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Fu Y, Chen L, Lv N, Wang J, Yu S, Fang Q, Xin W. miR-135b-5p/PDE3B Axis Regulates Gemcitabine Resistance in Pancreatic Cancer Through Epithelial-Mesenchymal Transition. Mol Carcinog 2025; 64:1119-1130. [PMID: 40170518 DOI: 10.1002/mc.23914] [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: 11/19/2024] [Revised: 03/11/2025] [Accepted: 03/18/2025] [Indexed: 04/03/2025]
Abstract
Gemcitabine-based chemotherapy is an effective treatment for pancreatic cancer (PC), but gemcitabine resistance frequently compromises the therapeutic efficacy, resulting in clinical chemotherapeutic failure and a poor prognosis for patients. In this study, we investigated the mechanisms of gemcitabine chemoresistance in PC by examining the roles of microRNAs linked to gemcitabine resistance and their downstream signaling pathways. In vitro experiments were performed to alter miR-135b-5p levels in PC parental and drug-resistant cells to probe its function. miR-135b-5p targets PDE3B was confirmed by using RNA-seq technology to screen for gemcitabine-resistance-associated mRNAs in PC. A series of rescue experiments were performed after cotransfection, demonstrating that PDE3B could reverse miR-135b-5p-mediated chemoresistance and epithelial-mesenchymal transition (EMT). These findings indicate that the miR-135b-5p/PDE3B axis generates resistance by stimulating the EMT signaling pathway, which provides new insights into gemcitabine chemoresistance in PC.
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Affiliation(s)
- Yuxuan Fu
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Liangsheng Chen
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Neng Lv
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Jia Wang
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Shuwei Yu
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Qilu Fang
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
| | - Wenxiu Xin
- Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, China
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
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Chen Z, Xu L, Yuan Y, Zhang S, Xue R. Metabolic crosstalk between platelets and cancer: Mechanisms, functions, and therapeutic potential. Semin Cancer Biol 2025; 110:65-82. [PMID: 39954752 DOI: 10.1016/j.semcancer.2025.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/17/2025]
Abstract
Platelets, traditionally regarded as passive mediators of hemostasis, are now recognized as pivotal regulators in the tumor microenvironment, establishing metabolic feedback loops with tumor and immune cells. Tumor-derived signals trigger platelet activation, which induces rapid metabolic reprogramming, particularly glycolysis, to support activation-dependent functions such as granule secretion, morphological changes, and aggregation. Beyond self-regulation, platelets influence the metabolic processes of adjacent cells. Through direct mitochondrial transfer, platelets reprogram tumor and immune cells, promoting oxidative phosphorylation. Additionally, platelet-derived cytokines, granules, and extracellular vesicles drive metabolic alterations in immune cells, fostering suppressive phenotypes that facilitate tumor progression. This review examines three critical aspects: (1) the distinctive metabolic features of platelets, particularly under tumor-induced activation; (2) the metabolic crosstalk between activated platelets and other cellular components; and (3) the therapeutic potential of targeting platelet metabolism to disrupt tumor-promoting networks. By elucidating platelet metabolism, this review highlights its essential role in tumor biology and its therapeutic implications.
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Affiliation(s)
- Zhixue Chen
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Lin Xu
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yejv Yuan
- The First Affiliated Hospital of Anhui University of Science and Technology, Huainan 232001, China
| | - Si Zhang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
| | - Ruyi Xue
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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Wu L, Liang F, Chen C, Zhang Y, Huang H, Pan Y. Identification of prognostic and therapeutic biomarkers associated with macrophage and lipid metabolism in pancreatic cancer. Sci Rep 2025; 15:14584. [PMID: 40281115 PMCID: PMC12032141 DOI: 10.1038/s41598-025-99144-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 04/17/2025] [Indexed: 04/29/2025] Open
Abstract
Although macrophages and lipid metabolism significantly influence the progression of various cancers, their precise roles in pancreatic cancer (PC) remain unclear. This study focuses on identifying and validating biomarkers associated with macrophage-related genes (MRGs) and lipid metabolism-related genes (LMRGs), providing new targets and strategies for therapeutic intervention. This research utilized datasets from TCGA-PAAD, GSE62452, and GSE57495. Candidate genes were identified by overlapping differentially expressed genes with MRGs from WGCNA and LMRGs. Regression analyses were performed to pinpoint potential biomarkers and construct a risk model, which underwent evaluation. A nomogram was subsequently developed and validated. Additional analyses, including functional enrichment, somatic mutation profiling, immune landscape assessment, and RT-qPCR, were performed to investigate the underlying biological mechanisms in PC. The study identified ADH1A, ACACB, CD36, CERS4, PDE3B, ALOX5, and CRAT as biomarkers for PC. RT-qPCR results revealed reduced expression of ADH1A, ACACB, CD36, CERS4, PDE3B, and CRAT in tumor samples compared to adjacent tissues, whereas ALOX5 expression was significantly elevated in tumor samples. A risk model utilizing these biomarkers classified PC patients into high- and low-risk cohorts, with high-risk patients showing lower survival probabilities. Subsequently, risk score and N stage were identified as independent prognostic factors, leading to the development of a nomogram. Notably, both risk cohorts showed significant enrichment in the "cell cycle" pathway. Furthermore, TP53 mutations were prevalent in both high-risk (76%) and low-risk (50%) cohorts. Correlation analysis indicated that PVRL2 (an immunosuppressive factor), CD276 (an immunoactivator), and CCL20 (a chemotactic factor) had the highest positive correlation with the risk score. In this study, ADH1A, ACACB, CD36, CERS4, PDE3B, ALOX5, and CRAT were identified as biomarkers for PC, with their expression levels validated in clinical samples. These findings offered a potential theoretical foundation for developing targeted treatments for PC.
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Affiliation(s)
- Lili Wu
- Department of Surgical Nursing, Fujian Medical University Union Hospital, Fuzhou, People's Republic of China
| | - Feihong Liang
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China
- The Cancer Center, Fujian Medical University Union Hospital, Fuzhou, People's Republic of China
| | - Changgan Chen
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China
| | - Yaxin Zhang
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China
| | - Heguang Huang
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China
| | - Yu Pan
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China.
- Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, People's Republic of China.
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Kast RE. IC Regimen: Delaying Resistance to Lorlatinib in ALK Driven Cancers by Adding Repurposed Itraconazole and Cilostazol. Cells 2024; 13:1175. [PMID: 39056757 PMCID: PMC11274432 DOI: 10.3390/cells13141175] [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: 06/21/2024] [Revised: 07/06/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
Lorlatinib is a pharmaceutical ALK kinase inhibitor used to treat ALK driven non-small cell lung cancers. This paper analyses the intersection of past published data on the physiological consequences of two unrelated drugs from general medical practice-itraconazole and cilostazol-with the pathophysiology of ALK positive non-small cell lung cancer. A conclusion from that data analysis is that adding itraconazole and cilostazol may make lorlatinib more effective. Itraconazole, although marketed worldwide as a generic antifungal drug, also inhibits Hedgehog signaling, Wnt signaling, hepatic CYP3A4, and the p-gp efflux pump. Cilostazol, marketed worldwide as a generic thrombosis preventative drug, acts by inhibiting phosphodiesterase 3, and, by so doing, lowers platelets' adhesion, thereby partially depriving malignant cells of the many tumor trophic growth factors supplied by platelets. Itraconazole may enhance lorlatinib effectiveness by (i) reducing or stopping a Hedgehog-ALK amplifying feedback loop, by (ii) increasing lorlatinib's brain levels by p-gp inhibition, and by (iii) inhibiting growth drive from Wnt signaling. Cilostazol, surprisingly, carries minimal bleeding risk, lower than that of aspirin. Risk/benefit assessment of the combination of metastatic ALK positive lung cancer being a low-survival disease with the predicted safety of itraconazole-cilostazol augmentation of lorlatinib favors a trial of this drug trio in ALK positive lung cancer.
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Tsuda N, Tian Y, Fujimoto M, Kuramoto J, Makiuchi S, Ojima H, Gotoh M, Hiraoka N, Yoshida T, Kanai Y, Arai E. DNA methylation status of the SPHK1 and LTB genes underlies the clinicopathological diversity of non-alcoholic steatohepatitis-related hepatocellular carcinomas. J Cancer Res Clin Oncol 2023; 149:5109-5125. [PMID: 36348017 PMCID: PMC10349775 DOI: 10.1007/s00432-022-04445-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/19/2022] [Indexed: 11/09/2022]
Abstract
PURPOSE This study was performed to identify the DNA methylation profiles underlying the clinicopathological diversity of non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinomas (HCCs). METHODS: Genome-wide DNA methylation analysis of 88 liver tissue samples was performed using the Infinium assay. RESULTS Principal component analysis revealed that distinct DNA methylation profiles differing from such profiles in normal control liver tissue had already been established in non-cancerous liver tissue showing NASH, which is considered to be a precancerous condition. Hierarchical clustering separated 26 NASH-related HCCs into Cluster I (n = 8) and Cluster II (n = 18). Such epigenetic clustering was significantly correlated with histopathological diversity, i.e. poorer tumor differentiation, tumor steatosis and development of a scirrhous HCC component. Significant differences in DNA methylation levels between the two clusters were accumulated in molecular pathways participating in cell adhesion and cytoskeletal remodeling, as well as cell proliferation and apoptosis. Among tumor-related genes characterizing Clusters I and II, differences in the levels of DNA methylation and mRNA expression for the SPHK1, INHBA, LTB and PDE3B genes were correlated with poorer tumor differentiation. 5-Aza-2'-deoxycytidine treatment of HCC cells revealed epigenetic regulation of the SPHK1 and LTB genes. Knockdown experiments showed that SPHK1 promotes cell proliferation, represses apoptosis and enhances migration, whereas LTB enhances migration of HCC cells. DNA hypomethylation resulting in increased expression of SPHK1 and LTB in poorly differentiated HCCs may underlie the aggressive phenotype of such HCCs. CONCLUSION These data indicate that DNA methylation profiles may determine the clinicopathological heterogeneity of NASH-related HCCs via alterations of tumor-related gene expression.
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Affiliation(s)
- Noboru Tsuda
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Ying Tian
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Mao Fujimoto
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Junko Kuramoto
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Satomi Makiuchi
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Hidenori Ojima
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Masahiro Gotoh
- Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo, 104-0045, Japan
| | - Nobuyoshi Hiraoka
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, 104-0045, Japan
| | - Teruhiko Yoshida
- Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo, 104-0045, Japan
| | - Yae Kanai
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan.
| | - Eri Arai
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan.
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Sim KH, Shu MS, Kim S, Kim JY, Choi BH, Lee YJ. Cilostazol Induces Apoptosis and Inhibits Proliferation of Hepatocellular Carcinoma Cells by Activating AMPK. BIOTECHNOL BIOPROC E 2021. [DOI: 10.1007/s12257-021-0002-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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CircSCAP aggravates oxidized low-density lipoprotein-induced macrophage injury by upregulating PDE3B via miR-221-5p in atherosclerosis. J Cardiovasc Pharmacol 2021; 78:e749-e760. [PMID: 34321402 DOI: 10.1097/fjc.0000000000001118] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/03/2021] [Indexed: 11/25/2022]
Abstract
ABSTRACT Atherosclerosis (AS) is a major risk factor for cardiovascular disease, in which circular RNAs (circRNAs) play important regulatory roles. This research aimed to explore the biological role of circSCAP (hsa_circ_0001292) in AS development. Real-time PCR or western blot assay was conducted to analyze RNA or protein expression. Cell proliferation and apoptosis were analyzed by CCK-8 assay and flow cytometry. The levels of lipid accumulation-associated indicators and oxidative stress factors were detected using commercial kits. The levels of inflammatory cytokines were examined using enzyme-linked immunosorbent assay (ELISA). Intermolecular interaction was verified via dual-luciferase reporter analysis or RNA pull-down analysis. CircSCAP and phosphodiesterase 3B (PDE3B) levels were elevated, whereas miR-221-5p level was decreased in AS patients and oxidized low-density lipoprotein (ox-LDL)-induced THP-1 cells. CircSCAP absence suppressed lipid deposition, inflammation, and oxidative stress in ox-LDL-induced THP-1 cells. MiR-221-5p was a target of circSCAP, and anti-miR-221-5p largely reversed si-circSCAP-induced effects in ox-LDL-induced THP-1 cells. PDE3B was a target of miR-221-5p, and PDE3B overexpression largely counteracted miR-221-5p accumulation-mediated effects in ox-LDL-induced THP-1 cells. NF-κB signaling pathway was regulated by circSCAP/miR-221-5p/PDE3B axis in ox-LDL-induced THP-1 cells. In conclusion, circSCAP facilitated lipid accumulation, inflammation, and oxidative stress in ox-LDL-induced THP-1 macrophages by regulating miR-221-5p/PDE3B axis.
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AKT-mediated regulation of chromatin ubiquitylation and tumorigenesis through Mel18 phosphorylation. Oncogene 2021; 40:2422-2436. [PMID: 33664452 DOI: 10.1038/s41388-020-01602-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 11/25/2020] [Accepted: 12/03/2020] [Indexed: 01/31/2023]
Abstract
Polycomb repressor complex 1 (PRC1) is linked to the regulation of gene expression and histone ubiquitylation conformation, which contributes to carcinogenesis. However, the upstream regulators of PRC1 biogenesis machinery remain obscure. Here, we report that the polycomb group-related mammalian gene Mel18 is a target of the protein kinase AKT. AKT phosphorylates Mel18 at T334 to disrupt the interaction between Mel18 and other PRC1 members, leading to attenuated PRC1-dependent ubiquitylation of histone H2A at Lys119. As such, PRC1 target genes, many of which are known oncogenes, are derepressed upon T334-Mel18 phosphorylation, which promotes malignant behaviours, including cell proliferation, tumour formation, migration and invasion, bone and brain metastatic lesion formation. Notably, a positive correlation between AKT activity and pT334-Mel18 is observed, and prognostic models based on p-AKT and pT334-Mel18 that predicted overall survival and distant metastasis-free survival in breast cancer patients are established. These findings have implications for understanding the role of AKT and its associated proteins in chromatin ubiquitylation, and also indicate the AKT-Mel18-H2AK119ub axis as a novel prognostic biomarker and therapeutic target for cancer patients.
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Hao N, Shen W, Du R, Jiang S, Zhu J, Chen Y, Huang C, Shi Y, Xiang R, Luo Y. Phosphodiesterase 3A Represents a Therapeutic Target that Drives Stem Cell–like Property and Metastasis in Breast Cancer. Mol Cancer Ther 2019; 19:868-881. [PMID: 31871268 DOI: 10.1158/1535-7163.mct-18-1233] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 02/19/2019] [Accepted: 12/03/2019] [Indexed: 11/16/2022]
MESH Headings
- Animals
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Breast Neoplasms/drug therapy
- Breast Neoplasms/enzymology
- Breast Neoplasms/pathology
- Breast Neoplasms/secondary
- Cell Proliferation
- Cilostazol/pharmacology
- Cyclic Nucleotide Phosphodiesterases, Type 3/chemistry
- Cyclic Nucleotide Phosphodiesterases, Type 3/genetics
- Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism
- Female
- Gene Expression Regulation, Enzymologic/drug effects
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Microfilament Proteins/metabolism
- Middle Aged
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/enzymology
- Neoplastic Stem Cells/metabolism
- Phosphodiesterase 3 Inhibitors/pharmacology
- Prognosis
- Protein Transport
- Signal Transduction
- Tumor Cells, Cultured
- Vesicular Transport Proteins/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Na Hao
- Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Immunology, School of Medicine, Nankai University, Tianjin, China
- Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College, Beijing, China
- International Joint Center for Biomedical Research of the Ministry of Education, Tianjin, China
| | - Wenzhi Shen
- Department of Immunology, School of Medicine, Nankai University, Tianjin, China
- Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College, Beijing, China
- Department of Pathology and Institute of Precision Medicine, Jining Medical University, Jining, China
| | - Renle Du
- Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shan Jiang
- Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Junyong Zhu
- Department of Galactophore, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Yanan Chen
- Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Chongbiao Huang
- Senior Ward, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research, Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Yi Shi
- Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Rong Xiang
- Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Immunology, Institute of Basic Medical Science, Chinese Academy of Medical Science, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Yunping Luo
- Department of Immunology, School of Medicine, Nankai University, Tianjin, China.
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Kasamatsu A, Uzawa K, Hayashi F, Kita A, Okubo Y, Saito T, Kimura Y, Miyamoto I, Oka N, Shiiba M, Ito C, Toshimori K, Miki T, Yamauchi M, Tanzawa H. Deficiency of lysyl hydroxylase 2 in mice causes systemic endoplasmic reticulum stress leading to early embryonic lethality. Biochem Biophys Res Commun 2019; 512:486-491. [DOI: 10.1016/j.bbrc.2019.03.091] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 03/16/2019] [Indexed: 10/27/2022]
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Anti-platelet treatments in cancer: Basic and clinical research. Thromb Res 2018; 164 Suppl 1:S106-S111. [PMID: 29703466 DOI: 10.1016/j.thromres.2017.12.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 12/27/2017] [Indexed: 02/07/2023]
Abstract
Over the past few decades the central role that platelets play in cancer development and progression, and especially in metastasis, has been elucidated. The molecular mechanisms responsible for initiating and mediating tumor cell-induced platelet aggregation and secretion have been largely unravelled. Considerable mechanistic insight into how platelets contribute to tumor angiogenesis, immunoevasion and cancer cell invasion have been clarified and, consequently, platelets have been identified as potential new drug targets for cancer therapy. This article gives an overview of the platelet-targeted pharmacologic approaches that have been attempted in the prevention of cancer development, progression and metastasis, including the application of antiplatelet drugs currently used for cardiovascular disease and of new and novel strategies.
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Ravindranathan P, Pasham D, Balaji U, Cardenas J, Gu J, Toden S, Goel A. A combination of curcumin and oligomeric proanthocyanidins offer superior anti-tumorigenic properties in colorectal cancer. Sci Rep 2018; 8:13869. [PMID: 30218018 PMCID: PMC6138725 DOI: 10.1038/s41598-018-32267-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 08/31/2018] [Indexed: 01/02/2023] Open
Abstract
Combining anti-cancer agents in cancer therapies is becoming increasingly popular due to improved efficacy, reduced toxicity and decreased emergence of resistance. Here, we test the hypothesis that dietary agents such as oligomeric proanthocyanidins (OPCs) and curcumin cooperatively modulate cancer-associated cellular mechanisms to inhibit carcinogenesis. By a series of in vitro assays in colorectal cancer cell lines, we showed that the anti-tumorigenic properties of the OPCs-curcumin combination were superior to the effects of individual compounds. By RNA-sequencing based gene-expression profiling in six colorectal cancer cell lines, we identified the cooperative modulation of key cancer-associated pathways such as DNA replication and cell cycle pathways. Moreover, several pathways, including protein export, glutathione metabolism and porphyrin metabolism were more effectively modulated by the combination of OPCs and curcumin. We validated genes belonging to these pathways, such as HSPA5, SEC61B, G6PD, HMOX1 and PDE3B to be cooperatively modulated by the OPCs-curcumin combination. We further confirmed that the OPCs-curcumin combination more potently suppresses colorectal carcinogenesis and modulated expression of genes identified by RNA-sequencing in mice xenografts and in colorectal cancer patient-derived organoids. Overall, by delineating the cooperative mechanisms of action of OPCs and curcumin, we make a case for the clinical co-administration of curcumin and OPCs as a treatment therapy for patients with colorectal cancer.
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Affiliation(s)
- Preethi Ravindranathan
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
| | - Divya Pasham
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
| | - Uthra Balaji
- Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Jacob Cardenas
- Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Jinghua Gu
- Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Shusuke Toden
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA.
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Wang S, Li Z, Xu R. Human Cancer and Platelet Interaction, a Potential Therapeutic Target. Int J Mol Sci 2018; 19:ijms19041246. [PMID: 29677116 PMCID: PMC5979598 DOI: 10.3390/ijms19041246] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 03/30/2018] [Accepted: 04/16/2018] [Indexed: 12/12/2022] Open
Abstract
Cancer patients experience a four-fold increase in thrombosis risk, indicating that cancer development and progression are associated with platelet activation. Xenograft experiments and transgenic mouse models further demonstrate that platelet activation and platelet-cancer cell interaction are crucial for cancer metastasis. Direct or indirect interaction of platelets induces cancer cell plasticity and enhances survival and extravasation of circulating cancer cells during dissemination. In vivo and in vitro experiments also demonstrate that cancer cells induce platelet aggregation, suggesting that platelet-cancer interaction is bidirectional. Therefore, understanding how platelets crosstalk with cancer cells may identify potential strategies to inhibit cancer metastasis and to reduce cancer-related thrombosis. Here, we discuss the potential function of platelets in regulating cancer progression and summarize the factors and signaling pathways that mediate the cancer cell-platelet interaction.
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Affiliation(s)
- Shike Wang
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
| | - Zhenyu Li
- Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, University of Kentucky, 741 South Limestone Street, Lexington, KY 40536, USA.
| | - Ren Xu
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
- Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, KY 40536, USA.
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Gresele P, Momi S, Malvestiti M, Sebastiano M. Platelet-targeted pharmacologic treatments as anti-cancer therapy. Cancer Metastasis Rev 2018; 36:331-355. [PMID: 28707198 DOI: 10.1007/s10555-017-9679-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Platelets act as multifunctional cells participating in immune response, inflammation, allergy, tissue regeneration, and lymphoangiogenesis. Among the best-established aspects of a role of platelets in non-hemostatic or thrombotic disorders, there is their participation in cancer invasion and metastasis. The interaction of many different cancer cells with platelets leads to platelet activation, and on the other hand platelet activation is strongly instrumental to the pro-carcinogenic and pro-metastatic activities of platelets. It is thus obvious that over the last years a lot of interest has focused on the possible chemopreventive effect of platelet-targeted pharmacologic treatments. This article gives an overview of the platelet-targeted pharmacologic approaches that have been attempted in the prevention of cancer development, progression, and metastasis, including the application of anti-platelet drugs currently used for cardiovascular disease and of new and novel pharmacologic strategies. Despite the fact that very promising results have been obtained with some of these approaches in pre-clinical models, with the exclusion of aspirin, clinical evidence of a beneficial effect of anti-platelet agents in cancer is however still largely missing. Future studies with platelet-targeted drugs in cancer must carefully deal with design issues, and in particular with the careful selection of patients, and/or explore novel platelet targets in order to provide a solution to the critical issue of the risk/benefit profile of long-term anti-platelet therapy in the prevention of cancer progression and dissemination.
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Affiliation(s)
- P Gresele
- Section of Internal and Cardiovascular Medicine, Department of Medicine, University of Perugia, Via Enrico dal Pozzo, 06126, Perugia, Italy.
| | - S Momi
- Section of Internal and Cardiovascular Medicine, Department of Medicine, University of Perugia, Via Enrico dal Pozzo, 06126, Perugia, Italy
| | - M Malvestiti
- Section of Internal and Cardiovascular Medicine, Department of Medicine, University of Perugia, Via Enrico dal Pozzo, 06126, Perugia, Italy
| | - M Sebastiano
- Section of Internal and Cardiovascular Medicine, Department of Medicine, University of Perugia, Via Enrico dal Pozzo, 06126, Perugia, Italy
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Peng T, Gong J, Jin Y, Zhou Y, Tong R, Wei X, Bai L, Shi J. Inhibitors of phosphodiesterase as cancer therapeutics. Eur J Med Chem 2018; 150:742-756. [PMID: 29574203 DOI: 10.1016/j.ejmech.2018.03.046] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 02/26/2018] [Accepted: 03/16/2018] [Indexed: 01/05/2023]
Abstract
Phosphodiesterases (PDEs) are a class of enzymes that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which is involved in many physiological processes including visual transduction, cell proliferation and differentiation, cell-cycle regulation, gene expression, inflammation, apoptosis, and metabolic function. PDEs are composed of 11 different families and each family contains different subtypes. The distribution, expression, regulation mode and sensitivity to inhibitors of each subtype are different, and they are involved in cancer, inflammation, asthma, depression, erectile dysfunction and other pathological processes of development. A large number of studies have shown that PDEs play an important role in the development of tumors by affecting the intracellular level of cAMP and/or cGMP and PDEs could become diagnostic markers or therapeutic targets. This review will give a brief overview of the expression and regulation of PDE families in the process of tumorigenesis and their anti-tumor inhibitors, which may guide the design of novel therapeutic drugs targeting PDEs for anticancer agent.
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Affiliation(s)
- Ting Peng
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Jun Gong
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Yongzhe Jin
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Yanping Zhou
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Rongsheng Tong
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Xin Wei
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Lan Bai
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Jianyou Shi
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, Chengdu, 610072, China.
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16
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Kachroo P, Szymczak S, Heinsen FA, Forster M, Bethune J, Hemmrich-Stanisak G, Baker L, Schrappe M, Stanulla M, Franke A. NGS-based methylation profiling differentiates TCF3-HLF and TCF3-PBX1 positive B-cell acute lymphoblastic leukemia. Epigenomics 2018; 10:133-147. [DOI: 10.2217/epi-2017-0080] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim: To determine whether methylation differences between mostly fatal TCF3-HLF and curable TCF3-PBX1 pediatric acute lymphoblastic leukemia subtypes can be associated with differential gene expression and remission. Materials & methods: Five (extremely rare) TCF3-HLF versus five (very similar) TCF3-PBX1 patients were sampled before and after remission and analyzed using reduced representation bisulfite sequencing and RNA-sequencing. Results: We identified 7000 differentially methylated CpG sites between subtypes, of which 78% had lower methylation levels in TCF3-HLF. Gene expression was negatively correlated with CpG sites in 23 genes. KBTBD11 clearly differed in methylation and expression between subtypes and before and after remission in TCF3-HLF samples. Conclusion: KBTBD11 hypomethylation may be a promising potential target for further experimental validation especially for the TCF3-HLF subtype.
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Affiliation(s)
- Priyadarshini Kachroo
- Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel 24105, Germany
- Channing Laboratory, Department of Medicine, Brigham & Women's Hospital & Harvard Medical School, Boston, MA 02115, USA
| | - Silke Szymczak
- Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel 24105, Germany
- Institute of Medical Informatics & Statistics, Christian Albrechts University of Kiel, Kiel 24105, Germany
| | - Femke-Anouska Heinsen
- Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel 24105, Germany
| | - Michael Forster
- Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel 24105, Germany
| | - Jörn Bethune
- Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel 24105, Germany
| | - Georg Hemmrich-Stanisak
- Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel 24105, Germany
| | - Lewis Baker
- Department of Applied Mathematics, University of Colorado, Boulder, CO 80309, USA
| | - Martin Schrappe
- Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel 24105, Germany
| | - Martin Stanulla
- Pediatric Hematology & Oncology, Hannover Medical School, Hannover 30625, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel 24105, Germany
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17
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Feigin ME, Garvin T, Bailey P, Waddell N, Chang DK, Kelley DR, Shuai S, Gallinger S, McPherson JD, Grimmond SM, Khurana E, Stein LD, Biankin AV, Schatz MC, Tuveson DA. Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma. Nat Genet 2017; 49:825-833. [PMID: 28481342 PMCID: PMC5659388 DOI: 10.1038/ng.3861] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 04/10/2017] [Indexed: 12/15/2022]
Abstract
The contributions of coding mutations to tumorigenesis are relatively well known; however, little is known about somatic alterations in noncoding DNA. Here we describe GECCO (Genomic Enrichment Computational Clustering Operation) to analyze somatic noncoding alterations in 308 pancreatic ductal adenocarcinomas (PDAs) and identify commonly mutated regulatory regions. We find recurrent noncoding mutations to be enriched in PDA pathways, including axon guidance and cell adhesion, and newly identified processes, including transcription and homeobox genes. We identified mutations in protein binding sites correlating with differential expression of proximal genes and experimentally validated effects of mutations on expression. We developed an expression modulation score that quantifies the strength of gene regulation imposed by each class of regulatory elements, and found the strongest elements were most frequently mutated, suggesting a selective advantage. Our detailed single-cancer analysis of noncoding alterations identifies regulatory mutations as candidates for diagnostic and prognostic markers, and suggests new mechanisms for tumor evolution.
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Affiliation(s)
- Michael E Feigin
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
- Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York, USA
| | - Tyler Garvin
- Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
| | - Peter Bailey
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK
| | - Nicola Waddell
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - David K Chang
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK
- The Kinghorn Cancer Centre, Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia
- Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia
- South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales, Australia
| | - David R Kelley
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA
| | - Shimin Shuai
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Steven Gallinger
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Division of General Surgery, Toronto General Hospital, Toronto, Ontario, Canada
| | - John D McPherson
- Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Sean M Grimmond
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK
- Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
| | - Ekta Khurana
- Sandra and Edward Meyer Cancer Center, Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA
| | - Lincoln D Stein
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- Informatics and Biocomputing, Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Andrew V Biankin
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK
- South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales, Australia
- West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland, UK
| | - Michael C Schatz
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
- Department of Computer Science, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA
| | - David A Tuveson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
- Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York, USA
- Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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18
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Xie XQ, Zhao QH, Wang H, Gu KS. Dysregulation of mRNA profile in cisplatin-resistant gastric cancer cell line SGC7901. World J Gastroenterol 2017; 23:1189-1202. [PMID: 28275299 PMCID: PMC5323444 DOI: 10.3748/wjg.v23.i7.1189] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Revised: 11/24/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To explore novel therapeutic target of cisplatin resistance in human gastric cancer.
METHODS The sensitivity of SGC7901 cells and cisplatin-resistant SGC7901 cells (SGC7901/DDP) for cisplatin were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. High-quality total RNA which isolated from SGC7901/DDP cells and SGC7901 cells were used for mRNA microarray analysis. Results were analyzed bioinformatically to predict their roles in the development of cisplatin resistance and the expression of 13 dysregulated mRNAs we selected were validated by quantitative real-time polymerase chain reaction (qRT-PCR).
RESULTS SGC7901/DDP cells highly resistant to cisplatin demonstrated by MTT assay. A total of 1308 mRNAs (578 upregulated and 730 downregulated) were differentially expressed (fold change ≥ 2 and P-value < 0.05) in the SGC7901/DDP cells compared with SGC7901 cells. The expression of mRNAs detected by qRT-PCR were consistent with the microarray results. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway and protein-protein interaction analysis demonstrated that the differentially expressed mRNAs were enriched in PI3K-Akt, Notch, MAPK, ErbB, Jak-STAT, NF-kappaB signaling pathways which may be involved in cisplatin resistance. Several genes such as PDE3B, VEGFC, IGFBP3, TLR4, HIPK2 and EGF may associated with drug resistance of gastric cancer cells to cisplatin.
CONCLUSION Exploration of those altered mRNAs may provide more promising strategy in diagnosis and therapy for gastric cancer with cisplatin resistance.
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Chao TH, Chen IC, Lee CH, Chen JY, Tsai WC, Li YH, Tseng SY, Tsai LM, Tseng WK. Cilostazol Enhances Mobilization of Circulating Endothelial Progenitor Cells and Improves Endothelium-Dependent Function in Patients at High Risk of Cardiovascular Disease. Angiology 2016; 67:638-46. [DOI: 10.1177/0003319715606249] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
This is the first study to investigate the vasculoangiogenic effects of cilostazol on endothelial progenitor cells (EPCs) and flow-mediated dilatation (FMD) in patients at high risk of cardiovascular disease (CVD). This double-blind, placebo-controlled study included 71 patients (37 received 200 mg/d cilostazol and 34 received placebo for 12 weeks). Use of cilostazol, but not placebo, significantly increased circulating EPC (kinase insert domain receptor+CD34+) counts (percentage changes: 149.0% [67.9%-497.8%] vs 71.9% [−31.8% to 236.5%], P = .024) and improved triglyceride and high-density lipoprotein cholesterol levels ( P = .002 and P = .003, respectively). Plasma levels of vascular endothelial growth factor (VEGF)-A165 and FMD significantly increased (72.5% [32.9%-120.4%] vs −5.8% [−46.0% to 57.6%], P = .001; 232.8% ± 83.1% vs −46.9% ± 21.5%, P = .003, respectively) in cilostazol-treated patients. Changes in the plasma triglyceride levels significantly inversely correlated with the changes in the VEGF-A165 levels and FMD. Cilostazol significantly enhanced the mobilization of EPCs and improved endothelium-dependent function by modifying some metabolic and angiogenic markers in patients at high risk of CVD.
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Affiliation(s)
- Ting-Hsing Chao
- Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan
| | - I-Chih Chen
- Department of Internal Medicine, Tainan Municipal Hospital, Tainan, Taiwan
| | - Cheng-Han Lee
- Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan
| | - Ju-Yi Chen
- Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan
| | - Wei-Chuan Tsai
- Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan
| | - Yi-Heng Li
- Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan
| | - Shih-Ya Tseng
- Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan
- Department of Biological Science, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Liang-Miin Tsai
- Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan
| | - Wei-Kung Tseng
- Division of Cardiology, Department of Internal Medicine, E-Da University College of Medicine and Hospital, Kaohsiung, Taiwan
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Tanzawa H, Uzawa K, Kasamatsu A, Endo-Sakamoto Y, Saito K, Ogawara K, Shiiba M. Targeting gene therapies enhance sensitivity to chemo- and radiotherapy of human oral squamous cell carcinoma. ACTA ACUST UNITED AC 2015. [DOI: 10.1016/s1348-8643(15)00020-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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21
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Fukumoto C, Nakashima D, Kasamatsu A, Unozawa M, Shida-Sakazume T, Higo M, Ogawara K, Yokoe H, Shiiba M, Tanzawa H, Uzawa K. WWP2 is overexpressed in human oral cancer, determining tumor size and poor prognosis in patients: downregulation of WWP2 inhibits the AKT signaling and tumor growth in mice. Oncoscience 2014; 1:807-20. [PMID: 25621296 PMCID: PMC4303889 DOI: 10.18632/oncoscience.101] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 11/27/2014] [Indexed: 01/14/2023] Open
Abstract
The WW domain containing E3 ubiquitin protein ligase 2 (WWP2) encodes a member of the Nedd4 family of E3 ligases, which catalyzes the final step of the ubiquitination cascade. WWP2 is involved in tumoral growth with degradation of the tumor suppressor phosphatase and tensin homologue deleted on chromosome TEN (PTEN). However, little is known about the mechanisms and roles of WWP2 in human malignancies including oral squamous cell carcinomas (OSCCs). We found frequent WWP2 overexpression in all OSCC-derived cell lines examined that was associated with cellular growth by accelerating the cell cycle in the G1 phase via degradation of PTEN and activation of the PI3K/AKT signaling pathway. Our in vivo data of WWP2 silencing showed dramatic inhibition of tumoral growth with increased expression of PTEN. Our 104 primary OSCCs had significantly higher expression of WWP2 than their normal counterparts. Moreover, among the clinical variables analyzed, enhanced WWP2 expression was correlated with primary tumoral size and poor prognosis. These data suggested that WWP2 overexpression contributes to neoplastic promotion via the PTEN/PI3K/AKT pathway in OSCCs. WWP2 is likely to be a biomarker of tumoral progression and prognosis and a potential therapeutic target for development of anticancer drugs in OSCCs.
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Affiliation(s)
- Chonji Fukumoto
- Department of Oral Science, Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba, Japan
| | - Dai Nakashima
- Department of Oral Science, Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba, Japan
| | - Atsushi Kasamatsu
- Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Inohana, Chuo-ku, Chiba, Japan
| | - Motoharu Unozawa
- Department of Oral Science, Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba, Japan
| | - Tomomi Shida-Sakazume
- Department of Oral Science, Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba, Japan
| | - Morihiro Higo
- Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Inohana, Chuo-ku, Chiba, Japan
| | - Katsunori Ogawara
- Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Inohana, Chuo-ku, Chiba, Japan
| | - Hidetaka Yokoe
- Department of Oral and Maxillofacial Surgery Research Institute, National Defense Medical College Hospital, Tokorozawa, Japan
| | - Masashi Shiiba
- Department of Medical Oncology, Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba, Japan
| | - Hideki Tanzawa
- Department of Oral Science, Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba, Japan ; Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Inohana, Chuo-ku, Chiba, Japan
| | - Katsuhiro Uzawa
- Department of Oral Science, Graduate School of Medicine, Chiba University, Inohana, Chuo-ku, Chiba, Japan ; Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Inohana, Chuo-ku, Chiba, Japan
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Ahmad F, Murata T, Shimizu K, Degerman E, Maurice D, Manganiello V. Cyclic nucleotide phosphodiesterases: important signaling modulators and therapeutic targets. Oral Dis 2014; 21:e25-50. [PMID: 25056711 DOI: 10.1111/odi.12275] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 07/09/2014] [Indexed: 02/06/2023]
Abstract
By catalyzing hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. As these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A, and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multimolecular signaling/regulatory complexes, called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners.
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Affiliation(s)
- F Ahmad
- Cardiovascular and Pulmonary Branch, National Heart, Lung and Blood Institute, Bethesda, MD, USA
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