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Zhao LX, Zhang K, Shen BB, Li JN. Mesenchymal stem cell-derived exosomes for gastrointestinal cancer. World J Gastrointest Oncol 2021; 13:1981-1996. [PMID: 35070036 PMCID: PMC8713327 DOI: 10.4251/wjgo.v13.i12.1981] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/15/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) malignancies, a series of malignant conditions originating from the digestive system, include gastric cancer, hepatocellular carcinoma, pancreatic cancer, and colorectal cancer. GI cancers have been regarded as the leading cancer-related cause of death in recent years. Therefore, it is essential to develop effective treatment strategies for GI malignancies. Mesenchymal stem cells (MSCs), a type of distinct non-hematopoietic stem cells and an important component of the tumor microenvironment, play important roles in regulating GI cancer development and progression through multiple mechanisms, such as secreting cytokines and direct interactions. Currently, studies are focusing on the anti-cancer effect of MSCs on GI malignancies. However, the effects and functional mechanisms of MSC-derived exosomes on GI cancer are less studied. MSC-derived exosomes can regulate GI tumor growth, drug response, metastasis, and invasion through transplanting proteins and miRNA to tumor cells to activate the specific signal pathway. Besides, the MSC-derived exosomes are also seen as an important drug delivery system and have shown potential in anti-cancer treatment. This study aims to summarize the effect and biological functions of MSC-derived exosomes on the development of GI cancers and discuss their possible clinical applications for the treatment of GI malignancies.
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Affiliation(s)
- Lin-Xian Zhao
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Kai Zhang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
| | - Bing-Bing Shen
- Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Jian-Nan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
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2
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Montero J, Gstalder C, Kim DJ, Sadowicz D, Miles W, Manos M, Cidado JR, Paul Secrist J, Tron AE, Flaherty K, Stephen Hodi F, Yoon CH, Letai A, Fisher DE, Haq R. Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies. Nat Commun 2019; 10:5157. [PMID: 31727958 PMCID: PMC6856172 DOI: 10.1038/s41467-019-12477-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 08/06/2019] [Indexed: 12/15/2022] Open
Abstract
Most targeted cancer therapies fail to achieve complete tumor regressions or attain durable remissions. To understand why these treatments fail to induce robust cytotoxic responses despite appropriately targeting oncogenic drivers, here we systematically interrogated the dependence of cancer cells on the BCL-2 family of apoptotic proteins after drug treatment. We observe that multiple targeted therapies, including BRAF or EGFR inhibitors, rapidly deplete the pro-apoptotic factor NOXA, thus creating a dependence on the anti-apoptotic protein MCL-1. This adaptation requires a pathway leading to destabilization of the NOXA mRNA transcript. We find that interruption of this mechanism of anti-apoptotic adaptive resistance dramatically increases cytotoxic responses in cell lines and a murine melanoma model. These results identify NOXA mRNA destabilization/MCL-1 adaptation as a non-genomic mechanism that limits apoptotic responses, suggesting that sequencing of MCL-1 inhibitors with targeted therapies could overcome such widespread and clinically important resistance. MAPK-targeted therapies fail to achieve complete remission. Here, the authors show that anti-apoptosis resistance is acquired in these targeted therapies through the mRNA destabilization of NOXA which leads to dependence on MCL-1, and that sequential combination of MCL-1 inhibition with targeted therapies overcomes this resistance.
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Affiliation(s)
- Joan Montero
- Division of Hematologic Neoplasia/Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA.,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA.,Institute for Bioengineering of Catalonia, C/Baldiri Reixac 15-21, Ed. Hèlix 3ª planta · 08028, Barcelona, Spain
| | - Cécile Gstalder
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA.,Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA
| | - Daniel J Kim
- Department of Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, 44 Fruit Street, Boston, MA, 02114, USA
| | - Dorota Sadowicz
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA.,Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA
| | - Wayne Miles
- Department of Molecular Genetics, The Ohio State University, 820 Biomedical Research Tower 460 West 12th Avenue, Columbus, 43210, OH, USA
| | - Michael Manos
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA
| | - Justin R Cidado
- Bioscience, Oncology IMED Biotech Unit, AstraZeneca, 35 Gatehouse Dr, Waltham, Boston, 02451, MA, USA
| | - J Paul Secrist
- Bioscience, Oncology IMED Biotech Unit, AstraZeneca, 35 Gatehouse Dr, Waltham, Boston, 02451, MA, USA.,LifeMine Therapeutics, 100 Acorn Park Drive, 6th Floor Cambridge, Cambridge, MA, 02140, USA
| | - Adriana E Tron
- Bioscience, Oncology IMED Biotech Unit, AstraZeneca, 35 Gatehouse Dr, Waltham, Boston, 02451, MA, USA
| | - Keith Flaherty
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, 44 Fruit Street, Boston, MA, 02114, USA
| | - F Stephen Hodi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA
| | - Charles H Yoon
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, 02115, USA
| | - Anthony Letai
- Division of Hematologic Neoplasia/Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA.,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA
| | - David E Fisher
- Department of Dermatology and Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, 44 Fruit Street, Boston, MA, 02114, USA. .,Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, 44 Fruit Street, Boston, MA, 02114, USA.
| | - Rizwan Haq
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA. .,Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, 02115, MA, USA.
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Yi Y, Liu Y, Wu W, Wu K, Zhang W. The role of miR-106p-5p in cervical cancer: from expression to molecular mechanism. Cell Death Discov 2018; 4:36. [PMID: 30275981 PMCID: PMC6148547 DOI: 10.1038/s41420-018-0096-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 07/29/2018] [Accepted: 08/06/2018] [Indexed: 02/06/2023] Open
Abstract
This study aims to investigate the role of miR-106b-5p in cervical cancer by performing a comprehensive analysis on its expression and identifying its putative molecular targets and pathways based on The Cancer Genome Atlas (TCGA) dataset, Gene Expression Omnibus (GEO) dataset, and literature review. Significant upregulation of miR-106b-5p in cervical cancer is confirmed by meta-analysis with the data from TCGA, GEO, and literature. Moreover, the expression of miR-106b-5p is significantly correlated with the number of metastatic lymph nodes. Our bioinformatics analyses show that miR-106b could promote cervical cancer progression by modulating the expression of GSK3B, VEGFA, and PTK2 genes. Importantly, these three genes play a crucial role in PI3K-Akt signaling, focal adhesion, and cancer. Both the expression of miR-106b-5p and key genes are upregulated in cervical cancer. Several explanations could be implemented for this upregulation. However, the specific mechanism needs to be investigated further.
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Affiliation(s)
- Yuexiong Yi
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei People's Republic of China
| | - Yanyan Liu
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei People's Republic of China
| | - Wanrong Wu
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei People's Republic of China
| | - Kejia Wu
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei People's Republic of China
| | - Wei Zhang
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071 Hubei People's Republic of China
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The control of inflammation via the phosphorylation and dephosphorylation of tristetraprolin: a tale of two phosphatases. Biochem Soc Trans 2017; 44:1321-1337. [PMID: 27911715 PMCID: PMC5095909 DOI: 10.1042/bst20160166] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 07/25/2016] [Accepted: 07/28/2016] [Indexed: 12/14/2022]
Abstract
Twenty years ago, the first description of a tristetraprolin (TTP) knockout mouse highlighted the fundamental role of TTP in the restraint of inflammation. Since then, work from several groups has generated a detailed picture of the expression and function of TTP. It is a sequence-specific RNA-binding protein that orchestrates the deadenylation and degradation of several mRNAs encoding inflammatory mediators. It is very extensively post-translationally modified, with more than 30 phosphorylations that are supported by at least two independent lines of evidence. The phosphorylation of two particular residues, serines 52 and 178 of mouse TTP (serines 60 and 186 of the human orthologue), has profound effects on the expression, function and localisation of TTP. Here, we discuss the control of TTP biology via its phosphorylation and dephosphorylation, with a particular focus on recent advances and on questions that remain unanswered.
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Hao GM, Lv TT, Wu Y, Wang HL, Xing W, Wang Y, Li C, Zhang ZJ, Wang ZL, Wang W, Han J. The Hippo signaling pathway: a potential therapeutic target is reversed by a Chinese patent drug in rats with diabetic retinopathy. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:187. [PMID: 28372586 PMCID: PMC5379696 DOI: 10.1186/s12906-017-1678-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 03/11/2017] [Indexed: 01/12/2023]
Abstract
BACKGROUND The Hippo signaling pathway is reported to be involved in angiogenesis, but the roles of the Hippo pathway in diabetic retinopathy have not been addressed. Fufang Xueshuantong Capsule has been used to treat diabetic retinopathy in China; however, the effect of Fufang Xueshuantong Capsule on the Hippo pathway has not been investigated. METHODS In this study, diabetes was induced in Sprague-Dawley rats with intraperitoneal injection of streptozotocin. Twenty weeks later, Fufang Xueshuantong Capsule was administered for 12 weeks. When the administration ended, the eyes were isolated for western blot and immunohistochemistry analyses. The levels of P- mammalian sterile 20-like (MST), large tumor suppressor homolog (Lats), P- yes-associated protein (YAP), transcriptional co-activator with PDZ binding motif (TAZ) and TEA domain family members (TEAD) were measured. RESULTS Diabetic rats had a decreased P-MST level in the inner plexiform layer and reduced expression of P-YAP in the photoreceptor layers of their eyes. In addition, diabetic rats displayed remarkable increases in Lats, TAZ and TEAD in their retinas. Furthermore, Fufang Xueshuantong Capsule restored the changes in the Hippo pathway. CONCLUSIONS The Hippo signaling pathway is important for the progression of diabetic retinopathy and will hopefully be a targeted therapeutic approach for the prevention of diabetic retinopathy.
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6
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Dysregulation of TTP and HuR plays an important role in cancers. Tumour Biol 2016; 37:14451-14461. [DOI: 10.1007/s13277-016-5397-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 09/09/2016] [Indexed: 12/16/2022] Open
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Abstract
Chronic inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are clinically and socioeconomically important diseases globally. Currently the mainstay of anti-inflammatory therapy in respiratory diseases is corticosteroids. Although corticosteroids have proven clinical efficacy in asthma, many asthmatic inflammatory conditions (e.g., infection, exacerbation, and severe asthma) are not responsive to corticosteroids. Moreover, despite an understanding that COPD progression is driven by inflammation, we currently do not have effective anti-inflammatory strategies to combat this disease. Hence, alternative anti-inflammatory strategies are required. p38 mitogen-activated protein kinase (MAPK) has emerged as an important signaling molecule driving airway inflammation, and pharmacological inhibitors against p38 MAPK may provide potential therapies for chronic respiratory disease. In this review, we discuss some of the recent in vitro and in vivo studies targeting p38 MAPK, but suggest that p38 MAPK inhibitors may prove less effective than originally considered because they may block anti-inflammatory molecules along with proinflammatory responses. We propose that an alternative strategy may be to target an anti-inflammatory molecule farther downstream of p38 MAPK, i.e., tristetraprolin (TTP). TTP is an mRNA-destabilizing, RNA-binding protein that enhances the decay of mRNAs, including those encoding proteins implicated in chronic respiratory diseases. We suggest that understanding the molecular mechanism of TTP expression and its temporal regulation will guide future development of novel anti-inflammatory pharmacotherapeutic approaches to combat respiratory disease.
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Affiliation(s)
- Pavan Prabhala
- Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia
| | - Alaina J Ammit
- Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia
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Nagashima T, Inoue N, Yumoto N, Saeki Y, Magi S, Volinsky N, Sorkin A, Kholodenko BN, Okada-Hatakeyama M. Feedforward regulation of mRNA stability by prolonged extracellular signal-regulated kinase activity. FEBS J 2015; 282:613-29. [PMID: 25491268 PMCID: PMC4334673 DOI: 10.1111/febs.13172] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 12/03/2014] [Accepted: 12/05/2014] [Indexed: 01/08/2023]
Abstract
Extracellular signal-regulated kinase (ERK) plays a central role in signal transduction networks and cell fate decisions. Sustained ERK activation induces cell differentiation, whereas transient ERK results in the proliferation of several types of cells. Sustained ERK activity stabilizes the proteins of early-response gene products. However, the effect of ERK activity duration on mRNA stability is unknown. We analyzed the quantitative relationship between the duration of four ERK activity kinetics and the mRNA expression profile in growth factor-treated cells. Time-course transcriptome analysis revealed that the cells with prolonged ERK activity generally showed sustained mRNA expression of late response genes but not early or mid genes. Selected late response genes decayed more rapidly in the presence of a specific ERK inhibitor than a general transcription inhibitor and the decay rate was not related to the number of AU-rich elements. Our results suggest that sustained ERK activity plays an important role in the lifespan of the mRNA encoded by late response genes, in addition to the previously demonstrated role in protein stabilization of early-response genes, including transcription factors regulating the transcription of mid and late genes. This double-positive regulation of ligand-induced genes, also termed feedforward regulation, is critical in cell fate decisions.
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Affiliation(s)
- Takeshi Nagashima
- Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS), Tsurumi-ku, Yokohama, Kanagawa, Japan
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9
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Brooks SA, Blackshear PJ. Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action. BIOCHIMICA ET BIOPHYSICA ACTA 2013; 1829:666-79. [PMID: 23428348 PMCID: PMC3752887 DOI: 10.1016/j.bbagrm.2013.02.003] [Citation(s) in RCA: 310] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Revised: 01/25/2013] [Accepted: 02/04/2013] [Indexed: 12/14/2022]
Abstract
Changes in mRNA stability and translation are critical control points in the regulation of gene expression, particularly genes encoding growth factors, inflammatory mediators, and proto-oncogenes. Adenosine and uridine (AU)-rich elements (ARE), often located in the 3' untranslated regions (3'UTR) of mRNAs, are known to target transcripts for rapid decay. They are also involved in the regulation of mRNA stability and translation in response to extracellular cues. This review focuses on one of the best characterized ARE binding proteins, tristetraprolin (TTP), the founding member of a small family of CCCH tandem zinc finger proteins. In this survey, we have reviewed the current status of TTP interactions with mRNA and proteins, and discussed current thinking about TTP's mechanism of action to promote mRNA decay. We also review the proposed regulation of TTP's functions by phosphorylation. Finally, we have discussed emerging evidence for TTP operating as a translational regulator. This article is part of a Special Issue entitled: RNA Decay mechanisms.
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Affiliation(s)
- Seth A. Brooks
- Veterans Affairs Medical Center, White River Junction, Vermont, USA
- Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA
| | - Perry J. Blackshear
- The Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
- Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina USA
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10
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Ross CR, Brennan-Laun SE, Wilson GM. Tristetraprolin: roles in cancer and senescence. Ageing Res Rev 2012; 11:473-84. [PMID: 22387927 DOI: 10.1016/j.arr.2012.02.005] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Revised: 02/09/2012] [Accepted: 02/10/2012] [Indexed: 12/17/2022]
Abstract
Cancer and senescence are both complex transformative processes that dramatically alter many features of cell physiology and their interactions with surrounding tissues. Developing the wide range of cellular features characteristic of these conditions requires profound alterations in global gene expression patterns, which can be achieved by suppressing, activating, or uncoupling cellular gene regulatory pathways. Many genes associated with the initiation and development of tumors are regulated at the level of mRNA decay, frequently through the activity of AU-rich mRNA-destabilizing elements (AREs) located in their 3'-untranslated regions. As such, cellular factors that recognize and control the decay of ARE-containing mRNAs can influence tumorigenic or senescent phenotypes mediated by products of these transcripts. In this review, we discuss evidence showing how suppressed expression and/or activity of the ARE-binding protein tristetraprolin (TTP) can contribute to these processes. Next, we outline current findings linking TTP suppression to exacerbation of individual tumorigenic phenotypes, and the roles of specific TTP substrate mRNAs in mediating these effects. Finally, we survey potential mechanisms that cells may employ to suppress TTP expression in cancer, and propose potential diagnostic and therapeutic strategies that may exploit the relationship between TTP expression and tumor progression or senescence.
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Affiliation(s)
- Christina R Ross
- Department of Biochemistry and Molecular Biology and Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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Miller BW, Hay JM, Prigent SA, Dickens M. Post-transcriptional regulation of VEGF-A mRNA levels by mitogen-activated protein kinases (MAPKs) during metabolic stress associated with ischaemia/reperfusion. Mol Cell Biochem 2012; 367:31-42. [PMID: 22562302 DOI: 10.1007/s11010-012-1316-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2011] [Accepted: 04/18/2012] [Indexed: 01/11/2023]
Abstract
Angiogenesis is a well-characterised response to the metabolic stresses that occur during ischaemia/reperfusion, but the signalling pathways that regulate it are poorly understood. We tested whether activation of mitogen-activated protein kinases (MAPKs) was involved in regulating the expression of pro-angiogenic growth factors by the metabolic stresses associated with ischaemia/reperfusion in H9c2 rat cardiomyoblasts. Metabolic stress had no effect on vascular endothelial growth factor (VEGF) mRNA levels, but recovery after metabolic inhibition led to a strong induction of VEGF-A mRNA (3.8 ± 0.5-fold at 4 h), a modest rise in VEGF-C mRNA levels (1.7 ± 0.3-fold at 4 h), with no effect on VEGF-B or -D. A VEGF-A promoter reporter construct was unresponsive to metabolic inhibition/recovery and increases in VEGF-A mRNA were not blocked by the transcription inhibitor actinomycin D suggesting that increases in VEGF mRNA were due to enhanced VEGF-A mRNA stability. In addition, studies using reporter constructs demonstrated that regions within the 5' untranslated region (UTR) contributed to enhanced mRNA stability following recovery from metabolic stress. Increases in VEGF-A mRNA were abolished by inhibition of extracellular signal-regulated kinase or c-jun N-terminal kinase MAPKs, suggesting that these kinases may promote angiogenesis in response to metabolic stress during ischaemia/reperfusion by increasing VEGF-A message stability.
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Affiliation(s)
- Bryan W Miller
- Department of Biochemistry, University of Leicester, Leicester, UK
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Chade AR, Kelsen S. Reversal of renal dysfunction by targeted administration of VEGF into the stenotic kidney: a novel potential therapeutic approach. Am J Physiol Renal Physiol 2012; 302:F1342-50. [PMID: 22357917 DOI: 10.1152/ajprenal.00674.2011] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Renal microvascular (MV) damage and loss contribute to the progression of renal injury in renovascular disease (RVD). Whether a targeted intervention in renal microcirculation could reverse renal damage is unknown. We hypothesized that intrarenal vascular endothelial growth factor (VEGF) therapy will reverse renal dysfunction and decrease renal injury in experimental RVD. Unilateral renal artery stenosis (RAS) was induced in 14 pigs, as a surrogate of chronic RVD. Six weeks later, renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified in vivo in the stenotic kidney using multidetector computed tomography (CT). Then, intrarenal rhVEGF-165 or vehicle was randomly administered into the stenotic kidneys (n = 7/group), they were observed for 4 additional wk, in vivo studies were repeated, and then renal MV density was quantified by 3D micro-CT, and expression of angiogenic factors and fibrosis was determined. RBF and GFR, MV density, and renal expression of VEGF and downstream mediators such as p-ERK 1/2, Akt, and eNOS were significantly reduced after 6 and at 10 wk of untreated RAS compared with normal controls. Remarkably, administration of VEGF at 6 wk normalized RBF (from 393.6 ± 50.3 to 607.0 ± 45.33 ml/min, P < 0.05 vs. RAS) and GFR (from 43.4 ± 3.4 to 66.6 ± 10.3 ml/min, P < 0.05 vs. RAS) at 10 wk, accompanied by increased angiogenic signaling, augmented renal MV density, and attenuated renal scarring. This study shows promising therapeutic effects of a targeted renal intervention, using an established clinically relevant large-animal model of chronic RAS. It also implies that disruption of renal MV integrity and function plays a pivotal role in the progression of renal injury in the stenotic kidney. Furthermore, it shows a high level of plasticity of renal microvessels to a single-dose VEGF-targeted intervention after established renal injury, supporting promising renoprotective effects of a novel potential therapeutic intervention to treat chronic RVD.
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Affiliation(s)
- Alejandro R Chade
- Dept. of Physiology and Biophysics, Dept. of Medicine, Univ. of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216-4505, USA.
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Zhu W, Huang L, Li Y, Zhang X, Gu J, Yan Y, Xu X, Wang M, Qian H, Xu W. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Lett 2011; 315:28-37. [PMID: 22055459 DOI: 10.1016/j.canlet.2011.10.002] [Citation(s) in RCA: 378] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Revised: 09/26/2011] [Accepted: 10/05/2011] [Indexed: 12/18/2022]
Abstract
Mesenchymal stem cells (MSCs) can promote tumor growth in a mouse xenograft model, but the exact mechanism remains unclear. In this study, we investigated the effects of bone marrow MSC-derived exosomes (MSC-exosomes) on tumor growth in vitro and in vivo. Our results showed that MSC-exosomes promoted tumor growth in vivo. MSC-exosomes enhanced vascular endothelial growth factor (VEGF) expression in tumor cells by activating extracellular signal-regulated kinase1/2 (ERK1/2) pathway. Inhibition of ERK1/2 activation reserved the increase of VEGF level by MSC-exosomes. Our findings demonstrate a new mechanism through which MSC-exosome-mediated cell-cell interactions may contribute to tumor progression.
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Affiliation(s)
- Wei Zhu
- School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, China
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14
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He LF, Wang TT, Gao QY, Zhao GF, Huang YH, Yu LK, Hou YY. Stanniocalcin-1 promotes tumor angiogenesis through up-regulation of VEGF in gastric cancer cells. J Biomed Sci 2011; 18:39. [PMID: 21672207 PMCID: PMC3142497 DOI: 10.1186/1423-0127-18-39] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2011] [Accepted: 06/14/2011] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Stanniocalcin-1(STC-1) is up-regulated in several cancers including gastric cancer. Evidences suggest that STC-1 is associated with carcinogenesis and angiogenic process. However, it is unclear on the exact role for STC-1 in inducing angiogenesis and tumorigeneisis. METHOD BGC/STC cells (high-expression of STC-1) and BGC/shSTC cells (low- expression of STC-1) were constructed to investigate the effect of STC-1 on the xenograft tumor growth and angiogenesis in vitro and in vivo. ELISA assay was used to detect the expression of vascular endothelial growth factor (VEGF) in the supernatants. Neutralizing antibody was used to inhibit VEGF expression in supernatants. The expression of phosphorylated -PKCβII, phosphorylated -ERK1/2 and phosphorylated -P38 in the BGC treated with STC-1protein was detected by western blot. RESULTS STC-1 could promote angiogenesis in vitro and in vivo, and the angiogenesis was consistent with VEGF expression in vitro. Inhibition of VEGF expression in supernatants with neutralizing antibody markedly abolished angiogenesis induced by STC-1 in vitro. The process of STC-1-regulated VEGF expression was mediated via PKCβII and ERK1/2. CONCLUSIONS STC-1 promotes the expression of VEGF depended on the activation of PKCβII and ERK1/2 pathways. VEGF subsequently enhances tumor angiogenesis which in turn promotes the gastric tumor growth.
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Affiliation(s)
- Ling-fang He
- Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China
| | - Ting-ting Wang
- Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China
| | - Qian-ying Gao
- Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China
| | - Guang-feng Zhao
- Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China
| | - Ya-hong Huang
- Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China
| | - Li-ke Yu
- First Department of Respiratory Medicine, Nanjing Chest Hospital, 215 Guangzhou Road, Nanjing, PR China
| | - Ya-yi Hou
- Immunology and Reproductive Biology Lab, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China
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Ion channels in inflammation. Pflugers Arch 2011; 461:401-21. [PMID: 21279380 DOI: 10.1007/s00424-010-0917-y] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2010] [Revised: 12/19/2010] [Accepted: 12/19/2010] [Indexed: 12/12/2022]
Abstract
Most physical illness in vertebrates involves inflammation. Inflammation causes disease by fluid shifts across cell membranes and cell layers, changes in muscle function and generation of pain. These disease processes can be explained by changes in numbers or function of ion channels. Changes in ion channels have been detected in diarrhoeal illnesses, pyelonephritis, allergy, acute lung injury and systemic inflammatory response syndromes involving septic shock. The key role played by changes in ion transport is directly evident in inflammation-induced pain. Expression or function of all major categories of ion channels like sodium, chloride, calcium, potassium, transient receptor potential, purinergic receptor and acid-sensing ion channels can be influenced by cyto- and chemokines, prostaglandins, leukotrienes, histamine, ATP, reactive oxygen species and protons released in inflammation. Key pathways in this interaction are cyclic nucleotide, phosphoinositide and mitogen-activated protein kinase-mediated signalling, direct modification by reactive oxygen species like nitric oxide, ATP or protons and disruption of the cytoskeleton. Therapeutic interventions to modulate the adverse and overlapping effects of the numerous different inflammatory mediators on each ion transport system need to target adversely affected ion transport systems directly and locally.
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Nakabayashi H, Shimizu K. HA1077, a Rho kinase inhibitor, suppresses glioma-induced angiogenesis by targeting the Rho-ROCK and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signal pathways. Cancer Sci 2010; 102:393-9. [DOI: 10.1111/j.1349-7006.2010.01794.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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