ferroptosis over a prolonged period. Fortunately, further investigations of ferroptosis and the development of nanotechnology have demonstrated that nanoparticles (NPs) are more efficient in inducing ferroptosis than drugs alone, which opens up new perspectives for cancer therapy. OBJECTIVE In order to organize a profile of recent advance in NPs for inducing ferroptosis in cancer therapy, and NPs were comprehensively classified in a new light.Materials and methods: We comprehensively searched the databases such as PubMed and Embase. The time limit for searching was from the establishment of the database to 2023.11. All literatures were related to "ferroptosis", "nanoparticles", "nanodelivery systems", "tumors", "cancer". RESULTS We summarized and classified the available NPs from a new perspective. The NPs were classified into six categories based on their properties: (1) iron oxide NPs (2) iron - based conversion NPs (3) core-shell structure (4) organic framework (5) silica NPs (6) lipoprotein NPs. According to the therapeutic types of NPs, they can be divided into categories: (1) NPs induced ferroptosis-related immunotherapy (2) NPs loaded with drugs (3) targeted therapy of NPs (4) multidrug resistance therapy (5) gene therapy with NPs (6) energy conversion therapy. CONCLUSIONS The insights gained from this review can provide ideas for the development of original NPs and nanodelivery systems, pave the way for related nanomaterials application in clinical cancer therapy, and advance the application and development of nanotechnology in the medical field.
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Affiliation(s)
- Ziying Wang
- School of Nursing, Shandong Second Medical University, Weifang, Shandong, China
| | - Miaomiao Zhao
- Department of Pathology, Shandong Second Medical University, Weifang, Shandong, China
| | - Xiaotong Huang
- School of Nursing, Shandong Second Medical University, Weifang, Shandong, China
| | - Yuxin Wang
- School of Pharmacy, Binzhou Medical College, Yantai, Shandong, China
| | - Wentong Li
- Department of Pathology, Shandong Second Medical University, Weifang, Shandong, China
| | - Jianhong Qiao
- Department of Outpatient, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Xiao Yang
- School of Nursing, Shandong Second Medical University, Weifang, Shandong, China
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Li W, Lyu W, Liu S, Ruan F, Zhang X. GLP1R boosts survival, migration and invasion of endometrial cancer cells and protects against ferroptotic cell death. J OBSTET GYNAECOL 2024; 44:2301324. [PMID: 38269495 DOI: 10.1080/01443615.2023.2301324] [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: 01/17/2023] [Accepted: 12/29/2023] [Indexed: 01/26/2024]
Abstract
BACKGROUND Despite the strong evidence concerning carcinogenic roles of glucagon-like peptide 1 receptor (GLP1R), the role of this gene in endometrial cancer (EC) remains elusive. This study investigated the properties of GLP1R on EC in vitro. METHODS The expression of GLP1R in EC was detected by RT-qPCR, immunohistochemistry, and western blotting. Cell viability, cell cycle, apoptosis, migration, invasion and ferroptosis were assessed through CCK-8, flow cytometry, wound healing, transwell, DCFH-DA and western blotting, respectively. RESULTS We found that GLP1R was up-regulated in EC than normal specimens. It had the highest expression in AN3CA cells. Cell viability, migration and invasion were significantly reduced, while cell cycle arrest and apoptosis were induced following GLP1R knockdown. The malignant biological behaviours of AN3CA cells were investigated when treated with exendin-4 (GLP1R agonist). Moreover, GLP1R lowered intracellular ROS level and expression of SLC7A11, and FTH1, but mitigated GPX4 expression in AN3CA cells. CONCLUSION In a word, GLP1R was up-regulated in EC and its up-regulation facilitated the proliferative and metastatic potentials, and protected cells from ferroptosis, thereby accelerating EC progression. These data emphasised the potency of GLP1R as a therapeutic agent against EC.
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Affiliation(s)
- Wu Li
- Department of Gynecology, Women's Hospital School of Medicine Zhejiang University, Hangzhou City, China
| | - Wen Lyu
- Department of Gynecology, Tongde Hospital of Zhejiang Province, Hangzhou City, China
| | - Songjun Liu
- Department of Gynecology, Tongde Hospital of Zhejiang Province, Hangzhou City, China
| | - Fan Ruan
- Department of Gynecology, Tongde Hospital of Zhejiang Province, Hangzhou City, China
| | - Xinmei Zhang
- Department of Gynecology, Women's Hospital School of Medicine Zhejiang University, Hangzhou City, China
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Song K, Ma C, Maswikiti EP, Gu B, Wang B, Wang N, Jiang P, Chen H. Downregulation of ALDH5A1 suppresses cisplatin resistance in esophageal squamous cell carcinoma by regulating ferroptosis signaling pathways. Mol Carcinog 2024; 63:1892-1906. [PMID: 38923019 DOI: 10.1002/mc.23778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 05/24/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024]
Abstract
This study explores the specific role and underlying mechanisms of ALDH5A1 in the chemoresistance of esophageal squamous cell carcinoma (ESCC). The levels of cleaved caspase-3, 4-hydroxynonenal (4-HNE), intracellular Fe2+, and lipid reactive oxygen species (ROS) were evaluated via immunofluorescence. Cell viability and migration were quantified using cell counting kit-8 assays and wound healing assays, respectively. Flow cytometry was utilized to analyze cell apoptosis and ROS production. The concentrations of malondialdehyde (MDA) and reduced glutathione were determined by enzyme-linked immunosorbent assay. Proteome profiling was performed using data-independent acquisition. Additionally, a xenograft mouse model of ESCC was established to investigate the relationship between ALDH5A1 expression and the cisplatin (DDP)-resistance mechanism in vivo. ALDH5A1 is overexpressed in both ESCC patients and ESCC/DDP cells. Silencing of ALDH5A1 significantly enhances the inhibitory effects of DDP treatment on the viability and migration of KYSE30/DDP and KYSE150/DDP cells and promotes apoptosis. Furthermore, it intensifies DDP's suppressive effects on tumor volume and weight in nude mice. Gene ontology biological process analysis has shown that ferroptosis plays a crucial role in both KYSE30/DDP cells and KYSE30/DDP cells transfected with si-ALDH5A1. Our in vitro and in vivo experiments demonstrate that DDP treatment promotes the accumulation of ROS, lipid ROS, MDA, LPO, and intracellular Fe2+ content, increases the levels of proteins that promote ferroptosis (ACSL4 and FTH1), and decreases the expression of anti-ferroptosis proteins (SLC7A11, FTL, and GPX4). Silencing of ALDH5A1 further amplifies the regulatory effects of DDP both in vitro and in vivo. ALDH5A1 potentially acts as an oncogene in ESCC chemoresistance. Silencing of ALDH5A1 can reduce DDP resistance in ESCC through promoting ferroptosis signaling pathways. These findings suggest a promising strategy for the treatment of ESCC in clinical practice.
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Affiliation(s)
- Kewei Song
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of Public Health, Jining No. 1 People's Hospital, Jining, China
| | - Chenhui Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | | | - Baohong Gu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Bofang Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Na Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Pei Jiang
- Translational Pharmaceutical Laboratory, Jining No. 1 People's Hospital, Jining, China
| | - Hao Chen
- Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, China
- Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, China
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Ning F, Wei D, Yu H, Song T, Li Z, Ma H, Sun Y. Construction of a Multifunctional Upconversion Nanoplatform Based on Autophagy Inhibition and Photodynamic Therapy Combined with Chemotherapy for Antitumor Therapy. Mol Pharm 2024; 21:4297-4311. [PMID: 39106330 DOI: 10.1021/acs.molpharmaceut.4c00203] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/09/2024]
Abstract
Inhibition of autophagy increases the sensitivity of tumor cells to radiotherapy and chemotherapy and improves the therapeutic effect on tumors. Recently, photodynamic therapy (PDT) combined with chemotherapy has been proven to further improve the efficiency of cancer treatment. As such, combining autophagy inhibition with PDT and chemotherapy may represent a potentially effective new strategy for cancer treatment. However, currently widely studied autophagy inhibitors inevitably produce various toxic side effects due to their inherent pharmacological activity. To overcome this constraint, in this study, we designed an ideal multifunctional upconversion nanoplatform, UCNP-Ce6-EPI@mPPA + NIR (MUCEN). Control, UCNP-EPI@mPPA (MUE), UCNP-EPI@mPPA + NIR (MUEN), Ce6-EPI@mPPA (MCE), Ce6-EPI@mPPA + NIR (MCEN), and UCNP-Ce6-EPI@mPPA (MUCE) groups were set up separately as controls. Based on a combination of autophagy inhibition and PDT, the average particle size of MUCEN was 197 nm, which can simultaneously achieve the double encapsulation of chlorine e6 (Ce6) and epirubicin (EPI). In vitro tests revealed that MUCE was efficiently endocytosed by 4T1 cells under near-infrared light irradiation. Further, in vivo tests revealed that MUCE dramatically inhibited tumor growth. Immunohistochemistry results indicated that MUCE efficiently increased the expression of autophagy inhibitors p62 and LC3 in tumor tissues. The synergistic effect of autophagy inhibition and PDT with MUCE exhibited superior tumor suppression, providing an innovative approach to cancer treatment.
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Affiliation(s)
- Fang Ning
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266071, China
| | - Dengshuai Wei
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266071, China
| | - Hongli Yu
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266071, China
| | - Tingting Song
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266071, China
| | - Zhipeng Li
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266071, China
| | - Hongmei Ma
- Department of Gynecology, Qingdao Municipal Hospital, Qingdao 266000, China
| | - Yong Sun
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao 266071, China
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Luo Z, Li Y, Xu B, Yu T, Luo M, You P, Niu X, Li J. Overexpression of ESYT3 improves radioimmune responses through activating cGAS-STING pathway in lung adenocarcinoma. Exp Hematol Oncol 2024; 13:77. [PMID: 39103908 DOI: 10.1186/s40164-024-00546-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 07/26/2024] [Indexed: 08/07/2024] Open
Abstract
BACKGROUND Radiotherapy can modulate systemic antitumor immunity, while immune status in the tumor microenvironment also influences the efficacy of radiotherapy, but relevant molecular mechanisms are poorly understood in lung adenocarcinoma (LUAD). METHODS In this study, we innovatively proposed a radiotherapy response classification for LUAD, and discovered ESYT3 served as a tumor suppressor and radioimmune response sensitizer. ESYT3 expression was measured both in radioresistant and radiosensitive LUAD tissues and cells. The influence of ESYT3 on radiotherapy sensitivity and resistance was then investigated. Interaction between ESYT3 and STING was evaluated through multiple immunofluorescent staining and coimmunoprecipitation, and downstream molecules were further analyzed. In vivo models were constructed to assess the combination treatment efficacy of ESYT3 overexpression with radiotherapy. RESULTS We found that radioresistant subtype presented immunosuppressive state and activation of DNA damage repair pathways than radiosensitive subtype. ESYT3 expression was remarkably attenuated both in radioresistant LUAD tissues and cells. Clinically, low ESYT3 expression was linked with radioresistance. Overexpression of ESYT3 enabled to alleviate radioresistance, and sensitize LUAD cells to DNA damage induced by irradiation. Mechanically, ESYT3 directly interacted with STING, and activated cGAS-STING signaling, subsequently increasing the generation of type I IFNs as well as downstream chemokines CCL5 and CXCL10, thus improving radioimmune responses. The combination treatment of ESYT3 overexpression with radiotherapy had a synergistic anticancer effect in vitro and in vivo. CONCLUSIONS In summary, low ESYT3 expression confers resistance to radiotherapy in LUAD, and its overexpression can improve radioimmune responses through activating cGAS-STING-dependent pathway, thus providing an alternative combination therapeutic strategy for LUAD patients.
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Affiliation(s)
- Zan Luo
- Department of Radiation Oncology, The Second Affiliated Hospital of Nanchang Medical College), Jiangxi Cancer Hospital, Nanchang, Jiangxi, 330029, China
- Jiangxi Key Laboratory of Oncology, The Second Affiliated Hospital of Nanchang Medical College), Jiangxi Cancer Hospital, Nanchang, Jiangxi, 330029, China
| | - Ying Li
- Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430079, Hubei, China
| | - Bin Xu
- Laboratory of Tumor Metastasis, The Second Affiliated Hospital of Nanchang Medical College), Jiangxi Health Committee Key (JHCK), Jiangxi Cancer Hospital, Nanchang, Jiangxi, 330029, China.
| | - Tenghua Yu
- Department of Breast Surgery, The Second Affiliated Hospital of Nanchang Medical College), Jiangxi Cancer Hospital, Nanchang, Jiangxi, 330029, China
| | - Mingming Luo
- Jiangxi Clinical Research Center for Cancer, The Second Affiliated Hospital of Nanchang Medical College), Jiangxi Cancer Hospital, Nanchang, Jiangxi, 330029, China
| | - PeiMeng You
- Department of Radiation Oncology, Jiangxi Key Laboratory of Translational Cancer Research, Cancer Hospital of Nanchang University, Jiangxi Cancer Hospital of Nanchang University), Nanchang, Jiangxi, 330029, China
| | - Xing Niu
- Experimental Center of BIOQGene, YuanDong International Academy Of Life Sciences, Hong Kong, Hong Kong, 999077, China.
- China Medical University, Shenyang, Liaoning, 110122, China.
| | - Junyu Li
- Department of Radiation Oncology, The Second Affiliated Hospital of Nanchang Medical College), Jiangxi Cancer Hospital, Nanchang, Jiangxi, 330029, China.
- Jiangxi Key Laboratory of Oncology, The Second Affiliated Hospital of Nanchang Medical College), Jiangxi Cancer Hospital, Nanchang, Jiangxi, 330029, China.
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Yu L, Chen Y, Chen Y, Luo K. The crosstalk between metabolic reprogramming and epithelial-mesenchymal transition and their synergistic roles in distant metastasis in breast cancer. Medicine (Baltimore) 2024; 103:e38462. [PMID: 38875364 PMCID: PMC11175907 DOI: 10.1097/md.0000000000038462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/07/2024] [Accepted: 05/14/2024] [Indexed: 06/16/2024] Open
Abstract
BACKGROUND Metabolic reprogramming (MR) and epithelial-mesenchymal transition (EMT) are crucial phenomena involved in the distant metastasis of breast cancer (BRCA). This study aims to assess the risk of distant metastasis in BRCA patients based on MR and EMT processes and investigate their underlying mechanisms. METHODS Gene sets related to EMT and MR were downloaded. MR-related genes (MRG) and EMT-related genes (ERG) were obtained. Principal Component Analysis method was used to define the EMT Potential Index (EPI) and MR Potential Index (MPI) to quantify the EMT and MR levels in each tumor tissue. A linear scoring model, the Metastasis Score, was derived using the union of MRGs and ERGs to evaluate the risk of distant metastasis/recurrence in BRCA. The Metastasis Score was then validated in multiple datasets. Additionally, our study explored the underlying mechanism of the Metastasis Score and its association with tumor immunity, focusing on HPRT1 gene expression in breast cancer tissues of transfer and untransferred groups using experimental methods. RESULTS A total of 59 MRGs and 30 ERGs were identified in the present study. Stratifying the dataset based on EPI and MPI revealed significantly lower survival rates (P < .05) in the MPI_high and EPI_high groups. Kaplan-Meier analysis indicated the lowest survival rate in the EPI-high + MPI-high group. The Metastasis Score demonstrated its ability to distinguish prognoses in GSE2034, GSE17705, and TCGA-BRCA datasets. Additionally, differences in mutated genes were found between the high- and the low-Metastasis Score groups, displaying significant associations with immune cell infiltration and anti-tumor immune status. Notably, the 13 genes included in the Metastasis Score showed a strong association with prognosis and tumor immunity. Immunohistochemistry and western blot results revealed high expression of the HPRT1 gene in the transfer group. CONCLUSION This study established the Metastasis Score as a reliable tool for evaluating the risk of distant metastasis/recurrence in BRCA patients. Additionally, we identified key genes involved in MR and EMT crosstalk, offering valuable insights into their roles in tumor immunity and other relevant aspects.
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Affiliation(s)
- Liyan Yu
- Department of Breast Surgery, Guangdong Medical University Affiliated Hospital, Zhanjiang, P.R. China
| | - Yongni Chen
- Department of Breast Surgery, Guangdong Medical University Affiliated Hospital, Zhanjiang, P.R. China
| | - Yingyu Chen
- Department of Breast Surgery, Guangdong Medical University Affiliated Hospital, Zhanjiang, P.R. China
| | - Kangwei Luo
- Department of Breast Surgery, Guangdong Medical University Affiliated Hospital, Zhanjiang, P.R. China
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Chao P, Zhang X, Zhang L, Wang Y, Wusiman M, Aimaijiang G, Chen X, Yang Y. Characterization of the m 6A regulators' landscape highlights the clinical significance of acute myocardial infarction. Front Immunol 2024; 15:1308978. [PMID: 38571952 PMCID: PMC10987706 DOI: 10.3389/fimmu.2024.1308978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 02/13/2024] [Indexed: 04/05/2024] Open
Abstract
Objective Acute myocardial infarction (AMI) is a severe cardiovascular disease that threatens human life and health globally. N6-methyladenosine (m6A) governs the fate of RNAs via m6A regulators. Nevertheless, how m6A regulators affect AMI remains to be deciphered. To solve this issue, an integrative analysis of m6A regulators in AMI was conducted. Methods We acquired transcriptome profiles (GSE59867, GSE48060) of peripheral blood samples from AMI patients and healthy controls. Key m6A regulators were used for LASSO, and consensus clustering was conducted. Next, the m6A score was also computed. Immune cell infiltration, ferroptosis, and oxidative stress were evaluated. In-vitro and in-vivo experiments were conducted to verify the role of the m6A regulator ALKBH5 in AMI. Results Most m6A regulators presented notable expression alterations in circulating cells of AMI patients versus those of controls. Based on key m6A regulators, we established a gene signature and a nomogram for AMI diagnosis and risk prediction. AMI patients were classified into three m6A clusters or gene clusters, respectively, and each cluster possessed the unique properties of m6A modification, immune cell infiltration, ferroptosis, and oxidative stress. Finally, the m6A score was utilized to quantify m6A modification patterns. Therapeutic targeting of ALKBH5 greatly alleviated apoptosis and intracellular ROS in H/R-induced H9C2 cells and NRCMs. Conclusion Altogether, our findings highlight the clinical significance of m6A regulators in the diagnosis and risk prediction of AMI and indicate the critical roles of m6A modification in the regulation of immune cell infiltration, ferroptosis, and oxidative stress.
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Affiliation(s)
- Peng Chao
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regeneration Research, Urumqi, Xinjiang Uygur Autonomous Region, China
| | - Xueqin Zhang
- Department of Nephrology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Lei Zhang
- Department of Endocrinology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Yong Wang
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Miriban Wusiman
- Department of Nephrology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Gulizere Aimaijiang
- Department of Nephrology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Xiaoyang Chen
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Yining Yang
- Department of Cardiology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
- Xinjiang Key Laboratory of Cardiovascular Homeostasis and Regeneration Research, Urumqi, Xinjiang Uygur Autonomous Region, China
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11
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Han Z, Luo W, Shen J, Xie F, Luo J, Yang X, Pang T, Lv Y, Li Y, Tang X, He J. Non-coding RNAs are involved in tumor cell death and affect tumorigenesis, progression, and treatment: a systematic review. Front Cell Dev Biol 2024; 12:1284934. [PMID: 38481525 PMCID: PMC10936223 DOI: 10.3389/fcell.2024.1284934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 01/08/2024] [Indexed: 11/02/2024] Open
Abstract
Cell death is ubiquitous during development and throughout life and is a genetically determined active and ordered process that plays a crucial role in regulating homeostasis. Cell death includes regulated cell death and non-programmed cell death, and the common types of regulatory cell death are necrosis, apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis. Apoptosis, Necrosis and necroptosis are more common than autophagy, ferroptosis and pyroptosis among cell death. Non-coding RNAs are regulatory RNA molecules that do not encode proteins and include mainly microRNAs, long non-coding RNAs, and circular RNAs. Non-coding RNAs can act as oncogenes and tumor suppressor genes, with significant effects on tumor occurrence and development, and they can also regulate tumor cell autophagy, ferroptosis, and pyroptosis at the transcriptional or post-transcriptional level. This paper reviews the recent research progress on the effects of the non-coding RNAs involved in autophagy, ferroptosis, and pyroptosis on tumorigenesis, tumor development, and treatment, and looks forward to the future direction of this field, which will help to elucidate the molecular mechanisms of tumorigenesis and tumor development, as well as provide a new vision for the treatment of tumors.
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Affiliation(s)
- Zeping Han
- Central Laboratory, Guangzhou Panyu Central Hospital, Guangzhou, China
- Rehabilitation Medicine Institute of Panyu District, Guangzhou, China
| | - Wenfeng Luo
- Central Laboratory, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Jian Shen
- Central Laboratory, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Fangmei Xie
- Central Laboratory, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Jinggen Luo
- Department of General Surgery, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Xiang Yang
- Department of Gynaecology and Obstetrics, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Ting Pang
- Clinical Laboratory, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Yubing Lv
- Clinical Laboratory, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Yuguang Li
- He Xian Memorial Hospital, Southern Medical University, Guangzhou, China
| | - Xingkui Tang
- Department of General Surgery, Guangzhou Panyu Central Hospital, Guangzhou, China
| | - Jinhua He
- Central Laboratory, Guangzhou Panyu Central Hospital, Guangzhou, China
- Rehabilitation Medicine Institute of Panyu District, Guangzhou, China
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Zhang YX, Lv J, Bai JY, Pu X, Dai EL. Identification of key biomarkers of the glomerulus in focal segmental glomerulosclerosis and their relationship with immune cell infiltration based on WGCNA and the LASSO algorithm. Ren Fail 2023; 45:2202264. [PMID: 37096442 PMCID: PMC10132234 DOI: 10.1080/0886022x.2023.2202264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023] Open
Abstract
OBJECTIVE The aim of our study was to identify key biomarkers of glomeruli in focal glomerulosclerosis (FSGS) and analyze their relationship with the infiltration of immune cells. METHODS The expression profiles (GSE108109 and GSE200828) were obtained from the GEO database. The differentially expressed genes (DEGs) were filtered and analyzed by gene set enrichment analysis (GSEA). MCODE module was constructed. Weighted gene coexpression network analysis (WGCNA) was performed to obtain the core gene modules. Least absolute shrinkage and selection operator (LASSO) regression was applied to identify key genes. ROC curves were employed to explore their diagnostic accuracy. Transcription factor prediction of the key biomarkers was performed using the Cytoscape plugin IRegulon. The analysis of the infiltration of 28 immune cells and their correlation with the key biomarkers were performed. RESULTS A total of 1474 DEGs were identified. Their functions were mostly related to immune-related diseases and signaling pathways. MCODE identified five modules. The turquoise module of WGCNA had significant relevance to the glomerulus in FSGS. TGFB1 and NOTCH1 were identified as potential key glomerular biomarkers in FSGS. Eighteen transcription factors were obtained from the two hub genes. Immune infiltration showed significant correlations with T cells. The results of immune cell infiltration and their relationship with key biomarkers implied that NOTCH1 and TGFB1 were enhanced in immune-related pathways. CONCLUSION TGFB1 and NOTCH1 may be strongly correlated with the pathogenesis of the glomerulus in FSGS and are new candidate key biomarkers. T-cell infiltration plays an essential role in the FSGS lesion process.
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Affiliation(s)
- Yun Xia Zhang
- College of Integrated Traditional and Western Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, China
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Juan Lv
- College of Integrated Traditional and Western Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, China
- Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Jun Yuan Bai
- College of Integrated Traditional and Western Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, China
- Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou, China
| | - XiaoWei Pu
- College of Integrated Traditional and Western Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - En Lai Dai
- College of Integrated Traditional and Western Medicine, Gansu University of Traditional Chinese Medicine, Lanzhou, China
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Wang H, Chen W, Cui Y, Gong H, Li H. KIAA1429 protects hepatocellular carcinoma cells from ferroptotic cell death with a m 6 A-dependent posttranscriptional modification of SLC7A11. J Cell Mol Med 2023; 27:4118-4132. [PMID: 37830241 PMCID: PMC10746954 DOI: 10.1111/jcmm.17997] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 09/14/2023] [Accepted: 10/05/2023] [Indexed: 10/14/2023] Open
Abstract
N6 -methyladenosine (m6 A) modification represents the most abundant internal methylation of eukaryotic RNAs. KIAA1429 acts as a key component of the m6 A methyltransferase complex, but its function and mechanism in ferroptotic cell death of hepatocellular carcinoma (HCC) are barely defined. We found that KIAA1429 suppression triggered ferroptosis in HCC cells according to increased cell death, iron and MDA levels, C11-BODIPY-positive cells, ROS production and decreased GSH level. Ferroptosis inhibitors ferrostatin-1 (0.5 μM) and liproxstatin-1 (10 μM) blocked KIAA1429 suppression-induced ferroptosis of HCC cells. In addition, overexpressed KIAA1429 notably heightened the activity of cystine/glutamate antiporter (SLC7A11). SLC7A11 up-regulation partially hindered KIAA1429 inhibition-mediated ferroptosis of HCC cells. The regulation SLC7A11 by KIAA1429 was attenuated by global m6 A inhibitor cycloleucine (40 μM). RNA immunoprecipitation confirmed the binding of KIAA1429 to m6 A on SLC7A11 transcript. Additionally, it was proven that KIAA1429 inhibition mitigated HCC growth in subcutaneous xenograft mice through SLC7A11. Altogether, our findings first propose that KIAA1429 protects HCC cells from ferroptosis with a m6 A-dependent post-transcriptional modification of SLC7A11 and offer a novel insight into the dysregulated epi-transcriptomics in the context of HCC.
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Affiliation(s)
- Houhong Wang
- Department of General SurgeryThe Affiliated Bozhou Hospital of Anhui Medical UniversityBozhouAnhuiChina
| | - Wenli Chen
- Department of General SurgeryThe Affiliated Bozhou Hospital of Anhui Medical UniversityBozhouAnhuiChina
| | - Yayun Cui
- Division of Life Sciences and Medicine, Department of Cancer Radiotherapy, The First Affiliated Hospital of USTCUniversity of Science and Technology of China (Anhui Provincial Cancer Hospital)HefeiAnhuiChina
| | - Huihui Gong
- Faculty of Health and Life SciencesOxford Brookes UniversityOxfordUnited Kingdom
| | - Heng Li
- Department of Comprehensive SurgeryAnhui Provincial Cancer Hospital, West District of The First Affiliated Hospital of USTCHefeiAnhuiChina
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Wang C, He Z. Multi-omics analysis reveals CLIC1 as a therapeutic vulnerability of gliomas. Front Pharmacol 2023; 14:1279370. [PMID: 38027011 PMCID: PMC10663228 DOI: 10.3389/fphar.2023.1279370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 10/24/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction: Despite advances in comprehending cancer biology, malignant gliomas remain incurable. The present work conducted a multi-omics analysis for investigating the significance of chloride intracellular channel 1 (CLIC1) in gliomas. Methods: Multi-omics data of glioma covering transcriptomics, genomics, DNA methylation and single-cell transcriptomics from multiple public cohorts were enrolled for analyzing CLIC1. In vitro experiments were conducted to measure apoptosis and cell mobility in U251 and U373 glioma cells following transfection of CLIC1 siRNAs. Results: Elevated CLIC1 expression was proven to stably and independently estimate worse survival outcomes. CLIC1 expression was higher in more advanced stage, wild-type IDH and unmethylated MGMT samples. Tumorigenic and anticancer immunity pathways were remarkably enriched in CLIC1-up-regulated tumors. Additionally, CLIC1 was positively linked with cancer-immunity cycle, stromal activation, DNA damage repair and cell cycle. Suppressing CLIC1 resulted in apoptosis and attenuated cell motility of glioma cells. More frequent genomic alterations were found in CLIC1-up-regulated tumors. CLIC1 expression presented a remarkably negative connection to DNA methylation. High CLIC1 expression samples were more sensitive to camptothecin, cisplatin, doxorubicin, erlotinib, paclitaxel, rapamycin, clofarabine, tanespimycin, methotrexate, everolimus, TAK-733, trametinib and AZD8330. Tumors with upregulated CLIC1 presented abundant immune cell infiltration, higher expression of immune-checkpoints and -modulators and similar transcriptome profiling, indicative of well response to immune-checkpoint blockade (ICB). Nevertheless, due to elevated TIDE score, tumors with CLIC1 upregulation appeared to be resistant to ICB. Single-cell analysis unveiled that CLIC1 was expressed ubiquitously in tumor cells and tumor microenvironment. Conclusions: Overall, CLIC1 was a promising treatment vulnerability in glioma.
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Affiliation(s)
- Chengcheng Wang
- Department of Pharmacy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, China
| | - Zheng He
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, China
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15
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Wang X, Zhou L, Wang H, Chen W, Jiang L, Ming G, Wang J. Metabolic reprogramming, autophagy, and ferroptosis: Novel arsenals to overcome immunotherapy resistance in gastrointestinal cancer. Cancer Med 2023; 12:20573-20589. [PMID: 37860928 PMCID: PMC10660574 DOI: 10.1002/cam4.6623] [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: 04/19/2023] [Revised: 09/05/2023] [Accepted: 09/29/2023] [Indexed: 10/21/2023] Open
Abstract
BACKGROUND Gastrointestinal cancer poses a serious health threat owing to its high morbidity and mortality. Although immune checkpoint blockade (ICB) therapies have achieved meaningful success in most solid tumors, the improvement in survival in gastrointestinal cancers is modest, owing to sparse immune response and widespread resistance. Metabolic reprogramming, autophagy, and ferroptosis are key regulators of tumor progression. METHODS A literature review was conducted to investigate the role of the metabolic reprogramming, autophagy, and ferroptosis in immunotherapy resistance of gastrointestinal cancer. RESULTS Metabolic reprogramming, autophagy, and ferroptosis play pivotal roles in regulating the survival, differentiation, and function of immune cells within the tumor microenvironment. These processes redefine the nutrient allocation blueprint between cancer cells and immune cells, facilitating tumor immune evasion, which critically impacts the therapeutic efficacy of immunotherapy for gastrointestinal cancers. Additionally, there exists profound crosstalk among metabolic reprogramming, autophagy, and ferroptosis. These interactions are paramount in anti-tumor immunity, further promoting the formation of an immunosuppressive microenvironment and resistance to immunotherapy. CONCLUSIONS Consequently, it is imperative to conduct comprehensive research on the roles of metabolic reprogramming, autophagy, and ferroptosis in the resistance of gastrointestinal tumor immunotherapy. This understanding will illuminate the clinical potential of targeting these pathways and their regulatory mechanisms to overcome immunotherapy resistance in gastrointestinal cancers.
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Affiliation(s)
- Xiangwen Wang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Liwen Zhou
- Department of StomatologyThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Hongpeng Wang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Wei Chen
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Lei Jiang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Guangtao Ming
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Jun Wang
- Department of General SurgeryThe First Hospital of Lanzhou UniversityLanzhouChina
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16
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Wang HH, Chen WL, Cui YY, Gong HH, Li H. Cellular senescence throws new insights into patient classification and pharmacological interventions for clinical management of hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:1567-1594. [PMID: 37746655 PMCID: PMC10514726 DOI: 10.4251/wjgo.v15.i9.1567] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 07/10/2023] [Accepted: 08/06/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND Cellular senescence, a state of stable growth arrest, is intertwined with human cancers. However, characterization of cellular senescence-associated phenotypes in hepatocellular carcinoma (HCC) remains unexplored. AIM To address this issue, we delineated cellular senescence landscape across HCC. METHODS We enrolled two HCC datasets, TCGA-LIHC and International Cancer Genome Consortium (ICGC). Unsupervised clustering was executed to probe tumor heterogeneity based upon cellular senescence genes. Least absolute shrinkage and selection operator algorithm were utilized to define a cellular senescence-relevant scoring system. TRNP1 expression was measured in HCCs and normal tissues through immunohistochemistry, immunoblotting and quantitative real-time polymerase chain reaction. The influence of TMF-regulated nuclear protein (TRNP)1 on HCC senescence and growth was proven via a series of experiments. RESULTS TCGA-LIHC patients were classified as three cellular senescence subtypes, named C1-3. The robustness and reproducibility of these subtypes were proven in the ICGC cohort. C2 had the worst overall survival, C1 the next, and C3 the best. C2 presented the highest levels of immune checkpoints, abundance of immune cells, and immunogenetic indicators. Thus, C2 might possibly respond to immunotherapy. C2 had the lowest somatic mutation rate, while C1 presented the highest copy number variations. A cellular senescence-relevant gene signature was generated, which can predict patient survival, and chemo- or immunotherapeutic response. Experimentally, it was proven that TRNP1 presented the remarkable upregulation in HCCs. TRNP1 knockdown induced apoptosis and senescence of HCC cells and attenuated tumor growth. CONCLUSION These findings provide a systematic framework for assessing cellular senescence in HCC, which decode the tumor heterogeneity and tailor the pharmacological interventions to improve clinical management.
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Affiliation(s)
- Hou-Hong Wang
- Department of General Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou 236800, Anhui Province, China
| | - Wen-Li Chen
- Department of General Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou 236800, Anhui Province, China
| | - Ya-Yun Cui
- Department of Cancer Radiotherapy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (Anhui Provincial Cancer Hospital), Hefei 230000, Anhui Province, China
| | - Hui-Hui Gong
- Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, United Kingdom
| | - Heng Li
- Department of Comprehensive Surgery, Anhui Provincial Cancer Hospital, West District of The First Affiliated Hospital of USTC, Hefei 230000, Anhui Province, China
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Ai J, Tan Y, Liu B, Song Y, Wang Y, Xia X, Fu Q. Systematic establishment and verification of an epithelial-mesenchymal transition gene signature for predicting prognosis of oral squamous cell carcinoma. Front Genet 2023; 14:1113137. [PMID: 37636263 PMCID: PMC10447895 DOI: 10.3389/fgene.2023.1113137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 07/11/2023] [Indexed: 08/29/2023] Open
Abstract
Objective: Epithelial-mesenchymal transition (EMT) is linked to an unfavorable prognosis in oral squamous cell carcinoma (OSCC). Here, we aimed to develop an EMT gene signature for OSCC prognosis. Methods: In TCGA dataset, prognosis-related EMT genes with p < 0.05 were screened in OSCC. An EMT gene signature was then conducted with LASSO method. The efficacy of this signature in predicting prognosis was externally verified in the GSE41613 dataset. Correlations between this signature and stromal/immune scores and immune cell infiltration were assessed by ESTIMATE and CIBERSORT algorithms. GSEA was applied for exploring significant signaling pathways activated in high- and low-risk phenotypes. Expression of each gene was validated in 40 paired OSCC and normal tissues via RT-qPCR. Results: A prognostic 9-EMT gene signature was constructed in OSCC. High risk score predicted poorer clinical outcomes than low risk score. ROCs confirmed the well performance on predicting 1-, 3- and 5-year survival. Multivariate cox analysis revealed that this signature was independently predictive of OSCC prognosis. The well predictive efficacy was validated in the GSE41613 dataset. Furthermore, this signature was distinctly related to stromal/immune scores and immune cell infiltration in OSCC. Distinct pathways were activated in two subgroups. After validation, AREG, COL5A3, DKK1, GAS1, GPX7 and PLOD2 were distinctly upregulated and SFRP1 was downregulated in OSCC than normal tissues. Conclusion: Our data identified and verified a robust EMT gene signature in OSCC, which provided a novel clinical tool for predicting prognosis and several targets against OSCC therapy.
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Affiliation(s)
- Jun Ai
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Yaqin Tan
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Bo Liu
- Department of Urology, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yuhong Song
- Department of Stomatology, Shenzhen Longhua District Central Hospital, Shenzhen, China
| | - Yanqin Wang
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Xin Xia
- Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Qicheng Fu
- Department of Stomatology, Shenzhen Longhua District Central Hospital, Shenzhen, China
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Li K, Yang Y, Ma M, Lu S, Li J. Hypoxia-based classification and prognostic signature for clinical management of hepatocellular carcinoma. World J Surg Oncol 2023; 21:216. [PMID: 37481543 PMCID: PMC10362578 DOI: 10.1186/s12957-023-03090-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 06/29/2023] [Indexed: 07/24/2023] Open
Abstract
OBJECTIVE Intratumoral hypoxia is an essential feature of hepatocellular carcinoma (HCC). Herein, we investigated the hypoxia-based heterogeneity and relevant clinical implication in HCC. METHODS Three HCC cohorts: TCGA-LIHC, LICA-FR, and LIRI-JP were retrospectively gathered. Consensus clustering analysis was utilized for hypoxia-based classification based upon transcriptome of hypoxia genes. Through LASSO algorithm, a hypoxia-relevant prognostic signature was built. Immunotherapeutic response was inferred through analyzing immune checkpoints, T cell inflamed score, TIDE score, and TMB score. RNF145 expression was measured in normoxic or hypoxic HCC cells. In RNF145-knockout cells, CCK-8, TUNEL, and scratch tests were implemented. RESULTS HCC patients were classified into two hypoxia subtypes, with more advanced stages and poorer prognosis in cluster2 than cluster1. The heterogeneity in tumor infiltrating immune cells and genetic mutation was found between subtypes. The hypoxia-relevant prognostic model was proposed, composed of ANLN, CBX2, DLGAP5, FBLN2, FTCD, HMOX1, IGLV1-44, IL33, LCAT, LPCAT1, MKI67, PFN2, RNF145, S100A9, and SPP1). It was predicted that high-risk patients presented worse prognosis with an independent and reliable manner. Based upon high expression of immune checkpoints (CD209, CTLA4, HAVCR2, SIRPA, TNFRSF18, TNFRSF4, and TNFRSF9), high T cell inflamed score, low TIDE score and high TMB score, high-risk patients might respond to immunotherapy. Experimental validation showed that RNF145 was upregulated in hypoxic HCC cells, RNF145 knockdown attenuated proliferation and migration, but aggravated apoptosis in HCC cells. CONCLUSION Altogether, the hypoxia-based classification and prognostic signature might be useful for prognostication and guiding treatment of HCC.
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Affiliation(s)
- Ke Li
- Ruigu Medical Laboratory of Guangxi Medical University Co., LTD, Nanning, Guangxi, China
| | - Yanfang Yang
- Guangxi Zhuoqiang Technology Co. LTD, Nanning, Guangxi, China.
| | - Mingwei Ma
- The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Suping Lu
- Foresea Life Insurance Nanning Hospital, Nanning, Guangxi, China
| | - Junjie Li
- Guangxi Zhuoqiang Technology Co. LTD, Nanning, Guangxi, China
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Wang M, Wu H, Wu R, Tan Y, Chang Q. Application of multiple machine learning approaches to determine key pyroptosis molecules in type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2023; 14:1112507. [PMID: 37538791 PMCID: PMC10394840 DOI: 10.3389/fendo.2023.1112507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 06/15/2023] [Indexed: 08/05/2023] Open
Abstract
Objective Pyroptosis, a lytic and inflammatory programmed cell death, has been implicated in type 2 diabetes mellitus (T2DM) and its complications. Nonetheless, it remains elusive exactly which pyroptosis molecule exerts an essential role in T2DM, and this study aims to solve such issue. Methods Transcriptional profiling datasets of T2DM, i.e., GSE20966, GSE95849, and GSE26168, were acquired. Four machine learning models, namely, random forest, support vector machine, extreme gradient boosting, and generalized linear modeling, were built based on pyroptosis genes. A nomogram of key pyroptosis genes was also generated, and the clinical value was appraised via calibration curves and decision curve analysis. Immune infiltration was inferred utilizing CIBERSORT. Drug-druggable target relationships were acquired from the Drug Gene Interaction Database. Through WGCNA, key pyroptosis-relevant genes were selected. Results Most pyroptosis genes exhibited upregulation in T2DM relative to controls, indicating the activity of pyroptosis in T2DM. The SVM model composed of BAK1, CHMP2B, NLRP6, PLCG1, and TIRAP exhibited the best performance in T2DM diagnosis, with AUC = 1. The nomogram can predict the risk of T2DM for clinical practice. NK cells resting exhibited a lower abundance in T2DM versus normal specimens, with a higher abundance of neutrophils. NLRP6 was positively linked with neutrophils. Drugs (keracyanin, 9,10-phenanthrenequinone, diclofenac, phosphomethylphosphonic acid adenosyl ester, acetaminophen, cefixime, aspirin, ustekinumab) potentially targeted the key pyroptosis genes. Additionally, CHMP2B-relevant genes were determined. Conclusion Altogether, this work proposes the key pyroptosis genes in T2DM, which might become possible molecules for the management and treatment of T2DM and its complications.
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Affiliation(s)
- Min Wang
- Department of Clinical Laboratory, The Affiliated People’s Hospital of Shandong First Medical University, Jinan, China
| | - He Wu
- Department of Endocrinology, The Affiliated People’s Hospital of Shandong First Medical University, Jinan, China
| | - Ronghua Wu
- Department of Endocrinology, The Third People’s Hospital of Jinan, Jinan, China
| | - Yongshun Tan
- Department of Nephrology, The Affiliated People’s Hospital of Shandong First Medical University, Jinan, China
| | - Qingqing Chang
- Department of Endocrinology, The Affiliated People’s Hospital of Shandong First Medical University, Jinan, China
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Zhang D, Zhao Y, Wang S, Wang X, Sun Y. A Prognostic Model of Angiogenesis and Neutrophil Extracellular Traps Related Genes Manipulating Tumor Microenvironment in Colon Cancer. J Cancer 2023; 14:2109-2127. [PMID: 37497410 PMCID: PMC10367930 DOI: 10.7150/jca.85778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 06/26/2023] [Indexed: 07/28/2023] Open
Abstract
Colon adenocarcinoma (COAD) is one of the most common carcinomas worldwide. The main causes of cancer-related mortality of COAD are metastases. The fundamental processes for how angiogenesis and neutrophil extracellular traps (NETs) contributing to tumor progression and metastasis are still uncertain. In our study, The Cancer Genome Atlas (TCGA)-COAD dataset (train set) and GSE17536 (test set) were analyzed. Angiogenesis potential index (API) and NETs potential index (NPI) based on angiogenesis and NETs-related genes were respectively built using bioinformatic methods and machine learning algorithms. Subjects were split into groups with low API/NPI or high API/NPI. Survival analysis showed the high API and high NPI patients with the worst survival compared with the others. Between the high API/NPI group and the other groups, differentially expressed genes (DEGs) were found. A four-gene signature (TIMP1, FSL3, CALB2, and FABP4) was included in a risk model based on least absolute shrinkage and selection operator (LASSO) analysis. Additionally, the model displayed a significant association with many immune microenvironment characteristics. Finally, we verified the clinical significance of CALB2 expression and its role to promote the invasion and migration of colon cancer cells in vitro.
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Affiliation(s)
- Dongsheng Zhang
- Department of Colorectal Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Colorectal Institute of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Yan Zhao
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Shirui Wang
- Department of Colorectal Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Colorectal Institute of Nanjing Medical University, Nanjing, China
- The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Xiaowei Wang
- Department of Colorectal Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Colorectal Institute of Nanjing Medical University, Nanjing, China
| | - Yueming Sun
- Department of Colorectal Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Colorectal Institute of Nanjing Medical University, Nanjing, China
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Zhou J, Yang S, Zhu D, Li H, Miao X, Gu M, Xu W, Zhang Y, Tang W, Shen R, Zha J, Zhu J, Yuan Z, Gu X. The crosstalk between anoikis and epithelial-mesenchymal transition and their synergistic roles in predicting prognosis in colon adenocarcinoma. Front Oncol 2023; 13:1184215. [PMID: 37350934 PMCID: PMC10284081 DOI: 10.3389/fonc.2023.1184215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 05/17/2023] [Indexed: 06/24/2023] Open
Abstract
Anoikis and epithelial-mesenchymal transition (EMT) are significant phenomena occurring in distant metastasis of colon adenocarcinoma (COAD). A comprehensive understanding of their crosstalk and the identification of key genes are vital for treating the distant metastasis of COAD. The objective of this study was to design and validate accurate prognostic predictors for COAD patients based on the anoikis and EMT processes. We obtained gene signatures from various databases and performed univariate and multivariate Cox regression analyses, principal component analysis (PCA). The COAD patients were categorized into the worst prognosis group, the Anoikis Potential Index (API) Low + EMT Potential Index (EPI) High group and the others group. Then we utilized gene set enrichment analysis (GSEA) to identify differentially expressed genes and to establish a prognostic risk model. The model classified patients into high- or low-risk groups, with patients in the high-risk group displaying worse survival status. A nomogram was established to predict overall survival rates, demonstrating high specificity and sensitivity. Additionally, we connected the risk model to the tumor microenvironment (TME) using single-sample GSEA and the MCP counter tool, as well as evaluated the sensitivity to common chemotherapeutic drugs, such as Gefitinib and Gemcitabine. Lastly, cell and tissue experiments suggested a positive correlation among anoikis resistance, EMT, and liver/lung metastasis of COAD. This is the first study to comprehensively analyze the crosstalk between anoikis and EMT and offers new therapeutic targets for COAD metastasis patients.
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Affiliation(s)
- Jiahui Zhou
- Department of Gastrointestinal Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Sheng Yang
- Department of Colorectal Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Colorectal Institute of Nanjing Medical University, Nanjing, China
| | - Dawei Zhu
- Department of Gastrointestinal Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Hao Li
- Department of Gastrointestinal Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Xinsheng Miao
- Department of Gastrointestinal Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Menghui Gu
- Department of Gastrointestinal Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Wei Xu
- Department of Gastrointestinal Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Yan Zhang
- Department of Gastrointestinal Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Wei Tang
- Department of Gastrointestinal Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Renbin Shen
- Department of Gastrointestinal Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Jianhua Zha
- Department of Gastrointestinal Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Jianhua Zhu
- Department of Gastrointestinal Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Zheng Yuan
- Department of Gastrointestinal Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Xinhua Gu
- Department of Gastrointestinal Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
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Yang C, Jiang Y, Hu F, Li Q, Qi B. Implications of CRNDE in prognosis, tumor immunity, and therapeutic sensitivity in low grade glioma patients. Cancer Cell Int 2023; 23:93. [PMID: 37194105 DOI: 10.1186/s12935-023-02930-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 04/18/2023] [Indexed: 05/18/2023] Open
Abstract
BACKGROUND Colorectal tumor differentially expressed (CRNDE) is specifically expressed in human brains and is the most highly expressed lncRNA in gliomas. Nevertheless, its implications in low grade glioma (LGG) are still indistinct. This study presented systematic analyses of CRNDE in LGG biology. METHODS We retrospectively retrieved TCGA, CGGC and GSE16011 LGG cohorts. Survival analysis was conducted for evaluating the prognostic significance of CRNDE in LGG. A CRNDE-based nomogram was established, and its predictive performance was verified. Signaling pathways underlying CRNDE were analyzed through ssGSEA and GSEA approaches. The abundance of immune cells and activity of cancer-immunity cycle were estimated with ssGSEA approach. Immune checkpoints, HLAs, chemokines, and immunotherapeutic response indicators (TIDE, and TMB) was quantified. U251 and SW1088 cells were transfected with specific shRNAs of CRNDE, and flow cytometry (apoptosis) and western blot (β-catenin and Wnt5a) assays were conducted. RESULTS Up-regulated CRNDE was found in LGG, and was linked to unfavorable clinical outcomes. The CRNDE-based nomogram enabled to accurately predict patients' prognosis. High CRNDE expression was linked to more genomic variations, activity of tumorigenic pathways, tumor immunity (increase in infiltration of immune cells, expression of immune checkpoints, HLAs and chemokines, and cancer-immunity cycle), and therapeutic sensitivity. CRNDE knockdown mitigated malignant phenotypes of LGG cells. CONCLUSIONS Our study determined CRNDE as a novel predictor for patient prognosis, tumor immunity and therapeutic response in LGG. Assessment of CRNDE expression is a promising approach for predicting the therapeutic benefits of LGG patients.
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Affiliation(s)
- Chen Yang
- Department of Neurosurgery, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, 361015, Fujian, China
| | - Yingchuan Jiang
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Fan Hu
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Qiuping Li
- Department of Neurosurgery, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, 361015, Fujian, China.
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Biao Qi
- Department of Neurosurgery, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, 361015, Fujian, China.
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Cao S, Chen C, Gu D, Wang Z, Xu G. Establishment and external verification of an oxidative stress-related gene signature to predict clinical outcomes and therapeutic responses of colorectal cancer. Front Pharmacol 2023; 13:991881. [PMID: 36860211 PMCID: PMC9968941 DOI: 10.3389/fphar.2022.991881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 10/11/2022] [Indexed: 02/15/2023] Open
Abstract
Objective: Accumulated evidence highlights the biological significance of oxidative stress in tumorigenicity and progression of colorectal cancer (CRC). Our study aimed to establish a reliable oxidative stress-related signature to predict patients' clinical outcomes and therapeutic responses. Methods: Transcriptome profiles and clinical features of CRC patients were retrospectively analyzed from public datasets. LASSO analysis was used to construct an oxidative stress-related signature to predict overall survival, disease-free survival, disease-specific survival, and progression-free survival. Additionally, antitumor immunity, drug sensitivity, signaling pathways, and molecular subtypes were analyzed between different risk subsets through TIP, CIBERSORT, oncoPredict, etc. approaches. The genes in the signature were experimentally verified in the human colorectal mucosal cell line (FHC) along with CRC cell lines (SW-480 and HCT-116) through RT-qPCR or Western blot. Results: An oxidative stress-related signature was established, composed of ACOX1, CPT2, NAT2, NRG1, PPARGC1A, CDKN2A, CRYAB, NGFR, and UCN. The signature displayed an excellent capacity for survival prediction and was linked to worse clinicopathological features. Moreover, the signature correlated with antitumor immunity, drug sensitivity, and CRC-related pathways. Among molecular subtypes, the CSC subtype had the highest risk score. Experiments demonstrated that CDKN2A and UCN were up-regulated and ACOX1, CPT2, NAT2, NRG1, PPARGC1A, CRYAB, and NGFR were down-regulated in CRC than normal cells. In H2O2-induced CRC cells, their expression was notably altered. Conclusion: Altogether, our findings constructed an oxidative stress-related signature that can predict survival outcomes and therapeutic response in CRC patients, thus potentially assisting prognosis prediction and adjuvant therapy decisions.
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Affiliation(s)
- Sha Cao
- Department of Oncology, The First People’s Hospital of Lianyungang, Lianyungang, China
| | - Cheng Chen
- Department of Oncology, The First People’s Hospital of Lianyungang, Lianyungang, China
| | - Dezhi Gu
- Department of Gastrointestinal Surgery, The First People’s Hospital of Lianyungang, Lianyungang, China
| | - Zhengdong Wang
- Department of Gastrointestinal Surgery, The First People’s Hospital of Lianyungang, Lianyungang, China
| | - Guanghui Xu
- Department of Oncology, The First People’s Hospital of Lianyungang, Lianyungang, China,*Correspondence: Guanghui Xu,
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Pan X, Xu X, Wang L, Zhang S, Chen Y, Yang R, Chen X, Cheng B, Xia J, Ren X. BASP1 is a prognostic biomarker associated with immunotherapeutic response in head and neck squamous cell carcinoma. Front Oncol 2023; 13:1021262. [PMID: 36776328 PMCID: PMC9911441 DOI: 10.3389/fonc.2023.1021262] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 01/16/2023] [Indexed: 01/28/2023] Open
Abstract
Backgrounds Immunotherapy is effective in a subset of head and neck squamous cell carcinoma (HNSCC). However, the unfavorable response rate and inadequate biomarkers for stratifying patients have primarily limited its clinical application. Considering transcriptional factors (TFs) play essential roles in regulating immune activity during HNSCC progression, we comprehensively analyzed the expression alterations of TFs and their prognostic values. Methods Gene expression datasets and clinical information of HNSCC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repository. Then, Brain abundant membrane attached signal protein 1 (BASP1) was screened out of differentially expressed TFs by univariate and multivariate survival analysis. Tumor immune dysfunction and exclusion (TIDE) was applied to analyze the response to immunotherapy of BASP1high/low patients. Meanwhile, GO, KEGG and GSEA analyses were used to enrich the pathways between the BASP1high and BASP1low groups. Single-sample gene set enrichment analysis (ssGSEA), CIBERSORT, EPIC and quanTiseq algorithms were applied to explore immune infiltrations. Also, immune cycle analysis was conducted by ssGSEA. Additionally, lipid peroxidation, glutathione and reactive oxygen species were performed to detect the ferroptosis alternations. Results BASP1 was upregulated and associated with poor survival in HNSCC patients. BASP1high patients exhibited better response rates to anti-PD-1 immunotherapy and higher expressions of immune checkpoint inhibitors. GO, KEGG and GSEA analyses indicated that the expression of BASP1 was related to several immune-related pathways and immunogenic ferroptosis signature. The infiltration of activated CD8+ T cells was authenticated to be decreased in BASP1high patients. Furthermore, BASP1 was identified to be positively correlated with T cell dysfunction and immune escape. Moreover, silencing BASP1 triggered ferroptosis in HNSCC cells, representing as increased LDH, lipid peroxidation and ROS levels, and reduced glutathione synthesis. Conclusions We demonstrated that BASP1 suppressed immunogenic ferroptosis to induce immunosuppressive tumor microenvironment. BASP1 plays a critical role in immune response, and might be a promising classifier for selecting HNSCC patients who benefit from current immunotherapy.
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Affiliation(s)
- Xue Pan
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Xun Xu
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Lixuan Wang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Siyuan Zhang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Yingyao Chen
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Rongchun Yang
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Xijuan Chen
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Bin Cheng
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China,*Correspondence: Xianyue Ren, ; Juan Xia, ; Bin Cheng,
| | - Juan Xia
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China,*Correspondence: Xianyue Ren, ; Juan Xia, ; Bin Cheng,
| | - Xianyue Ren
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China,*Correspondence: Xianyue Ren, ; Juan Xia, ; Bin Cheng,
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Tong X, Tang R, Xiao M, Xu J, Wang W, Zhang B, Liu J, Yu X, Shi S. Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research. J Hematol Oncol 2022; 15:174. [PMID: 36482419 PMCID: PMC9733270 DOI: 10.1186/s13045-022-01392-3] [Citation(s) in RCA: 436] [Impact Index Per Article: 145.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 11/30/2022] [Indexed: 12/13/2022] Open
Abstract
Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various biological activities, including the clearance of aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target for the development of cancer medications in recent years. However, because tumor cells show avoidance to apoptosis, which causes treatment resistance and recurrence, numerous studies have been devoted to alternative cancer cell mortality processes, namely necroptosis, pyroptosis, ferroptosis, and cuproptosis; these RCD modalities have been extensively studied and shown to be crucial to cancer therapy effectiveness. Furthermore, evidence suggests that tumor cells undergoing regulated death may alter the immunogenicity of the tumor microenvironment (TME) to some extent, rendering it more suitable for inhibiting cancer progression and metastasis. In addition, other types of cells and components in the TME undergo the abovementioned forms of death and induce immune attacks on tumor cells, resulting in enhanced antitumor responses. Hence, this review discusses the molecular processes and features of necroptosis, pyroptosis, ferroptosis, and cuproptosis and the effects of these novel RCD modalities on tumor cell proliferation and cancer metastasis. Importantly, it introduces the complex effects of novel forms of tumor cell death on the TME and the regulated death of other cells in the TME that affect tumor biology. It also summarizes the potential agents and nanoparticles that induce or inhibit novel RCD pathways and their therapeutic effects on cancer based on evidence from in vivo and in vitro studies and reports clinical trials in which RCD inducers have been evaluated as treatments for cancer patients. Lastly, we also summarized the impact of modulating the RCD processes on cancer drug resistance and the advantages of adding RCD modulators to cancer treatment over conventional treatments.
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Affiliation(s)
- Xuhui Tong
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Rong Tang
- Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Mingming Xiao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jiang Liu
- Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Shanghai Pancreatic Cancer Institute, No. 270 Dong'An Road, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Wang H. Network pharmacology- and molecular docking-based approaches to unveil the pharmacological mechanisms of dihydroartemisinin against esophageal carcinoma. Front Genet 2022; 13:1017520. [PMID: 36506308 PMCID: PMC9732420 DOI: 10.3389/fgene.2022.1017520] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/22/2022] [Indexed: 11/27/2022] Open
Abstract
Objective: Dihydroartemisinin (DHA) is an active metabolite of artemisinin and its derivatives, which is a potent drug extensively applied in clinical treatment of malaria. The antitumor properties of DHA have received increasing attention. However, there is no systematic summary on the pharmacological mechanisms of DHA against esophageal carcinoma (ESCA). The present study implemented network pharmacology- and molecular docking-based approaches to unveil the pharmacological mechanisms of DHA against ESCA. Methods: DHA targets were accessed through integrating the SwissTargetPrediction, HERB, as well as BATMAN-TCM platforms. In TCGA-ESCA dataset, genes with differential expression were screened between 161 ESCA and 11 normal tissue specimens. DHA targets against ESCA were obtained through intersection. Their biological significance was evaluated with functional enrichment analysis. A prognostic signature was established via uni- and multivariate cox regression analyses. DHA-target interactions were predicted via molecular docking. Molecular dynamics simulation was implemented to examine the stability of DHA binding to potential targets. Results: The study predicted 160 DHA targets as well as 821 genes with differential expression in ESCA. Afterwards, 16 DHA targets against ESCA were obtained, which remarkably correlated to cell cycle progression. The ADORA2B- and AURKA-based prognostic signature exhibited the reliability and independency in survival prediction. The stable docking of DHA-ADORA2B and DHA-AURKA was confirmed. Conclusion: Collectively, this study systematically revealed the basis and mechanism of DHA against ESCA through targeting multi-target and multi-pathway mechanisms, and thus offered theoretical and scientific basis for the clinical application of DHA.
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Fang K, Xu Z, Jiang S, Yan C, Tang D, Huang Y. Integrated profiling uncovers prognostic, immunological, and pharmacogenomic features of ferroptosis in triple-negative breast cancer. Front Immunol 2022; 13:985861. [PMID: 36505498 PMCID: PMC9732280 DOI: 10.3389/fimmu.2022.985861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 11/04/2022] [Indexed: 11/27/2022] Open
Abstract
Objective Ferroptosis is an iron-dependent type of regulated cell death triggered by the toxic buildup of lipid peroxides on cell membranes. Nonetheless, the implication of ferroptosis in triple-negative breast cancer (TNBC), which is the most aggressive subtype of breast carcinoma, remains unexplored. Methods Three TNBC cohorts-TCGA-TNBC, GSE58812, and METABRIC-were adopted. Consensus molecular subtyping on prognostic ferroptosis-related genes was implemented across TNBC. Ferroptosis classification-relevant genes were selected through weighted co-expression network analysis (WGCNA), and a ferroptosis-relevant scoring system was proposed through the LASSO approach. Prognostic and immunological traits, transcriptional and post-transcriptional modulation, therapeutic response, and prediction of potential small-molecule agents were conducted. Results Three disparate ferroptosis patterns were identified across TNBC, with prognostic and immunological traits in each pattern. The ferroptosis-relevant scoring system was proposed, with poorer overall survival in high-risk patients. This risk score was strongly linked to transcriptional and post-transcriptional mechanisms. The high-risk group had a higher response to anti-PD-1 blockade or sunitinib, and the low-risk group had higher sensitivity to cisplatin. High relationships of risk score with immunological features were observed across pan-cancer. Two Cancer Therapeutics Response Portal (CTRP)-derived agents (SNX-2112 and brefeldin A) and PRISM-derived agents (MEK162, PD-0325901, PD-318088, Ro-4987655, and SAR131675) were predicted, which were intended for high-risk patients. Conclusion Altogether, our findings unveil prognostic, immunological, and pharmacogenomic features of ferroptosis in TNBC, highlighting the potential clinical utility of ferroptosis in TNBC therapy.
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Affiliation(s)
- Kun Fang
- Department of Surgery, Yinchuan Maternal and Child Health Hospital, Yinchuan, China,*Correspondence: Kun Fang,
| | - Zhengjie Xu
- Department of Surgery, Yinchuan Maternal and Child Health Hospital, Yinchuan, China
| | - Suxiao Jiang
- Department of Surgery, Yinchuan Maternal and Child Health Hospital, Yinchuan, China
| | - Changsheng Yan
- Department of Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Desheng Tang
- Department of Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yan Huang
- Department of Surgery, Affiliated Hospital of Ningxia Medical University, Yinchuan, China
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Ferulic Acid Mitigates Growth and Invasion of Esophageal Squamous Cell Carcinoma through Inducing Ferroptotic Cell Death. DISEASE MARKERS 2022; 2022:4607966. [PMID: 36267458 PMCID: PMC9578864 DOI: 10.1155/2022/4607966] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/02/2022] [Accepted: 09/06/2022] [Indexed: 11/17/2022]
Abstract
Objective Ferroptosis is an iron- and ROS-dependent form of cell death initiated by lipid peroxidation. The rapidly developing study of ferroptosis has facilitated its application in cancer therapeutics. The current study is aimed at investigating the functional property of ferulic acid (FA, a phenolic acid substance) on inducing ferroptosis in antiesophageal squamous cell carcinoma (ESCC). Methods ESCC cells were administrated with gradient doses of FA or with ferroptosis inhibitor deferoxamine. Cellular growth was measured with CCK-8 and colony formation experiments. LDH, caspase-3, MDA, SOD, GSH, and iron were assayed with corresponding kits. Apoptotic level was evaluated through Annexin V-FITC apoptosis staining, with migration and invasion utilizing Transwell assays. Through quantitative RT-PCR, angiogenesis-relevant genes VEGFA and PDGFB were detected. ROS generation was measured via DCFH-DA probe. Immunoblotting was conducted for monitoring ACSL4, SLC7A11, HO-1, and GPX4. Results FA administration observably mitigated cellular viability and colony formation capacity and motivated LDH release, caspase-3 activity, and apoptosis in EC-1 and TE-4 cells. In addition, migration and invasion together with angiogenesis of ESCC cells were restraint by FA. FA exposure led to the increase of MDA content, ROS production, and iron load as well as the reduction of SOD activity and GSH content. Also, FA augmented the activities of ACSL4 and HO-1, with lessening SLC7A11 and GPX4. Nonetheless, deferoxamine restrained the effect of FA on ESCC ferroptosis. Conclusion Altogether, FA may act as a ferroptosis inducer and thus attenuates cell growth and invasion of ESCC, which boosts the clinical application of FA in ESCC therapeutics.
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Zhang L, Jiang B, Lan Z, Yang C, Yao Y, Lin J, Wei Q. Immune infiltration landscape on prognosis and therapeutic response and relevant epigenetic and transcriptomic mechanisms in lung adenocarcinoma. Front Immunol 2022; 13:983570. [PMID: 36275753 PMCID: PMC9582346 DOI: 10.3389/fimmu.2022.983570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 09/20/2022] [Indexed: 12/04/2022] Open
Abstract
Objective Lung adenocarcinoma (LUAD) is the most prevalent lung cancer subtype, but its immune infiltration features are not comprehensively understood. To address the issue, the present study was initiated to describe the immune infiltrations across LUAD from cellular compositional, functional, and mechanism perspectives. Methods We adopted five LUAD datasets (GSE32863, GSE43458, GSE75037, TCGA-LUAD, and GSE72094). Differentially expressed genes between LUAD and controls were selected for co-expression network analysis. Risky immune cell types were determined for classifying LUAD patients as diverse subtypes, followed by a comparison of antitumor immunity and therapeutic response between subtypes. Then, LUAD- and subtype-related key module genes affected by DNA methylation were determined for quantifying a scoring scheme. EXO1 was chosen for functional analysis via in vitro assays. Results Two immune cell infiltration-based subtypes (C1 and C2) were established across LUAD, with poorer prognostic outcomes and lower infiltration of immune cell types in C1. Additionally, C1 presented higher responses to immune checkpoint blockade and targeted agents (JNK inhibitor VIII, BI-D1870, RO-3306, etc.). The scoring system (comprising GAPDH, EXO1, FYN, CFTR, and KLF4) possessed higher accuracy in estimating patients’ prognostic outcomes. EXO1 upregulation contributed to the growth, migration, and invasion of LUAD cells. In addition, EXO1 facilitated PD-L1 and sPD-L1 expression in LUAD cells. Conclusion Altogether, our findings offer a comprehensive understanding of the immune infiltration landscape on prognosis and therapeutic response of LUAD as well as unveil potential epigenetic and transcriptomic mechanisms, which might assist personalized treatment.
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Affiliation(s)
- Liangming Zhang
- Department of Pulmonary and Critical Care Medicine, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Nanning, Nanning, China
| | - Biwang Jiang
- Department of Pulmonary and Critical Care Medicine, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Nanning, Nanning, China
| | - Zhuxiang Lan
- Department of Pulmonary and Critical Care Medicine, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Nanning, Nanning, China
| | - Chaomian Yang
- Department of Pulmonary and Critical Care Medicine, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Nanning, Nanning, China
| | - Yien Yao
- Department of Pulmonary and Critical Care Medicine, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Nanning, Nanning, China
| | - Jie Lin
- Department of Pulmonary and Critical Care Medicine, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Nanning, Nanning, China
- *Correspondence: Qiu Wei, ; Jie Lin,
| | - Qiu Wei
- Department of Pulmonary and Critical Care Medicine, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning, China
- Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Nanning, Nanning, China
- *Correspondence: Qiu Wei, ; Jie Lin,
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Prognostic Value of an Integrin-Based Signature in Hepatocellular Carcinoma and the Identification of Immunological Role of LIMS2. DISEASE MARKERS 2022; 2022:7356297. [PMID: 36212176 PMCID: PMC9537015 DOI: 10.1155/2022/7356297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/06/2022] [Accepted: 09/07/2022] [Indexed: 11/18/2022]
Abstract
Objective Evidence proves that integrins affect almost every step of hepatocellular carcinoma (HCC) progression. The current study aimed at constructing an integrin-based signature for prognostic prediction of HCC. Methods TCGA-LIHC and ICGC-LIRI-JP cohorts were retrospectively analyzed. Integrin genes were analyzed via univariate Cox regression, followed by generation of a prognostic signature with LASSO approach. Independent factors were input into the nomogram. WGCNA was adopted to select this signature-specific genes. Gene Ontology (GO) enrichment together with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to explore the function of the dysregulated genes. The abundance of tumor microenvironment components was estimated with diverse popular computational methods. The relative importance of genes from this signature was estimated through random-forest method. Results Eight integrin genes (ADAM15, CDC42, DAB2, ITGB1BP1, ITGB5, KIF14, LIMS2, and SELP) were adopted to define an integrin-based signature. Each patient was assigned the riskScore. High-riskScore subpopulation exhibited worse overall survival, with satisfying prediction efficacy. Also, the integrin-based signature was independent of routine clinicopathological parameters. The nomogram (comprising integrin-based signature, and stage) accurately inferred prognostic outcome, with the excellent net benefit. Genes with the strongest positive interaction to low-riskScore were primarily linked to biosynthetic, metabolic, and catabolic processes and immune pathways; those with the strongest association with high-riskScore were principally associated with diverse tumorigenic signaling. The integrin-based signature was strongly linked with tumor microenvironment components. Among the genes from this signature, LIMS2 possessed the highest importance, and its expression was proven through immunohistochemical staining. Conclusion Altogether, our study defined a quantitative integrin-based signature that reliably assessed HCC prognosis and tumor microenvironment features, which possessed the potential as a tool for prognostic prediction.
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Wang Z, Liu J, Li M, Lian L, Cui X, Ng TW, Zhu M. Integrated bioinformatics analysis uncovers characteristic genes and molecular subtyping system for endometriosis. Front Pharmacol 2022; 13:932526. [PMID: 36059959 PMCID: PMC9428290 DOI: 10.3389/fphar.2022.932526] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: Endometriosis is a chronic inflammatory estrogen-dependent disease with the growth of endometrial tissues outside the uterine cavity. Nevertheless, the etiology of endometriosis is still unclear. Integrated bioinformatics analysis was implemented to reveal the molecular mechanisms underlying this disease.Methods: A total of four gene expression datasets (GSE7305, GSE11691, GSE23339, and GSE25628) were retrieved from the GEO, which were merged into a meta-dataset, followed by the removal of batch effects via the sva package. Weighted gene co-expression network analysis (WGCNA) was implemented, and endometriosis-related genes were screened under normal and endometriosis conditions. Thereafter, characteristic genes were determined via Lasso analysis. The diagnostic performance was estimated via receiver operating characteristic curves, and epigenetic and post-transcriptional modifications were analyzed. Small molecular compounds were predicted. Unsupervised clustering analysis was conducted via non-negative matrix factorization algorithm. The enriched pathways were analyzed via gene set enrichment analysis or GSVA. Immune features were evaluated according to immune-checkpoints, HLA, receptors, chemokines, and immune cells.Results: In total, four characteristic genes (BGN, AQP1, ELMO1, and DDR2) were determined for endometriosis, all of which exhibited the favorable efficacy in diagnosing endometriosis. Their aberrant levels were modulated by epigenetic and post-transcriptional modifications. In total, 51 potential drugs were predicted against endometriosis. The characteristic genes exhibited remarkable associations with immunological function. Three subtypes were classified across endometriosis, with different mechanisms and immune features.Conclusion: Our study reveals the characteristic genes and novel molecular subtyping of endometriosis, contributing to the early diagnosis and intervention in endometriosis.
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Affiliation(s)
| | | | | | | | - Xiaojie Cui
- *Correspondence: Maoshu Zhu, Tai-Wei Ng, ; Xiaojie Cui,
| | - Tai-Wei Ng
- *Correspondence: Maoshu Zhu, Tai-Wei Ng, ; Xiaojie Cui,
| | - Maoshu Zhu
- *Correspondence: Maoshu Zhu, Tai-Wei Ng, ; Xiaojie Cui,
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M6A Modifier-Mediated Methylation Characterized by Diverse Prognosis, Tumor Microenvironment, and Immunotherapy Response in Hepatocellular Carcinoma. JOURNAL OF ONCOLOGY 2022; 2022:2513813. [PMID: 36016585 PMCID: PMC9398803 DOI: 10.1155/2022/2513813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/31/2022] [Accepted: 07/05/2022] [Indexed: 11/18/2022]
Abstract
Objective. Emerging evidence highlights the clinical implications of N6-methyladenosine (m6A) modification in HCC. Yet, the roles of m6A modification in modulating cancer immunity and shaping tumor microenvironment (TME) are undefined in hepatocellular carcinoma (HCC). Methods. Here, m6A modification classification was determined for HCC through 23 m6A modifier levels by employing consensus clustering approach. Prognosis analysis was presented for comparing the differences in survival outcomes. The ssGSEA and ESTIMATE approaches were adopted for evaluating the abundances of tumor-infiltrating immune cell populations. The m6A scoring system was computed for reflecting m6A modification classification via PCA algorithm. Results. Three m6A modifier-mediated modification patterns were established among HCC specimens, which were characterized by different prognosis, signaling pathways, and TME features. After extracting m6A phenotype-associated DEGs, we determined m6A scores in individual HCC and stratified patients into high- and low-score groups. Patients with low m6A score displayed the survival advantage and higher sensitivity to gemcitabine. Moreover, those with low m6A score possessed the better anti-PD-1/PD-L1 therapeutic response in the IMvigor210 immunotherapy cohort. Conclusion. Our findings highlighted that m6A modification exerted a nonnegligible role in remodeling diverse and complex TME. Quantification of the m6A modification patterns of individual HCC may enhance the comprehension of TME features and facilitate immunotherapeutic plans.
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Xiao J, Zheng L, Liu J. Comprehensive Analysis of the Aberrance and Functional Significance of Ferroptosis in Gastric Cancer. Front Pharmacol 2022; 13:919490. [PMID: 35903347 PMCID: PMC9315307 DOI: 10.3389/fphar.2022.919490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 06/06/2022] [Indexed: 12/24/2022] Open
Abstract
Objective: Ferroptosis is a type of iron-dependent necrosis related to cancer. Nevertheless, the features of ferroptosis in gastric cancer (GC) remain poorly understood. This study conducted a systematic analysis of ferroptosis regulators in GC. Methods: We gathered five GC cohorts, namely, TCGA-STAD, GSE84437, GSE62254, GSE26901, and GSE15459. Unsupervised clustering analysis was adopted to cluster GC patients into different ferroptosis subtypes based on ferroptosis regulators. Immune cell infiltration and hallmark pathway activity were estimated via ssGSEA. The ferroptosis index was developed with the PCA computational method. Response to chemotherapy agents and small molecular compounds was inferred via GDSC, CTRP, and PRISM projects. Two anti-PD-1 therapy cohorts were gathered and the potential of FPI in predicting immune response was assessed. Results: Expression profiles, genetic mutations, DNA methylation, prognostic implications, and drug sensitivity of ferroptosis regulators were characterized in GC. Three ferroptosis subtypes were clustered with distinct prognosis, hallmark pathway activity, and tumor-infiltrating immune cells. Ferroptosis levels were quantified based on the expression of prognostic ferroptosis-related signatures. The significant relationships between FPI and clinicopathological characteristics were observed. Furthermore, high FPI was in relation to poor prognosis, inflamed tumor microenvironment (TME) as well as high sensitivity to chemotherapy agents (docetaxel and cisplatin), and CTRP- and PRISM-derived compounds. Also, FPI acted as a promising predictor of immune response. Conclusion: Collectively, our findings identified a novel ferroptosis-based subtype classification of GC, and revealed the potential of ferroptosis in forming TME diversity and complexity, and guiding individualized treatment.
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Affiliation(s)
- Jun Xiao
- Department of Gastrointestinal Surgery, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
- Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
| | - Lingyan Zheng
- Department of Anus Intestine Surgery, Fuzhou Second Hospital Affiliated to Xiamen University, Fuzhou, China
| | - Jingfeng Liu
- Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
- Department of Hepatopancreatobiliary Surgical Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, China
- *Correspondence: Jingfeng Liu,
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Epithelial to Mesenchymal Transition Relevant Subtypes with Distinct Prognosis and Responses to Chemo- or Immunotherapies in Osteosarcoma. J Immunol Res 2022; 2022:1377565. [PMID: 35836470 PMCID: PMC9274235 DOI: 10.1155/2022/1377565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/09/2022] [Accepted: 06/13/2022] [Indexed: 11/17/2022] Open
Abstract
Objective Currently, clinical classification of osteosarcoma cannot accurately predict the survival outcomes and responses to chemo- or immunotherapies. Our goal was to classify osteosarcoma patients into clinical/biological subtypes based on EMT molecules. Methods This study retrospectively curated the RNA expression profiling of osteosarcoma patients from the TARGET and GSE21257 cohorts. Consensus clustering analyses were conducted in accordance with the expression profiling of prognostic EMT genes derived from univariate analyses. Immunological features were evaluated through immune cell infiltration, immune checkpoint expression, and activity of cancer immunity cycle. Drug sensitivity was estimated with the GDSC database. WGCNA approach was adopted to determine the EMT-derived genes. Following univariate analyses, a multivariate cox regression model was developed and externally verified. Predictive independency was evaluated with uni- and multivariate analyses. GSEA was presented to uncover relevant molecular mechanisms. Results Prognostic EMT genes across osteosarcoma patients were stratified into distinct subtypes, namely, subtypes A and B. Patients in subtype B presented desirable prognosis, high immune activation, and enhanced sensitivity to cisplatin. Meanwhile, patients in subtype A were more sensitive to gemcitabine. In total, 86 EMT-derived hub genes were determined, and an EMT score was conducted for osteosarcoma prognosis. Following external verification, this EMT score was reliably and independently predictive of patients' survival outcomes. Additionally, it was positively linked to steroid biosynthesis. Conclusion Overall, our findings proposed EMT-relevant molecular subtypes and signatures for predicting prognosis and therapeutic responses, contributing to personalized treatment and clinical implication for osteosarcoma.
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Zhang L, Wang X. An Immune-Related Gene Signature Can Predict Clinical Outcomes and Immunotherapeutic Response in Oral Squamous Cell Carcinoma. Front Genet 2022; 13:870133. [PMID: 35860473 PMCID: PMC9289552 DOI: 10.3389/fgene.2022.870133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 05/27/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: Immune landscape is a key feature that affects cancer progression, survival, and treatment response. Herein, this study sought to comprehensively characterize the immune-related genes (IRGs) in oral squamous cell carcinoma (OSCC) and conduct an immune-related risk score (IRS) model for prognosis and therapeutic response prediction.Methods: Transcriptome profiles and follow-up data of OSCC cohorts were curated from TCGA, GSE41613, and IMvigor210 datasets. An IRS model was established through univariate Cox, Random Survival Forest, and multivariate Cox analyses. Prognostic significance was evaluated with Kaplan–Meier curves, ROC, uni- and multivariate Cox, and subgroup analyses. A nomogram was conducted and assessed with C-index, ROC, calibration curves, and decision curve analyses. Immune cell infiltration and immune response were estimated with ESTIMATE and ssGSEA methods.Results: An IRS model was constructed for predicting the overall survival and disease-free survival of OSCC, containing MASP1, HBEGF, CCL22, CTSG, LBP, and PLAU. High-risk patients displayed undesirable prognosis, and the predictive efficacy of this model was more accurate than conventional clinicopathological indicators. Multivariate Cox analyses demonstrated that this model was an independent risk factor. The nomogram combining IRS, stage, and age possessed high clinical application values. The IRS was positively associated with a nonflamed tumor microenvironment. Moreover, this signature enabled to predict immunotherapeutic response and sensitivity to chemotherapeutic agents (methotrexate and paclitaxel).Conclusion: Collectively, our study developed a robust IRS model with machine learning method to stratify OSCC patients into subgroups with distinct prognosis and benefits from immunotherapy, which might assist identify biomarkers and targets for immunotherapeutic schemes.
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Li Z, Zhang W, Bai J, Li J, Li H. Emerging Role of Helicobacter pylori in the Immune Evasion Mechanism of Gastric Cancer: An Insight Into Tumor Microenvironment-Pathogen Interaction. Front Oncol 2022; 12:862462. [PMID: 35795038 PMCID: PMC9252590 DOI: 10.3389/fonc.2022.862462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/25/2022] [Indexed: 11/19/2022] Open
Abstract
Helicobacter pylori (H. pylori) infection is the strongest causative factor of gastric cancer. Growing evidence suggests that the complex crosstalk of H. pylori and the tumor microenvironment (TME) exerts a profound influence on gastric cancer progression. Hence, there is emerging interest to in-depth comprehension of the mechanisms of interplay between H. pylori and the TME. This review discusses the regulatory mechanisms underlying the crosstalk between H. pylori infection and immune and stromal cells, including tumor-associated macrophages (TAMs), neutrophils, dendritic cells, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, B and T cells, cancer associated fibroblasts (CAFs), and mesenchymal stem cells (MSCs), within the TME. Such knowledge will deepen the understanding about the roles of H. pylori in the immune evasion mechanism in gastric cancer and contribute to the development of more effective treatment regimens against H. pylori-induced gastric cancer.
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Affiliation(s)
- Zhifang Li
- Shanxi Medical University, Taiyuan, China
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Wenqing Zhang
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Jinyang Bai
- Shanxi Traditional Chinese Medicine Hospital, Taiyuan, China
| | - Jing Li
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Hong Li
- The Second Hospital of Shanxi Medical University, Taiyuan, China
- *Correspondence: Hong Li,
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Shao H, Zhang Y, Liu Y, Yang Y, Tang X, Li J, Jia C. Establishment and Verification of a Gene Signature for Diagnosing Type 2 Diabetics by WGCNA, LASSO Analysis, and In Vitro Experiments. BIOMED RESEARCH INTERNATIONAL 2022; 2022:4446342. [PMID: 35655479 PMCID: PMC9152403 DOI: 10.1155/2022/4446342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 05/03/2022] [Indexed: 11/29/2022]
Abstract
Objective The incidence and prevalence of type 2 diabetes are increasing with age. Nevertheless, there is lack of sensitive diagnostic tools and effective therapeutic regimens. We aimed to establish and verify a practical and valid diagnostic tool for this disease. Methods WGCNA was presented on the expression profiling of type 2 diabetic and normal islets in combined GSE25724 and GSE38642 datasets. By LASSO Cox regression analyses, a gene signature was constructed based on the genes in diabetes-related modules. ROC curves were plotted for assessing the diagnostic efficacy. Correlations between the genes and immune cell infiltration and pathways were analyzed. BST2 and BTBD1 expression was verified in glucotoxicity-induced and normal islet β cells. The influence of BST2 on β cell dysfunction was investigated under si-BST2 transfection. Results Totally, 14 coexpression modules were constructed, and red and cyan modules displayed the correlations to diabetes. The LASSO gene signature (BST2, BTBD1, IFIT1, IFIT3, and RTP4) was developed. The AUCs in the combined datasets and GSE20966 dataset were separately 0.914 and 0.910, confirming the excellent performance in diagnosing type 2 diabetes. Each gene in the model was distinctly correlated to immune cell infiltration and key signaling pathways (TGF-β and P53, etc.). The abnormal expression of BST2 and BTBD1 was confirmed in glucotoxicity-induced β cells. BST2 knockdown ameliorated β cell dysfunction and altered the activation of TGF-β and P53 pathways. Conclusion Our findings propose a gene signature with high efficacy to diagnose type 2 diabetes, which could assist and improve early diagnosis and therapy.
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Affiliation(s)
- Huaming Shao
- Laboratory Medicine, The Huikang Hospital of Qingdao University Medical Group, Qingdao, 266520 Shandong, China
| | - Yong Zhang
- Department of Orthopedics, The Huikang Hospital of Qingdao University Medical Group, Qingdao, 266520 Shandong, China
| | - Yishuai Liu
- Laboratory Medicine, Weifang Traditional Chinese Hospital, Weifang, 261041 Shandong, China
| | - Yan Yang
- Laboratory Medicine, The Huikang Hospital of Qingdao University Medical Group, Qingdao, 266520 Shandong, China
| | - Xiaozhu Tang
- Laboratory Medicine, The Huikang Hospital of Qingdao University Medical Group, Qingdao, 266520 Shandong, China
| | - Jiajia Li
- Laboratory Medicine, The Huikang Hospital of Qingdao University Medical Group, Qingdao, 266520 Shandong, China
| | - Changxin Jia
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, 266000 Shandong, China
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Zhao F, Tian H, Liu X, Guan Y, Zhu Y, Ren P, Zhang J, Dong Y, Fu L. Homeobox A1 Facilitates Immune Escape and Alleviates Oxidative Stress in Lung Adenocarcinoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4102666. [PMID: 35633885 PMCID: PMC9136634 DOI: 10.1155/2022/4102666] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/07/2022] [Accepted: 04/19/2022] [Indexed: 02/07/2023]
Abstract
Objective Recent studies have demonstrated that homeobox A1 (HOXA1) is upregulated in lung cancer due to RNA modifications (N6-methyladenosine), but the specific function of HOXA1 in lung adenocarcinoma (LUAD) remains indistinct. Herein, we investigated the role of HOXA1 in LUAD biology. Methods This study presented pancancer analysis of associations of HOXA1 with prognosis, TMB, and immune checkpoints. The expression of HOXA1 was detected in LUAD and normal tissues with immunohistochemistry and western blot. Through least absolute shrinkage and selection operator (LASSO) analysis, HOXA1-derived gene model was conducted in LUAD. Correlations of HOXA1 with immune cell infiltrations, immune checkpoints, HLAs, and chemotherapeutic sensitivity were evaluated. Colony formation, proliferation, and migration of LUAD cells with si-HOXA1 transfection were investigated, and the effects of HOXA1 on T cell exhaustion were assessed in vitro. Results HOXA1 expression was a risk factor of overall survival, disease-specific survival, and progression-free interval of LUAD. HOXA1 exhibited prominent associations with immune cell infiltration, immune checkpoints, and HLAs. HOXA1-derived gene signature reliably and independently predicted LUAD outcomes. Also, high-risk cases presented increased sensitivity to cisplatin, paclitaxel, docetaxel, vinorelbine, and etoposide. HOXA1 knockdown exhibited an inhibitory effect on proliferation and migration abilities of LUAD cells. Silencing HOXA1 weakened the expression of antioxidative stress markers Nrf2/HO-1 and T cell exhaustion marker CD155 in LUAD cells. Moreover, LUAD cells with HOXA1 knockdown enhanced the CD8+ T cell response. Conclusion Our data support the oncogenic function and prognostic significance of HOXA1 that facilitates immune escape and alleviates oxidative stress of LUAD.
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Affiliation(s)
- Fen Zhao
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong University, Jinan, 250117 Shandong, China
| | - Hui Tian
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, 250012 Shandong, China
| | - Xinchao Liu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong, China
- Cheeloo College of Medicine, Shandong University, Jinan, 250012 Shandong, China
| | - Yuanxiazi Guan
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong, China
| | - Ying Zhu
- Affiliated Hospital of Heze Medical College, Heze, 274008 Shandong, China
| | - Peng Ren
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, 250012 Shandong, China
| | - Jianbo Zhang
- Departments of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong, China
| | - Yinjun Dong
- Department of Thoracic surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong, China
| | - Lei Fu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong, China
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Yang Y, Yi X, Cai Y, Zhang Y, Xu Z. Immune-Associated Gene Signatures and Subtypes to Predict the Progression of Atherosclerotic Plaques Based on Machine Learning. Front Pharmacol 2022; 13:865624. [PMID: 35559253 PMCID: PMC9086243 DOI: 10.3389/fphar.2022.865624] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/21/2022] [Indexed: 11/25/2022] Open
Abstract
Objective: Experimental and clinical evidence suggests that atherosclerosis is a chronic inflammatory disease. Our study was conducted for uncovering the roles of immune-associated genes during atherosclerotic plaque progression. Methods: Gene expression profiling of GSE28829, GSE43292, GSE41571, and GSE120521 datasets was retrieved from the GEO database. Three machine learning algorithms, least absolute shrinkage, and selection operator (LASSO), random forest, and support vector machine–recursive feature elimination (SVM-RFE) were utilized for screening characteristic genes among atherosclerotic plaque progression- and immune-associated genes. ROC curves were generated for estimating the diagnostic efficacy. Immune cell infiltrations were estimated via ssGSEA, and immune checkpoints were quantified. CMap analysis was implemented to screen potential small-molecule compounds. Atherosclerotic plaque specimens were classified using a consensus clustering approach. Results: Seven characteristic genes (TNFSF13B, CCL5, CCL19, ITGAL, CD14, GZMB, and BTK) were identified, which enabled the prediction of progression of atherosclerotic plaques. Higher immune cell infiltrations and immune checkpoint expressions were found in advanced-stage than in early-stage atherosclerotic plaques and were positively linked to characteristic genes. Patients could clinically benefit from the characteristic gene-based nomogram. Several small molecular compounds were predicted based on the characteristic genes. Two subtypes, namely, C1 immune subtype and C2 non-immune subtype, were classified across atherosclerotic plaques. The characteristic genes presented higher expression in C1 than in C2 subtypes. Conclusion: Our findings provide several promising atherosclerotic plaque progression- and immune-associated genes as well as immune subtypes, which might enable to assist the design of more accurately tailored cardiovascular immunotherapy.
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Affiliation(s)
- Yujia Yang
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xu Yi
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yue Cai
- Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yuan Zhang
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhiqiang Xu
- Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
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