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Liu S, Wu T, Song X, Quan L, Wang X, Liu Q, Zhou X. Single-cell sequencing reveals PTX3 involvement in ovarian cancer metastasis. J Ovarian Res 2024; 17:235. [PMID: 39580424 PMCID: PMC11585133 DOI: 10.1186/s13048-024-01558-2] [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: 02/15/2024] [Accepted: 11/13/2024] [Indexed: 11/25/2024] Open
Abstract
BACKGROUND Pentraxin 3 (PTX3) has been associated with the development and progression of various malignant tumors. However, its roles and the mechanisms underlying its involvement in ovarian cancer (OC) peritoneal metastasis remain unclear. METHODS Single-cell RNA sequencing (scRNA-seq) and immunohistochemistry (IHC) were conducted to determine the expression profiles, potential functionalities, and underlying mechanisms of PTX3 within the context of OC. To assess the proliferative response of OC cells, we utilized both EdU (5-ethynyl-2' -deoxyuridine) and CCK8 assays. The role of PTX3 in facilitating cell migration and invasion was quantified through the use of Transwell assays. The protein expression levels were meticulously analyzed via Western blotting. Furthermore, to explore the interactions between proteins, we conducted immunofluorescence (IF) staining and co-immunoprecipitation (Co-IP) experiments. To determine the factors responsible for the upregulation of PTX3, we performed both coculture and suspension assays, providing a comprehensive approach to understanding the regulatory mechanisms involved. RESULTS This study confirmed, for the first time, that the expression of PTX3 in OC metastatic lesions is greater than that in primary lesions and that tumor cells with high PTX3 expression have greater metastatic ability. PTX3 can activate the EMT and NF-κB signaling pathways in OC cells and can interact with the TLR4 and CD44 receptors in OC cells. Additionally, PTX3's modulation of the EMT and NF-κB pathways is partially dependent on its interaction with TLR4. Furthermore, this study revealed the intercellular regulatory network related to PTX3 in OC cells via bioinformatic analysis. High levels of PTX3 in OC cells potentially enhance the attraction of dendritic cells (DCs) and CD4 + T cells while diminishing the recruitment of B cells and CD8 + T cells. Finally, this study indicated that PTX3 upregulation was driven by multiple factors, including specific transcription factors (TFs) and modifications within the tumor microenvironment (TME). CONCLUSIONS Our research revealed the contribution of PTX3 to the peritoneal dissemination process in OC patients, identifying a novel potential biomarker and therapeutic target for this disease.
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Affiliation(s)
- Shuangyan Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, China
| | - Tianhao Wu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, China
| | - Xueying Song
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, China
| | - Linru Quan
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, China
| | - Xinyi Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, China
| | - Qing Liu
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, China.
| | - Xin Zhou
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, China.
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Jung H, Kang J, Han KM, Kim H. Prognostic Value of Pentraxin3 Protein Expression in Human Malignancies: A Systematic Review and Meta-Analysis. Cancers (Basel) 2024; 16:3754. [PMID: 39594709 PMCID: PMC11593206 DOI: 10.3390/cancers16223754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 10/30/2024] [Accepted: 11/01/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Pentraxin 3 (PTX3), a member of the pentraxin superfamily, plays diverse roles in immunity and inflammation. Its dual role in tumorigenesis, exhibiting both protumoral and antitumoral effects, has been the subject of conflicting reports. High PTX3 expression levels in serum and tumor tissues have been associated with poor prognosis in various malignancies, suggesting its potential as a prognostic biomarker. Through this meta-analysis, we aim to comprehensively assess the prognostic significance of PTX3 protein expression in human malignancies and evaluate its potential as a pan-cancer prognostic marker. METHODS A systematic literature search was conducted across the PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library databases. Studies were included if they assessed the association between PTX3 protein expression and overall survival (OS) in cancer patients. Hazard ratios (HRs) were pooled using a random-effects model. Subgroup analyses were performed based on the method of PTX3 assessment, and publication bias was evaluated using Egger's and Begg's tests. RESULTS Nine studies encompassing 1215 patients were included in the analysis. High PTX3 expression was significantly associated with poorer OS (HR = 1.89, 95% CI = 1.55-2.32, p < 0.01) with no significant heterogeneity (I2 = 0%). Subgroup analysis revealed consistent results across different assessment methods (immunohistochemistry: HR = 1.93, p < 0.01; immunoassay: HR = 1.86, p < 0.01). However, publication bias was detected (Egger's test, p = 0.03). CONCLUSIONS High PTX3 protein expression is associated with a poor prognosis in various malignancies, supporting its potential as a prognostic biomarker.
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Affiliation(s)
| | | | | | - Hyunchul Kim
- Department of Pathology, CHA Ilsan Medical Center, Goyang-si 10414, Gyeonggi-do, Republic of Korea (J.K.); (K.-M.H.)
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Xie H, Ruan G, Wei L, Zhang H, Shi J, Lin S, Liu C, Liu X, Zheng X, Chen Y, Deng L, Shi H. Obesity-associated metabolic inflammation promotes triple-negative breast cancer progression through the interleukin-6/STAT3/pentraxin 3/matrix metalloproteinase 7 axis. Int Immunopharmacol 2024; 136:112332. [PMID: 38805776 DOI: 10.1016/j.intimp.2024.112332] [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: 04/19/2024] [Revised: 05/18/2024] [Accepted: 05/21/2024] [Indexed: 05/30/2024]
Abstract
BACKGROUND This study aimed to investigate the regulatory mechanism of the adipose factor interleukin (IL)-6 in promoting pentraxin 3 (PTX3) expression in triple-negative breast cancer (TNBC). METHODS We established an in vitro coculture model of mature adipocytes and TNBC cells using a Transwell system. Cell scratch, Transwell migration, and matrix invasion assays were used to evaluate the migration and invasion abilities of TNBC cells cocultured with adipocytes. Next, we used lentivirus-mediated functional depletion experiments to study PTX3's role in the adipocyte-dependent migration of TNBC cells. RESULTS After coculturing TNBC cells with adipocytes, PTX3 expression was upregulated, which accompanied enhanced cell migration and invasion. Using GEO data and RNA-seq analysis, we identified PTX3 as a key target gene influenced by the adipose TNBC microenvironment. IL-6 upregulation in the conditioned medium of mature adipocytes and in the serum of high-fat diet mice was associated with this effect, and the recombinant protein IL-6 significantly promoted the migration and invasion of TNBC cells along with the phosphorylation of intracellular STAT3 and the upregulation of PTX3. PTX3 knockdown inhibited TNBC cell migration and eliminated the enhanced migration caused by coculturing with adipocytes. Furthermore, in vivo experiments confirmed that the PTX3 knockdown reduced obesity-induced lung metastasis. Subsequent experiments with cytokines and drug inhibitors confirmed that adipocyte-derived IL-6 promoted PTX3 expression by activating the STAT3 signaling pathway. Additionally, bioinformatic analysis indicated that PTX3 promotes TNBC metastasis by regulating the matrix metalloproteinase (MMP) family. CONCLUSION Our study elucidated Obesity-related metabolic inflammation promotes the progression via the IL-6/STAT3/PTX3/MMP7 axis.
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Affiliation(s)
- Hailun Xie
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
| | - Guotian Ruan
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
| | - Lishuang Wei
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
| | - Heyang Zhang
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
| | - Jinyu Shi
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
| | - Shiqi Lin
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
| | - Chenan Liu
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
| | - Xiaoyue Liu
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
| | - Xin Zheng
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
| | - Yue Chen
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
| | - Li Deng
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China.
| | - Hanping Shi
- Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, China; Key Laboratory of Cancer FSMP for State Market Regulation, Beijing, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China.
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Scuderi SA, Ardizzone A, Salako AE, Pantò G, De Luca F, Esposito E, Capra AP. Pentraxin 3: A Main Driver of Inflammation and Immune System Dysfunction in the Tumor Microenvironment of Glioblastoma. Cancers (Basel) 2024; 16:1637. [PMID: 38730589 PMCID: PMC11083335 DOI: 10.3390/cancers16091637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 04/12/2024] [Accepted: 04/22/2024] [Indexed: 05/13/2024] Open
Abstract
Brain tumors are a heterogeneous group of brain neoplasms that are highly prevalent in individuals of all ages worldwide. Within this pathological framework, the most prevalent and aggressive type of primary brain tumor is glioblastoma (GB), a subtype of glioma that falls within the IV-grade astrocytoma group. The death rate for patients with GB remains high, occurring within a few months after diagnosis, even with the gold-standard therapies now available, such as surgery, radiation, or a pharmaceutical approach with Temozolomide. For this reason, it is crucial to continue looking for cutting-edge therapeutic options to raise patients' survival chances. Pentraxin 3 (PTX3) is a multifunctional protein that has a variety of regulatory roles in inflammatory processes related to extracellular matrix (ECM). An increase in PTX3 blood levels is considered a trustworthy factor associated with the beginning of inflammation. Moreover, scientific evidence suggested that PTX3 is a sensitive and earlier inflammation-related marker compared to the short pentraxin C-reactive protein (CRP). In several tumoral subtypes, via regulating complement-dependent and macrophage-associated tumor-promoting inflammation, it has been demonstrated that PTX3 may function as a promoter of cancer metastasis, invasion, and stemness. Our review aims to deeply evaluate the function of PTX3 in the pathological context of GB, considering its pivotal biological activities and its possible role as a molecular target for future therapies.
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Affiliation(s)
- Sarah Adriana Scuderi
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, Italy; (S.A.S.); (A.A.); (A.E.S.); (F.D.L.); (A.P.C.)
| | - Alessio Ardizzone
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, Italy; (S.A.S.); (A.A.); (A.E.S.); (F.D.L.); (A.P.C.)
| | - Ayomide Eniola Salako
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, Italy; (S.A.S.); (A.A.); (A.E.S.); (F.D.L.); (A.P.C.)
- University of Florence, 50121 Florence, Italy
| | - Giuseppe Pantò
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98125 Messina, Italy;
| | - Fabiola De Luca
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, Italy; (S.A.S.); (A.A.); (A.E.S.); (F.D.L.); (A.P.C.)
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, Italy; (S.A.S.); (A.A.); (A.E.S.); (F.D.L.); (A.P.C.)
| | - Anna Paola Capra
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, Italy; (S.A.S.); (A.A.); (A.E.S.); (F.D.L.); (A.P.C.)
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Zajkowska M, Mroczko B. The Role of Pentraxin 3 in Gastrointestinal Cancers. Cancers (Basel) 2023; 15:5832. [PMID: 38136377 PMCID: PMC10741769 DOI: 10.3390/cancers15245832] [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: 11/10/2023] [Revised: 12/06/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Gastrointestinal cancers have become a huge problem worldwide as the number of new cases continues to increase. Due to the growing need to explore new biomarkers and therapeutic targets for the detection and treatment of cancerous lesions, we sought to elucidate the role of Pentraxin-3 in the progression of cancerous lesions, as it is involved in the process of angiogenesis and inflammation. Statistically significant changes in the concentration of this parameter have emerged in many gastrointestinal cancer patients. Moreover, it is related to the advancement of cancer, as well as processes leading to the development of those changes. In the case of studies concerning tissue material, both increased and decreased tissue expression of the tested parameter were observed and were dependent on the type of cancer. In the case of cell lines, both human and animal, a significant increase in Pentraxin 3 gene expression was observed, which confirmed the changes observed at the protein level. In conclusion, it can be assumed that PTX3, both at the level of gene expression and protein concentrations, is highly useful in the detection of gastrointestinal cancers, and its use as a biomarker and/or therapeutic target may be useful in the future.
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Affiliation(s)
- Monika Zajkowska
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
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Li D, Hao Z, Nan Y, Chen Y. Role of long pentraxin PTX3 in cancer. Clin Exp Med 2023; 23:4401-4411. [PMID: 37438568 DOI: 10.1007/s10238-023-01137-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 07/05/2023] [Indexed: 07/14/2023]
Abstract
Cancer has become a leading cause of death and disease burden worldwide, closely related to rapid socioeconomic development. However, the fundamental reason is the lack of comprehensive understanding of the mechanism of cancer, accurate identification of preclinical cancer, and effective treatment of the disease. Therefore, it is particularly urgent to study specific mechanisms of cancer and develop effective prediction and treatment methods. Long Pentraxin PTX3 is a soluble pattern recognition molecule produced by various cells in inflammatory sites, which plays a role as a promoter or suppressor of cancer in multiple tumors through participating in innate immune response, neovascularization, energy metabolism, invasion, and metastasis mechanisms. Based on this, this article mainly reviews the role of PTX3 in various cancers.
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Affiliation(s)
- Duo Li
- Department of Respiratory Medicine, Tangdu Hospital, Air Force Military Medical University, Xi'an 710038, China
| | - Zhaozhao Hao
- Department of Respiratory Medicine, Tangdu Hospital, Air Force Military Medical University, Xi'an 710038, China
| | - Yandong Nan
- Department of Respiratory Medicine, Tangdu Hospital, Air Force Military Medical University, Xi'an 710038, China.
| | - Yanwei Chen
- Department of Respiratory Medicine, Tangdu Hospital, Air Force Military Medical University, Xi'an 710038, China
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Giacomini A, Turati M, Grillo E, Rezzola S, Ghedini GC, Schuind AC, Foglio E, Maccarinelli F, Faletti J, Filiberti S, Chambery A, Valletta M, Melocchi L, Gofflot S, Chiavarina B, Turtoi A, Presta M, Ronca R. The PTX3/TLR4 autocrine loop as a novel therapeutic target in triple negative breast cancer. Exp Hematol Oncol 2023; 12:82. [PMID: 37749607 PMCID: PMC10519006 DOI: 10.1186/s40164-023-00441-y] [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: 03/16/2023] [Accepted: 09/04/2023] [Indexed: 09/27/2023] Open
Abstract
BACKGROUND The pattern recognition receptor long pentraxin-3 (PTX3) plays conflicting roles in cancer by acting as an oncosuppressor or as a pro-tumor mediator depending on tumor context. Triple negative breast cancer (TNBC) represents the most aggressive histotype of breast cancer, characterized by the lack of efficacious therapeutic targets/approaches and poor prognosis. Thus, the characterization of new molecular pathways and/or alternative druggable targets is of great interest in TNBC. METHODS The expression of PTX3 in BC tumor samples and in BC cell lines has been analyzed using the Gene Expression-Based Outcome for Breast Cancer Online (GOBO), qPCR, Western blot and ELISA assay. The contribution of tumor and stromal cells to PTX3 production in TNBC was assessed by analyzing single cell RNA sequencing data and RNAscope performed on TNBC tumor samples. In order to investigate the effects of PTX3 in TNBC, different cell lines were engineered to knock-down (MDA-MB-231 and BT549 cells) or overexpress (MDA-MB-468 and E0771 cells) PTX3. Finally, using these engineered cells, in vitro (including gene expression profiling and gene set enrichment analyses) and in vivo (orthotopic tumor models in immune-compromised and immune competent mice) analyses were performed to assess the role and the molecular mechanism(s) exerted by PTX3 in TNBC. RESULTS In silico and experimental data indicate that PTX3 is mainly produced by tumor cells in TNBC and that its expression levels correlate with tumor stage. Accordingly, gene expression and in vitro results demonstrate that PTX3 overexpression confers a high aggressive/proliferative phenotype and fosters stem-like features in TNBC cells. Also, PTX3 expression induces a more tumorigenic potential when TNBC cells are grafted orthotopically in vivo. Conversely, PTX3 downregulation results in a less aggressive behavior of TNBC cells. Mechanistically, our data reveal that PTX3 drives the activation of the pro-tumorigenic Toll-like receptor 4 (TLR4) signaling pathway in TNBC, demonstrating for the first time that the PTX3/TLR4 autocrine stimulation loop contributes to TNBC aggressiveness and that TLR4 inhibition significantly impacts the growth of PTX3-producing TNBC cells. CONCLUSION Altogether, these data shed light on the role of tumor-produced PTX3 in TNBC and uncover the importance of the PTX3/TLR4 axis for therapeutic and prognostic exploitation in TNBC.
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Affiliation(s)
- Arianna Giacomini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
| | - Marta Turati
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Elisabetta Grillo
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Sara Rezzola
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Gaia Cristina Ghedini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Ander Churruca Schuind
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Eleonora Foglio
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Federica Maccarinelli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Jessica Faletti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Serena Filiberti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Angela Chambery
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania 'Luigi Vanvitelli', Caserta, Italy
| | - Mariangela Valletta
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), University of Campania 'Luigi Vanvitelli', Caserta, Italy
| | - Laura Melocchi
- Pathology Unit, Fondazione Poliambulanza Hospital Institute, Brescia, 25121, Italy
| | | | - Barbara Chiavarina
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, University of Montpellier, Montpellier, France
| | - Andrei Turtoi
- Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, University of Montpellier, Montpellier, France
| | - Marco Presta
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Roberto Ronca
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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McCarthy GA, Di Niro R, Finan JM, Jain A, Guo Y, Wyatt C, Guimaraes A, Waugh T, Keith D, Morgan T, Sears R, Brody J. Deletion of the mRNA stability factor ELAVL1 (HuR) in pancreatic cancer cells disrupts the tumor microenvironment integrity. NAR Cancer 2023; 5:zcad016. [PMID: 37089813 PMCID: PMC10113877 DOI: 10.1093/narcan/zcad016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 03/08/2023] [Accepted: 04/06/2023] [Indexed: 04/25/2023] Open
Abstract
Stromal cells promote extensive fibrosis in pancreatic ductal adenocarcinoma (PDAC), which is associated with poor prognosis and therapeutic resistance. We report here for the first time that loss of the RNA-binding protein human antigen R (HuR, ELAVL1) in PDAC cells leads to reprogramming of the tumor microenvironment. In multiple in vivo models, CRISPR deletion of ELAVL1 in PDAC cells resulted in a decrease of collagen deposition, accompanied by a decrease of stromal markers (i.e. podoplanin, α-smooth muscle actin, desmin). RNA-sequencing data showed that HuR plays a role in cell-cell communication. Accordingly, cytokine arrays identified that HuR regulates the secretion of signaling molecules involved in stromal activation and extracellular matrix organization [i.e. platelet-derived growth factor AA (PDGFAA) and pentraxin 3]. Ribonucleoprotein immunoprecipitation analysis and transcription inhibition studies validated PDGFA mRNA as a novel HuR target. These data suggest that tumor-intrinsic HuR supports extrinsic activation of the stroma to produce collagen and desmoplasia through regulating signaling molecules (e.g. PDGFAA). HuR-deficient PDAC in vivo tumors with an altered tumor microenvironment are more sensitive to the standard of care gemcitabine, as compared to HuR-proficient tumors. Taken together, we identified a novel role of tumor-intrinsic HuR in its ability to modify the surrounding tumor microenvironment and regulate PDGFAA.
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Affiliation(s)
- Grace A McCarthy
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
| | - Roberto Di Niro
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
| | - Jennifer M Finan
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
| | - Aditi Jain
- The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Yifei Guo
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
| | - Cory R Wyatt
- Department of Diagnostic Radiology, Oregon Health & Science University, Portland, OR 97239, USA
- Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR 97239, USA
| | - Alexander R Guimaraes
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
- Department of Diagnostic Radiology, Oregon Health & Science University, Portland, OR 97239, USA
- Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR 97239, USA
| | - Trent A Waugh
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
| | - Dove Keith
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
| | - Terry K Morgan
- Department of Pathology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Rosalie C Sears
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, USA
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR 97201, USA
| | - Jonathan R Brody
- Department of Surgery, Oregon Health & Science University, Portland, OR 97239, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR 97201, USA
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97201, USA
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9
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PARP Inhibitor Inhibits the Vasculogenic Mimicry through a NF-κB-PTX3 Axis Signaling in Breast Cancer Cells. Int J Mol Sci 2022; 23:ijms232416171. [PMID: 36555812 PMCID: PMC9785325 DOI: 10.3390/ijms232416171] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/04/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
Poly (ADP-ribose) polymerase inhibitors (PARPi) are targeted therapies that inhibit PARP proteins which are involved in a variety of cell functions. PARPi may act as modulators of angiogenesis; however, the relationship between PARPi and the vasculogenic mimicry (VM) in breast cancer remains unclear. To determine whether PARPi regulate the vascular channel formation, we assessed whether the treatment with olaparib, talazoparib and veliparib inhibits the vascular channel formation by breast cancer cell lines. Here, we found that PARPi act as potent inhibitors of the VM formation in triple negative breast cancer cells, independently of the BRCA status. Mechanistically, we find that PARPi trigger and inhibit the NF-κB signaling, leading to the inhibition of the VM. We further show that PARPi decrease the expression of the angiogenic factor PTX3. Moreover, PTX3 rescued the PARPi-inhibited VM inhibition. In conclusion, our results indicate that PARPi, by targeting the VM, may provide a new therapeutic approach for triple negative breast cancer.
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10
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Bogdan M, Meca AD, Turcu-Stiolica A, Oancea CN, Kostici R, Surlin MV, Florescu C. Insights into the Relationship between Pentraxin-3 and Cancer. Int J Mol Sci 2022; 23:15302. [PMID: 36499628 PMCID: PMC9739619 DOI: 10.3390/ijms232315302] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 11/21/2022] [Accepted: 11/29/2022] [Indexed: 12/11/2022] Open
Abstract
Although cancer can be cured if detected early and treated effectively, it is still a leading cause of death worldwide. Tumor development can be limited by an appropiate immune response, but it can be promoted by chronic extensive inflammation through metabolic dysregulation and angiogenesis. In the past decade, numerous efforts have been made in order to identify novel candidates with predictive values in cancer diagnostics. In line with this, researchers have investigated the involvement of pentraxin-3 (PTX-3) in cellular proliferation and immune escape in various types of cancers, although it has not been clearly elucidated. PTX-3 is a member of the long pentraxin subfamily which plays an important role in regulating inflammation, innate immunity response, angiogenesis, and tissue remodeling. Increased synthesis of inflammatory biomarkers and activation of different cellular mechanisms can induce PTX-3 expression in various types of cells (neutrophils, monocytes, lymphocytes, myeloid dendritic cells, fibroblasts, and epithelial cells). PTX-3 has both pro- and anti-tumor functions, thus dual functions in oncogenesis. This review elucidates the potential usefulness of PTX-3 as a serum biomarker in cancer. While future investigations are needed, PTX-3 is emerging as a promising tool for cancer's diagnosis and prognosis, and also treatment monitoring.
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Affiliation(s)
- Maria Bogdan
- Department of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy, 200349 Craiova, Romania
| | - Andreea-Daniela Meca
- Department of Pharmacology, Faculty of Pharmacy, University of Medicine and Pharmacy, 200349 Craiova, Romania
| | - Adina Turcu-Stiolica
- Department of Pharmacoeconomics, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Carmen Nicoleta Oancea
- Department of Biochemistry, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Roxana Kostici
- Department of Toxicology, Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Marin Valeriu Surlin
- Department of General Surgery, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Cristina Florescu
- Department of Cardiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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11
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Zhang H, Wang R, Wang Z, Wu W, Zhang N, Zhang L, Hu J, Luo P, Zhang J, Liu Z, Feng S, Peng Y, Liu Z, Cheng Q. Molecular insight into pentraxin-3: Update advances in innate immunity, inflammation, tissue remodeling, diseases, and drug role. Biomed Pharmacother 2022; 156:113783. [PMID: 36240615 DOI: 10.1016/j.biopha.2022.113783] [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: 07/14/2022] [Revised: 09/28/2022] [Accepted: 09/28/2022] [Indexed: 11/20/2022] Open
Abstract
Pentraxin-3 (PTX3) is the prototype of the long pentraxin subfamily, an acute-phase protein consisting of a C-terminal pentraxin domain and a unique N-terminal domain. PTX3 was initially isolated from human umbilical vein endothelial cells and human FS-4 fibroblasts. It was subsequently found to be also produced by synoviocytes, chondrocytes, osteoblasts, smooth muscle cells, myeloid dendritic cells, epithelial cells, and tumor cells. Various modulatory factors, such as miRNAs, cytokines, drugs, and hypoxic conditions, could regulate the expression level of PTX3. PTX3 is essential in regulating innate immunity, inflammation, angiogenesis, and tissue remodeling. Besides, PTX3 may play dual (pro-tumor and anti-tumor) roles in oncogenesis. PTX3 is involved in the occurrence and development of many non-cancerous diseases, including COVID-19, and might be a potential biomarker indicating the prognosis, activity,and severity of diseases. In this review, we summarize and discuss the potential roles of PTX3 in the oncogenesis and pathogenesis of non-cancerous diseases and potential targeted therapies based on PTX3.
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Affiliation(s)
- Hao Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, China; Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, China
| | - Ruixuan Wang
- Department of Oncology, Xiangya Hospital, Central South University, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, China
| | - Zeyu Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, China
| | - Wantao Wu
- Department of Oncology, Xiangya Hospital, Central South University, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, China
| | - Nan Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, China; One-third Lab, College of Bioinformatics Science and Technology, Harbin Medical University, China
| | - Longbo Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, China; Department of Neurosurgery, and Department of Cellular & Molecular Physiology,Yale University School of Medicine, USA; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, China
| | - Jason Hu
- Department of Neonatology, Yale University School of Medicine, USA
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, China
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, China
| | - Songshan Feng
- Department of Neurosurgery, Xiangya Hospital, Central South University, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, China
| | - Yun Peng
- Department of Geriatrics, Xiangya Hospital, Central South University, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, China
| | - Zhengzheng Liu
- Department of Oncology, Xiangya Hospital, Central South University, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, China.
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, China.
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12
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Yu Z, Yang H, Song K, Fu P, Shen J, Xu M, Xu H. Construction of an immune-related gene signature for the prognosis and diagnosis of glioblastoma multiforme. Front Oncol 2022; 12:938679. [PMID: 35982954 PMCID: PMC9379258 DOI: 10.3389/fonc.2022.938679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 07/04/2022] [Indexed: 12/30/2022] Open
Abstract
Background Increasing evidence has suggested that inflammation is related to tumorigenesis and tumor progression. However, the roles of immune-related genes in the occurrence, development, and prognosis of glioblastoma multiforme (GBM) remain to be studied. Methods The GBM-related RNA sequencing (RNA-seq), survival, and clinical data were acquired from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases. Immune-related genes were obtained from the Molecular Signatures Database (MSigDB). Differently expressed immune-related genes (DE-IRGs) between GBM and normal samples were identified. Prognostic genes associated with GBM were selected by Kaplan-Meier survival analysis, Least Absolute Shrinkage and Selection Operator (LASSO)-penalized Cox regression analysis, and multivariate Cox analysis. An immune-related gene signature was developed and validated in TCGA and CGGA databases separately. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore biological functions of the signature. The correlation between immune cell infiltration and the signature was analyzed by single-sample gene set enrichment analysis (ssGSEA), and the diagnostic value was investigated. The gene set enrichment analysis (GSEA) was performed to explore the potential function of the signature genes in GBM, and the protein-protein interaction (PPI) network was constructed. Results Three DE-IRGs [Pentraxin 3 (PTX3), TNFSF9, and bone morphogenetic protein 2 (BMP2)] were used to construct an immune-related gene signature. Receiver operating characteristic (ROC) curves and Cox analyses confirmed that the 3-gene-based prognostic signature was a good independent prognostic factor for GBM patients. We found that the signature was mainly involved in immune-related biological processes and pathways, and multiple immune cells were disordered between the high- and low-risk groups. GSEA suggested that PTX3 and TNFSF9 were mainly correlated with interleukin (IL)-17 signaling pathway, nuclear factor kappa B (NF-κB) signaling pathway, tumor necrosis factor (TNF) signaling pathway, and Toll-like receptor signaling pathway, and the PPI network indicated that they could interact directly or indirectly with inflammatory pathway proteins. Quantitative real-time PCR (qRT-PCR) indicated that the three genes were significantly different between target tissues. Conclusion The signature with three immune-related genes might be an independent prognostic factor for GBM patients and could be associated with the immune cell infiltration of GBM patients.
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Affiliation(s)
- Ziye Yu
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Center for Neurological Disorders Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Huan Yang
- Department of Nursing, Huashan Hospital, Fudan University, Shanghai, China
| | - Kun Song
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Center for Neurological Disorders Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Pengfei Fu
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Center for Neurological Disorders Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jingjing Shen
- Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, China
| | - Ming Xu
- Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, China
| | - Hongzhi Xu
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Center for Neurological Disorders Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Clinical Medical Center of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
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13
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Kamal MA, Siddiqui I, Belgiovine C, Barbagallo M, Paleari V, Pistillo D, Chiabrando C, Schiarea S, Bottazzi B, Leone R, Avigni R, Migliore R, Spaggiari P, Gavazzi F, Capretti G, Marchesi F, Mantovani A, Zerbi A, Allavena P. Oncogenic KRAS-Induced Protein Signature in the Tumor Secretome Identifies Laminin-C2 and Pentraxin-3 as Useful Biomarkers for the Early Diagnosis of Pancreatic Cancer. Cancers (Basel) 2022; 14:2653. [PMID: 35681634 PMCID: PMC9179463 DOI: 10.3390/cancers14112653] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
KRAS mutations characterize pancreatic cell transformation from the earliest stages of carcinogenesis, and are present in >95% of pancreatic ductal adenocarcinoma (PDAC) cases. In search of novel biomarkers for the early diagnosis of PDAC, we identified the proteins secreted by the normal human pancreatic cell line (HPDE) recently transformed by inducing the overexpression of the KRASG12V oncogene. We report a proteomic signature of KRAS-induced secreted proteins, which was confirmed in surgical tumor samples from resected PDAC patients. The putative diagnostic performance of three candidates, Laminin-C2 (LAMC2), Tenascin-C (TNC) and Pentraxin-3 (PTX3), was investigated by ELISA quantification in two cohorts of PDAC patients (n = 200) eligible for surgery. Circulating levels of LAMC2, TNC and PTX3 were significantly higher in PDAC patients compared to the healthy individuals (p < 0.0001). The Receiver Operating Characteristics (ROC) curve showed good sensitivity (1) and specificity (0.63 and 0.85) for LAMC2 and PTX3, respectively, but not for TNC, and patients with high levels of LAMC2 had significantly shorter overall survival (p = 0.0007). High levels of LAMC2 and PTX3 were detected at early stages (I−IIB) and in CA19-9-low PDAC patients. In conclusion, pancreatic tumors release LAMC2 and PTX3, which can be quantified in the systemic circulation, and may be useful in selecting patients for further diagnostic imaging.
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Affiliation(s)
- Mohammad Azhar Kamal
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Imran Siddiqui
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Cristina Belgiovine
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Marialuisa Barbagallo
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Valentina Paleari
- Biobank, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (V.P.); (D.P.)
| | - Daniela Pistillo
- Biobank, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (V.P.); (D.P.)
| | - Chiara Chiabrando
- Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri-IRCCS, 20156 Milan, Italy; (C.C.); (S.S.)
| | - Silvia Schiarea
- Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri-IRCCS, 20156 Milan, Italy; (C.C.); (S.S.)
| | - Barbara Bottazzi
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Roberto Leone
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Roberta Avigni
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Roberta Migliore
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
| | - Paola Spaggiari
- Department of Pathology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy;
| | - Francesca Gavazzi
- Pancreatic Surgery Unit, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (F.G.); (G.C.); (A.Z.)
| | - Giovanni Capretti
- Pancreatic Surgery Unit, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (F.G.); (G.C.); (A.Z.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy
| | - Federica Marchesi
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20129 Milan, Italy
| | - Alberto Mantovani
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy
- The William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Alessandro Zerbi
- Pancreatic Surgery Unit, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (F.G.); (G.C.); (A.Z.)
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy
| | - Paola Allavena
- Department of Immunology, Humanitas Clinical and Research Center-IRCCS, 20089 Rozzano, Italy; (M.A.K.); (I.S.); (C.B.); (M.B.); (B.B.); (R.L.); (R.A.); (R.M.); (F.M.); (A.M.)
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Fan Z, Zheng Y, Li X, Deng X, Ba Y, Feng K, Su J, Wang H, Suo Z, Li L. Promoting role of pentraxin-3 in esophageal squamous cell carcinoma. Mol Ther Oncolytics 2022; 24:772-787. [PMID: 35317523 PMCID: PMC8908267 DOI: 10.1016/j.omto.2022.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 02/03/2022] [Indexed: 12/24/2022] Open
Abstract
Pentraxin 3 (PTX3) is an inflammatory molecule that is closely related to the proliferation, invasion, and metastasis of cancer. In order to explore the role of PTX3 in the occurrence and development of esophageal carcinoma (ESCA), we modified the PTX3 gene in ESCA cell lines to obtain the model of gene knockout and overexpression and studied cell proliferation, cycle, apoptosis, migration ability, energy metabolism, and sensitivity to chemotherapy and radiotherapy. We observed the increase in cell proliferation, cycle, apoptosis, migration ability, and sensitivity to chemotherapy and radiotherapy in the PTX3 knockout model, while in the PTX3 overexpression model, these phenomena were significantly reduced. Knockout of the PTX3 also resulted in decreased cell glycolysis and increased oxidative phosphorylation, which is consistent with other findings that PTX3 affects the tumorigenic ability of cells and their sensitivity to docetaxel. In ESCA, SOX9 directly regulates the expression of PTX3, while human leukocyte antigen (HLA)-system-related genes are significantly up-regulated when lacking PTX3. These results indicate that SOX9 may play a crucial role in regulating PTX3 and affecting the HLA system in ESCA.
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Affiliation(s)
- Zhirui Fan
- Department of Chinese and Western Integrative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Yuanyuan Zheng
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.,Internet Medical and System Applications of National Engineering Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Xiaoli Li
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Xiaoming Deng
- Department of Chinese and Western Integrative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Yan Ba
- Department of Chinese and Western Integrative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Kun Feng
- Department of Chinese and Western Integrative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Jin Su
- Department of Chinese and Western Integrative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Hui Wang
- Department of Chinese and Western Integrative Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Zhenhe Suo
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.,Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, 999026 Montebello, Oslo, Norway
| | - Lifeng Li
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.,Internet Medical and System Applications of National Engineering Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
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15
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Identification of Novel Biomarkers for Predicting Prognosis and Immunotherapy Response in Head and Neck Squamous Cell Carcinoma Based on ceRNA Network and Immune Infiltration Analysis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:4532438. [PMID: 34917682 PMCID: PMC8670464 DOI: 10.1155/2021/4532438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/23/2021] [Accepted: 11/19/2021] [Indexed: 12/14/2022]
Abstract
Objectives Patients with head and neck squamous cell carcinoma (HNSCC) have poor prognosis and show poor responses to immune checkpoint (IC) inhibitor (ICI) therapy. Competing endogenous RNA (ceRNA) networks, tumor-infiltrating immune cells (TIICs), and ICIs may influence tumor prognosis and response rates to ICI therapy. This study is aimed at identifying prognostic and IC-related biomarkers and key TIIC signatures to improve prognosis and ICI therapy response in HNSCC patients. Methods and Results Ninety-five long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and 1746 mRNAs were identified using three independent methods. We constructed a ceRNA network and estimated the proportions of 22 immune cell subtypes. Ten ceRNAs were related to prognosis according to Kaplan–Meier analysis. Two risk signatures based, respectively, on nine ceRNAs (ANLN, CFL2, ITGA5, KDELC1, KIF23, NFIA, PTX3, RELT, and TMC7) and three immune cell types (naïve B cells, neutrophils, and regulatory T cells) via univariate Cox regression, least absolute shrinkage and selection operator, and multivariate Cox regression analyses could accurately and independently predict the prognosis of HNSCC patients. Key mRNAs in the ceRNA network were significantly correlated with naïve B cells and regulatory T cells and with stage, grade, and immune and molecular subtype. Eight IC genes exhibited higher expression in tumor tissues and were correlated with eight key mRNAs in the ceRNA network in HNSCC patients with different HPV statuses according to coexpression and TIMER 2.0 analyses. Most drugs were effective in association with expression of these key signatures (ANLN, CFL2, ITGA5, KIF23, NFIA, PTX3, RELT, and TMC7) based on GSCALite analysis. The prognostic value of key biomarkers and associations between key ceRNAs and IC genes were validated using online databases. Eight key ceRNAs were confirmed to predict response to ICI in other cancers based on TIDE analysis. Conclusions We constructed two risk signatures to accurately predict prognosis in HNSCC. Key IC-related signatures may be associated with response to ICI therapy. Combinations of ICIs with inhibitors of eight key mRNAs may improve survival outcomes of HNSCC patients.
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Wesley UV, Sutton I, Clark PA, Cunningham K, Larrain C, Kuo JS, Dempsey RJ. Enhanced expression of pentraxin-3 in glioblastoma cells correlates with increased invasion and IL8-VEGF signaling axis. Brain Res 2021; 1776:147752. [PMID: 34906547 DOI: 10.1016/j.brainres.2021.147752] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 11/13/2021] [Accepted: 12/07/2021] [Indexed: 02/07/2023]
Abstract
Glioblastoma (GB) is highly invasive and resistant to multimodal treatment partly due to distorted vasculature and exacerbated inflammation. The aggressiveness of brain tumors may be attributed to the dysregulated release of angiogenic and inflammatory factors. The glycoprotein pentraxin-3 (PTX3) is correlated with the severity of some cancers. However, the mechanism responsible for the invasive oncogenic role of PTX3 in GB malignancy remains unclear. In this study, we examined the role of PTX3 in GB growth, angiogenesis, and invasion using in vitro and in vivo GB models, proteomic profiling, molecular and biochemical approaches. Under in vitro conditions, PTX3 over-expression in U87 cells correlated with cell cycle progression, increased migratory potential, and proliferation under hypoxic conditions. Conditioned media containing PTX3 enhanced the angiogenic potential of endothelial cells. While silencing of PTX3 by siRNA decreased the proliferation, migration, and angiogenic potential of U87 cells in vitro. Importantly, PTX3 over-expression increased tumor growth, angiogenesis, and invasion in an orthotopic mouse model. Higher levels of PTX3 in these tumors were associated with the upregulation of inflammatory and angiogenic markers including interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), but decreased levels of thrombospondin-1, an anti-angiogenic factor. Mechanistically, exogenous production of PTX3 triggered an IKK/NFκB signaling pathway that enhances the expression of the motility genes AHGEF7 and Rac1. Taken together, PTX3 expression is dysregulated in GB. PTX3 may augment invasion through enhanced angiogenesis in the GB microenvironment through the IL8-VEGF axis. Thus, PTX3 may represent a potential therapeutic target to mitigate the aggressive behavior of gliomas.
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Affiliation(s)
- Umadevi V Wesley
- Department of Neurosurgery, University of Wisconsin, Madison, WI 53792, United States.
| | - Ian Sutton
- Department of Neurosurgery, University of Wisconsin, Madison, WI 53792, United States
| | - Paul A Clark
- Department of Neurosurgery, University of Wisconsin, Madison, WI 53792, United States; Department of Human Oncology, University of Wisconsin, Madison, WI 53792, United States
| | - Katelin Cunningham
- Department of Neurosurgery, University of Wisconsin, Madison, WI 53792, United States
| | - Carolina Larrain
- Department of Neurosurgery, University of Wisconsin, Madison, WI 53792, United States
| | - John S Kuo
- Department of Neurosurgery, University of Wisconsin, Madison, WI 53792, United States; Department of Neurosurgery, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, United States; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, TAIWAN
| | - Robert J Dempsey
- Department of Neurosurgery, University of Wisconsin, Madison, WI 53792, United States.
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17
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Han Q, Deng H, Fan X, Wang X, Zhang X, Zhang K, Li N, Lv Y, Liu Z. Increased Serum Pentraxin 3 Levels are Associated with Poor Prognosis of Hepatitis B Virus-Related Hepatocellular Carcinoma. J Hepatocell Carcinoma 2021; 8:1367-1373. [PMID: 34805015 PMCID: PMC8598127 DOI: 10.2147/jhc.s337936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/28/2021] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a major cause of liver-related mortality. Serum pentraxin 3 (PTX3) has been revealed to be associated with the development of hepatitis B virus (HBV)-related HCC. This study evaluated whether serum PTX3 is related to the survival of HBV-related HCC patients. METHODS One hundred and seven patients with HBV-related HCC were included. Baseline serum PTX3 levels were quantified using quantitative immunoassay. The HCC patients were followed-up for a median of 24 months and divided into high serum PTX3 level and low PTX3 level groups according to the baseline serum PTX3 levels. The overall survivals of the HBV-related HCC patients according to the serum PTX3 levels were compared. Factors potentially influencing the prognosis of the patients with HBV-related HCC were analyzed. RESULTS HCC patients with high serum PTX3 levels [PTX3 > 9.25ng/mL (n=85)] had a shorter overall survival time than HCC patients with low serum PTX3 levels [PTX3 ≤ 9.25ng/mL (n=22)] (P = 0.049). HCC patients with serum PTX3 levels between >9.25ng/mL and ≤9.25ng/mL had significant difference in HCC histology grade. Multivariate analysis showed that PTX3 level was an independent risk factor related to the overall survival of HCC patients (hazard ratio: 1.058, 95% confidence interval: 1.031-1.085, P <0.001). CONCLUSION These results support the involvement of PTX3 in the disease progression of HCC and suggest the potential of using serum PTX3 levels as a biomarker for the prognostic prediction of HBV-related HCC patients.
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Affiliation(s)
- Qunying Han
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Huan Deng
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Xiude Fan
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Xiaoyun Wang
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Xiaoge Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Kun Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Na Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
- Institute of Advanced Surgical Technology and Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Zhengwen Liu
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
- Institute of Advanced Surgical Technology and Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
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18
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Carreras J, Kikuti YY, Hiraiwa S, Miyaoka M, Tomita S, Ikoma H, Ito A, Kondo Y, Itoh J, Roncador G, Martinez A, Colomo L, Hamoudi R, Ando K, Nakamura N. High PTX3 expression is associated with a poor prognosis in diffuse large B-cell lymphoma. Cancer Sci 2021; 113:334-348. [PMID: 34706126 PMCID: PMC8748251 DOI: 10.1111/cas.15179] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 10/19/2021] [Accepted: 10/20/2021] [Indexed: 12/02/2022] Open
Abstract
Tumor‐associated macrophages (TAMs) are associated with a poor prognosis of diffuse large B‐cell lymphoma (DLBCL). As macrophages are heterogeneous, the immune polarization and their pathological role warrant further study. We characterized the microenvironment of DLBCL by immunohistochemistry in a training set of 132 cases, which included 10 Epstein–Barr virus‐encoded small RNA (EBER)‐positive and five high‐grade B‐cell lymphomas, with gene expression profiling in a representative subset of 37 cases. Diffuse large B‐cell lymphoma had a differential infiltration of TAMs. The high infiltration of CD68 (pan‐macrophages), CD16 (M1‐like), CD163, pentraxin 3 (PTX3), and interleukin (IL)‐10‐positive macrophages (M2c‐like) and low infiltration of FOXP3‐positive regulatory T lymphocytes (Tregs) correlated with poor survival. Activated B cell‐like DLBCL was associated with high CD16, CD163, PTX3, and IL‐10, and EBER‐positive DLBCL with high CD163 and PTX3. Programmed cell death‐ligand 1 positively correlated with CD16, CD163, IL‐10, and RGS1. In a multivariate analysis of overall survival, PTX3 and International Prognostic Index were identified as the most relevant variables. The gene expression analysis showed upregulation of genes involved in innate and adaptive immune responses and macrophage and Toll‐like receptor pathways in high PTX3 cases. The prognostic relevance of PTX3 was confirmed in a validation set of 159 cases. Finally, in a series from Europe and North America (GSE10846, R‐CHOP‐like treatment, n = 233) high gene expression of PTX3 correlated with poor survival, and moderately with CSF1R, CD16, MITF, CD163, MYC, and RGS1. Therefore, the high infiltration of M2c‐like immune regulatory macrophages and low infiltration of FOXP3‐positive Tregs is associated with a poor prognosis in DLBCL, for which PTX3 is a new prognostic biomarker.
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Affiliation(s)
- Joaquim Carreras
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Yara Yukie Kikuti
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Shinichiro Hiraiwa
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Masashi Miyaoka
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Sakura Tomita
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Haruka Ikoma
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Atsushi Ito
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Yusuke Kondo
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Johbu Itoh
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
| | - Giovanna Roncador
- Monoclonal Antibodies Core Unit, Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain
| | - Antonio Martinez
- Department of Pathology, Hospital Clinic Barcelona, University of Barcelona, Institut d'investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Lluis Colomo
- Department of Pathology, Hospital del Mar, Institute Hospital del Mar d'Investigacions Mediques (IMIM), Barcelona, Spain
| | - Rifat Hamoudi
- Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.,Division of Surgery and Interventional Science, University College London, London, United Kingdom
| | - Kiyoshi Ando
- Department of Hematology and Oncology, Tokai University, School of Medicine, Isehara, Japan
| | - Naoya Nakamura
- Department of Pathology, Tokai University, School of Medicine, Isehara, Japan
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19
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Visconti VV, Greggi C, Fittipaldi S, Casamassima D, Tallarico M, Romano F, Botta A, Tarantino U. The long pentraxin PTX3: a novel serum marker to improve the prediction of osteoporosis and osteoarthritis bone-related phenotypes. J Orthop Surg Res 2021; 16:288. [PMID: 33931080 PMCID: PMC8086331 DOI: 10.1186/s13018-021-02440-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 04/20/2021] [Indexed: 12/13/2022] Open
Abstract
Background The long pentraxin PTX3 is generating great interest given the recent discovery of its involvement in bone metabolism. This study investigates the role of circulating PTX3 as a marker of bone-related phenotypes in patients with osteoporosis (OP) and osteoarthritis (OA). Methods Serum PTX3 levels were determined using an enzyme-linked immunosorbent assay (ELISA) in a total of OP (n=32), OA (n=19) patients and healthy controls (CTR; n=25). ROC curve analysis was carried out to evaluate the potential of PTX3 for the diagnosis of bone-related phenotypes. In addition, the association between PTX3 serum levels and biochemical markers was estimated by Spearman correlation analysis. Results Serum analysis reveals a statistically significant increase of PTX3 levels in OP and OA patients, compared to CTR subjects (**** p < 0.0001, **** p < 0.0001). ROC curve of PTX3 levels exhibits an excellent sensitivity and specificity for OP and OA diseases (**** p < 0.0001 and **** p < 0.0001, respectively). Moreover, serum PTX3 levels are positively associated with ALP (r = − 0.5257, p = 0.0083) and PTH levels (r = 0.4704, p = 0.0203) in OP patients. Conclusions These results confirm the pivotal role of PTX3 in bone metabolism and suggest its potential use as a predictor of OP and OA bone-related phenotypes. Supplementary Information The online version contains supplementary material available at 10.1186/s13018-021-02440-3.
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Affiliation(s)
- Virginia Veronica Visconti
- Department of Biomedicine and Prevention, Medical Genetics Section, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.,Department of Orthopaedics and Traumatology, "Policlinico Tor Vergata" Foundation, Viale Oxford 81, 00133, Rome, Italy
| | - Chiara Greggi
- Department of Biomedicine and Prevention, Medical Genetics Section, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.,Department of Orthopaedics and Traumatology, "Policlinico Tor Vergata" Foundation, Viale Oxford 81, 00133, Rome, Italy
| | - Simona Fittipaldi
- Department of Biomedicine and Prevention, Medical Genetics Section, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy
| | - Donato Casamassima
- Department of Orthopaedics and Traumatology, "Policlinico Tor Vergata" Foundation, Viale Oxford 81, 00133, Rome, Italy
| | - Mariagrazia Tallarico
- Department of Orthopaedics and Traumatology, "Policlinico Tor Vergata" Foundation, Viale Oxford 81, 00133, Rome, Italy
| | - Francesco Romano
- Department of Orthopaedics and Traumatology, "Policlinico Tor Vergata" Foundation, Viale Oxford 81, 00133, Rome, Italy
| | - Annalisa Botta
- Department of Biomedicine and Prevention, Medical Genetics Section, University of Rome "Tor Vergata", Via Montpellier 1, 00133, Rome, Italy.
| | - Umberto Tarantino
- Department of Orthopaedics and Traumatology, "Policlinico Tor Vergata" Foundation, Viale Oxford 81, 00133, Rome, Italy.,Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, Rome, 00133, Italy
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20
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The complexity of tumour angiogenesis based on recently described molecules. Contemp Oncol (Pozn) 2021; 25:33-44. [PMID: 33911980 PMCID: PMC8063899 DOI: 10.5114/wo.2021.105075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 11/23/2020] [Indexed: 12/13/2022] Open
Abstract
Tumour angiogenesis is a crucial factor associated with tumour growth, progression, and metastasis. The whole process is the result of an interaction between a wide range of different molecules, influencing each other. Herein we summarize novel discoveries related to the less known angiogenic molecules such as galectins, pentraxin-3, Ral-interacting protein of 76 kDa (RLIP76), long non-coding RNAs (lncRNAs), B7-H3, and delta-like ligand-4 (DLL-4) and their role in the process of tumour angiogenesis. These molecules influence the most important molecular pathways involved in the formation of blood vessels in cancer, including the vascular endothelial growth factor (VEGF)-vascular endothelial growth factor receptor interaction (VEGFR), HIF1-a activation, or PI3K/Akt/mTOR and JAK-STAT signalling pathways. Increased expression of galectins, RLIP76, and B7H3 has been proven in several malignancies. Pentraxin-3, which appears to inhibit tumour angiogenesis, shows reduced expression in tumour tissues. Anti-angiogenic treatment based mainly on VEGF inhibition has proved to be of limited effectiveness, leading to the development of drug resistance. The newly discovered molecules are of great interest as a potential source of new anti-cancer therapies. Their role as targets for new drugs and as prognostic markers in neoplasms is discussed in this review.
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21
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Chang X, Li D, Liu C, Zhang Z, Wang T. Pentraxin 3 is a diagnostic and prognostic marker for ovarian epithelial cancer patients based on comprehensive bioinformatics and experiments. Cancer Cell Int 2021; 21:193. [PMID: 33952272 PMCID: PMC8097951 DOI: 10.1186/s12935-021-01854-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/20/2021] [Accepted: 02/24/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Ovarian epithelial cancer is one of the leading malignant tumors in gynecology and lacks effective diagnostic and prognostic markers. Our study aims to screen and verify ovarian epithelial cancer biomarkers. METHODS GSE18520 and GSE26712 were downloaded from the GEO database. The "limma" and "WGCNA" packages were used to explore hub genes. The Kaplan-Meier Plotter database was used for survival analysis of the hub genes. Immunohistochemical analysis was used to identify the expression level of Pentraxin 3 in ovarian epithelial cancer samples. RESULTS In this study, we integrated and analyzed two datasets, GSE18520 and GSE26712, and a total of 238 differentially expressed genes (DEGs) were screened out. Enrichment analysis showed that these DEGs were related to collagen-containing extracellular matrix and other pathways. Further application of WGCNA (weighted gene coexpression network analysis) identified 15 gene modules, with the purple module showing the highest correlation with ovarian epithelial cancer. Twenty-five genes were shared between the purple module and DEGs, 13 genes were related to the prognosis of ovarian epithelial cancer patients, and the PTX3 gene had the highest hazardous risk (HR) value. We performed immunohistochemical analyses on the 255 Pentraxin-3 (PTX3)-based clinical samples. PTX3 was found to be overexpressed in ovarian epithelial cancer and related to the degree of differentiation. The Cox proportional hazard model indicates that high PTX3 expression is an independent risk factor for the prognosis of ovarian epithelial cancer patients. CONCLUSIONS In conclusion, through WGCNA and a series of comprehensive bioinformatics analyses, PTX3 was first identified as a novel diagnostic and prognostic biomarker for ovarian epithelial cancer.
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Affiliation(s)
- Xiaoying Chang
- Department of Pathology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping, Shenyang, 110004, China
| | - Dan Li
- Department of Pathology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping, Shenyang, 110004, China
| | - Chang Liu
- Department of Pathology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping, Shenyang, 110004, China
| | - Zhe Zhang
- Department of Pathology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping, Shenyang, 110004, China
| | - Tao Wang
- Department of Pathology, Shenyang KingMed Center for Clinical Laboratory Co., Ltd, Shenyang, 110164, China.
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22
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Wen Y, Cai W, Yang J, Fu X, Putha L, Xia Q, Windsor JA, Phillips AR, Tyndall JDA, Du D, Liu T, Huang W. Targeting Macrophage Migration Inhibitory Factor in Acute Pancreatitis and Pancreatic Cancer. Front Pharmacol 2021; 12:638950. [PMID: 33776775 PMCID: PMC7992011 DOI: 10.3389/fphar.2021.638950] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 01/29/2021] [Indexed: 02/05/2023] Open
Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in the pathogenesis of inflammation and cancer. It is produced by various cells and circulating MIF has been identified as a biomarker for a range of diseases. Extracellular MIF mainly binds to the cluster of differentiation 74 (CD74)/CD44 to activate downstream signaling pathways. These in turn activate immune responses, enhance inflammation and can promote cancer cell proliferation and invasion. Extracellular MIF also binds to the C-X-C chemokine receptors cooperating with or without CD74 to activate chemokine response. Intracellular MIF is involved in Toll-like receptor and inflammasome-mediated inflammatory response. Pharmacological inhibition of MIF has been shown to hold great promise in treating inflammatory diseases and cancer, including small molecule MIF inhibitors targeting the tautomerase active site of MIF and antibodies that neutralize MIF. In the current review, we discuss the role of MIF signaling pathways in inflammation and cancer and summarize the recent advances of the role of MIF in experimental and clinical exocrine pancreatic diseases. We expect to provide insights into clinical translation of MIF antagonism as a strategy for treating acute pancreatitis and pancreatic cancer.
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Affiliation(s)
- Yongjian Wen
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China.,Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.,Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | - Wenhao Cai
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China.,Liverpool Pancreatitis Research Group, Liverpool University Hospitals NHS Foundation Trust and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Jingyu Yang
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China
| | - Xianghui Fu
- Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
| | - Lohitha Putha
- School of Pharmacy, University of Otago, Dunedin, New Zealand
| | - Qing Xia
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China
| | - John A Windsor
- Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Anthony R Phillips
- Surgical and Translational Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.,Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | | | - Dan Du
- West China-Washington Mitochondria and Metabolism Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tingting Liu
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China
| | - Wei Huang
- Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital of Sichuan University, Chengdu, China.,Liverpool Pancreatitis Research Group, Liverpool University Hospitals NHS Foundation Trust and Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
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23
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Peran I, Dakshanamurthy S, McCoy MD, Mavropoulos A, Allo B, Sebastian A, Hum NR, Sprague SC, Martin KA, Pishvaian MJ, Vietsch EE, Wellstein A, Atkins MB, Weiner LM, Quong AA, Loots GG, Yoo SS, Assefnia S, Byers SW. Cadherin 11 Promotes Immunosuppression and Extracellular Matrix Deposition to Support Growth of Pancreatic Tumors and Resistance to Gemcitabine in Mice. Gastroenterology 2021; 160:1359-1372.e13. [PMID: 33307028 PMCID: PMC7956114 DOI: 10.1053/j.gastro.2020.11.044] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 11/12/2020] [Accepted: 11/21/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Pancreatic ductal adenocarcinomas (PDACs) are characterized by fibrosis and an abundance of cancer-associated fibroblasts (CAFs). We investigated strategies to disrupt interactions among CAFs, the immune system, and cancer cells, focusing on adhesion molecule CDH11, which has been associated with other fibrotic disorders and is expressed by activated fibroblasts. METHODS We compared levels of CDH11 messenger RNA in human pancreatitis and pancreatic cancer tissues and cells with normal pancreas, and measured levels of CDH11 protein in human and mouse pancreatic lesions and normal tissues. We crossed p48-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+ (KPC) mice with CDH11-knockout mice and measured survival times of offspring. Pancreata were collected and analyzed by histology, immunohistochemistry, and (single-cell) RNA sequencing; RNA and proteins were identified by imaging mass cytometry. Some mice were given injections of PD1 antibody or gemcitabine and survival was monitored. Pancreatic cancer cells from KPC mice were subcutaneously injected into Cdh11+/+ and Cdh11-/- mice and tumor growth was monitored. Pancreatic cancer cells (mT3) from KPC mice (C57BL/6), were subcutaneously injected into Cdh11+/+ (C57BL/6J) mice and mice were given injections of antibody against CDH11, gemcitabine, or small molecule inhibitor of CDH11 (SD133) and tumor growth was monitored. RESULTS Levels of CDH11 messenger RNA and protein were significantly higher in CAFs than in pancreatic cancer epithelial cells, human or mouse pancreatic cancer cell lines, or immune cells. KPC/Cdh11+/- and KPC/Cdh11-/- mice survived significantly longer than KPC/Cdh11+/+ mice. Markers of stromal activation entirely surrounded pancreatic intraepithelial neoplasias in KPC/Cdh11+/+ mice and incompletely in KPC/Cdh11+/- and KPC/Cdh11-/- mice, whose lesions also contained fewer FOXP3+ cells in the tumor center. Compared with pancreatic tumors in KPC/Cdh11+/+ mice, tumors of KPC/Cdh11+/- mice had increased markers of antigen processing and presentation; more lymphocytes and associated cytokines; decreased extracellular matrix components; and reductions in markers and cytokines associated with immunosuppression. Administration of the PD1 antibody did not prolong survival of KPC mice with 0, 1, or 2 alleles of Cdh11. Gemcitabine extended survival of KPC/Cdh11+/- and KPC/Cdh11-/- mice only or reduced subcutaneous tumor growth in mT3 engrafted Cdh11+/+ mice when given in combination with the CDH11 antibody. A small molecule inhibitor of CDH11 reduced growth of pre-established mT3 subcutaneous tumors only if T and B cells were present in mice. CONCLUSIONS Knockout or inhibition of CDH11, which is expressed by CAFs in the pancreatic tumor stroma, reduces growth of pancreatic tumors, increases their response to gemcitabine, and significantly extends survival of mice. CDH11 promotes immunosuppression and extracellular matrix deposition, and might be developed as a therapeutic target for pancreatic cancer.
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Affiliation(s)
- Ivana Peran
- Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia.
| | - Sivanesan Dakshanamurthy
- Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Matthew D. McCoy
- Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA,Innovation Center for Biomedical Informatics, Georgetown University, Washington, DC, USA
| | | | | | - Aimy Sebastian
- Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA, USA
| | - Nicholas R. Hum
- Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA, USA,School of Natural Sciences, University of California Merced, Merced, CA, USA
| | - Sara C. Sprague
- Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Kelly A. Martin
- Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA, USA
| | - Michael J. Pishvaian
- Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Eveline E. Vietsch
- Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Anton Wellstein
- Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Michael B. Atkins
- Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | - Louis M. Weiner
- Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
| | | | - Gabriela G. Loots
- Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA, USA,School of Natural Sciences, University of California Merced, Merced, CA, USA,Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, USA
| | | | - Shahin Assefnia
- Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, District of Columbia.
| | - Stephen W. Byers
- Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
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Sun YH, Chou YH, Wang CH, Hsiao YH, Lee CY, Yang SF, Wang PH. Impact of pentraxin 3 genetic variants on uterine cervical cancer clinicopathologic characteristics. Int J Med Sci 2021; 18:2339-2346. [PMID: 33967610 PMCID: PMC8100632 DOI: 10.7150/ijms.57886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 03/24/2021] [Indexed: 02/01/2023] Open
Abstract
The aims of this study were to investigate the relationships among pentraxin 3 (PTX3) genetic variants and development and clinicopathological characteristics of uterine cervical cancer, and patient survival in Taiwanese women. The study enrolled 125 patients with invasive cancer and 98 patients with precancerous lesions of uterine cervix, and 325 control women. PTX3 genetic variants rs2120243, rs3816527, rs2305619 and rs1840680 were selected and their genotypic distributions were determined by real-time polymerase chain reaction. Our results indicated that patients with genotype CC in PTX3 rs2120243 and genotype GG in rs1840680 had more chance to have adenocarcinoma but not squamous cell carcinoma, as compared to those with CA/AA and those with GA/AA, respectively. No other clinicopatholgical characteristics were associated with PTX3 genetic variants. In addition, PTX3 genetic variants were not associated with 5 years survival of cervical cancer patients. In conclusions, PTX3 genetic variants are not associated with carcinogenesis and clinicopathological variables of uterine cervix and patient survival in Taiwanese women. The only independent predictor for the 5 years survival is pelvic lymph node metastasis.
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Affiliation(s)
- Yi-Hung Sun
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Obstetrics and Gynecology, Chi-Mei Foundation Medical Center, Tainan, Taiwan
| | - Ying-Hsiang Chou
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Imaging and Radiological Sciences, Chung Shan Medical University, Taichung, Taiwan.,Department of Radiation Oncology, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chun-Hao Wang
- Department of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Hsuan Hsiao
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan
| | - Chung-Yuan Lee
- Department of Obstetrics and Gynecology, Chiayi Chang Gung Memorial Hospital Chiayi, Taiwan.,Department of Nursing, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Po-Hui Wang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan
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25
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Deng H, Fan X, Wang X, Zeng L, Zhang K, Zhang X, Li N, Han Q, Lv Y, Liu Z. Serum pentraxin 3 as a biomarker of hepatocellular carcinoma in chronic hepatitis B virus infection. Sci Rep 2020; 10:20276. [PMID: 33219288 PMCID: PMC7680106 DOI: 10.1038/s41598-020-77332-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 11/06/2020] [Indexed: 12/14/2022] Open
Abstract
Biomarkers for early diagnosis of hepatocellular carcinoma (HCC) are needed in chronic hepatitis B virus (HBV) infection, a leading cause of HCC. We evaluated whether measurement of serum pentraxin 3 (PTX3) could improve diagnosis of HCC in chronic HBV infection. Data from patients with HBV-related chronic hepatitis (n = 159), cirrhosis (n = 99) and HCC (n = 107), and healthy controls (n = 151) were analyzed. Serum PTX3 concentration was measured by immunoassay. Area under the receiver operating characteristic curve (AUC) was applied to assess diagnostic accuracy. PTX3 levels were significantly higher in HBV patients than in healthy controls (P < 0.001) and in HCC than in chronic hepatitis (P < 0.001) or cirrhosis patients (P < 0.001). PTX3 was an independent risk factor of HCC [odds ratio (OR) 1.617, P < 0.001] and could distinguish HCC in chronic HBV infection [cutoff 9.231 ng/mL, AUC 0.929 with 95% confidence interval (CI) of 0.898-0.953], including α-fetoprotein (AFP) negative [cutoff 8.985 ng/mL, AUC (95%CI) 0.947 (0.908-0.973)] and early-stage HCC [cutoff 9.359 ng/mL, AUC (95%CI) 0.920 (0.885-0.947)]. Combination of PTX3 with AFP improved the discrimination of early HCC from chronic HBV infection [AUC (95%CI) 0.948 (0.918-0.970)]. In short, PTX3 measurement could identify HCC, including AFP-negative and early-stage HCC, in chronic HBV infection.
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MESH Headings
- Adolescent
- Adult
- Aged
- Biomarkers, Tumor/blood
- Biopsy
- C-Reactive Protein/analysis
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Case-Control Studies
- DNA, Viral/isolation & purification
- Diagnosis, Differential
- Disease Progression
- Early Detection of Cancer/methods
- Female
- Hepatitis B virus/genetics
- Hepatitis B virus/isolation & purification
- Hepatitis B, Chronic/blood
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/pathology
- Hepatitis B, Chronic/virology
- Humans
- Liver/diagnostic imaging
- Liver/pathology
- Liver Cirrhosis/blood
- Liver Cirrhosis/diagnosis
- Liver Cirrhosis/pathology
- Liver Cirrhosis/virology
- Liver Neoplasms/blood
- Liver Neoplasms/diagnosis
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Male
- Middle Aged
- Neoplasm Staging
- Prognosis
- ROC Curve
- Risk Factors
- Serum Amyloid P-Component/analysis
- Young Adult
- alpha-Fetoproteins/analysis
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Affiliation(s)
- Huan Deng
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi Province, People's Republic of China
| | - Xiude Fan
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi Province, People's Republic of China
| | - Xiaoyun Wang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi Province, People's Republic of China
| | - Lu Zeng
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi Province, People's Republic of China
| | - Kun Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi Province, People's Republic of China
| | - Xiaoge Zhang
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi Province, People's Republic of China
| | - Na Li
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi Province, People's Republic of China
| | - Qunying Han
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi Province, People's Republic of China
| | - Yi Lv
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China
| | - Zhengwen Liu
- Department of Infectious Diseases, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an, 710061, Shaanxi Province, People's Republic of China.
- Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, People's Republic of China.
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26
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Netti GS, Lucarelli G, Spadaccino F, Castellano G, Gigante M, Divella C, Rocchetti MT, Rascio F, Mancini V, Stallone G, Carrieri G, Gesualdo L, Battaglia M, Ranieri E. PTX3 modulates the immunoflogosis in tumor microenvironment and is a prognostic factor for patients with clear cell renal cell carcinoma. Aging (Albany NY) 2020; 12:7585-7602. [PMID: 32345771 PMCID: PMC7202504 DOI: 10.18632/aging.103169] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 03/31/2020] [Indexed: 01/05/2023]
Abstract
Pentraxin-3 (PTX3) belongs to the pentraxine family, innate immune regulators involved in angiogenesis, proliferation and immune escape in cancer. Here, we evaluated PTX3 tissue expression and serum levels as biomarkers of clear cell renal cell carcinoma (ccRCC) and analyzed the possible role of complement system activation on tumor site. A 10-year retrospective cohort study including patients undergoing nephrectomy for ccRCC was also performed. PTX3 expression was elevated in both neoplastic renal cell lines and tissues, while it was absent in both normal renal proximal tubular cells (HK2) and normal renal tissues. Analysis of complement system activation on tumor tissues showed the co-expression of PTX3 with C1q, C3aR, C5R1 and CD59, but not with C5b-9 terminal complex. RCC patients showed higher serum PTX3 levels as compared to non-neoplastic patients (p<0.0001). Higher PTX3 serum levels were observed in patients with higher Fuhrman grade (p<0.01), lymph node (p<0.0001), and visceral metastases (p<0.001). Patients with higher PTX3 levels also showed significantly lower survival rates (p=0.002). Our results suggest that expression of PTX3 can affect the immunoflogosis in the ccRCC microenvironment, by activating the classical pathway of CS (C1q) and releasing pro-angiogenic factors (C3a, C5a). The up-regulation of CD59 also inhibits the complement-mediated cellular lysis.
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Affiliation(s)
- Giuseppe Stefano Netti
- Clinical Pathology Unit and Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 71122, Foggia, Italy
| | - Giuseppe Lucarelli
- Urology and Renal Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Federica Spadaccino
- Clinical Pathology Unit and Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 71122, Foggia, Italy
| | - Giuseppe Castellano
- Nephrology Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Margherita Gigante
- Clinical Pathology Unit and Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 71122, Foggia, Italy
| | - Chiara Divella
- Nephrology Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Maria Teresa Rocchetti
- Clinical Pathology Unit and Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 71122, Foggia, Italy
| | - Federica Rascio
- Nephrology Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 71122, Foggia, Italy
| | - Vito Mancini
- Urology and Renal Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 71122, Foggia, Italy
| | - Giovanni Stallone
- Nephrology Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 71122, Foggia, Italy
| | - Giuseppe Carrieri
- Urology and Renal Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 71122, Foggia, Italy
| | - Loreto Gesualdo
- Nephrology Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Michele Battaglia
- Urology and Renal Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Elena Ranieri
- Clinical Pathology Unit and Center of Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto 71122, Foggia, Italy
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27
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Takov K, He Z, Johnston HE, Timms JF, Guillot PV, Yellon DM, Davidson SM. Small extracellular vesicles secreted from human amniotic fluid mesenchymal stromal cells possess cardioprotective and promigratory potential. Basic Res Cardiol 2020; 115:26. [PMID: 32146560 PMCID: PMC7060967 DOI: 10.1007/s00395-020-0785-3] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 02/21/2020] [Indexed: 12/13/2022]
Abstract
Mesenchymal stromal cells (MSCs) exhibit antiapoptotic and proangiogenic functions in models of myocardial infarction which may be mediated by secreted small extracellular vesicles (sEVs). However, MSCs have frequently been harvested from aged or diseased patients, while the isolated sEVs often contain high levels of impurities. Here, we studied the cardioprotective and proangiogenic activities of size-exclusion chromatography-purified sEVs secreted from human foetal amniotic fluid stem cells (SS-hAFSCs), possessing superior functional potential to that of adult MSCs. We demonstrated for the first time that highly pure (up to 1.7 × 1010 particles/µg protein) and thoroughly characterised SS-hAFSC sEVs protect rat hearts from ischaemia-reperfusion injury in vivo when administered intravenously prior to reperfusion (38 ± 9% infarct size reduction, p < 0.05). SS-hAFSC sEVs did not protect isolated primary cardiomyocytes in models of simulated ischaemia-reperfusion injury in vitro, indicative of indirect cardioprotective effects. SS-hAFSC sEVs were not proangiogenic in vitro, although they markedly stimulated endothelial cell migration. Additionally, sEVs were entirely responsible for the promigratory effects of the medium conditioned by SS-hAFSC. Mechanistically, sEV-induced chemotaxis involved phosphatidylinositol 3-kinase (PI3K) signalling, as its pharmacological inhibition in treated endothelial cells reduced migration by 54 ± 7% (p < 0.001). Together, these data indicate that SS-hAFSC sEVs have multifactorial beneficial effects in a myocardial infarction setting.
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Affiliation(s)
- Kaloyan Takov
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Zhenhe He
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Harvey E Johnston
- EGA Institute for Women's Health, University College London, London, UK
| | - John F Timms
- EGA Institute for Women's Health, University College London, London, UK
| | - Pascale V Guillot
- EGA Institute for Women's Health, University College London, London, UK
| | - Derek M Yellon
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK
| | - Sean M Davidson
- The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.
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28
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Silencing of PTX3 alleviates LPS-induced inflammatory pain by regulating TLR4/NF-κB signaling pathway in mice. Biosci Rep 2020; 40:221905. [PMID: 31957804 PMCID: PMC7000368 DOI: 10.1042/bsr20194208] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/07/2020] [Accepted: 01/09/2020] [Indexed: 02/03/2023] Open
Abstract
Pentraxin 3 (PTX3), an inflammatory marker and a pattern recognition receptor, plays an important role in promoting the progress of tumor and inflammatory diseases. However, the role of PTX3 in the pathogenesis of inflammatory pain diseases is rarely reported. The purpose of the present study is to investigate the effect of PTX3 on the progression of inflammatory pain and the special molecular mechanism. A mouse BV2 microglia cell activation-mediated inflammatory model was developed with Lipopolysaccharide (LPS) induction, and a mouse inflammatory pain model was established with LPS injection. The effect of PTX3 on microglia inflammatory activation was verified by measuring pro-inflammatory cytokines expression. The mechanical hyperalgesia testing, the thermal preference testing and the cold allodynia testing were used to measure the response of mice to mechanical pain, heat stimulation and cold stimulation, respectively. The results revealed that the expression of PTX3 was decreased in the LPS-induced inflammatory pain mice model. Silencing of PTX3 down-regulated LPS-induced inflammatory factors, including IL-6, NO and TNF-α, and alleviated LPS-induced inflammatory pain in BV2 cells. In addition, overexpression of TLR4 reversed the inhibitory effect of si-PTX3 on LPS-induced inflammatory response in BV2 cells. What is more, silencing of PTX3 inhibited TLR4/NF-κB signaling pathway. Collectively, it suggests that silencing of PTX3 alleviates LPS-induced inflammatory response of BV2 cells potentially by regulating the TLR4/NF-κB signaling pathway.
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29
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Zubair H, Patel GK, Khan MA, Azim S, Zubair A, Singh S, Srivastava SK, Singh AP. Proteomic Analysis of MYB-Regulated Secretome Identifies Functional Pathways and Biomarkers: Potential Pathobiological and Clinical Implications. J Proteome Res 2020; 19:794-804. [PMID: 31928012 DOI: 10.1021/acs.jproteome.9b00641] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Earlier we have shown important roles of MYB in pancreatic tumor pathobiology. To better understand the role of MYB in the tumor microenvironment and identify MYB-associated secreted biomarker proteins, we conducted mass spectrometry analysis of the secretome from MYB-modulated and control pancreatic cancer cell lines. We also performed in silico analyses to determine MYB-associated biofunctions, gene networks, and altered biological pathways. Our data demonstrated significant modulation (p < 0.05) of 337 secreted proteins in MYB-silenced MiaPaCa cells, whereas 282 proteins were differentially present in MYB-overexpressing BxPC3 cells, compared to their respective control cells. Alteration of several phenotypes such as cellular movement, cell death and survival, inflammatory response, protein synthesis, etc. was associated with MYB-induced differentially expressed proteins (DEPs) in secretomes. DEPs from MYB-silenced MiaPaCa PC cells were suggestive of the downregulation of genes primarily associated with glucose metabolism, PI3K/AKT signaling, and oxidative stress response, among others. DEPs from MYB-overexpressing BxPC3 cells suggested the enhanced release of proteins associated with glucose metabolism and cellular motility. We also observed that MYB positively regulated the expression of four proteins with potential biomarker properties, i.e., FLNB, ENO1, ITGB1, and INHBA. Mining of publicly available databases using Oncomine and UALCAN demonstrated that these genes are overexpressed in pancreatic tumors and associated with reduced patient survival. Altogether, these data provide novel avenues for future investigations on diverse biological functions of MYB, specifically in the tumor microenvironment, and could also be exploited for biomarker development.
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Affiliation(s)
- Haseeb Zubair
- Department of Pathology, College of Medicine , University of South Alabama , Mobile , Alabama 36617 , United States.,Mitchell Cancer Institute , University of South Alabama , 1660 Springhill Avenue , Mobile , Alabama 36604 , United States
| | - Girijesh Kumar Patel
- Mitchell Cancer Institute , University of South Alabama , 1660 Springhill Avenue , Mobile , Alabama 36604 , United States
| | - Mohammad Aslam Khan
- Department of Pathology, College of Medicine , University of South Alabama , Mobile , Alabama 36617 , United States.,Mitchell Cancer Institute , University of South Alabama , 1660 Springhill Avenue , Mobile , Alabama 36604 , United States
| | - Shafquat Azim
- Mitchell Cancer Institute , University of South Alabama , 1660 Springhill Avenue , Mobile , Alabama 36604 , United States
| | - Asif Zubair
- Molecular and Computational Biology, School of Biological Sciences, Dornsife College of Letters, Arts and Sciences , University of Southern California , Los Angeles , California 90089 , United States
| | - Seema Singh
- Department of Pathology, College of Medicine , University of South Alabama , Mobile , Alabama 36617 , United States.,Mitchell Cancer Institute , University of South Alabama , 1660 Springhill Avenue , Mobile , Alabama 36604 , United States.,Department of Biochemistry and Molecular Biology, College of Medicine , University of South Alabama , Mobile , Alabama 36688 , United States
| | - Sanjeev Kumar Srivastava
- Department of Pathology, College of Medicine , University of South Alabama , Mobile , Alabama 36617 , United States.,Mitchell Cancer Institute , University of South Alabama , 1660 Springhill Avenue , Mobile , Alabama 36604 , United States
| | - Ajay Pratap Singh
- Department of Pathology, College of Medicine , University of South Alabama , Mobile , Alabama 36617 , United States.,Mitchell Cancer Institute , University of South Alabama , 1660 Springhill Avenue , Mobile , Alabama 36604 , United States.,Department of Biochemistry and Molecular Biology, College of Medicine , University of South Alabama , Mobile , Alabama 36688 , United States
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30
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Cui X, Zhang H, Cao A, Cao L, Hu X. Cytokine TNF-α promotes invasion and metastasis of gastric cancer by down-regulating Pentraxin3. J Cancer 2020; 11:1800-1807. [PMID: 32194791 PMCID: PMC7052870 DOI: 10.7150/jca.39562] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 12/20/2019] [Indexed: 01/04/2023] Open
Abstract
As a novel multifaceted player in cancer, Pentraxin3(PTX3) was recognized to be a possible factor related with tumor development. Recent researches have indicated that PTX3 is involved in immune response, inflammation, as well as cancer, and is greatly controlled by numerous cytokines. Tumor necrosis factor (TNF-α) is an imperative cytokine that demonstrates an extensive array of biological consequences in gastric cancer advancement. Here, we inspected the expression of PTX3 in gastric carcinoma tissues along with gastric cell lines and established that PTX3 was suggestively inferior in gastric cancer tissue and cells. The treatment of the gastric cell lines BGC-823 as well as SGC-7901 with rhTNF-α caused substantial decrease in the expression of PTX3. Furthermore, PTX3 controlled the capability of cell migration, invasion as well as epithelial-mesenchymal transition (EMT) in gastric cancer cell lines mediated by TNF-α. Additionally, PTX3 upregulation inhibited tumorigenicity in vivo and could be reversed by exogenous TNF-α. Conversely, overexpression of PTX3 inhibited progress both in vitro as well as in vivo in gastric cancer mediated by TNF-α. Further studies are necessary to demonstrate the mechanism of interaction between PTX3 and cytokines.
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Affiliation(s)
- Xinye Cui
- Department of General Surgery, The First Affiliated Hospital, Dalian Medical University, Dalian 116011,China
| | - Han Zhang
- Department of Pathology, Dalian Medical University, Dalian 116044, People's Republic of China
| | - An'na Cao
- Department of Pathology, Dalian Medical University, Dalian 116044, People's Republic of China
| | - Liang Cao
- Department of General Surgery, The First Affiliated Hospital, Dalian Medical University, Dalian 116011,China
| | - Xiang Hu
- Department of General Surgery, The First Affiliated Hospital, Dalian Medical University, Dalian 116011,China
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31
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Sanghera C, Teh JJ, Pinato DJ. The systemic inflammatory response as a source of biomarkers and therapeutic targets in hepatocellular carcinoma. Liver Int 2019; 39:2008-2023. [PMID: 31433891 DOI: 10.1111/liv.14220] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 08/10/2019] [Accepted: 08/13/2019] [Indexed: 12/12/2022]
Abstract
The pathogenesis of hepatocellular carcinoma (HCC) strongly relates to inflammation, with chronic up-regulation of pro-inflammatory mediators standing as a potential unifying mechanism that underscores the origin and progression of HCC independent of aetiology. Activation of the diverse pro-inflammatory mediators either within the tumour or its microenvironment is part of an active cross-talk between the progressive HCC and the host, which is known to influence clinical outcomes including recurrence after radical treatments and long-term survival. A number of clinical biomarkers to measure the severity of cancer-related inflammation are now available, most of which emerge from routine blood parameters including neutrophil, lymphocyte, platelet counts, as well as albuminaemia and C-reactive protein levels. In this review, we summarise the body of evidence supporting the biologic qualification of inflammation-based scores in HCC and review their potential in facilitating the prognostic assessment and treatment allocation in the individual patient. We also discuss the evidence to suggest modulation of tumour-promoting inflammation may act as a source of novel therapeutic strategies in liver cancer.
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Affiliation(s)
| | - Jhia J Teh
- Department of Medicine, Imperial College London, London, UK
| | - David J Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
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32
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Yeh CM, Lin CW, Chuang CY, Liu YF, Chou CH, Yang SF, Chen MK. Functional Genetic Variant of Long Pentraxin 3 Gene Is Associated With Clinical Aspects of Oral Cancer in Male Patients. Front Oncol 2019; 9:581. [PMID: 31334115 PMCID: PMC6616059 DOI: 10.3389/fonc.2019.00581] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 06/14/2019] [Indexed: 12/18/2022] Open
Abstract
Long pentraxin 3 (PTX3) is produced by various cell types and is correlated with tumor progression in various tumor types. However, the clinical significance of PTX3 polymorphisms in oral cancer and their correlation with the risk of cancer are still unclear. In this study, we assessed the influence of PTX3 gene polymorphisms and environmental factors on susceptibility to oral tumorigenesis. We recruited 865 cases with oral cancer and 1,189 controls. Four single-nucleotide variations of the PTX3 gene (rs1840680, rs2305619, rs3816527, and rs2120243) were verified using a real-time polymerase chain reaction in control participants and cases with oral cancer. We found that rs3816527 in smokers was correlated with the development of late-stage cancer (odds ratio [OR], 2.328; 95% confidence interval [CI], 1.078-5.027) and increased lymph node metastasis (OR, 2.152; 95% CI, 1.047-4.422). Moreover, additional bioinformatics analysis results showed that the rs3816527 C allele variant to the A allele exhibited the strongest exonic splicing enhancer activity. In conclusion, our results suggested that PTX3 rs3816527 plays a role in oral cancer development.
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Affiliation(s)
- Chia-Ming Yeh
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan.,Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Chiao-Wen Lin
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.,Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Chun-Yi Chuang
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Otolaryngology, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yu-Fan Liu
- Department of Biomedical Sciences, College of Medicine Sciences and Technology, Chung Shan Medical University, Taichung, Taiwan
| | - Chia-Hsuan Chou
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Mu-Kuan Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan.,Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital, Changhua, Taiwan
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33
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Rathore M, Girard C, Ohanna M, Tichet M, Ben Jouira R, Garcia E, Larbret F, Gesson M, Audebert S, Lacour JP, Montaudié H, Prod'Homme V, Tartare-Deckert S, Deckert M. Cancer cell-derived long pentraxin 3 (PTX3) promotes melanoma migration through a toll-like receptor 4 (TLR4)/NF-κB signaling pathway. Oncogene 2019; 38:5873-5889. [PMID: 31253871 DOI: 10.1038/s41388-019-0848-9] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 03/30/2019] [Accepted: 04/28/2019] [Indexed: 01/23/2023]
Abstract
Cutaneous melanoma is one of the most aggressive cancers characterized by a high plasticity, a propensity for metastasis, and drug resistance. Melanomas are composed of phenotypically diverse subpopulations of tumor cells with heterogeneous molecular profiles that reflect intrinsic invasive abilities. In an attempt to identify novel factors of the melanoma invasive cell state, we previously investigated the nature of the invasive secretome by using a comparative proteomic approach. Here, we have extended this analysis to show that PTX3, an acute phase inflammatory glycoprotein, is one such factor secreted by invasive melanoma to promote tumor cell invasiveness. Elevated PTX3 production was observed in the population of MITFlow invasive cells but not in the population of MITFhigh differentiated melanoma cells. Consistently, MITF knockdown increased PTX3 expression in MITFhigh proliferative and poorly invasive cells. High levels of PTX3 were found in tissues and blood of metastatic melanoma patients, and in BRAF inhibitor-resistant melanoma cells displaying a mesenchymal invasive MITFlow phenotype. Genetic silencing of PTX3 in invasive melanoma cells dramatically impaired migration and invasion in vitro and in experimental lung extravasation assay in xenografted mice. In contrast, addition of melanoma-derived or recombinant PTX3, or expression of PTX3 enhanced motility of low migratory cells. Mechanistically, autocrine production of PTX3 by melanoma cells triggered an IKK/NFκB signaling pathway that promotes migration, invasion, and expression of the EMT factor TWIST1. Finally, we found that TLR4 and MYD88 knockdown inhibited PTX3-induced melanoma cell migration, suggesting that PTX3 functions through a TLR4-dependent pathway. Our work reveals that tumor-derived PTX3 contributes to melanoma cell invasion via targetable inflammation-related pathways. In addition to providing new insights into the biology of melanoma invasive behavior, this study underscores the notion that secreted PTX3 represents a potential biomarker and therapeutic target in a subpopulation of MITFlow invasive and/or refractory melanoma.
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Affiliation(s)
- M Rathore
- Université Côte d'Azur, INSERM, C3M, Nice, France
- Equipe labellisée Ligue Contre le Cancer 2016, Nice, France
- The Hormel Institute, University of Minnesota, Austin, MN, USA
| | - C Girard
- Université Côte d'Azur, INSERM, C3M, Nice, France
- Equipe labellisée Ligue Contre le Cancer 2016, Nice, France
| | - M Ohanna
- Université Côte d'Azur, INSERM, C3M, Nice, France
- Equipe labellisée Ligue Contre le Cancer 2016, Nice, France
| | - M Tichet
- Université Côte d'Azur, INSERM, C3M, Nice, France
- Laboratory of Translational Oncology, ISREC, EPFL, Lausanne, Switzerland
| | - R Ben Jouira
- Université Côte d'Azur, INSERM, C3M, Nice, France
| | - E Garcia
- Université Côte d'Azur, INSERM, C3M, Nice, France
| | - F Larbret
- Université Côte d'Azur, INSERM, C3M, Nice, France
- Equipe labellisée Ligue Contre le Cancer 2016, Nice, France
| | - M Gesson
- Université Côte d'Azur, INSERM, C3M, Nice, France
| | - S Audebert
- Aix-Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France
| | - J-P Lacour
- Université Côte d'Azur, CHU Nice, Nice, France
| | - H Montaudié
- Université Côte d'Azur, CHU Nice, Nice, France
| | - V Prod'Homme
- Université Côte d'Azur, INSERM, C3M, Nice, France
- Equipe labellisée Ligue Contre le Cancer 2016, Nice, France
| | - S Tartare-Deckert
- Université Côte d'Azur, INSERM, C3M, Nice, France.
- Equipe labellisée Ligue Contre le Cancer 2016, Nice, France.
| | - M Deckert
- Université Côte d'Azur, INSERM, C3M, Nice, France.
- Equipe labellisée Ligue Contre le Cancer 2016, Nice, France.
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Mantovani A, Ponzetta A, Inforzato A, Jaillon S. Innate immunity, inflammation and tumour progression: double-edged swords. J Intern Med 2019; 285:524-532. [PMID: 30873708 PMCID: PMC7174018 DOI: 10.1111/joim.12886] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Components of the cellular and the humoral arm of the immune system are essential elements of the tumour microenvironment (TME). The TME includes tumour-associated macrophages which have served as a paradigm for the cancer-promoting inflammation. Cytokines, IL-1 in particular, and complement have emerged as important players in tumour promotion. On the other hand, myeloid cells, innate lymphoid cells and complement have the potential, if unleashed, to mediate anticancer resistance. Targeting checkpoints restraining innate immunity, macrophages and natural killer (NK) cells in particular holds promise as a therapeutic strategy.
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Affiliation(s)
- A Mantovani
- Humanitas Clinical and Research Center - IRCCS, via Manzoni 56, 20089, Rozzano, (Mi), Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele Milan, Italy.,The William Harvey Research Institute, Queen Mary University of London, London, EC1M 6BQ, UK
| | - A Ponzetta
- Humanitas Clinical and Research Center - IRCCS, via Manzoni 56, 20089, Rozzano, (Mi), Italy
| | - A Inforzato
- Humanitas Clinical and Research Center - IRCCS, via Manzoni 56, 20089, Rozzano, (Mi), Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele Milan, Italy
| | - S Jaillon
- Humanitas Clinical and Research Center - IRCCS, via Manzoni 56, 20089, Rozzano, (Mi), Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele Milan, Italy
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35
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Doni A, Stravalaci M, Inforzato A, Magrini E, Mantovani A, Garlanda C, Bottazzi B. The Long Pentraxin PTX3 as a Link Between Innate Immunity, Tissue Remodeling, and Cancer. Front Immunol 2019; 10:712. [PMID: 31019517 PMCID: PMC6459138 DOI: 10.3389/fimmu.2019.00712] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 03/15/2019] [Indexed: 12/20/2022] Open
Abstract
The innate immune system comprises a cellular and a humoral arm. Humoral pattern recognition molecules include complement components, collectins, ficolins, and pentraxins. These molecules are involved in innate immune responses by recognizing microbial moieties and damaged tissues, activating complement, exerting opsonic activity and facilitating phagocytosis, and regulating inflammation. The long pentraxin PTX3 is a prototypic humoral pattern recognition molecule that, in addition to providing defense against infectious agents, plays several functions in tissue repair and regulation of cancer-related inflammation. Characterization of the PTX3 molecular structure and biochemical properties, and insights into its interactome and multiple roles in tissue damage and remodeling support the view that microbial and matrix recognition are evolutionarily conserved functions of humoral innate immunity molecules.
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Affiliation(s)
- Andrea Doni
- Humanitas Clinical and Research Institute-IRCCS, Milan, Italy
| | - Matteo Stravalaci
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Antonio Inforzato
- Humanitas Clinical and Research Institute-IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Elena Magrini
- Humanitas Clinical and Research Institute-IRCCS, Milan, Italy
| | - Alberto Mantovani
- Humanitas Clinical and Research Institute-IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy.,The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Cecilia Garlanda
- Humanitas Clinical and Research Institute-IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
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Targeting AU-rich element-mediated mRNA decay with a truncated active form of the zinc-finger protein TIS11b/BRF1 impairs major hallmarks of mammary tumorigenesis. Oncogene 2019; 38:5174-5190. [DOI: 10.1038/s41388-019-0784-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 01/20/2019] [Accepted: 03/02/2019] [Indexed: 12/19/2022]
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37
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Ahmmed B, Kampo S, Khan M, Faqeer A, Kumar SP, Yulin L, Liu JW, Yan Q. Rg3 inhibits gemcitabine-induced lung cancer cell invasiveness through ROS-dependent, NF-κB- and HIF-1α-mediated downregulation of PTX3. J Cell Physiol 2019; 234:10680-10697. [PMID: 30628067 DOI: 10.1002/jcp.27731] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Accepted: 10/22/2018] [Indexed: 12/14/2022]
Abstract
PTX3, a member of the long pentraxin subfamily, associated with innate immunity is indispensable for resistance to some cancer. Gemcitabine, an analog of cytosine arabinoside, has shown restrained benefits because of profound chemoresistance. The PTX3 expression on GEM in human lung cancer cells have not yet been clarified; the present study aimed to show reactive oxygen species (ROS) mediatory PTX3 expression through distinct mechanisms. Whereas ginsenoside Rg3 is a herbal medicine with strong antitumor activity. Furthermore, we tested the hypothesis; Rg3 abrogates GEM-induced production of ROS-mediated activation of Akt and extracellular signal-regulated kinase (ERK) pathways and inhibits nuclear piling-up of nuclear factor kappa B (NF-κB) and HIF-1α. On the basis of time and dose-dependent manner, our data demonstrated that GEM-induced PTX3 expression was dependent on ROS generation as it was abrogated by pretreatment of lung cancer cells with the free radical scavenger N-acetyl-l-cysteine. Our data demonstrated that PTX3 upregulation by GEM correlated with the time-dependent escalation of NF-κB and HIF-1α in the nucleus resulted from phosphorylation-induced degradation of IκBα, whereas HIF-1α upregulation was NF-κB-dependent. Increase in ROS expression in lung cancer cells on GEM treatment preceded the nuclear accumulation of NF-κB and HIF-1α and suppression of ROS diminished these effects. ERK1/2 and Akt activation mediated the effect of ROS on NF-κB and HIF-1α and their pharmacological inhibition suppressed GEM-induced PTX3. Our study findings reinforced the role regarding PTX3 signaling in GEM-induced resistance and pointed toward an unintended and undesired effect of chemotherapy and to get an active regimen; the synergy was associated with NF-κB downregulation in lung cancer.
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Affiliation(s)
- Bulbul Ahmmed
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, China
| | - Sylvanus Kampo
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Muhammad Khan
- Department of Zoology, University of Punjab, Quaid-e-Azam Campus, Lahore, Pakistan
| | - Abdullah Faqeer
- Department of Biochemistry and Molecular Biology, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | | | - Li Yulin
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, China
| | - Ji Wei Liu
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Qiu Yan
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, China
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38
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Ahmmed B, Khan MN, Nisar MA, Kampo S, Zheng Q, Li Y, Yan Q. Tunicamycin enhances the suppressive effects of cisplatin on lung cancer growth through PTX3 glycosylation via AKT/NF-κB signaling pathway. Int J Oncol 2018; 54:431-442. [PMID: 30483742 PMCID: PMC6317655 DOI: 10.3892/ijo.2018.4650] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 07/05/2018] [Indexed: 12/22/2022] Open
Abstract
Long pentraxin-3 (PTX3) is an inflammatory molecule related to cancer proliferation, invasion, and metastasis. Many studies have highlighted the significance of glycosylated molecules in immune modulation, inflammation and cancer progression. Moreover, aberrant glycosylation of cancer cells is linked to chemoresistance. This study aimed to develop effective therapeutic strategies for deglycosylation of PTX3 (dePTX3) in order to enhance chemosensitivity to cisplatin (Cis) in lung cancer treatment. The A549 and SPCA1 cells were used to determine the role of PTX3 glycosylation in lung cancer growth. Our results revealed that PTX3 was higher in both human lung cancer tissues and serum in comparison with control. Furthermore, we found that deglycosylated PTX3 (dePTX3) by tunicamycin (TM), which is N-glycan precursor biosynthesis blocker, and PNGase F significantly reduced the survival and migration of lung cancer cells. To further confirm this, we also generated glycosylation-site mutant of PTX3 (mPTX3) to characterize the loss of glyco-function. dePTX3 and TM enhanced the suppressive effects of Cis on lung cancer cell growth, migration and invasion compared to individual treatment. Treatment with a combination of TM and Cis significantly inactivated AKT/NF-κB signaling pathway and induced apoptosis. In conclusion, these findings suggest that PTX3 is an important mediator of lung cancer progression, and dePTX3 by TM enhances the anticancer effects of Cis. The deglycosylation in chemotherapy may represent a potential novel therapeutic strategy against lung cancer.
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Affiliation(s)
- Bulbul Ahmmed
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Laboratory of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Muhammad Noman Khan
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Laboratory of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Muhammad Azhar Nisar
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Laboratory of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Sylvanus Kampo
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Laboratory of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Qin Zheng
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Laboratory of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Yulin Li
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Laboratory of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
| | - Qiu Yan
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Laboratory of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
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39
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Garlanda C, Bottazzi B, Magrini E, Inforzato A, Mantovani A. PTX3, a Humoral Pattern Recognition Molecule, in Innate Immunity, Tissue Repair, and Cancer. Physiol Rev 2018; 98:623-639. [PMID: 29412047 DOI: 10.1152/physrev.00016.2017] [Citation(s) in RCA: 132] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Innate immunity includes a cellular and a humoral arm. PTX3 is a fluid-phase pattern recognition molecule conserved in evolution which acts as a key component of humoral innate immunity in infections of fungal, bacterial, and viral origin. PTX3 binds conserved microbial structures and self-components under conditions of inflammation and activates effector functions (complement, phagocytosis). Moreover, it has a complex regulatory role in inflammation, such as ischemia/reperfusion injury and cancer-related inflammation, as well as in extracellular matrix organization and remodeling, with profound implications in physiology and pathology. Finally, PTX3 acts as an extrinsic oncosuppressor gene by taming tumor-promoting inflammation in murine and selected human tumors. Thus evidence suggests that PTX3 is a key homeostatic component at the crossroad of innate immunity, inflammation, tissue repair, and cancer. Dissecting the complexity of PTX3 pathophysiology and human genetics paves the way to diagnostic and therapeutic exploitation.
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Affiliation(s)
- Cecilia Garlanda
- Humanitas Clinical and Research Center, Rozzano, Milan , Italy ; Humanitas University, Rozzano, Milan , Italy ; Department of Medical Biotechnologies and Translational Medicine, University of Milan , Milan , Italy ; and The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Barbara Bottazzi
- Humanitas Clinical and Research Center, Rozzano, Milan , Italy ; Humanitas University, Rozzano, Milan , Italy ; Department of Medical Biotechnologies and Translational Medicine, University of Milan , Milan , Italy ; and The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Elena Magrini
- Humanitas Clinical and Research Center, Rozzano, Milan , Italy ; Humanitas University, Rozzano, Milan , Italy ; Department of Medical Biotechnologies and Translational Medicine, University of Milan , Milan , Italy ; and The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Antonio Inforzato
- Humanitas Clinical and Research Center, Rozzano, Milan , Italy ; Humanitas University, Rozzano, Milan , Italy ; Department of Medical Biotechnologies and Translational Medicine, University of Milan , Milan , Italy ; and The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Alberto Mantovani
- Humanitas Clinical and Research Center, Rozzano, Milan , Italy ; Humanitas University, Rozzano, Milan , Italy ; Department of Medical Biotechnologies and Translational Medicine, University of Milan , Milan , Italy ; and The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
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40
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Liu B, Zhao Y, Guo L. Increased serum pentraxin-3 level predicts poor prognosis in patients with colorectal cancer after curative surgery, a cohort study. Medicine (Baltimore) 2018; 97:e11780. [PMID: 30290589 PMCID: PMC6200527 DOI: 10.1097/md.0000000000011780] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Pentraxin-3 (PTX3) is a glycoprotein involved in inflammation and immune regulation of cancer. The aim of this study was to evaluate the serum PTX3 level in patients with colorectal cancer (CRC) and analyze its prognostic significance.A total of 263 consecutive patients underwent radical resection for primary CRC and 126 healthy controls were enrolled in this study. Serum PTX3 level was measured within the day before surgery though enzyme-linked immunosorbent assays, comparing with the level of healthy control. Baseline demographic and clinical characteristics were recorded. The association between serum PTX3 level and survival outcome was analyzed by the Kaplan-Meier with Log-Rank test and Cox regression methods.Mean serum PTX3 level in CRC patients was higher than that of healthy control (13.8 ± 3.2ng/mL versus 3.3 ± 1.2ng/mL, P < .001). Finally, 55 (20.9%) patients out of all 263 patients studied had died during following-up period. All patients were divided into 2 groups using the optimal cutoff value (12.6 ng/mL) of PTX3 level using a sensitivity of 68.0% and a specificity of 71.7% as optimal conditions from receiver operating curve analysis. Patients with a PTX3≥12.6ng/mL had poorer 5 years overall survival rate (76.6% versus 67.8%, P = .025) patients with a PTX3 < 12.6ng/mL in univariate analysis and serum PTX3 level also been confirmed as an independent predictor for survival for CRC in multivariate analysis (Hazard ratio, 1.468; 95% [confidence interval] CI, 1.081-1.976; P < .001).Serum PTX3 level can serve as an independent prognostic biomarker for CRC patients after curative resection.
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Affiliation(s)
- Bin Liu
- Department of Gastroenterology
| | - Yangying Zhao
- The Health Check Center, The Second Hospital of Shandong University, Jinan, China
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41
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Erreni M, Manfredi AA, Garlanda C, Mantovani A, Rovere-Querini P. The long pentraxin PTX3: A prototypical sensor of tissue injury and a regulator of homeostasis. Immunol Rev 2018; 280:112-125. [PMID: 29027216 DOI: 10.1111/imr.12570] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Tissue damage frequently occurs. The immune system senses it and enforces homeostatic responses that lead to regeneration and repair. The synthesis of acute phase molecules is emerging as a crucial event in this program. The prototypic long pentraxin PTX3 orchestrates the recruitment of leukocytes, stabilizes the provisional matrix in order to facilitate leukocyte and stem progenitor cells trafficking, promotes swift and safe clearance of dying cells and of autoantigens, limiting autoimmunity and protecting the vasculature. These non-redundant actions of PTX3 are necessary for the resolution of inflammation. Recent studies have highlighted the mechanisms by which PTX3 adapts the functions of innate immune cells, orchestrates tissue repair and contributes to select the appropriate acquired immune response in various tissues. Conversely, PTX3 continues to be produced in diseases where the inflammatory response does not resolve. It is therefore a valuable biomarker for more precise and personalized stratification of patients, often independently predicting clinical evolution and outcome. There is strong promise for novel therapies based on understanding the mechanisms with which PTX3 plays its homeostatic role, especially in regulating leukocyte migration and the resolution of inflammatory processes.
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Affiliation(s)
- Marco Erreni
- IRCCS Humanitas Clinical and Research Center, Milan, Italy.,Humanitas University, Milan, Italy
| | - Angelo A Manfredi
- Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
| | - Cecilia Garlanda
- IRCCS Humanitas Clinical and Research Center, Milan, Italy.,Humanitas University, Milan, Italy
| | - Alberto Mantovani
- IRCCS Humanitas Clinical and Research Center, Milan, Italy.,Humanitas University, Milan, Italy
| | - Patrizia Rovere-Querini
- Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
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42
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Incidence and risk factors for venous thromboembolism in patients with pretreated advanced pancreatic carcinoma. Oncotarget 2018; 9:16883-16890. [PMID: 29682191 PMCID: PMC5908292 DOI: 10.18632/oncotarget.24721] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 02/28/2018] [Indexed: 01/05/2023] Open
Abstract
Patients with pancreatic carcinoma are at an increased risk of venous thromboembolism (VTE), which is a major cause of morbidity and mortality in various types of cancer. The aim of this study was to determine the incidence and clinical significance of VTE in patients with pancreatic carcinoma, and to identify biomarkers for the detection of VTE in these patients. The eligibility criteria were chemo-naïve patients with primary pancreatic carcinoma, an Eastern Cooperative Oncology Group performance status of 0–2, and adequate organ function. All patients were screened for VTE using compression ultrasonography and dynamic computed tomography. The primary endpoint was the incidence of VTE, which we hypothesized would be between 10.0–20.0% for symptomatic and asymptomatic patients combined. Associations between clinical presentation and VTE were evaluated. VTE-associated markers were also investigated for their role in predicting prognosis. In total, 103 patients met the eligibility criteria. The overall cumulative incidence rate of VTE in patients with previously untreated pancreatic carcinoma was 16.5%. VTE occurrence was strongly associated with elevated serum D-dimer, fibrin degradation product, thrombin/antithrombin III complex, and prothrombin fragment 1 + 2 levels. The median overall survival time of VTE-positive and VTE-negative patients was 427 and 515 days, respectively. Approximately one-sixth of patients with advanced pancreatic carcinoma experienced VTE, although most were asymptomatic. Measurement of serum D-dimer, fibrin degradation product, thrombin/antithrombin III complex, and prothrombin fragment 1 + 2 levels may be useful for the early detection of VTE in patients with advanced pancreatic carcinoma.
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43
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Choi B, Lee EJ, Shin MK, Park YS, Ryu MH, Kim SM, Kim EY, Lee HK, Chang EJ. Upregulation of brain-derived neurotrophic factor in advanced gastric cancer contributes to bone metastatic osteolysis by inducing long pentraxin 3. Oncotarget 2018; 7:55506-55517. [PMID: 27458153 PMCID: PMC5342432 DOI: 10.18632/oncotarget.10747] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 07/11/2016] [Indexed: 12/23/2022] Open
Abstract
The brain-derived neurotrophic factor (BDNF) activates its receptor, tropomyosin receptor kinase B (TrkB; also called NTRK2) that has been shown to promote the malignant progression of several cancers. In this study, we investigated the clinical and biological significance of the BDNF/TrkB axis in the progression of human gastric cancer. The increased co-expression of the BDNF/TrkB axis was significantly correlated with bone metastatic properties in advanced gastric cancers. BDNF acting via TrkB receptors increased the levels of long pentraxin 3 (PTX3) that was related to bone metastatic status of gastric cancer by enhancing gastric cancer–osteoblastic niche interactions. In bone metastatic gastric cancer, PTX3 knockdown using small interfering RNA significantly inhibited BDNF-induced interactions of cancer cells with osteoblasts. Moreover, BDNF-derived PTX3 induction supported subsequent osteoclastogenesis, and this effect was significantly reversed by PTX3 silencing. These findings suggest that a functional interaction between BDNF/TrkB and PTX3 enhances the osteolysis of bone metastatic gastric cancer, thereby providing potential prognostic factors for the development of bone metastasis of gastric cancer.
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Affiliation(s)
- Bongkun Choi
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eun-Jin Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Min-Kyung Shin
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sang-Min Kim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eun-Young Kim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyung Keun Lee
- Department of Ophthalmology and Corneal Dystrophy Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Eun-Ju Chang
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Korea
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44
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Long pentraxin 3: A novel multifaceted player in cancer. Biochim Biophys Acta Rev Cancer 2017; 1869:53-63. [PMID: 29175552 DOI: 10.1016/j.bbcan.2017.11.004] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Revised: 11/22/2017] [Accepted: 11/22/2017] [Indexed: 01/12/2023]
Abstract
Since its discovery in 1992, long pentraxin 3 (PTX3) has been characterized as soluble patter recognition receptor, a key player of the innate immunity arm with non-redundant functions in pathogen recognition and inflammatory responses. As a component of the extra-cellular matrix milieu, PTX3 has been implicated also in wound healing/tissue remodeling, cardiovascular diseases, fertility, and infectious diseases. Consequently, PTX3 levels in biological fluids have been proposed as a fluid-phase biomarker in different pathological conditions. In the last decade, experimental evidences have shown that PTX3 may exert a significant impact also on different aspects of cancer biology, including tumor onset, angiogenesis, metastatic dissemination and immune-modulation. However, it remains unclear whether PTX3 acts as a good cop or bad cop in cancer. In this review, we will summarize and discuss the scientific literature data focusing on the role of PTX3 in experimental and human tumors, including its putative translational implications.
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Daigo K, Inforzato A, Barajon I, Garlanda C, Bottazzi B, Meri S, Mantovani A. Pentraxins in the activation and regulation of innate immunity. Immunol Rev 2017; 274:202-217. [PMID: 27782337 DOI: 10.1111/imr.12476] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Humoral fluid phase pattern recognition molecules (PRMs) are a key component of the activation and regulation of innate immunity. Humoral PRMs are diverse. We focused on the long pentraxin PTX3 as a paradigmatic example of fluid phase PRMs. PTX3 acts as a functional ancestor of antibodies and plays a non-redundant role in resistance against selected microbes in mouse and man and in the regulation of inflammation. This molecule interacts with complement components, thus modulating complement activation. In particular, PTX3 regulates complement-driven macrophage-mediated tumor progression, acting as an extrinsic oncosuppressor in preclinical models and selected human tumors. Evidence collected over the years suggests that PTX3 is a biomarker and potential therapeutic agent in humans, and pave the way to translation of this molecule into the clinic.
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Affiliation(s)
- Kenji Daigo
- Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano (Milan), Italy
| | - Antonio Inforzato
- Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano (Milan), Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Italy
| | | | - Cecilia Garlanda
- Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano (Milan), Italy
| | - Barbara Bottazzi
- Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano (Milan), Italy
| | - Seppo Meri
- Immunobiology Research Program, Research Programs Unit, Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki , Helsinki , Finland
| | - Alberto Mantovani
- Department of Inflammation and Immunology, Humanitas Clinical and Research Center, Rozzano (Milan), Italy.,Humanitas University, Rozzano, Italy
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Zhang J, Wang TY, Niu XC. Increased Plasma Levels of Pentraxin 3 Are Associated with Poor Prognosis of Colorectal Carcinoma Patients. TOHOKU J EXP MED 2017; 240:39-46. [PMID: 27568661 DOI: 10.1620/tjem.240.39] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Colorectal carcinoma (CRC) is one of the most common cancers globally. It is essential to identify a prognostic predictor for CRC. Pentraxin 3 (PTX3) is a glycoprotein that is secreted by a variety of human cells. It plays an important role in inflammation and immune regulation. Increasing evidence reveals that elevated PTX3 expression is related to poor prognosis in various cancers. The aim of the study was to determine the usefulness of plasma PTX3 level as a prognostic predictor in CRC. Total 184 CRC patients and 216 controls were included. Plasma levels of PTX3 were determined using Enzyme-linked immunosorbent assays. On admission, plasma PTX3 levels in CRC patients were higher than those in controls (11.8 ± 2.5 ng/ml vs. 3.1 ± 0.9 ng/ml, P < 0.001). After resection, plasma PTX3 levels in patients were decreased (6.0 ± 1.4 ng/ml, P = 0.007), and were elevated at the time of relapse (10.8 ± 2.8 ng/ml, P < 0.001). During the 60-month follow-up period, 108 patients suffered from relapse. Plasma PTX3 levels of ≥ 12 ng/ml on admission were associated with relapse (OR: 3.11, 95% CI: 1.74 ~ 6.29), and tumor-free survival rate in those patients with plasma PTX3 levels of ≥ 12 ng/ml was lower than that in other patients (P = 0.001). Furthermore, plasma PTX3 levels on admission showed positive linear correlations with plasma complement 3, 4 and 5b9 levels (P < 0.001, P < 0.001, P < 0.001). Therefore, we propose that PTX3 is an independent prognostic indicator in CRC.
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Affiliation(s)
- Jie Zhang
- Department of General Surgery, Dezhou People's Hospital
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Thomas C, Henry W, Cuiffo BG, Collmann AY, Marangoni E, Benhamo V, Bhasin MK, Fan C, Fuhrmann L, Baldwin AS, Perou C, Vincent-Salomon A, Toker A, Karnoub AE. Pentraxin-3 is a PI3K signaling target that promotes stem cell-like traits in basal-like breast cancers. Sci Signal 2017; 10:10/467/eaah4674. [PMID: 28223411 DOI: 10.1126/scisignal.aah4674] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Basal-like breast cancers (BLBCs) exhibit hyperactivation of the phosphoinositide 3-kinase (PI3K) signaling pathway because of the frequent mutational activation of the PIK3CA catalytic subunit and the genetic loss of its negative regulators PTEN (phosphatase and tensin homolog) and INPP4B (inositol polyphosphate-4-phosphatase type II). However, PI3K inhibitors have had limited clinical efficacy in BLBC management because of compensatory amplification of PI3K downstream signaling loops. Therefore, identification of critical PI3K mediators is paramount to the development of effective BLBC therapeutics. Using transcriptomic analysis of activated PIK3CA-expressing BLBC cells, we identified the gene encoding the humoral pattern recognition molecule pentraxin-3 (PTX3) as a critical target of oncogenic PI3K signaling. We found that PTX3 abundance is stimulated, in part, through AKT- and nuclear factor κB (NF-κB)-dependent pathways and that presence of PTX3 is necessary for PI3K-induced stem cell-like traits. We further showed that PTX3 expression is greater in tumor samples from patients with BLBC and that it is prognostic of poor patient survival. Our results thus reveal PTX3 as a newly identified PI3K-regulated biomarker and a potential therapeutic target in BLBC.
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Affiliation(s)
- Clémence Thomas
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Whitney Henry
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Benjamin G Cuiffo
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Anthony Y Collmann
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | | | | | - Manoj K Bhasin
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Cheng Fan
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | | | - Albert S Baldwin
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Charles Perou
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | | | - Alex Toker
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Antoine E Karnoub
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. .,Harvard Stem Cell Institute, Cambridge, MA 02138, USA.,Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
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Saha S, Xiong X, Chakraborty PK, Shameer K, Arvizo RR, Kudgus RA, Dwivedi SKD, Hossen MN, Gillies EM, Robertson JD, Dudley JT, Urrutia RA, Postier RG, Bhattacharya R, Mukherjee P. Gold Nanoparticle Reprograms Pancreatic Tumor Microenvironment and Inhibits Tumor Growth. ACS NANO 2016; 10:10636-10651. [PMID: 27758098 PMCID: PMC6939886 DOI: 10.1021/acsnano.6b02231] [Citation(s) in RCA: 124] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
Altered tumor microenvironment (TME) arising from a bidirectional crosstalk between the pancreatic cancer cells (PCCs) and the pancreatic stellate cells (PSCs) is implicated in the dismal prognosis in pancreatic ductal adenocarcinoma (PDAC), yet effective strategies to disrupt the crosstalk is lacking. Here, we demonstrate that gold nanoparticles (AuNPs) inhibit proliferation and migration of both PCCs and PSCs by disrupting the bidirectional communication via alteration of the cell secretome. Analyzing the key proteins identified from a functional network of AuNP-altered secretome in PCCs and PSCs, we demonstrate that AuNPs impair secretions of major hub node proteins in both cell types and transform activated PSCs toward a lipid-rich quiescent phenotype. By reducing activation of PSCs, AuNPs inhibit matrix deposition, enhance angiogenesis, and inhibit tumor growth in an orthotopic co-implantation model in vivo. Auto- and heteroregulations of secretory growth factors/cytokines are disrupted by AuNPs resulting in reprogramming of the TME. By utilizing a kinase dead mutant of IRE1-α, we demonstrate that AuNPs alter the cellular secretome through the ER-stress-regulated IRE1-dependent decay pathway (RIDD) and identify endostatin and matrix metalloproteinase 9 as putative RIDD targets. Thus, AuNPs could potentially be utilized as a tool to effectively interrogate bidirectional communications in the tumor microenvironment, reprogram it, and inhibit tumor growth by its therapeutic function.
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Affiliation(s)
- Sounik Saha
- Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States
| | - Xunhao Xiong
- Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States
| | - Prabir K. Chakraborty
- Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States
| | - Khader Shameer
- Institute of Next Generation Healthcare, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, New York 10029, United States
| | - Rochelle R. Arvizo
- Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, United States
| | - Rachel A. Kudgus
- Molecular Pharmacology and Experimental Therapeutics, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, United States
| | - Shailendra Kumar Dhar Dwivedi
- Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States
| | - Md. Nazir Hossen
- Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States
| | - Elizabeth M. Gillies
- Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States
| | - J. David Robertson
- Department of Chemistry and University of Missouri Research Reactor, University of Missouri, Columbia, Missouri 65211, United States
| | - Joel T. Dudley
- Institute of Next Generation Healthcare, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, New York, New York 10029, United States
| | - Raul A. Urrutia
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, United States
| | - Russell G. Postier
- Department of Surgery, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States
| | - Resham Bhattacharya
- Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States
| | - Priyabrata Mukherjee
- Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States
- Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, United States
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Basu S, Harris H, Wolk A, Rossary A, Caldefie-Chézet F, Vasson MP, Larsson A. Inflammatory F 2-isoprostane, prostaglandin F 2α, pentraxin 3 levels and breast cancer risk: The Swedish Mammography Cohort. Prostaglandins Leukot Essent Fatty Acids 2016; 113:28-32. [PMID: 27720037 DOI: 10.1016/j.plefa.2016.08.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 08/16/2016] [Accepted: 08/16/2016] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Breast cancer is a common cancer among women. Identifying cellular participation of F2-isoprostane, prostaglandin F2α (PGF2α) and pentraxin 3 (PTX3) in cancer we evaluated whether their prediagnostic systemic levels that originate from different inflammatory pathways were associated with breast cancer risk. METHODS Seventy-eight breast cancer cases diagnosed after blood collection and 797 controls from the Swedish Mammography Cohort were analysed for urinary F2-isoprostane, PGF2α and plasma PTX3 levels. RESULTS None of the biomarkers investigated were significantly associated with breast cancer risk. However, there was the suggestion of an inverse association with PTX3 with multivariable adjusted ORs (95% CI) of 0.56 (95% CI=0.29-1.06) and 0.67 (95% CI=0.35-1.28) for the second and third tertiles, respectively (ptrend=0.20). No associations were observed between F2-isoprostane (OR=0.87; 95% CI=0.48-1.57; ptrend=0.67) and PGF2α metabolite (OR=1.03; 95% CI=0.56-1.88; ptrend=0.91) comparing the top to bottom tertiles. CONCLUSIONS The systemic levels of F2-isoprostane, PGF2α and PTX3 witnessed in women who later developed breast cancer may not provide prognostic information regarding tumor development in spite of their known involvement in situ cellular context. These observations may indicate that other mechanisms exist in controlling cellular formation of F2-isoprostane, PGF2α and PTX3 and their systemic availability in breast cancer patients.
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Affiliation(s)
- Samar Basu
- Chaire d'Excellence Program, Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, CRNH-Auvergne, INRA-UDA, Clermont-Ferrand, France; Department of Public Health and Caring Sciences, Faculty of Medicine, Uppsala University, Uppsala, Sweden
| | - Holly Harris
- Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden; Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA; Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Alicja Wolk
- Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Adrien Rossary
- Chaire d'Excellence Program, Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, CRNH-Auvergne, INRA-UDA, Clermont-Ferrand, France
| | - Florence Caldefie-Chézet
- Chaire d'Excellence Program, Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, CRNH-Auvergne, INRA-UDA, Clermont-Ferrand, France
| | - Marie-Paule Vasson
- Chaire d'Excellence Program, Clermont Université, Université d'Auvergne, Unité de Nutrition Humaine, CRNH-Auvergne, INRA-UDA, Clermont-Ferrand, France; Centre Jean Perrin, Unicancer, Clermont-Ferrand, France; CHU Clermont-Ferrand, Unité d'Exploration Nutritionnelle, Clermont-Ferrand, France
| | - Anders Larsson
- Department of Medical Science, Faculty of Medicine, Uppsala University, Uppsala, Sweden
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Ying TH, Lee CH, Chiou HL, Yang SF, Lin CL, Hung CH, Tsai JP, Hsieh YH. Knockdown of Pentraxin 3 suppresses tumorigenicity and metastasis of human cervical cancer cells. Sci Rep 2016; 6:29385. [PMID: 27377307 PMCID: PMC4932528 DOI: 10.1038/srep29385] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 06/20/2016] [Indexed: 01/14/2023] Open
Abstract
Pentraxin 3 (PTX3) as an inflammatory molecule has been shown to be involved in immune response, inflammation, and cancer. However, the effects of PTX3 on the biological features of cervical cancer cells in vitro and in vivo have not been delineated. Immunohistochemical staining showed that increased PTX3 expression was significantly associated with tumor grade (P < 0.011) and differentiation (P < 0.019). Knocking down PTX3 with lentivirus-mediated small hairpin RNA (shRNA) in cervical cancer cell lines resulted in inhibited cell viability, diminished colony-forming ability, and induced cell cycle arrest at the G2/M phase of the cell cycle, along with downregulated expression of cyclin B1, cdc2, and cdc25c, and upregulated expression of p-cdc2, p-cdc25c, p21, and p27. Furthermore, knockdown of PTX3 significantly decreased the potential of migration and invasion of cervical cancer cells by inhibiting matrix metalloproteidase-2 (MMP-2), MMP-9, and urokinase plasminogen activator (uPA). Moreover, in vivo functional studies showed PTX3-knockdown in mice suppressed tumorigenicity and lung metastatic potential. Conversely, overexpression of PTX3 enhanced proliferation and invasion both in vitro and in vivo. Our results demonstrated that PTX3 contributes to tumorigenesis and metastasis of human cervical cancer cells. Further studies are warranted to demonstrate PTX3 as a novel therapeutic biomarker for human cervical cancer.
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Affiliation(s)
- Tsung-Ho Ying
- Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan.,Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chien-Hsing Lee
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan.,Division of Pediatric Surgery, Department of Surgery, Children's Hospital of China Medical University, Taichung, Taiwan
| | - Hui-Ling Chiou
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chu-Liang Lin
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan
| | - Chia-Hung Hung
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan
| | - Jen-Pi Tsai
- School of Medicine, Tzu Chi University, Hualien, Taiwan.,Division of Nephrology, Department of Internal Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Yi-Hsien Hsieh
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.,Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.,Clinical laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
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