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Li J, Bian X, Zhang C, Chen Y, Huang S, Zhao S, Li Y. Identifying prognostic biomarkers and immune interactions in ovarian cancer associated with perfluorooctanoic acid exposure: Insights from comparative toxicogenomics and molecular docking studies. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 291:117831. [PMID: 39955862 DOI: 10.1016/j.ecoenv.2025.117831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 01/28/2025] [Accepted: 01/30/2025] [Indexed: 02/18/2025]
Abstract
BACKGROUND Perfluorooctanoic acid (PFOA) exposure has been implicated in various health issues. This study aims to identify common genes associated with PFOA exposure and ovarian cancer, elucidate their biological functions, and explore their prognostic significance. METHODS We identified common genes linked to PFOA exposure and ovarian cancer using the Comparative Toxicogenomics Database. Protein-protein interaction and functional enrichment analyses were performed via Metascape. A PFOA-related risk model was developed using TCGA data and LASSO regression. Survival and expression analyses were conducted, and a prognostic nomogram was created. Tumor immune microenvironment interactions were investigated using ESTIMATE and ssGSEA methods. Molecular docking studies assessed the binding affinities between PFOA and target proteins. RESULTS Utilizing the Comparative Toxicogenomics Database, we identified 229 common genes linked to both PFOA exposure and ovarian cancer. A comprehensive protein-protein interaction (PPI) network analysis revealed distinct functional modules. Enrichment analysis indicated significant involvement of these genes in pathways like the PI3K-Akt signaling pathway and focal adhesion. Lasso regression identified seven key prognostic genes (ERBB2, CCNH, PDE2A, CXCL11, TIAM1, SLC9A1, and EPHA2), with survival analysis demonstrating that PFOA-related high risk group exhibited significantly worse overall survival. Expression analysis showed the dysregulation of key prognostic genes in tumor tissues, while immune correlation analysis indicated significant associations with the tumor microenvironment. Molecular docking and molecular dynamics simulations revealed strong binding affinities between PFOA and the PDE2A. CONCLUSION Overall, this research contributes to a deeper understanding of the health risks associated with PFOA exposure and highlights the importance of continued monitoring and regulation of environmental pollutants to safeguard public health.
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Affiliation(s)
- Jianing Li
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China
| | - Xiaofeng Bian
- Central Laboratory of Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China
| | - Caixia Zhang
- Central Laboratory of Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yirong Chen
- Central Laboratory of Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shijia Huang
- Central Laboratory of Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shuli Zhao
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China; Central Laboratory of Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
| | - Yanchuan Li
- Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China; Central Laboratory of Nanjing Medical University Affiliated Nanjing Hospital, Nanjing, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
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Zhang YK, Shi R, Meng RY, Lin SL, Zheng M. Erythropoietin-induced hepatocyte receptor A2 regulates effect of pyroptosis on gastrointestinal colorectal cancer occurrence and metastasis resistance. World J Gastrointest Oncol 2024; 16:3781-3797. [PMID: 39350985 PMCID: PMC11438782 DOI: 10.4251/wjgo.v16.i9.3781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 06/30/2024] [Accepted: 07/24/2024] [Indexed: 09/09/2024] Open
Abstract
Erythropoietin-induced hepatocyte receptor A2 (EphA2) is a receptor tyrosine kinase that plays a key role in the development and progression of a variety of tumors. This article reviews the expression of EphA2 in gastrointestinal (GI) colorectal cancer (CRC) and its regulation of pyroptosis. Pyroptosis is a form of programmed cell death that plays an important role in tumor suppression. Studies have shown that EphA2 regulates pyrodeath through various signaling pathways, affecting the occurrence, development and metastasis of GI CRC. The overexpression of EphA2 is closely related to the aggressiveness and metastasis of GI CRC, and the inhibition of EphA2 can induce pyrodeath and improve the sensitivity of cancer cells to treatment. In addition, EphA2 regulates intercellular communication and the microenvironment through interactions with other cytokines and receptors, further influencing cancer progression. The role of EphA2 in GI CRC and its underlying mechanisms provide us with new perspectives and potential therapeutic targets, which have important implications for future cancer treatment.
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Affiliation(s)
- Yu-Kun Zhang
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China
| | - Ran Shi
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China
| | - Ruo-Yu Meng
- Department of Minimally Invasive Comprehensive Treatment of Cancer, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Shui-Li Lin
- Department of Ana and Intestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Mei Zheng
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China
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Brooks A, Zhang Y, Chen J, Zhao CX. Cancer Metastasis-on-a-Chip for Modeling Metastatic Cascade and Drug Screening. Adv Healthc Mater 2024; 13:e2302436. [PMID: 38224141 DOI: 10.1002/adhm.202302436] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 01/06/2024] [Indexed: 01/16/2024]
Abstract
Microfluidic chips are valuable tools for studying intricate cellular and cell-microenvironment interactions. Traditional in vitro cancer models lack accuracy in mimicking the complexities of in vivo tumor microenvironment. However, cancer-metastasis-on-a-chip (CMoC) models combine the advantages of 3D cultures and microfluidic technology, serving as powerful platforms for exploring cancer mechanisms and facilitating drug screening. These chips are able to compartmentalize the metastatic cascade, deepening the understanding of its underlying mechanisms. This article provides an overview of current CMoC models, focusing on distinctive models that simulate invasion, intravasation, circulation, extravasation, and colonization, and their applications in drug screening. Furthermore, challenges faced by CMoC and microfluidic technologies are discussed, while exploring promising future directions in cancer research. The ongoing development and integration of these models into cancer studies are expected to drive transformative advancements in the field.
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Affiliation(s)
- Anastasia Brooks
- School of Chemical Engineering, University of Adelaide, Adelaide, 5005, Australia
| | - Yali Zhang
- School of Chemical Engineering, University of Adelaide, Adelaide, 5005, Australia
| | - Jiezhong Chen
- School of Chemical Engineering, University of Adelaide, Adelaide, 5005, Australia
| | - Chun-Xia Zhao
- School of Chemical Engineering, University of Adelaide, Adelaide, 5005, Australia
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Song L, Liu H, Li M, Yang Y, Dong H, Li J, Shao J, Zhi L, Sun H, Li Z, Sui H, Zhang Y, Wu C, Yin Y. Ribosomal Incorporation of Lithocholic Acid into Peptides for the De Novo Discovery Of Peptide-Lithocholic Acid Hybrid Macrocyclic Peptides. ACS Chem Biol 2024; 19:1440-1446. [PMID: 38901034 DOI: 10.1021/acschembio.4c00298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/22/2024]
Abstract
Peptide-bile acid hybrids offer promising drug candidates due to enhanced pharmacological properties, such as improved protease resistance and oral bioavailability. However, it remains unknown whether bile acids can be incorporated into peptide chains by the ribosome to produce a peptide-bile acid hybrid macrocyclic peptide library for target-based de novo screening. In this study, we achieved the ribosomal incorporation of lithocholic acid (LCA)-d-tyrosine into peptide chains. This led to the construction of a peptide-LCA hybrid macrocyclic peptide library, which enabled the identification of peptides TP-2C-4L3 (targeting Trop2) and EP-2C-4L5 (targeting EphA2) with strong binding affinities. Notably, LCA was found to directly participate in binding to EphA2 and confer on the peptides improved stability and resistance to proteases. Cell staining experiments confirmed the high specificity of the peptides for targeting Trop2 and EphA2. This study highlights the benefits of LCA in peptides and paves the way for de novo discovery of stable peptide-LCA hybrid drugs.
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Affiliation(s)
- Lulu Song
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266237, China
| | - Hongtan Liu
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P.R. China
| | - Maolin Li
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266237, China
| | - Yawen Yang
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266237, China
| | - Huilei Dong
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P.R. China
| | - Jinjing Li
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P.R. China
| | - Jiaqi Shao
- College of Sciences, Nanjing Agricultural University, Nanjing 210095, China
| | - Lixu Zhi
- College of Sciences, Nanjing Agricultural University, Nanjing 210095, China
| | - Hao Sun
- College of Sciences, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhifeng Li
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266237, China
| | - Haiyan Sui
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266237, China
| | - Youming Zhang
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266237, China
| | - Chuanliu Wu
- The MOE Key Laboratory of Spectrochemical Analysis and Instrumentation, State Key Laboratory of Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P.R. China
| | - Yizhen Yin
- State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266237, China
- Shandong Research Institute of Industrial Technology, Jinan 250101, China
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Ren Y, Ju Q, Zhang J, Gu W, Du J. MiR-302a-3p reduces cisplatin resistance of esophageal squamous cell carcinoma cells by targeting EphA2. J Chemother 2024; 36:72-81. [PMID: 37198946 DOI: 10.1080/1120009x.2023.2213490] [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: 07/08/2022] [Accepted: 04/22/2023] [Indexed: 05/19/2023]
Abstract
Platinum-based chemotherapy is a common clinical treatment for esophageal squamous cell carcinoma (ESCC), and chemoresistance is a major leading reason for cancer treatment failure. MiR-302a-3p is involved in the development of many diseases. Here, we investigated the role of miR-302a-3p in the cisplatin resistance of ESCC cells and explored its potential mechanism via molecular techniques. The expression of miR-302a-3p was significantly reduced, while the expressions of EphA2 were increased in ESCC tumor tissues and cells. EphA2 was one target gene of miR-302a-3p, and was negatively regulated by miR-302a-3p. By regulating EphA2, miR-302a-3p reduced the viability and promoted the apoptosis of ECA109 cells treated with cisplatin, suggesting that miR-302a-3p could enhance the sensitivity of ECA109 cells to cisplatin treatment by targeting EphA2. MiR-302a-3p plays an important role in reducing cisplatin resistance by inhibiting EphA2, suggesting that it may be a promising therapeutic strategy for cisplatin resistance in ESCC in the future.
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Affiliation(s)
- Yali Ren
- Department of Pharmacy, Nantong Health College of Jiangsu Province, Nantong, Jiangsu, China
| | - Qianqian Ju
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jinlin Zhang
- Department of Pharmacy, Tumor Hospital Affiliated to Nantong University, Nantong, Jiangsu, China
| | - Wei Gu
- Department of Pharmacy, Nantong Health College of Jiangsu Province, Nantong, Jiangsu, China
| | - Jin Du
- Department of Cardiothoracic Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu, China
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Zou J, Zhang K, Zhu J, Tu C, Guo J. Identification of therapeutic targets and prognostic biomarkers of the ephrin receptor subfamily in pancreatic adenocarcinoma. J Int Med Res 2024; 52:3000605231218559. [PMID: 38180878 PMCID: PMC10771058 DOI: 10.1177/03000605231218559] [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: 08/04/2023] [Accepted: 11/13/2023] [Indexed: 01/07/2024] Open
Abstract
OBJECTIVES We aimed to examine the significance of ephrin receptor A2 (EphA2) expression in pancreatic adenocarcinoma (PAAD) and its associated mechanism. METHODS EphA2 mRNA expression patterns were compared in pancreatic cancer and normal tissues using GEPIA. Kaplan-Meier analysis was used to examine the correlation between EphA2 expression and PAAD patient prognosis. EphA2 gene methylation and associations with tumor immune cell infiltration were analyzed with UALCAN and TIMER, respectively. EphA2-interacting proteins were investigated with GeneMANIA, while STRING helped predict potentially relevant signaling pathways. EphA2 protein expression was examined with immunohistochemistry (IHC) in PAAD patient tissues. RESULTS EphA2 was highly expressed in pancreatic cancer tissues and associated with pathological stage. PAAD patients with high EphA2 expression had shorter overall survival and disease-free survival times. EphA2 expression levels were significantly and positively associated with CD4+ T cell infiltration. EphA2 can interact with ENFNA1, ACP1, and CDC42. High EphA2 mRNA expression was enriched for regulation of cell size and cell proliferation. IHC assays suggested that pancreatic cancer tissues had higher EphA2 protein levels than normal pancreatic tissues. CONCLUSIONS EphA2 is highly expressed in PAAD and closely related to poor patient prognosis, and is therefore a potential biomarker and target for PAAD diagnosis and treatment.
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Affiliation(s)
- Jingjng Zou
- Lishui Municipal Central Hospital, Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Kun Zhang
- Lishui Municipal Central Hospital, Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | - Jinde Zhu
- Lishui Municipal Central Hospital, Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
| | | | - Jingqiang Guo
- Jingqiang Guo, Master of Medicine, 289 Kuocang Road, Lishui City, Zhejiang Province 32300, China.
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Vincenzi M, Mercurio FA, Leone M. EPHA2 Receptor as a Possible Therapeutic Target in Viral Infections. Curr Med Chem 2024; 31:5670-5701. [PMID: 37828671 DOI: 10.2174/0109298673256638231003111234] [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: 04/06/2023] [Revised: 08/02/2023] [Accepted: 08/24/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND The receptor tyrosine kinase EphA2 plays a role in many diseases, like cancer, cataracts, and osteoporosis. Interestingly, it has also been linked to viral infections. OBJECTIVE Herein, current literature has been reviewed to clarify EphA2 functions in viral infections and explore its potential role as a target in antiviral drug discovery strategies. METHODS Research and review articles along with preprints connecting EphA2 to different viruses have been searched through PubMed and the web. Structures of complexes between EphA2 domains and viral proteins have been retrieved from the PDB database. RESULTS EphA2 assumes a key role in Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein Barr virus (EBV) infections by directly binding, through its ligand binding domain, viral glycoproteins. For human cytomegalovirus (HCMV), the role of EphA2 in maintaining virus latency state, through cooperation with specific viral proteins, has also been speculated. In certain cells, with high EphA2 expression levels, following ligand stimulation, receptor activation might contribute to severe symptoms accompanying a few viral infections, including lung injuries often related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). CONCLUSION Since EphA2 works as a host receptor for certain viruses, it might be worth more deeply investigating known compounds targeting its extracellular ligand binding domain as antiviral therapeutics. Due to EphA2's function in inflammation, its possible correlation with SARS-CoV-2 cannot be excluded, but more experimental studies are needed in this case to undoubtedly attribute the role of this receptor in viral infections.
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Affiliation(s)
- Marian Vincenzi
- Institute of Biostructures and Bioimaging, National Research Council of Italy (CNR-IBB), Naples, Italy
| | - Flavia Anna Mercurio
- Institute of Biostructures and Bioimaging, National Research Council of Italy (CNR-IBB), Naples, Italy
| | - Marilisa Leone
- Institute of Biostructures and Bioimaging, National Research Council of Italy (CNR-IBB), Naples, Italy
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Yan S, Wang M. HCG11 inhibits salivary adenoid cystic carcinoma by upregulating EphA2 via binding to miR-1297. Oral Surg Oral Med Oral Pathol Oral Radiol 2023; 135:257-267. [PMID: 36396591 DOI: 10.1016/j.oooo.2022.08.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 08/04/2022] [Accepted: 08/28/2022] [Indexed: 11/28/2022]
Abstract
OBJECTIVE Ephrin receptor A2 (EphA2) was reported to be related to the tumorigenesis of salivary adenoid cystic carcinoma (SACC), which is a rare malignancy accounting for less than 1% of all oral and maxillofacial tumors. This research aimed to assess the molecular mechanisms of EphA2 in SACC. STUDY DESIGN The expression of long non-coding RNA human leukocyte antigen complex group 11 (HCG11), microRNA-1297 (miR-1297), and EphA2 in SACC cell lines compared with normal human salivary gland (HSG) cell line was measured by reverse transcription-quantitative polymerase chain reaction. EphA2 protein level was detected by western blot. 5-ethynyl-2'-deoxyuridine (EdU), colony formation, Transwell, and wounding healing experiments were applied to evaluate SACC cell proliferation, migration, and invasion. The relationship among HCG11, miR-1297, and EphA2 was confirmed by luciferase reporter, RNA pulldown, and RNA immunoprecipitation experiments. RESULTS HCG11 and EphA2 were downregulated while miR-1297 was upregulated in SACC cells. EphA2 overexpression suppressed SACC cell proliferation, migration, and invasion. HCG11 bound to miR-1297 to reduce the inhibition of miR-1297 on EphA2 expression. EphA2 knockdown reversed the suppression of HCG11 overexpression on SACC cell phenotypes. CONCLUSION This study identified the HCG11/miR-1297/EphA2 regulatory axis in SACC, which might provide novel therapeutic targets for SACC.
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Affiliation(s)
- Shujuan Yan
- Department of Oral and Maxillofacial Surgery, Changyi People's Hospital, Weifang 261300, Shandong, China
| | - Meng Wang
- Health Management Center, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, Shandong, China.
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Ferreira LAD, Rambo C, Gomes MJK, Ribeiro KDP, Nishimoto GDA, Tisatto LGDR, Fritzen LD, da Cruz YB, Kambara AL, Rodrigues MJVB, Nogueira GA, Salvador HD, Oliveira-Toré CDF, Reason IJDM, Telles JEQ, Tomiotto-Pellissier F. Nanoparticles and phototherapy combination as therapeutic alternative in prostate cancer: A scoping review. Eur J Pharmacol 2023; 939:175421. [PMID: 36435234 DOI: 10.1016/j.ejphar.2022.175421] [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: 07/04/2022] [Revised: 11/02/2022] [Accepted: 11/22/2022] [Indexed: 11/27/2022]
Abstract
Prostate cancer (CaP) is one of the most common types of cancers worldwide. Despite the existing surgical techniques, prostatectomy patients may experience tumor recurrence. In addition, castration-resistant cancers pose a challenge, especially given their lack of response to standard care. Thus, the development of more efficient therapies has become a field of great interest, and photothermal therapy (PTT) and photodynamic therapy (PDT) are promising alternatives, given their high capacity to cause cell injury and consequent tumor ablation. Phototherapy, along with chemotherapy, has also been shown to be more effective than pharmacotherapy alone. Free molecules used as photosensitizers are rapidly cleared from the body, do not accumulate in the tumor, and are primarily hydrophobic and require toxic solvents. Thus, the use of nanoparticles can be an effective strategy, given their ability to carry or bind to different molecules, protecting them from degradation and allowing their association with other surface ligands, which favors permeation and retention at the tumor site. Despite this, there is still a gap in the literature regarding the use of phototherapy in association with nanotechnology for the treatment of CaP. In this scoping review, it was found that most of the particles studied could act synergistically through PDT and PTT. In addition, fluorescent quenchers can act as diagnostic and therapeutic tools. However, future clinical studies should be performed to confirm the benefits and safety of the combination of nanoparticles and phototherapy for CaP.
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Affiliation(s)
| | - Camila Rambo
- Department of Medical Pathology, Federal University of Paraná, Curitiba, Paraná, Brazil
| | | | | | | | | | - Lucas Diego Fritzen
- Department of Medical Pathology, Federal University of Paraná, Curitiba, Paraná, Brazil
| | | | - Aline Lika Kambara
- Department of Medical Pathology, Federal University of Paraná, Curitiba, Paraná, Brazil
| | | | | | | | | | | | | | - Fernanda Tomiotto-Pellissier
- Department of Medical Pathology, Federal University of Paraná, Curitiba, Paraná, Brazil; Laboratory of Immunopathology of Neglected Diseases and Cancer (LIDNC), Department of Pathological Sciences, State University of Londrina, Londrina, Paraná, Brazil.
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Hunting for Novel Routes in Anticancer Drug Discovery: Peptides against Sam-Sam Interactions. Int J Mol Sci 2022; 23:ijms231810397. [PMID: 36142306 PMCID: PMC9499636 DOI: 10.3390/ijms231810397] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/02/2022] [Accepted: 09/02/2022] [Indexed: 01/10/2023] Open
Abstract
Among the diverse protein binding modules, Sam (Sterile alpha motif) domains attract attention due to their versatility. They are present in different organisms and play many functions in physiological and pathological processes by binding multiple partners. The EphA2 receptor contains a Sam domain at the C-terminus (EphA2-Sam) that is able to engage protein regulators of receptor stability (including the lipid phosphatase Ship2 and the adaptor Odin). Ship2 and Odin are recruited by EphA2-Sam through heterotypic Sam-Sam interactions. Ship2 decreases EphA2 endocytosis and consequent degradation, producing chiefly pro-oncogenic outcomes in a cellular milieu. Odin, through its Sam domains, contributes to receptor stability by possibly interfering with ubiquitination. As EphA2 is upregulated in many types of tumors, peptide inhibitors of Sam-Sam interactions by hindering receptor stability could function as anticancer therapeutics. This review describes EphA2-Sam and its interactome from a structural and functional perspective. The diverse design strategies that have thus far been employed to obtain peptides targeting EphA2-mediated Sam-Sam interactions are summarized as well. The generated peptides represent good initial lead compounds, but surely many efforts need to be devoted in the close future to improve interaction affinities towards Sam domains and consequently validate their anticancer properties.
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11
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Dai T, Liu Y, Cao R, Cao J. CBX7 regulates metastasis of basal-like breast cancer through Twist1/EphA2 pathway. Transl Oncol 2022; 24:101468. [PMID: 35843065 PMCID: PMC9294549 DOI: 10.1016/j.tranon.2022.101468] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 06/02/2022] [Accepted: 06/07/2022] [Indexed: 12/09/2022] Open
Abstract
CBX7 was down-regulated, while twist and EphA2 were up-regulated in BLBC. EphA2 or twist silencing inhibited BLBC cell proliferation and metastasis. Twist bond to EphA2 and increased the expression of EphA2. CBX7 blocked the binding of twist to EphA2 and inhibited EphA2 expression. CBX7 regulated BLBC growth and metastasis via Twist/EphA2 axis. Background Basal-like breast cancer (BLBC) is an important subtype of breast cancer. Twist1 is a key transcription factor in BLBC metastasis, which serves a key role in tumorigenesis. The potential mechanism of Twist1 in BLBC remains to be elucidated. Here, we explored the role and molecular mechanism of Twist1 in BLBC. Methods The levels of CBX7, Twist1 and EphA2 in BLBC tissues and cells were determined by Western blot. ChIP and dual-luciferase reporter assays confirmed the interaction between CBX7, Twist1 and EphA2 promoter. The cellular functions were analyzed by CCK-8, colony formation, wound healing and Transwell assays. Expression of EMT related proteins was analyzed by Western blot. IHC measured the expression of CBX7, Twist1 and EphA2 in tumor tissues. Results CBX7 was down-regulated in BLBC tissues and cells, whereas Twist1 and EphA2 were up-regulated. Twist1 silencing inhibited the cell migration, invasion and cancer metastasis of BLBC through targeting EphA2 and regulating EphA2 expression. Additionally, CBX7 blocked the binding of Twist1 to EphA2 promoter and inhibited EphA2 expression and suppressed BLBC growth and metastasis via Twist1/EphA2 axis. Conclusion CBX7 suppresses BLBC growth and metastasis through Twist1/EphA2 pathway. Our study may provide evidence and new therapeutic targets for the comprehensive treatment of BLBC.
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Affiliation(s)
- Tao Dai
- Department of Urology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha 410013 Hunan Province, PR China
| | - Yiqi Liu
- The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China
| | - Renxian Cao
- Institute of Clinical Medicine, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China
| | - Jingying Cao
- Department of Medicine Clinical Laboratory, The Third Xiangya Hospital of Central South University, Changsha 410013 Hunan Province, PR China.
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Evans BR, Yerly A, van der Vorst EPC, Baumgartner I, Bernhard SM, Schindewolf M, Döring Y. Inflammatory Mediators in Atherosclerotic Vascular Remodeling. Front Cardiovasc Med 2022; 9:868934. [PMID: 35600479 PMCID: PMC9114307 DOI: 10.3389/fcvm.2022.868934] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 04/11/2022] [Indexed: 12/23/2022] Open
Abstract
Atherosclerotic vascular disease remains the most common cause of ischemia, myocardial infarction, and stroke. Vascular function is determined by structural and functional properties of the arterial vessel wall, which consists of three layers, namely the adventitia, media, and intima. Key cells in shaping the vascular wall architecture and warranting proper vessel function are vascular smooth muscle cells in the arterial media and endothelial cells lining the intima. Pathological alterations of this vessel wall architecture called vascular remodeling can lead to insufficient vascular function and subsequent ischemia and organ damage. One major pathomechanism driving this detrimental vascular remodeling is atherosclerosis, which is initiated by endothelial dysfunction allowing the accumulation of intimal lipids and leukocytes. Inflammatory mediators such as cytokines, chemokines, and modified lipids further drive vascular remodeling ultimately leading to thrombus formation and/or vessel occlusion which can cause major cardiovascular events. Although it is clear that vascular wall remodeling is an elementary mechanism of atherosclerotic vascular disease, the diverse underlying pathomechanisms and its consequences are still insufficiently understood.
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Affiliation(s)
- Bryce R. Evans
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Anaïs Yerly
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Emiel P. C. van der Vorst
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- Institute for Molecular Cardiovascular Research (IMCAR) and Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Iris Baumgartner
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Sarah Maike Bernhard
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Marc Schindewolf
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Yvonne Döring
- Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
- *Correspondence: Yvonne Döring
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Mutation of the EPHA2 Tyrosine-Kinase Domain Dysregulates Cell Pattern Formation and Cytoskeletal Gene Expression in the Lens. Cells 2021; 10:cells10102606. [PMID: 34685586 PMCID: PMC8534143 DOI: 10.3390/cells10102606] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/20/2021] [Accepted: 09/27/2021] [Indexed: 12/13/2022] Open
Abstract
Genetic variations in ephrin type-A receptor 2 (EPHA2) have been associated with inherited and age-related forms of cataract in humans. Here, we have characterized the eye lens phenotype and transcript profile of germline Epha2 knock-in mutant mice homozygous for either a missense variant associated with age-related cataract in humans (Epha2-Q722) or a novel insertion-deletion mutation (Epha2-indel722) that were both located within the tyrosine-kinase domain of EPHA2. Confocal imaging of ex vivo lenses from Epha2-indel722 mice on a fluorescent reporter background revealed misalignment of epithelial-to-fiber cell meridional-rows at the lens equator and severe disturbance of Y-suture formation at the lens poles, whereas Epha2-Q722 lenses displayed mild disturbance of posterior sutures. Immunofluorescent labeling showed that EPHA2 was localized to radial columns of hexagonal fiber cell membranes in Epha2-Q722 lenses, whereas Epha2-indel722 lenses displayed disorganized radial cell columns and cytoplasmic retention of EPHA2. Immunoprecipitation/blotting studies indicated that EPHA2 formed strong complexes with Src kinase and was mostly serine phosphorylated in the lens. RNA sequencing analysis revealed differential expression of several cytoskeleton-associated genes in Epha2-mutant and Epha2-null lenses including shared downregulation of Lgsn and Clic5. Collectively, our data suggest that mutations within the tyrosine-kinase domain of EPHA2 result in lens cell patterning defects and dysregulated expression of several cytoskeleton-associated proteins.
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Wei Q, Li Z, Feng H, Ren L. Serum Exosomal EphA2 is a Prognostic Biomarker in Patients with Pancreatic Cancer. Cancer Manag Res 2021; 13:3675-3683. [PMID: 33994808 PMCID: PMC8112875 DOI: 10.2147/cmar.s304719] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/20/2021] [Indexed: 12/11/2022] Open
Abstract
Background Pancreatic cancer (PC) is one of the worst prognoses amongst all malignant diseases. It is therefore of great significance to identify biomarkers with predictive clinical value for the prognosis and recurrence of PC. Methods In our study, enzyme-linked immunosorbent assays (ELISA) were used to detect the expression of Exo-EphA2 in the serum of PC patients and controls. Kaplan–Meier curve and Cox regression analyses were used to evaluate the prognostic value of Exo-EphA2 expression in patients with primary and recurrent PC. Results The level of serum Exo-EphA2 was significantly higher in the PC group when compared to that of the control group. High expression of Exo-EphA2 in PC was associated with shorter overall survival (OS) and proved to be a significant negative prognostic factor in the multivariate analysis (HR = 1.04, 95% CI: 1.00–1.09, P <0.001). Additionally, we found that the level of serum Exo-EphA2 in recurrent PC patients (first recurrence < 12 months) was positively correlated with the level of Exo-EphA2 at primary diagnosis. Multivariate analysis showed that a high expression of Exo-EphA2 in recurrent PC was associated with shorter recurrence-free survival (RFS) (HR = 1.41, 95% CI: 1.10–1.70, P < 0.001). Conclusion High expression of serum Exo-EphA2 represents a novel biomarker for a poor prognosis in PC patients.
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Affiliation(s)
- Qian Wei
- Department of Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Ze Li
- Department of Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Honglei Feng
- Department of Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Li Ren
- Department of Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
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