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1
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Zhao SQ, Zheng HL, Zhong XT, Wang ZY, Su Y, Shi YY. Effects and mechanisms of Helicobacter pylori infection on the occurrence of extra-gastric tumors. World J Gastroenterol 2024; 30:4090-4103. [DOI: 10.3748/wjg.v30.i37.4090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 08/23/2024] [Accepted: 09/12/2024] [Indexed: 09/26/2024] Open
Abstract
Helicobacter pylori (H. pylori) colonizes the human stomach and many studies have discussed the mechanisms of H. pylori infection leading to gastric diseases, including gastric cancer. Additionally, increasing data have shown that the infection of H. pylori may contribute to the development of extra-gastric diseases and tumors. Inflammation, systemic immune responses, microbiome disorders, and hypergastrinemia caused by H. pylori infection are associated with many extra-gastric malignancies. This review highlights recent discoveries; discusses the relationship between H. pylori and various extra-gastric tumors, such as colorectal cancer, lung cancer, cholangiocarcinoma, and gallbladder carcinoma; and explores the mechanisms of extra-gastric carcinogenesis by H. pylori. Overall, these findings refine our understanding of the pathogenic processes of H. pylori, provide guidance for the clinical treatment and management of H. pylori-related extra-gastric tumors, and help improve prognosis.
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Affiliation(s)
- Shi-Qing Zhao
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China
- Health Science Center, Peking University, Beijing 100191, China
| | - Hui-Ling Zheng
- Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China
| | - Xiao-Tian Zhong
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China
- Health Science Center, Peking University, Beijing 100191, China
| | - Zi-Ye Wang
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China
- Health Science Center, Peking University, Beijing 100191, China
| | - Yi Su
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China
- Health Science Center, Peking University, Beijing 100191, China
| | - Yan-Yan Shi
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing 100191, China
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2
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Hwang SJ, Cho SH, Bang HJ, Hong JH, Kim KH, Lee HJ. 1,8-Dihydroxy-3-methoxy-anthraquinone inhibits tumor angiogenesis through HIF-1α downregulation. Biochem Pharmacol 2024; 220:115972. [PMID: 38072164 DOI: 10.1016/j.bcp.2023.115972] [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: 08/18/2023] [Revised: 12/02/2023] [Accepted: 12/05/2023] [Indexed: 12/26/2023]
Abstract
Photorhabdus luminescens is a gram-negative bioluminescent bacterium known as an intestinal bacterium that coexists in the digestive tract of insect-pathogenic nematodes. As part of our ongoing exploration to identify bioactive compounds from diverse natural resources, the chemical analysis of the cultures of P. luminescens KACC 12254 via LC/MS and TLC-based analyses enabled the isolation and identification of a major fluorescent compound. Its chemical structure was elucidated as 1,8-dihydroxy-3-methoxyanthraquinone (DMA) using HR-ESI-MS and NMR analysis. In this study, we conducted comprehensive investigations utilizing human colorectal cancer HCT116 cells, human umbilical cord vascular endothelial cells (HUVECs), and zebrafish embryos to assess the potential benefits of DMA in suppressing tumor angiogenesis. Our results convincingly demonstrate that DMA effectively suppresses the stability of hypoxia-inducible factor-1α (HIF-1α) protein and its target genes without inducing any cytotoxic effects. Furthermore, DMA demonstrates the ability to inhibit HIF-1α transcriptional activation and mitigate the production of reactive oxygen species (ROS). In our in vitro experiments, DMA exhibits notable inhibitory effects on VEGF-mediated tube formation, migration, and invasion in HUVECs. Additionally, in vivo investigations using zebrafish embryos confirm the antiangiogenic properties of DMA. Notably, DMA does not exhibit any adverse developmental or cardiotoxic effects in the in vivo setting. Moreover, we observe DMA's capability to restrain tumor growth through the downregulation of PI3K/AKT and c-RAF/ERK pathway. Collectively, these compelling findings underscore DMA's potential as a promising therapeutic candidate for targeted intervention against HIF-1α and angiogenesis in cancer treatment.
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Affiliation(s)
- Su Jung Hwang
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Seung Hye Cho
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Hye Jung Bang
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
| | - Joo-Hyun Hong
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea; Research Laboratories, ILDONG Pharmaceutical Co. Ltd., Hwaseong, Republic of Korea
| | - Ki Hyun Kim
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
| | - Hyo-Jong Lee
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
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3
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Zhang H, Han J, Zhang J, Miao J, Li F, Tang K, Zhou K, Duan B, Li W, Cheng J, Sun Y, Hou N, Huang C. Venlafaxine antagonizes the noradrenaline-promoted colon cancer progression by inhibiting the norepinephrine transporter. Cell Death Discov 2023; 9:152. [PMID: 37156838 PMCID: PMC10167232 DOI: 10.1038/s41420-023-01447-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 04/13/2023] [Accepted: 04/24/2023] [Indexed: 05/10/2023] Open
Abstract
Epidemiological studies have demonstrated that the use of antidepressants is associated with a decreased risk of colorectal cancer (CRC); however, the mechanisms behind this association are yet unknown. Adrenergic system contributes to the stress-related tumor progression, with norepinephrine (NE) mainly secreted from adrenergic nerve fibers. Norepinephrine serotonin reuptake inhibitors are successfully used antidepressants. This study demonstrates that a widely used antidepressant venlafaxine (VEN) antagonizes NE-promoted colon cancer in vivo and in vitro. Bioinformatic analysis suggested that NE transporter (NET, SLC6A2), a target of VEN, was closely associated with the prognosis of clinical patients with CRC. In addition, the knockdown of NET antagonized the effect of NE. The NET-protein phosphatase 2 scaffold subunit alpha/phosphorylated Akt/vascular endothelial growth factor pathway partially mediates the antagonizing effect of VEN on NE's actions in colon cancer cells. These were also confirmed by in vivo experiments. Our findings revealed for the first time that, in addition to its primary function as a transporter, NET also promotes NE-enhanced colon cancer cell proliferation, tumor angiogenesis, and tumor growth. This provides direct experimental and mechanistic evidence for the use of antidepressant VEN in the treatment of CRC and a therapeutic potential for repurposing existing drugs as an anti-cancer approach to improve the prognosis of patients with CRC.
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Affiliation(s)
- Huahua Zhang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, China
| | - Jiming Han
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, China
| | - Jing Zhang
- Medical Research and Experimental Center, Medical College, Yan'an University, Yan'an, 716000, China
| | - Jiyu Miao
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
- Department of Hematology, The Second Affiliated Hospital of Xian Jiaotong University, Xi'an, 710004, China
| | - Fang Li
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Kaijie Tang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Kai Zhou
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Baojun Duan
- Department of Medical Oncology of Shaanxi Provincial People's Hospital, Xi'an, 710068, China
| | - Wen Li
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Jing Cheng
- 3201 Affiliated Hospital of Medical College of Xi'an Jiaotong University, Hanzhong, 723000, China
| | - Ying Sun
- Department of Pathology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Ni Hou
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
- Institute of Genetics and Developmental Biology, Xi'an Jiaotong University, Xi'an, 710061, China.
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Chen Huang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
- Institute of Genetics and Developmental Biology, Xi'an Jiaotong University, Xi'an, 710061, China.
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, Xi'an Jiaotong University, Xi'an, 710061, China.
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4
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Fu J, Tang Y, Zhang Z, Tong L, Yue R, Cai L. Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis. Mol Med 2021; 27:90. [PMID: 34412590 PMCID: PMC8375043 DOI: 10.1186/s10020-021-00352-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 08/08/2021] [Indexed: 12/13/2022] Open
Abstract
Background It is known that increased gastrin concentration is negatively correlated with cardiovascular mortality, and plasma gastrin levels are increased in patients after myocardial infarction (MI). However, whether gastrin can play a protective role in MI remains unknown. Methods Adult C57BL/6 mice were subjected to ligation of the left anterior descending coronary artery (LAD) and subcutaneous infusion of gastrin (120 μg/Kg body weight/day, 100 μL in the pump) for 28 days after MI. Plasma gastrin concentrations were measured through an ELISA detection kit. Mice were analyzed by echocardiography after surgery. CD31 and VEGF expression were quantified using immunofluorescence staining or/and western blot to assess the angiogenesis in peri-infarct myocardium. Capillary-like tube formation and cell migration assays were performed to detect gastrin-induced angiogenesis. Results We found that gastrin administration significantly ameliorated MI-induced cardiac dysfunction and reduced fibrosis at 28 days in post-MI hearts. Additionally, gastrin treatment significantly decreased cardiomyocyte apoptosis and increased angiogenesis in the infarct border zone without influencing cardiomyocyte proliferation. In vitro results revealed that gastrin up-regulated the PI3K/Akt/vascular endothelial growth factor (VEGF) signaling pathway and promoted migration and tube formation of human coronary artery endothelial cells (HCAECs). Cholecystokinin 2 receptor (CCK2R) mediated the protective effect of gastrin since the CCK2R blocker CI988 attenuated the gastrin-mediated angiogenesis and cardiac function protection. Conclusion Our data revealed that gastrin promoted angiogenesis and improved cardiac function in post-MI mice, highlighting its potential as a therapeutic target candidate.
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Affiliation(s)
- Jinjuan Fu
- Department of Cardiology, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, College of Medicine, Southwest Jiaotong University, Chengdu, 610031, Sichuan, People's Republic of China.,College of Medicine, Southwest Jiaotong University, Chengdu, 610031, Sichuan, People's Republic of China
| | - Yuanjuan Tang
- College of Medicine, Southwest Jiaotong University, Chengdu, 610031, Sichuan, People's Republic of China
| | - Zhen Zhang
- Department of Cardiology, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, College of Medicine, Southwest Jiaotong University, Chengdu, 610031, Sichuan, People's Republic of China
| | - Lin Tong
- Department of Cardiology, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, College of Medicine, Southwest Jiaotong University, Chengdu, 610031, Sichuan, People's Republic of China
| | - Rongchuan Yue
- Department of Cardiology, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan, People's Republic of China.
| | - Lin Cai
- Department of Cardiology, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, College of Medicine, Southwest Jiaotong University, Chengdu, 610031, Sichuan, People's Republic of China. .,College of Medicine, Southwest Jiaotong University, Chengdu, 610031, Sichuan, People's Republic of China.
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5
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Singh P, Tiwari SP, Mehdi MM, Sharma R. Role of Bacterial Infection (H. pylori) in Colon Carcinogenesis and Therapeutic Approaches. COLON CANCER DIAGNOSIS AND THERAPY 2021:109-142. [DOI: 10.1007/978-3-030-64668-4_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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6
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Westwood DA, Patel O, Christophi C, Shulkes A, Baldwin GS. Progastrin: a potential predictive marker of liver metastasis in colorectal cancer. Int J Colorectal Dis 2017; 32:1061-1064. [PMID: 28432443 DOI: 10.1007/s00384-017-2822-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/11/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Staging of colorectal cancer often fails to discriminate outcomes of patients with morphologically similar tumours that exhibit different clinical behaviours. Data from several studies suggest that the gastrin family of growth factors potentiates colorectal cancer tumourigenesis. The aim of this study was to investigate whether progastrin expression may predict clinical outcome in colorectal cancer. METHODS Patients with colorectal adenocarcinoma of identical depth of invasion who had not received neoadjuvant therapy were included. The patients either had stage IIa disease with greater than 3-year disease-free survival without adjuvant therapy or stage IV disease with liver metastases on staging CT. Progastrin expression in tumour sections was scored with reference to the intensity and area of immunohistochemical staining. RESULTS Progastrin expression by stage IV tumours was significantly greater than stage IIa tumours with mean progastrin immunopositivity scores of 2.1 ± 0.2 versus 0.5 ± 0.2, respectively (P < 0.001). CONCLUSIONS This is the first study to show that progastrin expression may be predictive of aggressive tumour behaviour in patients with colorectal cancer and supports its clinical relevance and potential use as a biomarker.
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Affiliation(s)
- David A Westwood
- The University of Melbourne Department of Surgery, Austin Health, Heidelberg, Victoria, Australia.
| | - Oneel Patel
- The University of Melbourne Department of Surgery, Austin Health, Heidelberg, Victoria, Australia
| | - Christopher Christophi
- The University of Melbourne Department of Surgery, Austin Health, Heidelberg, Victoria, Australia
| | - Arthur Shulkes
- The University of Melbourne Department of Surgery, Austin Health, Heidelberg, Victoria, Australia
| | - Graham S Baldwin
- The University of Melbourne Department of Surgery, Austin Health, Heidelberg, Victoria, Australia
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7
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Kowalski-Chauvel A, Gouaze-Andersson V, Vignolle-Vidoni A, Delmas C, Toulas C, Cohen-Jonathan-Moyal E, Seva C. Targeting progastrin enhances radiosensitization of colorectal cancer cells. Oncotarget 2017; 8:58587-58600. [PMID: 28938581 PMCID: PMC5601677 DOI: 10.18632/oncotarget.17274] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 03/20/2017] [Indexed: 12/11/2022] Open
Abstract
A high percentage of advanced rectal cancers are resistant to radiation. Therefore, increasing the efficacy of radiotherapy by targeting factors involved in radioresistance seems to be an attractive strategy. Here we demonstrated that the pro-hormone progastrin (PG), known to be over-expressed in CRC, and recognized as a pro-oncogenic factor, is a radioresistance factor that can be targeted to sensitize resistant rectal cancers to radiations. First, we observed an increase in PG mRNA expression under irradiation. Our results also demonstrated that down-regulating PG mRNA expression using a shRNA strategy, significantly increases the sensitivity to irradiation (IR) in a clonogenic assay of different colorectal cancer cell lines. We also showed that the combination of PG gene down-regulation and IR strongly inhibits tumours progression in vivo. Then, we demonstrated that targeting PG gene radiosensitizes cancer cells by increasing radio-induced apoptosis shown by an increase in annexin V positive cells, caspases activation and PARP cleavage. We also observed the up-regulation of the pro-apoptotic pathway, JNK and the induction of the expression of pro-apoptotic factors such as BIM. In addition, we demonstrated in this study that inhibition of PG gene expression enhances radiation-induced DNA damage. Our data also suggest that, in addition to increase radio-induced apoptosis, targeting PG gene also leads to the inhibition of the survival pathways, AKT and ERK induced by IR. Taken together, our results highlight the role of PG in radioresistance and provide a preclinical proof of concept that PG represents an attractive target for sensitizing resistant rectal tumours to irradiation. .
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Affiliation(s)
- Aline Kowalski-Chauvel
- Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm/University Toulouse III Paul Sabatier, Toulouse, France
| | - Valerie Gouaze-Andersson
- Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm/University Toulouse III Paul Sabatier, Toulouse, France
| | - Alix Vignolle-Vidoni
- Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm/University Toulouse III Paul Sabatier, Toulouse, France
| | - Caroline Delmas
- Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm/University Toulouse III Paul Sabatier, Toulouse, France.,IUCT Oncopole, Toulouse, France
| | - Christine Toulas
- Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm/University Toulouse III Paul Sabatier, Toulouse, France.,IUCT Oncopole, Toulouse, France
| | - Elizabeth Cohen-Jonathan-Moyal
- Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm/University Toulouse III Paul Sabatier, Toulouse, France.,IUCT Oncopole, Toulouse, France
| | - Catherine Seva
- Cancer Research Center of Toulouse (CRCT), UMR1037 Inserm/University Toulouse III Paul Sabatier, Toulouse, France
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8
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Abstract
The existence of the hormone gastrin in the distal stomach (antrum) has been known for almost 110 years, and the physiological function of this amidated peptide in regulating gastric acid secretion via the CCK2 receptor is now well established. In this brief review we consider important additional roles of gastrin, including regulation of genes encoding proteins such as plasminogen activator inhibitors and matrix metalloproteinases that have important actions on extracellular matrix remodelling. These actions are, at least in part, effected by paracrine signalling pathways and make important contributions to maintaining functional integrity of the gastric epithelium. Recent studies also provide support for the idea that gastrin, in concert with other hormones, could potentially contribute a post-prandial incretin effect. We also review recent developments in the biology of other gastrin gene products, including the precursor progastrin, which causes proliferation of the colonic epithelium and in certain circumstances may induce cancer formation. Glycine-extended biosynthetic processing intermediates also have proliferative effects in colonic mucosa and in some oesophageal cancer cell lines. Whether these additional gene products exert their effects through the CCK2 receptor or a separate entity is currently a matter of debate.
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Affiliation(s)
- Rod Dimaline
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
| | - Andrea Varro
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
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9
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Yamagishi A, Matsumoto S, Watanabe A, Mizuguchi Y, Hara K, Kan H, Yamada T, Koizumi M, Shinji S, Matsuda A, Sasaki J, Shimada T, Uchida E. Gene profiling and bioinformatics analyses reveal time course differential gene expression in surgically resected colorectal tissues. Oncol Rep 2014; 31:1531-8. [PMID: 24573535 PMCID: PMC3975991 DOI: 10.3892/or.2014.3053] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 12/03/2013] [Indexed: 12/20/2022] Open
Abstract
It has previously been reported that gene profiles in surgically-resected colorectal cancer tissues are altered over time possibly due to the different tissue-acquisition methods and sample extraction timing that were used. However, the changes that occur are still not clearly understood. In the present study, time-dependent changes in gene expression profiling in colorectal surgical specimens were analyzed. Normal and tumor tissues at several time-points (0, 30, 60 and 120 min) were extracted, and RNA quality, microarray experiments, quantitative PCR and bioinformatics clustering were performed. Although RNA integrity was preserved 2 h after resection, inherent increased/decreased gene expression was observed from 30–120 min in approximately 10% of genes. Bioinformatics clustering could not distinguish case-by-case, probably due to gene profiling changes. Irregular changes in gene expression after surgical resection were found, which could be a crucial confounding factor for quantitative analyses.
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Affiliation(s)
- Aya Yamagishi
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Satoshi Matsumoto
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Atsushi Watanabe
- Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Yoshiaki Mizuguchi
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Keisuke Hara
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Hayato Kan
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Takeshi Yamada
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Michihiro Koizumi
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Seiichi Shinji
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Akihisa Matsuda
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Junpei Sasaki
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
| | - Takashi Shimada
- Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo 113-8603, Japan
| | - Eiji Uchida
- Surgery for Organ Function and Biological Regulation, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan
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10
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Tiberio L, Nascimbeni R, Villanacci V, Casella C, Fra A, Vezzoli V, Furlan L, Meyer G, Parrinello G, Baroni MD, Salerni B, Schiaffonati L. The decrease of mineralcorticoid receptor drives angiogenic pathways in colorectal cancer. PLoS One 2013; 8:e59410. [PMID: 23555666 PMCID: PMC3610652 DOI: 10.1371/journal.pone.0059410] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2012] [Accepted: 02/13/2013] [Indexed: 12/03/2022] Open
Abstract
Angiogenesis plays a crucial role in tumor growth and progression. Low expression of mineralocorticoid receptor (MR) in several malignant tumors correlates with disease recurrence and overall survival. Previous studies have shown that MR expression is decreased in colorectal cancer (CRC). Here we hypothesize that decreased MR expression can contribute to angiogenesis and poor patient survival in colorectal malignancies. In a cohort of CRC patients, we analyzed tumor MR expression, its correlation with tumor microvascular density and its impact on survival. Subsequently, we interrogated the role of MR in angiogenesis in an in vitro model, based on the colon cancer cell line HCT116, ingenierized to re-express a physiologically controlled MR. In CRC, decreased MR expression was associated with increased microvascular density and poor patient survival. In pchMR transfected HCT116, aldosterone or natural serum steroids largely inhibited mRNA expression levels of both VEGFA and its receptor 2/KDR. In CRC, MR activation may significantly decrease angiogenesis by directly inhibiting dysregulated VEGFA and hypoxia-induced VEGFA mRNA expression. In addition, MR activation attenuates the expression of the VEGF receptor 2/KDR, possibly dampening the activation of a VEGFA/KDR dependent signaling pathway important for the survival of tumor cells under hypoxic conditions.
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Affiliation(s)
- Laura Tiberio
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- * E-mail: (MDB); (LT)
| | - Riccardo Nascimbeni
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- First Unit of General Surgery, Brescia City Hospital, Brescia, Italy
| | | | - Claudio Casella
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- First Unit of General Surgery, Brescia City Hospital, Brescia, Italy
| | - Anna Fra
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Valeria Vezzoli
- Department of BioSciences, University of Milano, Milan, Italy
| | - Lucia Furlan
- Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy
| | - Giuliano Meyer
- Department of BioSciences, University of Milano, Milan, Italy
| | - Giovanni Parrinello
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Maurizio D. Baroni
- Department of Biology, University of Padova, Padova, Italy
- * E-mail: (MDB); (LT)
| | - Bruno Salerni
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- First Unit of General Surgery, Brescia City Hospital, Brescia, Italy
| | - Luisa Schiaffonati
- Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy
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11
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Kowalski-Chauvel A, Najib S, Tikhonova IG, Huc L, Lopez F, Martinez LO, Cohen-Jonathan-Moyal E, Ferrand A, Seva C. Identification of the F1-ATPase at the cell surface of colonic epithelial cells: role in mediating cell proliferation. J Biol Chem 2012; 287:41458-68. [PMID: 23055519 DOI: 10.1074/jbc.m112.382465] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
F1 domain of F(1)F(o)-ATPase was initially believed to be strictly expressed in the mitochondrial membrane. Interestingly, recent reports have shown that the F1 complex can serve as a cell surface receptor for apparently unrelated ligands. Here we show for the first time the presence of the F(1)-ATPase at the cell surface of normal or cancerous colonic epithelial cells. Using surface plasmon resonance technology and mass spectrometry, we identified a peptide hormone product of the gastrin gene (glycine-extended gastrin (G-gly)) as a new ligand for the F(1)-ATPase. By molecular modeling, we identified the motif in the peptide sequence (E(E/D)XY), that directly interacts with the F(1)-ATPase and the amino acids in the F(1)-ATPase that bind this motif. Replacement of the Glu-9 residue by an alanine in the E(E/D)XY motif resulted in a strong decrease of G-gly binding to the F(1)-ATPase and the loss of its biological activity. In addition we demonstrated that F(1)-ATPase mediates the growth effects of the peptide. Indeed, blocking F(1)-ATPase activity decreases G-gly-induced cell growth. The mechanism likely involves ADP production by the membrane F(1)-ATPase, which is induced by G-gly. These results suggest an important contribution of cell surface F(1)-ATPase in the pro-proliferative action of this gastrointestinal peptide.
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Affiliation(s)
- Aline Kowalski-Chauvel
- INSERM UMR 1037, Cancer Research Centre of Toulouse, Université Paul Sabatier Toulouse III, 31052 Toulouse, France
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Singh P, Sarkar S, Kantara C, Maxwell C. Progastrin Peptides Increase the Risk of Developing Colonic Tumors: Impact on Colonic Stem Cells. CURRENT COLORECTAL CANCER REPORTS 2012; 8:277-289. [PMID: 23226720 DOI: 10.1007/s11888-012-0144-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Pre-neoplastic lesions (ACF, aberrant-crypt-foci; Hp, hyperplastic/dysplastic polyps) are believed to be precursors of sporadic colorectal-tumors (Ad, adenomas; AdCA, adenocarcinomas). ACF/Hp likely originate due to abnormal growth of colonic-crypts in response to aberrant queues in the microenvironment of colonic-crypts. Thus identifying factors which regulate homeostatic vs aberrant proliferation/apoptosis of colonocytes, especially stem/progenitor cells, may lead to effective preventative/treatment strategies. Based on this philosophy, role of growth-factors/peptide-hormones, potentially available in the circulation/microenvironment of colonic-crypts is being examined extensively. Since the time gastrins were discovered as trophic (growth) factors for gastrointestinal-cells, the effect of gastrins on the growth of normal/cancer cells has been investigated, leading to many discoveries. Seminal discoveries made in the area of gastrins and colon-cancer, as it relates to molecular pathways associated with formation of colonic tumors will be reviewed, and possible impact on diagnostic/preventative/treatment strategies will be discussed.
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Affiliation(s)
- Pomila Singh
- Department of Neuroscience and Cell Biology, UTMB, Galveston TX 77555
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Xiao L, Kovac S, Chang M, Shulkes A, Baldwin GS, Patel O. Induction of gastrin expression in gastrointestinal cells by hypoxia or cobalt is independent of hypoxia-inducible factor (HIF). Endocrinology 2012; 153:3006-16. [PMID: 22593272 PMCID: PMC3380302 DOI: 10.1210/en.2011-2069] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Gastrin and its precursors have been shown to promote mitogenesis and angiogenesis in gastrointestinal tumors. Hypoxia stimulates tumor growth, but its effect on gastrin gene regulation has not been examined in detail. Here we have investigated the effect of hypoxia on the transcription of the gastrin gene in human gastric cancer (AGS) cells. Gastrin mRNA was measured by real-time PCR, gastrin peptides were measured by RIA, and gastrin promoter activity was measured by dual-luciferase reporter assay. Exposure to a low oxygen concentration (1%) increased gastrin mRNA concentrations in wild-type AGS cells (AGS) and in AGS cells overexpressing the gastrin receptor (AGS-cholecystokinin receptor 2) by 2.1 ± 0.4- and 4.1 ± 0.3-fold (P < 0.05), respectively. The hypoxia mimetic, cobalt chloride (300 μM), increased gastrin promoter activity in AGS cells by 2.4 ± 0.3-fold (P < 0.05), and in AGS-cholecystokinin receptor 2 cells by 4.0 ± 0.3-fold (P < 0.05), respectively. The observations that either deletion from the gastrin promoter of the putative binding sites for the transcription factor hypoxia-inducible factor 1 (HIF-1) or knockdown of either the HIF-1α or HIF-1β subunit did not affect gastrin promoter inducibility under hypoxia indicated that the hypoxic activation of the gastrin gene is likely HIF independent. Mutational analysis of previously identified Sp1 regulatory elements in the gastrin promoter also failed to abrogate the induction of promoter activity by hypoxia. The observations that hypoxia up-regulates the gastrin gene in AGS cells by HIF-independent mechanisms, and that this effect is enhanced by the presence of gastrin receptors, provide potential targets for gastrointestinal cancer therapy.
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Affiliation(s)
- Lin Xiao
- The University of Melbourne, Department of Surgery, Austin Health, Studley Road, Heidelberg, Victoria 3084, Australia
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Strofilas A, Lagoudianakis EE, Seretis C, Pappas A, Koronakis N, Keramidaris D, Koukoutsis I, Chrysikos I, Manouras I, Manouras A. Association of helicobacter pylori infection and colon cancer. J Clin Med Res 2012; 4:172-6. [PMID: 22719803 PMCID: PMC3376875 DOI: 10.4021/jocmr880w] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2012] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Gastrin has been shown to exert carcinogenic effect to the epithelium of the colon. This study examines whether hypergastrinemia and H. pylori infection -especially infection by the CagA+ strain- are statistically associated with colorectal cancer and examine possible correlations with the colorectal cancer stage and lymph node metastasis. METHODS In this prospective case-control study, fasting serum samples from 93 consecutive patients with colorectal cancer treated in a university surgical clinic were preoperatively collected and serum levels of gastrin were measured. A group of 20 age matched hernia patients were used as controls. The pathology report of the specimens was documented and statistical analysis of the data where performed with the spss 17 statistical suite. RESULTS H. pylori IgG antibodies was reported in 66/93 (71%) in the colorectal cancer group and 13/20 patients in the control group (65%), the difference having non-statistical significance (P = n.s). The prevalence of cagA protein expression in the anti- H. pylori IgG+ patients were higher in the colorectal cancer group (56% positivity), when compared to the control group (38,4% positivity) but the difference was not of statistical significance (P = n.s). The mean levels of serum gastrin levels in the two groups did not significantly differ (Ca group 51.1 ± 36.6 pg/mL vs Control 49.8 ± 17.6 P = n.s.). Patients with lymph node metastasis had higher serum gastrin levels than patients without metastasis and this difference was statistically significant. (53.6 vs 41.06 pg/mL P = 0.025). CONCLUSIONS Although the serum gastrin levels were not statistically different between the TNM stages of our patient cohort, our data found that serum gastrin levels were significantly higher in patients with lymph node metastasis. Whether gastrin is implicated in the ability of cancer cells to metastasize to the lymph nodes merits further research.
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Affiliation(s)
| | | | | | - Apostolos Pappas
- First Department of Propaedeutic Surgery, Hippocrateion Hospital, Athens Medical School, Athens, Greece
| | | | | | - Ilias Koukoutsis
- Second Department of Surgery, 401 Army General Hospital, Athens, Greece
| | - Ioannis Chrysikos
- Second Department of Surgery, 417 NIMTS-Nosileutiko Idrima Metohikou Tameiou Stratou (Military Veterans' Fund Hospital), Athens, Greece
| | - Ioannis Manouras
- First Department of Propaedeutic Surgery, Hippocrateion Hospital, Athens Medical School, Athens, Greece
| | - Andreas Manouras
- First Department of Propaedeutic Surgery, Hippocrateion Hospital, Athens Medical School, Athens, Greece
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