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Rodrigues P, Bangali H, Ali E, Nauryzbaevish AS, Hjazi A, Fenjan MN, Alawadi A, Alsaalamy A, Alasheqi MQ, Mustafa YF. The mechanistic role of NAT10 in cancer: Unraveling the enigmatic web of oncogenic signaling. Pathol Res Pract 2024; 253:154990. [PMID: 38056132 DOI: 10.1016/j.prp.2023.154990] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/23/2023] [Accepted: 11/27/2023] [Indexed: 12/08/2023]
Abstract
N-acetyltransferase 10 (NAT10), a versatile enzyme, has gained considerable attention as a significant player in the complex realm of cancer biology. Its enigmatic role in tumorigenesis extends across a wide array of cellular processes, impacting cell growth, differentiation, survival, and genomic stability. Within the intricate network of oncogenic signaling, NAT10 emerges as a crucial agent in multiple cancer types, such as breast, lung, colorectal, and leukemia. This compelling research addresses the intricate complexity of the mechanistic role of NAT10 in cancer development. By elucidating its active participation in essential physiological processes, we investigate the regulatory role of NAT10 in cell cycle checkpoints, coordination of chromatin remodeling, and detailed modulation of the delicate balance between apoptosis and cell survival. Perturbations in NAT10 expression and function have been linked to oncogenesis, metastasis, and drug resistance in a variety of cancer types. Furthermore, the bewildering interactions between NAT10 and key oncogenic factors, such as p53 and c-Myc, are deciphered, providing profound insights into the molecular underpinnings of cancer pathogenesis. Equally intriguing, the paradoxical role of NAT10 as a potential tumor suppressor or oncogene is influenced by context-dependent factors and the cellular microenvironment. This study explores the fascinating interplay of genetic changes, epigenetic changes, and post-translational modifications that shape the dual character of NAT10, revealing the delicate balance between cancer initiation and suppression. Taken together, this overview delves deeply into the enigmatic role of NAT10 in cancer, elucidating its multifaceted roles and its complex interplay with oncogenic networks.
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Affiliation(s)
- Paul Rodrigues
- Department of Computer Engineering, College of Computer Science, King Khalid University, Al-Faraa, Saudi Arabia.
| | - Harun Bangali
- Department of Computer Engineering, College of Computer Science, King Khalid University, Al-Faraa, Saudi Arabia
| | - Eyhab Ali
- College of Chemistry, Al-Zahraa University for Women, Karbala, Iraq
| | - Abdreshov Serik Nauryzbaevish
- Institute of Genetics and Physiology SC MSHE RK, Laboratory of Physiology Lymphatic System, Al-Farabi Kazakh National University, Almaty, Kazakhstan
| | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Mohammed N Fenjan
- College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
| | - Ahmed Alawadi
- College of Technical Engineering, the Islamic University, Najaf, Iraq; College of Technical Engineering, the Islamic University of Al Diwaniyah, Iraq; College of Technical Engineering, the Islamic University of Babylon, Iraq
| | - Ali Alsaalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
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2
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Tacchi F, Orozco-Aguilar J, Valero-Breton M, Cabello-Verrugio C. Bile Acids Alter the Autophagy and Mitogenesis in Skeletal Muscle Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1408:183-199. [PMID: 37093428 DOI: 10.1007/978-3-031-26163-3_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
Muscle atrophy decreases muscle mass with the subsequent loss of muscle function. Among the mechanisms that trigger sarcopenia is mitochondrial dysfunction. Mitochondria, whose primary function is to produce ATP, are dynamic organelles that present the process of formation (mitogenesis) and elimination (mitophagy). Failure of any of these processes contributes to mitochondrial malfunction. Mitogenesis is mainly controlled by Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α), a transcriptional coactivator that regulates the expression of TFAM, which participates in mitogenesis. Mitophagy is a process of selective autophagy. Autophagy corresponds to a degradative pathway of protein complexes and organelles. Liver disease caused sarcopenia and increased bile acids in the blood. We demonstrated that the treatment with cholic (CA) or deoxycholic (DCA) bile acids generates mitochondrial dysfunction and loss of biomass. This work assessed whether CA and DCA alter autophagy and mitogenesis. For this, western blot evaluated the autophagy process by determining the protein levels of the LC3II/LC3I ratio. In addition, we assessed mitogenesis using a luciferase-coupled plasmid reporter for the PGC-1α promoter and the protein levels of TFAM by western blot. Our results indicate that treatment with CA or DCA induces autophagy, represented by an increase in the LC3II/LC3I ratio. In addition, a decreased autophagic flux was observed. On the other hand, when treated with CA or DCA, a decrease in the activity of the PGC-1α promoter was observed. However, the levels of TFAM increased in myotubes incubated with CA and DCA. Our results demonstrate that CA and DCA modulate autophagy ad mitogenesis in C2C12 myotubes.
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Affiliation(s)
- Franco Tacchi
- Laboratory of Muscle Pathology, Fragility and Aging, Faculty of Life Sciences, Universidad Andres Bello, Santiago, 8370146, Chile
- Millennium Institute on Immunology and Immunotherapy, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago, Chile
| | - Josué Orozco-Aguilar
- Laboratory of Muscle Pathology, Fragility and Aging, Faculty of Life Sciences, Universidad Andres Bello, Santiago, 8370146, Chile
- Millennium Institute on Immunology and Immunotherapy, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago, Chile
- Laboratorio de Ensayos Biológicos (LEBi), Universidad de Costa Rica, San José, Costa Rica
- Facultad de Farmacia, Universidad de Costa Rica, San José, Costa Rica
| | - Mayalen Valero-Breton
- Laboratory of Muscle Pathology, Fragility and Aging, Faculty of Life Sciences, Universidad Andres Bello, Santiago, 8370146, Chile
- Millennium Institute on Immunology and Immunotherapy, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago, Chile
| | - Claudio Cabello-Verrugio
- Laboratory of Muscle Pathology, Fragility and Aging, Faculty of Life Sciences, Universidad Andres Bello, Santiago, 8370146, Chile.
- Millennium Institute on Immunology and Immunotherapy, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile.
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago, Chile.
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Abe I, Suzuki K, Kimura Y, Tamaki S, Endo Y, Ichida K, Muto Y, Watanabe F, Saito M, Konishi F, Rikiyama T. Enhancement of DNA hypomethylation alterations by gastric and bile acids promotes chromosomal instability in Barrett's epithelial cell line. Sci Rep 2022; 12:20710. [PMID: 36456615 PMCID: PMC9715700 DOI: 10.1038/s41598-022-25279-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022] Open
Abstract
Gastric and bile acid reflux leads to chronic inflammation, resulting in methylation alterations in Barrett's esophagus (BE) together with chromosomal instability (CIN). We investigated DNA hypomethylation following acid exposure and confirmed its significance in BE-related carcinogenesis by inducing CIN in vitro. OACP4C, an esophageal cancer cell line, and CP-A, a non-dysplastic cell line originating from BE, were exposed to acidic conditions using deoxycholic acid. CP-A exhibited substantially increased DNA hypomethylation of alpha satellite sequences in the centromere region, as well as increased levels of alpha satellite transcripts, but no changes were observed in the long interspersed nucleotide element-1 sequences distributed throughout the entire genome. These changes were not clearly found in OACP4C. Copy number changes at specific chromosomes were identified in CP-A, along with an increased number of cells exhibiting abnormal segregations, whereas these changes were rarely observed in OACP4C. The changes were maintained after several cell divisions. These findings suggest that alpha satellites are likely targets of DNA hypomethylation induced by acid exposure. CP-A was more sensitive to acid exposure than OACP4C, indicating that acid-induced DNA hypomethylation is involved in cancer development rather than progression, which could be involved in the underlying mechanism of esophagogastric junction carcinoma development.
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Affiliation(s)
- Iku Abe
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Koichi Suzuki
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Yasuaki Kimura
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Sawako Tamaki
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Yuhei Endo
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Kosuke Ichida
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Yuta Muto
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Fumiaki Watanabe
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Masaaki Saito
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
| | - Fumio Konishi
- Department of Surgery, Nerima-Hikarigaoka Hospital, 2-5-1, Hikarigaoka, Nerima-ku, Tokyo, 179-0072 Japan
| | - Toshiki Rikiyama
- grid.410804.90000000123090000Department of Surgery, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma-Cho, Omiya-Ku, Saitama, 330-8503 Japan
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Naa10p promotes cell invasiveness of esophageal cancer by coordinating the c-Myc and PAI1 regulatory axis. Cell Death Dis 2022; 13:995. [PMID: 36433943 PMCID: PMC9700753 DOI: 10.1038/s41419-022-05441-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 11/13/2022] [Accepted: 11/15/2022] [Indexed: 11/27/2022]
Abstract
N-α-acetyltransferase 10 protein, Naa10p, is involved in various cellular functions impacting tumor progression. Due to its capacity to acetylate a large spectrum of proteins, both oncogenic and tumor-suppressive roles of Naa10p have been documented. Here, we report an oncogenic role of Naa10p in promoting metastasis of esophageal cancer. NAA10 is more highly expressed in esophageal cancer tissues compared to normal tissues. Higher NAA10 expression also correlates with poorer survival of esophageal cancer patients. We found that NAA10 expression was transcriptionally regulated by the critical oncogene c-Myc in esophageal cancer. Furthermore, activation of the c-Myc-Naa10p axis resulted in upregulated cell invasiveness of esophageal cancer. This increased cell invasiveness was also elucidated to depend on the enzymatic activity of Naa10p. Moreover, Naa10p cooperated with Naa15p to interact with the protease inhibitor, PAI1, and prevent its secretion. This inhibition of PAI1 secretion may derive from the N-terminal acetylation effect of the Naa10p/Naa15p complex. Our results establish the significance of Naa10p in driving metastasis in esophageal cancer by coordinating the c-Myc-PAI1 axis, with implications for its potential use as a prognostic biomarker and therapeutic target for esophageal cancer.
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5
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Venkitachalam S, Babu D, Ravillah D, Katabathula RM, Joseph P, Singh S, Udhayakumar B, Miao Y, Martinez-Uribe O, Hogue JA, Kresak AM, Dawson D, LaFramboise T, Willis JE, Chak A, Garman KS, Blum AE, Varadan V, Guda K. The Ephrin B2 Receptor Tyrosine Kinase Is a Regulator of Proto-oncogene MYC and Molecular Programs Central to Barrett's Neoplasia. Gastroenterology 2022; 163:1228-1241. [PMID: 35870513 PMCID: PMC9613614 DOI: 10.1053/j.gastro.2022.07.045] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 06/20/2022] [Accepted: 07/12/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND & AIMS Mechanisms contributing to the onset and progression of Barrett's (BE)-associated esophageal adenocarcinoma (EAC) remain elusive. Here, we interrogated the major signaling pathways deregulated early in the development of Barrett's neoplasia. METHODS Whole-transcriptome RNA sequencing analysis was performed in primary BE, EAC, normal esophageal squamous, and gastric biopsy tissues (n = 89). Select pathway components were confirmed by quantitative polymerase chain reaction in an independent cohort of premalignant and malignant biopsy tissues (n = 885). Functional impact of selected pathway was interrogated using transcriptomic, proteomic, and pharmacogenetic analyses in mammalian esophageal organotypic and patient-derived BE/EAC cell line models, in vitro and/or in vivo. RESULTS The vast majority of primary BE/EAC tissues and cell line models showed hyperactivation of EphB2 signaling. Transcriptomic/proteomic analyses identified EphB2 as an endogenous binding partner of MYC binding protein 2, and an upstream regulator of c-MYC. Knockdown of EphB2 significantly impeded the viability/proliferation of EAC and BE cells in vitro/in vivo. Activation of EphB2 in normal esophageal squamous 3-dimensional organotypes disrupted epithelial maturation and promoted columnar differentiation programs, notably including MYC. EphB2 and MYC showed selective induction in esophageal submucosal glands with acinar ductal metaplasia, and in a porcine model of BE-like esophageal submucosal gland spheroids. Clinically approved inhibitors of MEK, a protein kinase that regulates MYC, effectively suppressed EAC tumor growth in vivo. CONCLUSIONS The EphB2 signaling is frequently hyperactivated across the BE-EAC continuum. EphB2 is an upstream regulator of MYC, and activation of EphB2-MYC axis likely precedes BE development. Targeting EphB2/MYC could be a promising therapeutic strategy for this often refractory and aggressive cancer.
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Affiliation(s)
- Srividya Venkitachalam
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Deepak Babu
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Durgadevi Ravillah
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Ramachandra M Katabathula
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Peronne Joseph
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Salendra Singh
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Bhavatharini Udhayakumar
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Yanling Miao
- Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Omar Martinez-Uribe
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina
| | - Joyce A Hogue
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina
| | - Adam M Kresak
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Dawn Dawson
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Thomas LaFramboise
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Joseph E Willis
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Amitabh Chak
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Katherine S Garman
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina
| | - Andrew E Blum
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio; Division of Gastroenterology, Northeast Ohio Veteran Affairs Healthcare System, Cleveland, Ohio
| | - Vinay Varadan
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
| | - Kishore Guda
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
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6
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Hassan MS, Cwidak N, Johnson C, Däster S, Eppenberger-Castori S, Awasthi N, Li J, Schwarz MA, von Holzen U. Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer. Front Pharmacol 2021; 12:746385. [PMID: 34621175 PMCID: PMC8490822 DOI: 10.3389/fphar.2021.746385] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/08/2021] [Indexed: 12/14/2022] Open
Abstract
Tumors with elevated c-Myc expression often exhibit a highly aggressive phenotype, and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cycle signaling can be therapeutically exploited to preferentially kill tumor cells. We therefore investigated whether exploiting elevated c-Myc expression is effective in treating esophageal cancer with the CDK inhibitor flavopiridol. We found frequent overexpression of c-Myc in human esophageal cancer cell lines and tissues. c-Myc overexpression correlated with accelerated esophageal cancer subcutaneous xenograft tumor growth. Esophageal cancer cells with elevated c-Myc expression were found preferentially more sensitive to induction of apoptosis by the CDK inhibition flavopiridol compared to esophageal cancer cells with lower c-Myc expression. In addition, we observed that flavopiridol alone or in combination with the chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with the targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth while significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to the CDK inhibitor flavopiridol, and that flavopiridol alone or in combination can be a potential therapy for c-Myc overexpressing esophageal cancer.
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Affiliation(s)
- Md Sazzad Hassan
- Department of Surgery, Indiana University School of Medicine, South Bend, IN, United States.,Harper Cancer Research Institute, South Bend, IN, United States
| | - Nicholas Cwidak
- Department of Surgery, Indiana University School of Medicine, South Bend, IN, United States
| | - Chloe Johnson
- University of Notre Dame, Notre Dame, IN, United States
| | | | | | - Niranjan Awasthi
- Department of Surgery, Indiana University School of Medicine, South Bend, IN, United States.,Harper Cancer Research Institute, South Bend, IN, United States
| | - Jun Li
- Harper Cancer Research Institute, South Bend, IN, United States.,University of Notre Dame, Notre Dame, IN, United States
| | - Margaret A Schwarz
- Harper Cancer Research Institute, South Bend, IN, United States.,Department of Pediatrics, Indiana University School of Medicine, South Bend, IN, United States
| | - Urs von Holzen
- Department of Surgery, Indiana University School of Medicine, South Bend, IN, United States.,Harper Cancer Research Institute, South Bend, IN, United States.,University of Basel, Basel, Switzerland.,Goshen Center for Cancer Care, Goshen, IN, United States
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7
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Pickering OJ, Breininger SP, Underwood TJ, Walters ZS. Histone Modifying Enzymes as Targets for Therapeutic Intervention in Oesophageal Adenocarcinoma. Cancers (Basel) 2021; 13:4084. [PMID: 34439236 PMCID: PMC8392153 DOI: 10.3390/cancers13164084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/03/2021] [Accepted: 08/10/2021] [Indexed: 12/24/2022] Open
Abstract
Oesophageal adenocarcinoma (OAC) has a dismal prognosis, where curable disease occurs in less than 40% of patients, and many of those with incurable disease survive for less than a year from diagnosis. Despite the widespread use of systematic chemotherapy in OAC treatment, many patients receive no benefit. New treatments are urgently needed for OAC patients. There is an emerging interest in epigenetic regulators in cancer pathogenesis, which are now translating into novel cancer therapeutic strategies. Histone-modifying enzymes (HMEs) are key epigenetic regulators responsible for dynamic covalent histone modifications that play roles in both normal and dysregulated cellular processes including tumorigenesis. Several HME inhibitors are in clinical use for haematological malignancies and sarcomas, with numerous on-going clinical trials for their use in solid tumours. This review discusses the current literature surrounding HMEs in OAC pathogenesis and their potential use in targeted therapies for this disease.
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Affiliation(s)
| | | | | | - Zoë S. Walters
- School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK; (O.J.P.); (S.P.B.); (T.J.U.)
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8
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Vyas M, Celli R, Singh M, Patel N, Aslanian HR, Boffa D, Deng Y, Ciarleglio MM, Laine L, Jain D. Intestinal metaplasia around the gastroesophageal junction is frequently associated with antral reactive gastropathy: implications for carcinoma at the gastroesophageal junction. Hum Pathol 2020; 105:67-73. [PMID: 32941964 PMCID: PMC11152084 DOI: 10.1016/j.humpath.2020.08.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 08/16/2020] [Accepted: 08/26/2020] [Indexed: 12/12/2022]
Abstract
Increasing evidence suggests that bile reflux (BR) plays a major role in mucosal injury, leading to adenocarcinoma of the proximal stomach and distal esophagus. However, gastric BR is difficult to diagnose and investigate. Reactive gastropathy (RG), in the absence of nonsteroidal anti-inflammatory drugs (NSAIDs) and other known causes, likely represents bile-mediated injury to the gastric mucosa. The goal of this study is to explore the association between antral RG and gastroesophageal junction (GEJ) mucosal inflammation and intestinal metaplasia (IM). The pathology database was searched for patients who had gastric biopsies with a diagnosis of antral RG and concurrent gastric cardia/GEJ/distal esophagus biopsies from 2013 to 2015. Age- and sex-matched patients with normal gastric antral biopsies served as controls. Biopsies from the GEJ region were evaluated for histological changes, including inflammation, antral and pancreatic metaplasia, RG, the type of gastric glands, proton pump inhibitor (PPI) changes, and IM. Detailed clinical history and medication use (including PPIs and NSAIDs) were recorded. IM in the GEJ region was more frequent in patients with antral RG than in controls (33.0% vs. 5.2%, 95% confidence interval [18.3-37.3%]). In addition, inflammation, other mucosal changes around the GEJ (RG and foveolar hyperplasia), antral IM, and PPI-associated mucosal changes were also more frequently seen in patients with antral RG. Our results show that antral RG is associated with mucosal injury and IM around GEJ, suggesting a role of BR. Further studies are needed to study duodenogastric-esophageal BR and its role in development of proximal gastric and distal esophageal adenocarcinoma.
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Affiliation(s)
- Monika Vyas
- Department of Surgical Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Romulo Celli
- Department of Surgical Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Manpreet Singh
- Department of Internal Medicine (Section of Digestive Diseases), Yale University School of Medicine, New Haven, CT, USA
| | - Natalie Patel
- Department of Surgical Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Harry R Aslanian
- Department of Internal Medicine (Section of Digestive Diseases), Yale University School of Medicine, New Haven, CT, USA
| | - Daniel Boffa
- Surgery, Yale School of Medicine, New Haven, CT, USA
| | - Yanhong Deng
- Yale Center for Analytical Sciences, Yale University School of Public Health, New Haven, CT, USA
| | - Maria M Ciarleglio
- Yale Center for Analytical Sciences, Yale University School of Public Health, New Haven, CT, USA
| | - Loren Laine
- Department of Internal Medicine (Section of Digestive Diseases), Yale University School of Medicine, New Haven, CT, USA; Department of Internal Medicine (Section of Digestive Diseases), VA-CT Healthcare System, West Haven, CT, USA
| | - Dhanpat Jain
- Department of Surgical Pathology, Yale University School of Medicine, New Haven, CT, USA.
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9
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Elwy AE, Elsaba TM, Abd Elzaher AR, Nassar MI. Prognostic Value of c-Myc Immunohistochemical Expression in Muscle Invasive Urothelial Carcinoma of the Urinary Bladder: A Retrospective Study. Asian Pac J Cancer Prev 2019; 20:3735-3746. [PMID: 31870116 PMCID: PMC7173398 DOI: 10.31557/apjcp.2019.20.12.3735] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Indexed: 12/24/2022] Open
Abstract
Objective: This study aimed to investigate the immunohistochemical expression of c-Myc in muscle invasive urothelial carcinoma (MIUC) of the urinary bladder and to evaluate the correlation of c-Myc expression with different clinicopathological parameters and outcome, including a relatively new histopathological tumor characteristic that is the growth pattern of tumor invasion. Methods: A total of 66 formalin-fixed and paraffin-embedded sections of MIUC obtained from radical cystectomy specimens were enrolled. The sections were stained with c-Myc antibody using immunohistochemistry technique. Results: Tumor cells showed variability in nuclear c-Myc expression according to the growth pattern of invasion. The median H-score of nuclear expression of infiltrative pattern was significantly higher than that of non-infiltrative pattern (p<0.001). Nuclear expression of c-Myc in tumor tissue had a significant association with poor prognostic factors (sarcomatoid variant (p<0.001), perineural invasion (p=0.037), lymphovascular invasion (p<0.001), lymph node metastasis (p<0.001), distant metastasis (p=0.042) and advanced stage grouping (p=0.001). Kaplan Meier survival analysis demonstrated that c-Myc expression could not be significantly correlated with overall survival or disease free survival rates. Conclusion: Nuclear c-Myc seems to have a prominent role in epithelial to mesenchymal transition with consequential in tumor progression and metastasis, while it is not as much useful to predict the clinical behavior of patients with MIUC.
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Affiliation(s)
- Amira Emad Elwy
- Department of Pathology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Tarek Mohamed Elsaba
- Department of Pathology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
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Kennedy L, Alpini G. Therapeutic Role of Sphingosine-1-Phosphate Receptor 2 in the Progression of Esophageal Adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:1949-1952. [PMID: 30026028 DOI: 10.1016/j.ajpath.2018.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 07/09/2018] [Accepted: 07/10/2018] [Indexed: 02/07/2023]
Abstract
This commentary highlights the article by Liu et al that provides novel mechanistic insights in how conjugated bile acids promote invasive growth of esophageal adenocarcinoma.
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Affiliation(s)
- Lindsey Kennedy
- Research Service, Central Texas Veterans Health Care System, Temple, Texas; Department of Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Gianfranco Alpini
- Research Service, Central Texas Veterans Health Care System, Temple, Texas; Department of Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas.
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11
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Zhu L, Zhang X, Fu X, Li Z, Sun Z, Wu J, Wang X, Wang F, Li X, Niu S, Ding M, Yang Z, Yang W, Yin M, Zhang L, Zhang M. TIPE2 suppresses progression and tumorigenesis of esophageal carcinoma via inhibition of the Wnt/β-catenin pathway. J Transl Med 2018; 16:7. [PMID: 29343267 PMCID: PMC5773041 DOI: 10.1186/s12967-018-1383-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 01/10/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Esophageal carcinoma is the eighth prevalent malignancy and ranks the sixth in carcinoma-related death worldwide. Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) has been identified as a tumor suppressor in multiple carcinomas. However, its roles and molecular mechanisms underlying esophageal carcinoma progression are still undefined till now. METHODS RT-qPCR assay was employed to detect the expression of TIPE2 mRNA. TIPE2 protein expression was measured by using western blot assay. Ad-V and Ad-TIPE2 adenoviruses were constructed to overexpress TIPE2. The effects of TIPE2 overexpression on cell proliferation, invasion and apoptosis were assessed by MTT and Edu incorporation assays, transwell invasion assay and flow cytometry analysis, respectively. The effect of TIPE2 overexpression on xenograft tumor growth was determined by measuring tumor volume and weight, together with immunohistochemistry assay. The effect of TIPE2 overexpression on the Wnt/β-catenin signaling pathway was evaluated by detecting the protein levels of β-catenin, c-Myc and cyclinD1 in EC9076 cells and xenograft tumors of esophageal carcinoma. RESULTS TIPE2 expression was downregulated in esophageal carcinoma tissues and cells. Adenovirus-mediated TIPE2 overexpression suppressed cell proliferation and invasion, and induced apoptosis in esophageal carcinoma cells. Enforced expression of TIPE2 inhibited tumor growth in vivo, as evidenced by the reduced tumor volume, tumor weight and proliferating cell nuclear antigen expression. Overexpression of TIPE2 inhibited the Wnt/β-catenin signaling pathway in esophageal carcinoma in vitro and in vivo. CONCLUSIONS These results suggest that TIPE2 suppressed progression and tumorigenesis of esophageal carcinoma via inhibition of the Wnt/β-catenin pathway.
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Affiliation(s)
- Linan Zhu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Xudong Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Xiaorui Fu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Zhaoming Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Zhenchang Sun
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Jingjing Wu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Xinhua Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Feng Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Xiangke Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Songtao Niu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Mengjie Ding
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Zhenzhen Yang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Wanqiu Yang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Meifeng Yin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Lei Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Νo. 1 Jianshe East Road, Zhengzhou, 450052 Henan People’s Republic of China
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12
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Morishita A, Gerber A, Gow CH, Zelonina T, Chada K, D’Armiento J. Cell Specific Matrix Metalloproteinase-1 Regulates Lung Metastasis Synergistically with Smoke Exposure. JOURNAL OF CANCER RESEARCH FORECAST 2018; 1:1014. [PMID: 30793116 PMCID: PMC6380525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
MMP1, a matrix metalloproteinase that degrades the extracellular matrix, is produced not only by cancer cells but also synthesized in stromal and inflammatory cells during tumorigenesis, invasion and lung metastasis. However, the function of MMP1 expression from host cells, especially tumor-associated macrophages (TAMs), and cells in the lung parenchyma remains to be elucidated. Here we demonstrate that in vitro macrophages co-cultured with tumor cells drastically enhance MMP1 expression, which is further exacerbated upon cigarette smoke exposure. In addition, in vivo, macrophage specific MMP1 was found to have a causative role in primary tumor development and lung metastasis, which was enhanced under smoke exposure as demonstrated in a transgenic mouse model that expressed human MMP1 specifically in macrophages (Mac-MMP1). In contrast, MMP1 from lung cells (Lung-MMP1) reduced colonization to the lung despite the fact that collagen deposition decreased in the Lung-MMP1 mouse tumors. These results demonstrate that the varying cellular source of MMP1 in tumors leads to the complexity observed in the tumor microenvironment. Furthermore, macrophage-specific inhibition of MMP1 secretion may be a potential therapy to aid in the reduction of lung metastasis.
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Affiliation(s)
- A Morishita
- Kagawa Daigaku, Gastroenterology and Neurology, 1-1 Saiwaicho, Takamatsu, Kagawa, JP 760-8523, Japan
| | - A Gerber
- Departments of Medicine, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA
| | - C-H Gow
- Departments of Medicine, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA
| | - T Zelonina
- Departments of Medicine, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA
| | - K Chada
- Department of Biochemistry and Molecular Biology, Rutgers-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854, USA
| | - J D’Armiento
- Departments of Medicine, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA,Correspondence: Jeanine D’Armiento, Department of Anesthesiology, Columbia University, College of Physicians and Surgeons, New York, NY 10033, USA.,
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13
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Wang X, Sun L, Wang X, Kang H, Ma X, Wang M, Lin S, Liu M, Dai C, Dai Z. Acidified bile acids enhance tumor progression and telomerase activity of gastric cancer in mice dependent on c-Myc expression. Cancer Med 2017; 6:788-797. [PMID: 28247570 PMCID: PMC5387128 DOI: 10.1002/cam4.999] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 12/05/2016] [Accepted: 12/07/2016] [Indexed: 02/06/2023] Open
Abstract
c-Myc overexpression has been implicated in several malignancies including gastric cancer. Here, we report that acidified bile acids enhance tumor progression and telomerase activity in gastric cancer via c-Myc activation both in vivo and in vitro. c-Myc mRNA and protein levels were assessed in ten primary and five local recurrent gastric cancer samples by quantitative real-time polymerase chain reaction and western blotting analysis. The gastric cancer cell line MGC803 was exposed to bile salts (100 μmol/L glycochenodeoxycholic acid and deoxycholic acid) in an acid medium (pH 5.5) for 10 min daily for 60 weeks to develop an MGC803-resistant cell line. Control MGC803 cells were grown without acids or bile salts for 60 weeks as a control. Cell morphology, proliferation, colony formation and apoptosis of MGC803-resistant cells were analyzed after 60 weeks. To determine the involvement of c-Myc in tumor progression and telomere aging in MGC803-resistant cells, we generated xenografts in nude mice and measured xenograft volume and in vivo telomerase activity. The c-Myc and hTERT protein and mRNA levels were significantly higher in local recurrent gastric cancer samples than in primary gastric cancer samples. MGC803-resistant cells showed a marked phenotypic change under normal growth conditions with more clusters and acini, and exhibited increased cell viability and colony formation and decreased apoptosis in vitro. These phenotypic changes were found to be dependent on c-Myc activation using the c-Myc inhibitor 10058-F4. MGC803-resistant cells also showed a c-Myc-dependent increase in xenograft growth and telomerase activity in vivo. In conclusion, these observations support the hypothesis that acidified bile acids enhance tumor progression and telomerase activity in gastric cancer and that these effects are dependent on c-Myc activity. These findings suggest that acidified bile acids play an important role in the malignant progression of local recurrent gastric cancer.
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Affiliation(s)
- Xiaolong Wang
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi710004China
| | - Lei Sun
- Department of General SurgeryThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi710004China
| | - Xijing Wang
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi710004China
| | - Huafeng Kang
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi710004China
| | - Xiaobin Ma
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi710004China
| | - Meng Wang
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi710004China
| | - Shuai Lin
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi710004China
| | - Meng Liu
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi710004China
| | - Cong Dai
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi710004China
| | - Zhijun Dai
- Department of OncologyThe Second Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxi710004China
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14
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Zhao C, Isenberg JS, Popel AS. Transcriptional and Post-Transcriptional Regulation of Thrombospondin-1 Expression: A Computational Model. PLoS Comput Biol 2017; 13:e1005272. [PMID: 28045898 PMCID: PMC5207393 DOI: 10.1371/journal.pcbi.1005272] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 11/29/2016] [Indexed: 01/09/2023] Open
Abstract
Hypoxia is an important physiological stress signal that drives angiogenesis, the formation of new blood vessels. Besides an increase in the production of pro-angiogenic signals such as vascular endothelial growth factor (VEGF), hypoxia also stimulates the production of anti-angiogenic signals. Thrombospondin-1 (TSP-1) is one of the anti-angiogenic factors whose synthesis is driven by hypoxia. Cellular synthesis of TSP-1 is tightly regulated by different intermediate biomolecules including proteins that interact with hypoxia-inducible factors (HIFs), transcription factors that are activated by receptor and intracellular signaling, and microRNAs which are small non-coding RNA molecules that function in post-transcriptional modification of gene expression. Here we present a computational model that describes the mechanistic interactions between intracellular biomolecules and cooperation between signaling pathways that together make up the complex network of TSP-1 regulation both at the transcriptional and post-transcriptional level. Assisted by the model, we conduct in silico experiments to compare the efficacy of different therapeutic strategies designed to modulate TSP-1 synthesis in conditions that simulate tumor and peripheral arterial disease microenvironment. We conclude that TSP-1 production in endothelial cells depends on not only the availability of certain growth factors but also the fine-tuned signaling cascades that are initiated by hypoxia.
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Affiliation(s)
- Chen Zhao
- Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
- * E-mail:
| | - Jeffrey S. Isenberg
- Vascular Medicine Institute, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Aleksander S. Popel
- Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
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15
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Xie G, Wang X, Huang F, Zhao A, Chen W, Yan J, Zhang Y, Lei S, Ge K, Zheng X, Liu J, Su M, Liu P, Jia W. Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis. Int J Cancer 2016; 139:1764-1775. [PMID: 27273788 PMCID: PMC5493524 DOI: 10.1002/ijc.30219] [Citation(s) in RCA: 173] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 05/02/2016] [Accepted: 05/30/2016] [Indexed: 12/12/2022]
Abstract
Dysregulated bile acids (BAs) are closely associated with liver diseases and attributed to altered gut microbiota. Here, we show that the intrahepatic retention of hydrophobic BAs including deoxycholate (DCA), taurocholate (TCA), taurochenodeoxycholate (TCDCA), and taurolithocholate (TLCA) were substantially increased in a streptozotocin and high fat diet (HFD) induced nonalcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) mouse model. Additionally chronic HFD-fed mice spontaneously developed liver tumors with significantly increased hepatic BA levels. Enhancing intestinal excretion of hydrophobic BAs in the NASH-HCC model mice by a 2% cholestyramine feeding significantly prevented HCC development. The gut microbiota alterations were closely correlated with altered BA levels in liver and feces. HFD-induced inflammation inhibited key BA transporters, resulting in sustained increases in intrahepatic BA concentrations. Our study also showed a significantly increased cell proliferation in BA treated normal human hepatic cell lines and a down-regulated expression of tumor suppressor gene CEBPα in TCDCA treated HepG2 cell line, suggesting that several hydrophobic BAs may collaboratively promote liver carcinogenesis.
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Affiliation(s)
- Guoxiang Xie
- Shanghai Key Laboratory of Diabetes Mellitus and Center for
Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth
People’s Hospital, Shanghai 200233, China
- University of Hawaii Cancer Center, Honolulu, Hawaii 96813,
USA
| | - Xiaoning Wang
- E-institute of Shanghai Municipal Education Committee, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education),
Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional
Chinese Medicine, Shanghai 201204, China
| | - Fengjie Huang
- Shanghai Key Laboratory of Diabetes Mellitus and Center for
Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth
People’s Hospital, Shanghai 200233, China
| | - Aihua Zhao
- Shanghai Key Laboratory of Diabetes Mellitus and Center for
Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth
People’s Hospital, Shanghai 200233, China
| | - Wenlian Chen
- University of Hawaii Cancer Center, Honolulu, Hawaii 96813,
USA
| | - Jingyu Yan
- E-institute of Shanghai Municipal Education Committee, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yunjing Zhang
- Shanghai Key Laboratory of Diabetes Mellitus and Center for
Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth
People’s Hospital, Shanghai 200233, China
| | - Sha Lei
- Shanghai Key Laboratory of Diabetes Mellitus and Center for
Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth
People’s Hospital, Shanghai 200233, China
| | - Kun Ge
- Shanghai Key Laboratory of Diabetes Mellitus and Center for
Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth
People’s Hospital, Shanghai 200233, China
| | - Xiaojiao Zheng
- Shanghai Key Laboratory of Diabetes Mellitus and Center for
Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth
People’s Hospital, Shanghai 200233, China
| | - Jiajian Liu
- Shanghai Key Laboratory of Diabetes Mellitus and Center for
Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth
People’s Hospital, Shanghai 200233, China
| | - Mingming Su
- University of Hawaii Cancer Center, Honolulu, Hawaii 96813,
USA
| | - Ping Liu
- E-institute of Shanghai Municipal Education Committee, Shanghai
University of Traditional Chinese Medicine, Shanghai 201203, China
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education),
Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional
Chinese Medicine, Shanghai 201204, China
| | - Wei Jia
- Shanghai Key Laboratory of Diabetes Mellitus and Center for
Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth
People’s Hospital, Shanghai 200233, China
- University of Hawaii Cancer Center, Honolulu, Hawaii 96813,
USA
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16
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Chen W, Chen X, Zhou S, Zhang H, Wang L, Xu J, Hu X, Yin W, Yan G, Zhang J. Design and synthesis of polyhydroxy steroids as selective inhibitors against AKR1B10 and molecular docking. Steroids 2016; 110:1-8. [PMID: 26968129 DOI: 10.1016/j.steroids.2016.03.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Revised: 02/24/2016] [Accepted: 03/01/2016] [Indexed: 01/18/2023]
Abstract
AKR1B10 is a member of the human aldo-keto reductase superfamily which is highly expressed in several types of cancers, and has been regarded as a promising cancer therapeutic target. In this paper, a series of polyhydroxy steroids were designed and synthesized to selectively inhibit AKR1B10 activity. The most selective compound, novel compound 6, has an IC50 of 0.83±0.07μM and a selectivity of more than 120-fold for AKR1B10/AKR1B1. Structure-activity relation analyses indicate that hydroxyl at C-19 can significantly improve the selective inhibition of AKR1B10. The binding mode of AKR1B10 and its inhibitors were studied.
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Affiliation(s)
- Wenli Chen
- School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University City, Guangzhou 510006, China; Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510080, China
| | - Xinying Chen
- School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Shujia Zhou
- School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Hong Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Ling Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Jun Xu
- School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Xiaopeng Hu
- School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University City, Guangzhou 510006, China
| | - Wei Yin
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510080, China
| | - Guangmei Yan
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510080, China
| | - Jingxia Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, 132 East Circle at University City, Guangzhou 510006, China.
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Martinucci I, de Bortoli N, Russo S, Bertani L, Furnari M, Mokrowiecka A, Malecka-Panas E, Savarino V, Savarino E, Marchi S. Barrett’s esophagus in 2016: From pathophysiology to treatment. World J Gastrointest Pharmacol Ther 2016; 7:190-206. [PMID: 27158534 PMCID: PMC4848241 DOI: 10.4292/wjgpt.v7.i2.190] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 11/05/2015] [Accepted: 03/18/2016] [Indexed: 02/06/2023] Open
Abstract
Esophageal complications caused by gastroesophageal reflux disease (GERD) include reflux esophagitis and Barrett’s esophagus (BE). BE is a premalignant condition with an increased risk of developing esophageal adenocarcinoma (EAC). The carcinogenic sequence may progress through several steps, from normal esophageal mucosa through BE to EAC. A recent advent of functional esophageal testing (particularly multichannel intraluminal impedance and pH monitoring) has helped to improve our knowledge about GERD pathophysiology, including its complications. Those findings (when properly confirmed) might help to predict BE neoplastic progression. Over the last few decades, the incidence of EAC has continued to rise in Western populations. However, only a minority of BE patients develop EAC, opening the debate regarding the cost-effectiveness of current screening/surveillance strategies. Thus, major efforts in clinical and research practice are focused on new methods for optimal risk assessment that can stratify BE patients at low or high risk of developing EAC, which should improve the cost effectiveness of screening/surveillance programs and consequently significantly affect health-care costs. Furthermore, the area of BE therapeutic management is rapidly evolving. Endoscopic eradication therapies have been shown to be effective, and new therapeutic options for BE and EAC have emerged. The aim of the present review article is to highlight the status of screening/surveillance programs and the current progress of BE therapy. Moreover, we discuss the recent introduction of novel esophageal pathophysiological exams that have improved the knowledge of the mechanisms linking GERD to BE.
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Disintegrin and metalloproteinases (ADAMs) expression in gastroesophageal reflux disease and in esophageal adenocarcinoma. Clin Transl Oncol 2016; 19:58-66. [PMID: 27026568 DOI: 10.1007/s12094-016-1503-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 03/15/2016] [Indexed: 01/26/2023]
Abstract
BACKGROUND Clinically useful marker molecules for the progression of gastroesophageal reflux disease and Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) are lacking. Many adenocarcinomas and inflammatory conditions exhibit increased expression of ADAMs, 'a disintegrin and metalloproteinases'. METHODS We assessed the expression of five ADAMs (9, 10, 12, 17, 19) in three esophageal cell lines (Het-1A, OE19, OE33) by RT-PCR and Western blotting, and in human samples of normal esophagus, esophagitis, BE, Barrett's dysplasia, and EAC by RT-PCR, and in selected samples by immunohistochemistry. RESULTS EAC patients showed increased mRNA expression of ADAMs 9, 12, 17 and 19, as compared to controls. At immunohistochemistry, ADAM9 and ADAM10 proteins were increased in EAC. Patient samples also showed increased mRNA expression of ADAM12 in esophagitis, of ADAM9 in BE, and of ADAMs 9, 12 and 19 in Barrett's dysplasia, as compared to controls. Two EAC cell lines showed increased ADAM9 mRNA. CONCLUSIONS ADAM9 expression is increased in EAC. Its predecessors show increased ADAM9 mRNA expression. The importance of the alterations in ADAM expression for the development of EAC, and their use as marker molecules, warrant further studies.
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19
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Bile acids induce Delta-like 1 expression via Cdx2-dependent pathway in the development of Barrett's esophagus. J Transl Med 2016; 96:325-37. [PMID: 26568294 DOI: 10.1038/labinvest.2015.137] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 09/22/2015] [Accepted: 10/10/2015] [Indexed: 02/06/2023] Open
Abstract
Crosstalk between the Notch signaling pathway and Caudal-related homeobox 2 (Cdx2) has important roles in the development of Barrett's esophagus (BE). We investigated the expression and function of the Notch signaling ligand Delta-like 1 (Dll1) during the development of BE. We determined the expression levels of Dll1 and intracellular signaling molecules related to Notch signaling ((Notch1, Hairy/enhancer of split 1 (Hes1), and Atonal homolog 1 (ATOH1)) in human esophageal squamous and Barrett's epithelium samples. Next, those expression levels in esophageal squamous cells (Het-1A) and Barrett's esophageal cells (CP-A and BAR-T) following stimulation with either bile acids or gamma-secretase inhibitor were investigated. Finally, changes in those expression levels following transfection of a Cdx2 or Dll1 expression vector into Het-1A cells were examined. In addition, changes in those expression levels following knockdown of Cdx2 or Dll1 in CP-A cells were also examined. Dll1 was found to be upregulated and localized in the cell membrane and cytoplasm in BE. Bile acids enhanced cytoplasmic expression of Dll1 in CP-A cells, while cleaved Notch1 expression did not change, suggesting lack of a Dll1 agonistic effect on Notch signaling. Cells transfected with Cdx2 revealed significantly enhanced Dll1, while forced expression of Dll1 enhanced ATOH1, Cdx2, and MUC2 expression levels. Nevertheless, enhanced Dll1 did not induce Hes1 expression, suggesting that Dll1 may primarily function as an intracellular signaling molecule and not a Notch agonistic ligand in the canonical pathway. In addition, knockdown of Cdx2 completely abrogated any increase in Dll1 expression upon treatment with bile acids. Our results revealed a novel function of Dll1: facilitation of intestinal metaplasia in conjunction with Cdx2 expression. Furthermore, they suggest that intracellular induction of Dll1 expression in esophageal epithelial cells due to Cdx2 induction in response to bile acids has important roles in BE development.
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20
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Hong J, Li D, Cao W. Rho Kinase ROCK2 Mediates Acid-Induced NADPH Oxidase NOX5-S Expression in Human Esophageal Adenocarcinoma Cells. PLoS One 2016; 11:e0149735. [PMID: 26901778 PMCID: PMC4764682 DOI: 10.1371/journal.pone.0149735] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 01/27/2016] [Indexed: 12/13/2022] Open
Abstract
Mechanisms of the progression from Barrett’s esophagus (BE) to esophageal adenocarcinoma (EA) are not fully understood. We have shown that NOX5-S may be involved in this progression. However, how acid upregulates NOX5-S is not well known. We found that acid-induced increase in NOX5-S expression was significantly decreased by the Rho kinase (ROCK) inhibitor Y27632 in BE mucosal biopsies and FLO-1 EA cells. In addition, acid treatment significantly increased the Rho kinase activity in FLO-1 cells. The acid-induced increase in NOX5-S expression and H2O2 production was significantly decreased by knockdown of Rho kinase ROCK2, but not by knockdown of ROCK1. Conversely, the overexpression of the constitutively active ROCK2, but not the constitutively active ROCK1, significantly enhanced the NOX5-S expression and H2O2 production. Moreover, the acid-induced increase in Rho kinase activity and in NOX5-S mRNA expression was blocked by the removal of calcium in both FLO-1 and OE33 cells. The calcium ionophore A23187 significantly increased the Rho kinase activity and NOX5-S mRNA expression. We conclude that acid-induced increase in NOX5-S expression and H2O2 production may depend on the activation of ROCK2, but not ROCK1, in EA cells. The acid-induced activation of Rho kinase may be mediated by the intracellular calcium increase. It is possible that persistent acid reflux present in BE patients may increase the intracellular calcium, activate ROCK2 and thereby upregulate NOX5-S. High levels of reactive oxygen species derived from NOX5-S may cause DNA damage and thereby contribute to the progression from BE to EA.
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Affiliation(s)
- Jie Hong
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, United States of America
- Department of Gastroenterology, Shanghai Jiao-Tong University School of Medicine Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Dan Li
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, United States of America
| | - Weibiao Cao
- Department of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, United States of America
- Department of Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, United States of America
- * E-mail:
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Chien LN, Huang YJ, Shao YHJ, Chang CJ, Chuang MT, Chiou HY, Yen Y. Proton pump inhibitors and risk of periampullary cancers--A nested case-control study. Int J Cancer 2015; 138:1401-9. [PMID: 26488896 PMCID: PMC4738410 DOI: 10.1002/ijc.29896] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 10/06/2015] [Indexed: 12/14/2022]
Abstract
Considerable attention has been focused on long-term use of proton pump inhibitor (PPI) medications in relation to increased risk of cancer via stimulation of DNA-damaged cells. The aim of this study is to examine the dose-dependent effect of PPI on periampullary cancers in a national population-based cohort. A nested case-control analysis was constructed based on Taiwan's National Health Insurance Research Database and the Taiwan Cancer Registry between the years 2000 and 2010. Cases involving patients diagnosed with periampullary cancers were selected and controls were matched to cases according to age, sex and observational period. A "PPI user" was defined as any patient receiving more than 28 cumulative defined daily doses as measured by prescription drug claims. Conditional logistic regression analysis was conducted to calculate odds ratios (ORs) and 95% confidence intervals (CIs) according to the level of PPI exposure. A total of 7,681 cases and 76,762 matched controls were included with a mean follow-up period of 6.6 years (SD: 2.0). The odds of PPI exposure in patients with periampullary cancers were higher than that of control patients with an adjusted OR of 1.35 (95% CIs: 1.16-1.57). Our results also showed that PPI exposure was slightly linked to periampullary cancers in dose-dependent manner. A similar association was observed in patients who solely took PPI but no eradication therapy for Helicobacter pylori infection. Long-term PPI use was associated with an increased risk of periampullary cancers in the current population-based study. Physicians must weigh potential risks of long-term maintenance against therapeutic benefit.
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Affiliation(s)
- Li-Nien Chien
- School of Health Care Administration, College of Management, Taipei Medical University, Taipei, Taiwan
| | - Yan-Jiun Huang
- Department of General Surgery, Taipei Medical University Hospital, Taipei, Taiwan.,Ph.D. Program for Translational Medicine, Taipei Medical University & Academia Sinica, Taipei, Taiwan
| | - Yu-Hsuan Joni Shao
- Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan
| | - Chen-Jung Chang
- Department of Gastroenterology, Taipei Medical University Hospital, Taipei, Taiwan
| | - Ming-Tsang Chuang
- School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
| | - Hung-Yi Chiou
- School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan
| | - Yun Yen
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
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Varghese S, Newton R, Ross-Innes CS, Lao-Sirieix P, Krishnadath KK, O'Donovan M, Novelli M, Wernisch L, Bergman J, Fitzgerald RC. Analysis of dysplasia in patients with Barrett's esophagus based on expression pattern of 90 genes. Gastroenterology 2015; 149:1511-1518.e5. [PMID: 26248086 DOI: 10.1053/j.gastro.2015.07.053] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Revised: 07/03/2015] [Accepted: 07/19/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Diagnoses of dysplasia, based on histologic analyses, dictate management decisions for patients with Barrett's esophagus (BE). However, there is much intra- and inter-observer variation in identification of dysplasia-particularly low-grade dysplasia. We aimed to identify a biomarker that could be used to assign patients with low-grade dysplasia to a low- or high-risk group. METHODS We performed a stringent histologic assessment of 150 frozen esophageal tissues samples collected from 4 centers in the United Kingdom (from 2000 through 2006). The following samples with homogeneous diagnoses were selected for gene expression profiling: 28 from patients with nondysplastic BE, 10 with low-grade dysplasia, 13 with high-grade dysplasia (HGD), and 8 from patients with esophageal adenocarcinoma. A leave-one-out cross-validation analysis was used identify a gene expression signature associated with HGD vs nondysplastic BE. Functional pathways associated with gene signature sets were identified using the MetaCore analysis. Gene expression signature sets were validated using gene expression data on BE and esophageal adenocarcinoma accessed through National Center for Biotechnology Information Gene Expression Omnibus, as well as a separate set of samples (n = 169) collected from patients who underwent endoscopy in the United Kingdom or the Netherlands and analyzed histologically. RESULTS We identified an expression pattern of 90 genes that could separate nondysplastic BE tissues from those with HGD (P < .0001). Genes in a pathway regulated by retinoic acid-regulated nuclear protein made the largest contribution to this gene set (P < .0001); the transcription factor MYC regulated at least 30% of genes within the signature (P < .0001). In the National Center for Biotechnology Information Gene Expression Omnibus validation set, the signature separated nondysplastic BE samples from esophageal adenocarcinoma samples (P = .0012). In the UK and Netherlands validation cohort, the signature identified dysplastic tissues with an area under the curve value of 0.87 (95% confidence interval: 0.82-0.93). Of samples with low-grade dysplasia (LGD), 64% were considered high risk according to the 90-gene signature; these patients had a higher rate of disease progression than those with a signature categorized as low risk (P = .047). CONCLUSIONS We identified an expression pattern of 90 genes in esophageal tissues of patients with BE that was associated with low- or high-risk for disease progression. This pattern might be used in combination with histologic analysis of biopsy samples to stratify patients for treatment. It would be most beneficial for analysis of patients without definitive evidence of HGD but for whom early endoscopic intervention is warranted.
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Affiliation(s)
- Sibu Varghese
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom
| | | | - Caryn S Ross-Innes
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom
| | - Pierre Lao-Sirieix
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom
| | | | - Maria O'Donovan
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom
| | - Marco Novelli
- GI Services, University College Hospital, NHS Foundation Trust, London, United Kingdom
| | | | | | - Rebecca C Fitzgerald
- MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom.
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Wang X, Zhou P, Sun X, Zheng J, Wei G, Zhang L, Wang H, Yao J, Lu S, Jia P. Acidified bile acids increase hTERT expression via c-myc activation in human gastric cancer cells. Oncol Rep 2015; 33:3038-44. [PMID: 25873431 DOI: 10.3892/or.2015.3908] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 02/24/2015] [Indexed: 11/06/2022] Open
Abstract
Human telomerase reverse transcriptase (hTERT) is upregulated in most cancer cell types as well in immortalized cells. The underlying mechanism for such upregulation, however, remains largely unknown. We report here that bile acids under acidified media increase hTERT expression via c-myc activation in primary human gastric cancer cell lines. Human gastric cancer MKN28, MGC803 and SGC7901 cells were treated with 100 µM deoxycholic acid (DCA) or chenodeoxycholic acid (CDCA) with or without acidified media in the presence or absence of the c-myc inhibitor 10058-F4 for 24 h. hTERT and c-myc protein levels were determined by western blot analysis. hTERT and c-myc mRNA levels were determined by RT-PCR. The promoter activities of hTERT and c-myc transcription were determined using promoter reporter luciferase assays for both. Telomerase enzyme activity was analyzed by stretch PCR. hTERT mRNA and protein levels were significantly increased by bile acids in acidified media and were accompanied with enhanced telomerase activity. No changes were found at a pH of 7.0 or with acidified media alone. Similarly, the mRNA and protein levels of c-myc were also increased by bile acids in acidified media but not at a pH of 7.0 or with acidified media alone. Importantly, pharmacologic inhibition of c-myc using 10058-F4 prevented hTERT induction by DCA or CDCA in gastric cancer cells under acidic conditions. Bile acids (DCA and CDCA) under acidic conditions increased hTERT expression in human gastric cancer cells by activation of c-myc transcription. This suggests that acidified bile acids may promote tumorigenesis and affect cell ageing via telomerase activation.
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Affiliation(s)
- Xiaolong Wang
- Department of General Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Peihua Zhou
- Department of General Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xuejun Sun
- Department of General Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jianbao Zheng
- Department of General Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Guangbing Wei
- Department of General Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Li Zhang
- Department of General Surgery, The Second Affiliated Hospital of the Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Hui Wang
- Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Jianfeng Yao
- Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Shaoying Lu
- Department of General Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Pengbo Jia
- The First People's Hospital of Xianyang City, Xianyang, Shaanxi 712000, P.R. China
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Nagathihalli NS, Beesetty Y, Lee W, Washington MK, Chen X, Lockhart AC, Merchant NB. Novel mechanistic insights into ectodomain shedding of EGFR Ligands Amphiregulin and TGF-α: impact on gastrointestinal cancers driven by secondary bile acids. Cancer Res 2014; 74:2062-72. [PMID: 24520077 DOI: 10.1158/0008-5472.can-13-2329] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Secondary bile acids (BA) such as deoxycholic acid (DCA) promote the development of several gastrointestinal malignancies, but how they mediate this effect is unclear. In this study, we offer evidence of a mechanism involving ectodomain shedding of the EGFR ligands amphiregulin (AREG) and TGF-α, which rely upon the cell surface protease TACE/ADAM-17. Specifically, we show that AREG participates in DCA-induced EGFR and STAT3 signaling, cell-cycle progression, and tumorigenicity in human colorectal cancer and pancreatic ductal adenocarcinoma (PDAC). TACE and AREG, but not TGF-α, were overexpressed in both colorectal cancer and PDAC tissues compared with normal tissues. Exposure of colorectal cancer and PDAC cells to DCA resulted in colocalization of Src and TACE to the cell membrane, resulting in AREG-dependent activation of EGFR, mitogen-activated protein kinase (MAPK), and STAT3 signaling. Src or TACE inhibition was sufficient to attenuate DCA-induced AREG, but not TGF-α shedding. We also examined a role for the BA transporter TGR5 in DCA-mediated EGFR and STAT3 signaling. RNA interference-mediated silencing of TGR5 or AREG inhibited DCA-induced EGFR, MAPK, and STAT3 signaling, blunted cyclin D1 expression and cell-cycle progression, and attenuated DCA-induced colorectal cancer or PDAC tumorigenicity. Together, our findings define an AREG-dependent signaling pathway that mediates the oncogenic effects of secondary BAs in gastrointestinal cancers, the targeting of which may enhance therapeutic responses in their treatment.
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Affiliation(s)
- Nagaraj S Nagathihalli
- Authors' Affiliations: Departments of Surgery, Cancer Biology, Pathology, and Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky; and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
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25
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Zhang R, Yin X, Shi H, Wu J, Shakya P, Liu D, Zhang J. Adiponectin modulates DCA-induced inflammation via the ROS/NF-κ B signaling pathway in esophageal adenocarcinoma cells. Dig Dis Sci 2014; 59:89-97. [PMID: 24096876 DOI: 10.1007/s10620-013-2877-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Accepted: 09/04/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND Deoxycholic acid (DCA) promotes the development and progression of esophageal adenocarcinoma (EAC) by inducing inflammation. Adiponectin is reported to have anti-inflammatory and anti-tumor effects. PURPOSE This study investigated the effects of two types of adiponectin, full-length adiponectin (f-Ad) and globular adiponectin (g-Ad), on DCA-induced inflammation, and investigated the involvement of the reactive oxygen species (ROS)/NF-κB signaling pathway in inflammation in EAC. METHODS OE19 cells were treated with DCA (50-300 μM) and/or f-Ad/g-Ad (10.0 μg/ml) or N-acetylcysteine (NAC). The viability of cells exposed to DCA was measured by use of the MTT assay. mRNA and protein levels of the inflammatory factors were examined by real-time PCR and ELISA. Intra-cellular ROS levels were determined by use of flow cytometry. Protein levels of total and p-NF-κB p65 were measured by western blot. RESULTS DCA induced dose and time-dependent cytotoxicity. mRNA and protein expression of TNF-α, IL-8, and IL-6 in cells treated with DCA alone were up-regulated, and intra-cellular ROS and p-NF-κB p65 protein levels were also increased. g-Ad promoted inflammatory factor production, ROS levels, and p-NF-κB p65 protein expression whereas f-Ad had a suppressive effect. When combined with DCA, g-Ad enhanced the pro-inflammatory effect of DCA whereas f-Ad, similar to NAC, suppressed the effect. CONCLUSION DCA has a pro-inflammatory effect in EAC. f-Ad has an anti-inflammatory effect whereas g-Ad seems to have a pro-inflammatory effect in an ROS/NF-κB p65-dependent manner. This indicates that f-Ad could be a potential anti-inflammatory reagent for cancer therapy.
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Affiliation(s)
- Rong Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, No. 157, Xi Wu Road, Xi'an, 710004, Shaanxi Province, China
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CIP2A expression and prognostic role in patients with esophageal adenocarcinoma. Med Oncol 2013; 30:684. [PMID: 23925667 DOI: 10.1007/s12032-013-0684-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Accepted: 07/30/2013] [Indexed: 12/17/2022]
Abstract
CIP2A is overexpressed in many cancers, including esophageal squamous cell carcinoma. The regulation of c-MYC and CIP2A expression is characterized by a positive feedback mechanism facilitating the expression of both of them and accelerating cancer cell proliferation in gastric cancer. Increased CIP2A expression is a predictor of poor survival in some cancers. The incidence of positive CIP2A immunostaining and its association with c-MYC and its predictive value in esophageal adenocarcinoma are unknown. All esophageal adenocarcinoma patients from 1990 to 2007 with sufficient material for analysis of CIP2A and c-MYC in two university hospitals were included in the study. In addition, biopsies from Barrett's epithelium from the cancer patients and control tissue from normal esophageal mucosa adjacent to the tumor were included. CIP2A was moderately or strongly positive in 77.9 %, and c-MYC in 93.8 % of the cancer specimens. These frequencies were statistically different from the expression in normal esophageal epithelium. In addition, there was a positive correlation between CIP2A and c-MYC expression (p = 0.018). According to adjusted Cox regression survival analysis, CIP2A and c-MYC had no effect on survival. However, among patients with stage IVA-IVB cancer, there was a trend toward poor prognosis in CIP2A-positive patients. The expression of CIP2A and c-MYC was associated with each other, and their overexpression was found in most cases of esophageal adenocarcinoma. However, CIP2A and c-MYC had no effect on survival.
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Zaïr ZM, Johnson GE, Griffiths AP, Jenkins GJ. Diagnostic correlation between the expression of the DNA repair enzyme N-methylpurine DNA glycosylase and esophageal adenocarcinoma onset: a retrospective pilot study. Dis Esophagus 2013; 26:644-50. [PMID: 23137018 DOI: 10.1111/dote.12003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
EAC in its early stages, when it can potentially be cured, is rarely symptomatic and is associated with high mortality rates because in part of late-stage diagnosis. Given that DNA repair is an important contributory factor of early-stage malignancy, our study focused on the expression of the base excision repair enzyme N-methylpurine DNA glycosylase (MPG) in EAC disease onset. MPG messenger RNA (mRNA) expression levels were determined using quantitative reverse transcriptase polymerase chain reaction from a maximum of 72 patient samples. Immunohistochemistry was further utilized for the detection of MPG protein, and semiquantitative analysis performed using an H-score approach was carried out on a total of 130 archival tissue samples of different esophageal pathologies. Nuclear localized MPG protein was detected in all nonmalignant tissues derived from the enterohepatic system, with H-score values of 3.9-5.5 ± 0.4-1.0. In cancerous tissues derived from the enterohepatic system, a 9.5-fold increase in the level of MPG mRNA expression was specifically observed in the malignant regions located within the esophagus region. Further analysis revealed a 9- and 14-fold increase in MPG mRNA expression in EAC tumor, node, metastasis stages II and III, respectively, suggesting MPG expression to correlate with EAC disease progression. Immunohistochemistry analysis further showed a sevenfold significant increase in MPG protein expression in EAC tissues. Intriguingly, there was a fivefold significant decrease in nuclear localized MPG protein expression in tissues derived from Barrett's esophagus and low-grade dysplasia. Such findings highlight a complex regulatory pattern governing DNA glycosylase base excision repair initiation, as normal tissue undergoes Barrett's metaplasia and later dedifferentiates to EAC. Indeed, disease-stage-specific alterations in the expression of MPG may highlight a potential role for MPG in determining EAC onset and thus potentially be of clinical relevance for early disease detection and increased patient survival.
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Affiliation(s)
- Z M Zaïr
- Institute of Life Sciences, School of Medicine, Swansea University, Swansea, UK.
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Clemons NJ, Phillips WA, Lord RV. Signaling pathways in the molecular pathogenesis of adenocarcinomas of the esophagus and gastroesophageal junction. Cancer Biol Ther 2013; 14:782-95. [PMID: 23792587 PMCID: PMC3909547 DOI: 10.4161/cbt.25362] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Esophageal adenocarcinoma develops in response to severe gastroesophageal reflux disease through the precursor lesion Barrett esophagus, in which the normal squamous epithelium is replaced by a columnar lining. The incidence of esophageal adenocarcinoma in the United States has increased by over 600% in the past 40 years and the overall survival rate remains less than 20% in the community. This review highlights some of the signaling pathways for which there is some evidence of a role in the development of esophageal adenocarcinoma. An increasingly detailed understanding of the biology of this cancer has emerged recently, revealing that in addition to the well-recognized alterations in single genes such as p53, p16, APC, and telomerase, there are interactions between the components of the reflux fluid, the homeobox gene Cdx2, and the Wnt, Notch, and Hedgehog signaling pathways.
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Affiliation(s)
- Nicholas J Clemons
- Surgical Oncology Research Laboratory; Peter MacCallum Cancer Centre; East Melbourne, Australia; Sir Peter MacCallum Department of Oncology; University of Melbourne, Melbourne, Australia; Department of Surgery (St. Vincent's Hospital); University of Melbourne; Melbourne, Australia
| | - Wayne A Phillips
- Surgical Oncology Research Laboratory; Peter MacCallum Cancer Centre; East Melbourne, Australia; Sir Peter MacCallum Department of Oncology; University of Melbourne, Melbourne, Australia; Department of Surgery (St. Vincent's Hospital); University of Melbourne; Melbourne, Australia
| | - Reginald V Lord
- St. Vincent's Centre for Applied Medical Research; Sydney, Australia; Notre Dame University School of Medicine; Sydney, Australia
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Curcumin abrogates bile-induced NF-κB activity and DNA damage in vitro and suppresses NF-κB activity whilst promoting apoptosis in vivo, suggesting chemopreventative potential in Barrett's oesophagus. Clin Transl Oncol 2012; 14:302-11. [PMID: 22484638 DOI: 10.1007/s12094-012-0799-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Curcumin has been suggested to possess anti-neoplastic properties. As oesophageal adenocarcinoma (OA) and Barrett's oesophagus (BO) represent a neoplastic series, we postulated that curcumin supplementation may slow neoplastic progression at this site. Our aim was to investigate the effects of curcumin in vitro and in vivo on markers of oesophageal cancer progression. METHODS We investigated the in vitro ability of curcumin to prevent bile acid-induced DNA damage using micronucleus assay and nuclear factor-kappaB (NF-κB) activity in the oesophageal cell lines (OE33) using real-time PCR of the extracted RNA. We also analysed NF-κB p65 activation in curcumin-pre-treated OE33 cells exposed to deoxycholic acid (DCA) using ELISA. In another pilot study, BO patients took a daily 500 mg curcumin tablet for 7 days prior to their endoscopy. In biopsies collected from these patients (n=33, 16 curcumin, 17 control), we examined NF-κB-driven gene expression (interleukin (IL)-8, inhibitor- kappaB (I-κB)) using real-time PCR of the extracted RNA from the biopsy sample. The apoptotic frequency was assessed by counting the number of apoptotic bodies in the epithelial cells from the Barrett's tissue with and without curcumin. RESULTS In vitro, curcumin (50 μM) significantly abrogated DNA damage and NF-κB activity induced by bile. Pretreating OE33 cells with curcumin (50 μM) completely abolished the ability of DCA (300 μM) to activate NF-κB. In vivo, IL-8 expression was non-significantly suppressed in the curcumin-supplemented patients compared to the squamous control tissue, whilst also showing a doubling in the apoptotic frequency compared to non-supplemented control patients. CONCLUSIONS Curcumin abrogated bile-driven effects in vitro. The in vivo data also suggests that curcumin supplementation had beneficial effects (increased apoptosis, potentially reduced NF-κB activity) in the Barrett's tissues themselves, despite poor delivery of the curcumin to the oesophagus.
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Cell culture models for studying the development of Barrett's esophagus: a systematic review. Cell Oncol (Dordr) 2012; 35:149-61. [PMID: 22476962 PMCID: PMC3396334 DOI: 10.1007/s13402-012-0076-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2012] [Indexed: 12/18/2022] Open
Abstract
Background Barrett’s esophagus (BE) is a premalignant condition caused by chronic gastroesophageal reflux. BE patients have an increased risk of developing esophageal adenocarcinoma (EAC). As many aspects of this condition are still unknown, there is a need for in vitro models to study BE development. Aim To review the literature on cell lines and incubation conditions for studying BE development. Methods A literature search was performed using PubMed, EMBASE and the Cochrane library, combining the words esophagus, cell line, culture, Barrett’s, bile, acid, exposure, reflux and adenocarcinoma. Results A wide range of cell lines and incubation conditions to study BE development have been reported. The most commonly used cell lines are derived from epithelium from patients with BE or EAC. A 25-minute incubation with 200 μM bile salts induced cell proliferation and Akt phosphorylation. However, increased CDX2 and MUC2 expression was only observed with longer incubations or higher bile salt concentrations. Two-hundred μM bile at pH 6 showed a higher toxicity to EAC cells than the same concentration at pH 7. Multiple 5-minute exposures with 200 μM bile at pH 4 or pH 7 increased CK8/18 and COX2 in BE epithelial cells. Conclusions Two-hundred μM conjugated primary or secondary bile salts at pH 4 for multiple short exposures is able to induce BE specific factors in BE cell lines. In SQ and EAC cell lines; however, higher concentrations of secondary bile salts for 8 h are needed to induce BE specific molecules. Due to the high variability in reported methods, it is difficult to determine the most effective in vitro setup for studying the development of BE.
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Dettmar PW, Strugala V, Tselepis C, Jankowski JA. The effect of alginates on deoxycholic-acid-induced changes in oesophageal mucosal biology at pH 4. JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION 2012; 18:317-33. [PMID: 17471768 DOI: 10.1163/156856207779996922] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Long-standing gastro-oesophageal reflux disease (GORD) can give rise to Barrett's oesophagus (BM), a metaplastic condition and precursor to oesophageal adenocarcinoma (AC). Oesophageal cancer was once rare but is now the 5th biggest cancer killer in the U.K. Reflux of bile acids into the oesophagus is implicated in the progression to BM as bile acids at pH 4 have been shown to induce c-myc expression, an oncogene upregulated in BM and AC. In the present study we investigated the role of the biopolymer alginate on bile acid induced molecular changes in oesophageal cell lines. OE21, OE33 and TE-7 oesophageal cell lines were exposed to 100 microM deoxycholic acid at pH 4 in the presence or absence of alginates. Levels of c-myc, E-cadherin, beta-catenin and Tcf signalling were determined by Real-Time PCR, Western blotting, immunofluoresence and reporter assays. All alginates tested were able to prevent the induction of c-myc by acidified deoxycholic acid in vitro. The upstream effects of acidified deoxycholic acid on E-cadherin, beta-catenin and Tcf signalling were also suppressed by alginate. Therefore, we have demonstrated that reflux of bile acids into the oesophagus initiates a potentially damaging molecular cascade of events using an in vitro model and that a biopolymer, alginate, can protect against these effects.
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Affiliation(s)
- Peter W Dettmar
- Technostics, The Deep Business Centre, Kingston Upon Hull, East Yorkshire, HU1 4BG, UK
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Winberg H, Lindblad M, Lagergren J, Dahlstrand H. Risk factors and chemoprevention in Barrett's esophagus--an update. Scand J Gastroenterol 2012; 47:397-406. [PMID: 22428928 DOI: 10.3109/00365521.2012.667145] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Barrett's esophagus (BO) is a precursor of esophageal adenocarcinoma (OAC), a cancer with a poor prognosis and an increasing incidence. Hence there is an interest in mapping causal factors underlying BO and finding strategies to reduce the risk of dysplasia progression in patients with BO. Here we review current knowledge on established as well as less risk factors for the development of BO. Additionally, we summarize today's status on the use of chemoprevention aiming to reduce the risk of cancer progression in BO patients. METHODS We searched Medline and the Cochrane Library using the MeSH terms "Barrett's esophagus" and "Barrett esophagus," both alone and combined with the terms "risk factor," "aetiology," "diet," or "prevention." Focus was on original contributions, systematic reviews, and meta-analyses. RESULTS Established risk factors for the development of BO include gastro-esophageal reflux, obesity, male gender, Caucasian ethnicity, and increasing age. Smoking might increase the risk of BO, while aspirin/NSAIDs, Helicobacter pylori infection, and specific "healthy" dietary factors may lower the risk. The potential value of using chemoprevention with proton pump inhibitors, aspirin/NSAIDs, or statins is still uncertain. CONCLUSIONS There is today a substantial knowledge of risk factors of BO. Certain diet may be protective of BO, albeit yet to be proven. The efficiency of chemoprevention in BO is currently addressed further in randomized clinical trials.
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Affiliation(s)
- Hanna Winberg
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Upper Gastrointestinal Research (UGIR), Stockholm, Sweden
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Theodorou D, Ayazi S, DeMeester SR, Zehetner J, Peyre CG, Grant KS, Augustin F, Oh DS, Lipham JC, Chandrasoma PT, Hagen JA, DeMeester TR. Intraluminal pH and goblet cell density in Barrett's esophagus. J Gastrointest Surg 2012; 16:469-74. [PMID: 22095525 DOI: 10.1007/s11605-011-1776-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Accepted: 10/31/2011] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Goblet cells in Barrett's esophagus (BE) vary in their density within the Barrett's segment. Exposure of Barrett's epithelium to bile acids is a major stimulant for goblet cell formation. The dissociation of bile acids into forms that penetrate Barrett's epithelium is known to be pH dependent. We hypothesized that variations in the esophageal luminal pH environment explains the variability in goblet cell density. The aim of this study was to correlate esophageal luminal pH with goblet cell density in patients with BE. METHODS A customized six-sensor pH catheter was positioned with the most distal sensor in the stomach and the remaining sensors located 1 cm below and 1, 3, 5, and 8 cm above the upper border of the lower esophageal sphincter in five normal subjects and six patients with long-segment BE. The luminal pH was measured by each sensor for 24-h and expressed as median pH. Patients with BE had four quadrant biopsies at levels corresponding to the location of the pH sensors. Goblet cell density was graded from 0 to 3 based on the number per high-power field. RESULTS In normal subjects, the median pH values recorded in the sensors within the lower esophageal sphincter (LES) and esophageal body were all above 5. In patients with BE, the median pH recorded by the sensor within the LES was 2.8 and increased progressively to 4.7 in the sensor at 8 cm above the LES. Goblet cell density was significantly lower in the distal Barrett's segment exposed to a median pH of 2.2 and increased in the proximal Barrett's segment exposed to a median pH of 4.4 (p = 0.003). CONCLUSION Patients with BE have a goblet cell gradient that correlates directly with an esophageal luminal pH gradient. This suggests that goblet cell differentiation is pH dependent and likely due to the effect of pH on bile acid dissociation.
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Affiliation(s)
- Dimitrios Theodorou
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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Subramaniam D, Ponnurangam S, Ramamoorthy P, Standing D, Battafarano RJ, Anant S, Sharma P. Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling. PLoS One 2012; 7:e30590. [PMID: 22363450 PMCID: PMC3281833 DOI: 10.1371/journal.pone.0030590] [Citation(s) in RCA: 177] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 12/19/2011] [Indexed: 12/21/2022] Open
Abstract
Background Curcumin inhibits the growth of esophageal cancer cell lines; however, the mechanism of action is not well understood. It is becoming increasingly clear that aberrant activation of Notch signaling has been associated with the development of esophageal cancer. Here, we have determined that curcumin inhibits esophageal cancer growth via a mechanism mediated through the Notch signaling pathway. Methodology/Principal Findings In this study, we show that curcumin treatment resulted in a dose and time dependent inhibition of proliferation and colony formation in esophageal cancer cell lines. Furthermore, curcumin treatment induced apoptosis through caspase 3 activation, confirmed by an increase in the ratio of Bax to Bcl2. Cell cycle analysis demonstrated that curcumin treatment induced cell death and down regulated cyclin D1 levels. Curcumin treatment also resulted in reduced number and size of esophagospheres. Furthermore, curcumin treatment led to reduced Notch-1 activation, expression of Jagged-1 and its downstream target Hes-1. This reduction in Notch-1 activation was determined to be due to the down-regulation of critical components of the γ-secretase complex proteins such as Presenilin 1 and Nicastrin. The combination of a known γ-secretase inhibitor DAPT and curcumin further decreased proliferation and induced apoptosis in esophageal cancer cells. Finally, curcumin treatment down-regulate the expressions of Notch-1 specific microRNAs miR-21 and miR-34a, and upregulated tumor suppressor let-7a miRNA. Conclusion/Significance Curcumin is a potent inhibitor of esophageal cancer growth that targets the Notch-1 activating γ-secretase complex proteins. These data suggest that Notch signaling inhibition is a novel mechanism of action for curcumin during therapeutic intervention in esophageal cancers.
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Affiliation(s)
- Dharmalingam Subramaniam
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, United States of America
- The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Kansas, United States of America
- * (D. Subramaniam); (PS)
| | - Sivapriya Ponnurangam
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Prabhu Ramamoorthy
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - David Standing
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Richard J. Battafarano
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Shrikant Anant
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, United States of America
- The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Kansas, United States of America
| | - Prateek Sharma
- Division of Gastroenterology and Hepatology, University of Kansas Medical Center, Kansas City, Kansas, United States of America
- The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Kansas, United States of America
- * (D. Subramaniam); (PS)
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Morita S, Matsumoto Y, Okuyama S, Ono K, Kitamura Y, Tomori A, Oyama T, Amano Y, Kinoshita Y, Chiba T, Marusawa H. Bile acid-induced expression of activation-induced cytidine deaminase during the development of Barrett's oesophageal adenocarcinoma. Carcinogenesis 2011; 32:1706-12. [PMID: 21890457 DOI: 10.1093/carcin/bgr194] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Activation-induced cytidine deaminase (AID) induces somatic mutations in various host genes of non-lymphoid tissues, thereby contributing to carcinogenesis. We recently demonstrated that Helicobacter pylori infection and/or proinflammatory cytokine stimulation triggers aberrant AID expression in gastric epithelial cells, causing mutations in the tumour-suppressor TP53 gene. The findings of the present study provide evidence of ectopic AID expression in Barrett's oesophagus and Barrett's oesophageal adenocarcinoma, a cancer that develops under chronic inflammatory conditions. Immunoreactivity for endogenous AID was observed in 24 of 28 (85.7%) specimens of the columnar cell-lined Barrett's oesophagus and in 20 of 22 (90.9%) of Barrett's adenocarcinoma, whereas weak or no AID protein expression was detectable in normal squamous epithelial cells of the oesophagus. We validated these results by analysing tissue specimens from another cohort comprising 16 cases with Barrett's oesophagus and four cases with Barrett's adenocarcinoma. In vitro treatment of human non-neoplastic oesophageal squamous-derived cells with sodium salt deoxycholic acid induced ectopic AID expression via the nuclear factor-kappaB activation pathway. These findings suggest that aberrant AID expression occurs in a substantial proportion of Barrett's epithelium, at least in part due to bile acid stimulation. Considering the genotoxic activity of AID, our current findings suggest that aberrant AID expression might enhance the susceptibility to genetic alterations in Barrett's columnar-lined epithelial cells, leading to cancer development.
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Affiliation(s)
- Shuko Morita
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
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McQuaid KR, Laine L, Fennerty MB, Souza R, Spechler SJ. Systematic review: the role of bile acids in the pathogenesis of gastro-oesophageal reflux disease and related neoplasia. Aliment Pharmacol Ther 2011; 34:146-65. [PMID: 21615439 DOI: 10.1111/j.1365-2036.2011.04709.x] [Citation(s) in RCA: 136] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Factors other than acid may play a role in gastro-oesophageal reflux disease (GERD) and its complications. AIM To assessed the role of bile acids in the pathogenesis of GERD, Barrett's oesophagus and Barrett's-related neoplasia. METHODS We conducted a systematic review of computerised bibliographic databases for original articles involving humans or human oesophageal tissue or cells that assessed exposure to or manipulation of bile acids. Outcomes assessed included GERD symptoms; gross oesophageal injury; Barrett's oesophagus and related neoplasia; and intermediate markers of inflammation, proliferation or neoplasia. RESULTS Eighty-three original articles were included. In in vivo studies, bile acids concentrations were higher in the oesophageal aspirates of patients with GERD than controls, and bile acids infusions triggered GERD symptoms, especially in high concentrations or in combination with acid. In ex vivo/in vitro studies, bile acids stimulated squamous oesophageal cells and Barrett's epithelial cells to produce inflammatory mediators (e.g., IL-8 and COX-2) and caused oxidative stress, DNA damage and apoptosis. They also induced squamous cells to change their gene expression pattern to resemble intestinal-type cells and caused Barrett's cells to increase expression of intestinal-type genes. CONCLUSIONS In aggregate, these studies suggest that bile acids may contribute to the pathogenesis of symptoms, oesophagitis and Barrett's metaplasia with related carcinogenesis in patients with GERD. However, all study results are not uniform and substantial differences in study parameters may explain at least some of this variation.
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Affiliation(s)
- K R McQuaid
- Veterans Affairs Medical Center and Department of Medicine, University of California, San Francisco, CA 94121, USA.
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Cronin J, Alhamdani A, Griffiths AP, Baxter JN, Brown T, Jenkins GJS. In vitro and ex vivo models of extended reflux exposure demonstrate that weakly acidic mixed reflux heightens NF-kB-mediated gene expression. Dis Esophagus 2011; 24:360-70. [PMID: 21143697 DOI: 10.1111/j.1442-2050.2010.01148.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The development of Barrett's esophagus and its progression to adenocarcinoma are clearly linked to reflux of acid and bile. Our objective in this study was to develop an optimized ex vivo biopsy culture technique to study the molecular signaling events induced after insult with individual refluxate constituents. We illustrate the utility of this method by showing results for NF-kB centered cell signaling, and compare the results with those obtained from esophageal cell lines. We show that upregulation of the two NF-kB target genes show differences in pH preference, with IL-8 being preferentially upregulated by DCA at neutral pH, and IkB being upregulated by neutral DCA, acidic DCA, and acid alone. This was found to be true in both cell lines and biopsy cultures. The maximum responses were noted in both models when mixed reflux (DCA at pH 6) was utilized, perhaps reflecting the pH preference of DCA (pKa 6.2). Both the optimized ex vivo models, and the in vitro cell lines show that bile and acid are capable of inducing NF-kB dependent gene expression, with some interesting differences in preferred transcriptional target. In conclusion, in both cells and cultured biopsies, similar reflux driven gene expression changes were noted, with maximum effects noted with DCA exposures at pH 6.
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Affiliation(s)
- J Cronin
- Institute of Life Science, Swansea UniversityDepartment of Surgery, Morriston Hospital, ABM Trust, MorristonDepartment of Histopathology, Morriston Hospital, ABM Trust, Morriston, Swansea, UK
| | - A Alhamdani
- Institute of Life Science, Swansea UniversityDepartment of Surgery, Morriston Hospital, ABM Trust, MorristonDepartment of Histopathology, Morriston Hospital, ABM Trust, Morriston, Swansea, UK
| | - A P Griffiths
- Institute of Life Science, Swansea UniversityDepartment of Surgery, Morriston Hospital, ABM Trust, MorristonDepartment of Histopathology, Morriston Hospital, ABM Trust, Morriston, Swansea, UK
| | - J N Baxter
- Institute of Life Science, Swansea UniversityDepartment of Surgery, Morriston Hospital, ABM Trust, MorristonDepartment of Histopathology, Morriston Hospital, ABM Trust, Morriston, Swansea, UK
| | - T Brown
- Institute of Life Science, Swansea UniversityDepartment of Surgery, Morriston Hospital, ABM Trust, MorristonDepartment of Histopathology, Morriston Hospital, ABM Trust, Morriston, Swansea, UK
| | - G J S Jenkins
- Institute of Life Science, Swansea UniversityDepartment of Surgery, Morriston Hospital, ABM Trust, MorristonDepartment of Histopathology, Morriston Hospital, ABM Trust, Morriston, Swansea, UK
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Pal J, Bertheau R, Buon L, Qazi A, Batchu RB, Bandyopadhyay S, Ali-Fehmi R, Beer DG, Weaver DW, Shmookler Reis RJ, Goyal RK, Huang Q, Munshi NC, Shammas MA. Genomic evolution in Barrett's adenocarcinoma cells: critical roles of elevated hsRAD51, homologous recombination and Alu sequences in the genome. Oncogene 2011; 30:3585-98. [PMID: 21423218 PMCID: PMC3406293 DOI: 10.1038/onc.2011.83] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
A prominent feature of most cancers including Barrett's adenocarcinoma (BAC) is genetic instability, which is associated with development and progression of disease. In this study, we investigated the role of recombinase (hsRAD51), a key component of homologous recombination (HR)/repair, in evolving genomic changes and growth of BAC cells. We show that the expression of RAD51 is elevated in BAC cell lines and tissue specimens, relative to normal cells. HR activity is also elevated and significantly correlates with RAD51 expression in BAC cells. The suppression of RAD51 expression, by short hairpin RNA (shRNA) specifically targeting this gene, significantly prevented BAC cells from acquiring genomic changes to either copy number or heterozygosity (P<0.02) in several independent experiments employing single-nucleotide polymorphism arrays. The reduction in copy-number changes, following shRNA treatment, was confirmed by Comparative Genome Hybridization analyses of the same DNA samples. Moreover, the chromosomal distributions of mutations correlated strongly with frequencies and locations of Alu interspersed repetitive elements on individual chromosomes. We conclude that the hsRAD51 protein level is systematically elevated in BAC, contributes significantly to genomic evolution during serial propagation of these cells and correlates with disease progression. Alu sequences may serve as substrates for elevated HR during cell proliferation in vitro, as they have been reported to do during the evolution of species, and thus may provide additional targets for prevention or treatment of this disease.
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Affiliation(s)
- J Pal
- Department of Adult Oncology, Dana Farber Cancer Institute, Boston, MA 02132, USA
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Seidl H, Gundling F, Schepp W, Schmidt T, Pehl C. Effect of low-proof alcoholic beverages on duodenogastro-esophageal reflux in health and GERD. Neurogastroenterol Motil 2011; 23:145-50, e29. [PMID: 20939854 DOI: 10.1111/j.1365-2982.2010.01614.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Alcoholic beverages are known to increase acidic gastro-esophageal reflux (GER) and the risk of esophagitis. Moreover, duodenogastro-esophageal reflux (DGER), containing bile acids, was shown to harmfully alter the esophageal mucosa, alone and synergistically with HCl and pepsin. However, studies directly addressing potential effects of different low proof alcoholic beverages on DGER in health and disease are missing. METHODS Bilitec readings for beer and white, rose, and red wine were obtained in vitro from pure and from mixtures with bile. One-hour DGER monitoring and pH-metry were performed in 12 healthy subjects and nine reflux patients with DGER after ingestion of a standardized liquid meal together with 300 mL of water, white wine, and in the volunteers, beer and rose wine. KEY RESULTS Bilitec measurement was found to be feasible in the presence of beer, white wine, and using a threshold of 0.25, rose wine. However, the presence of red wine resulted in extinction values above this threshold. The consumption of all investigated alcoholic beverages, especially of white wine, triggered increased acidic GER, both in healthy participants and patients with reflux disease. In contrast, no relevant DGER was found after intake of alcoholic beverages. CONCLUSIONS & INFERENCES Fiber-optic bilirubin monitoring can be used for DGER monitoring in combination with alcoholic beverages, except with red wine. Low-proof alcoholic beverages are a strong trigger of GER, but not of DGER, both in healthy subjects and patients with reflux disease.
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Affiliation(s)
- H Seidl
- Department of Gastroenterology, Hepatology and Gastroenterological Oncology, Bogenhausen Academic Teaching Hospital, Staedtisches Klinikum Muenchen GmbH, Munich, Germany.
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Abstract
While the normal inflammatory cascade is self-limiting and crucial for host protection against invading pathogens and in the repair of damaged tissue, a wealth of evidence suggests that chronic inflammation is the engine driving carcinogenesis. Over a period of almost 150 years the link between inflammation and cancer development has been well established. In this chapter we discuss the fundamental concepts and mechanisms behind normal inflammation as it pertains to wound healing. We further discuss the association of inflammation and its role in carcinogenesis, highlighting the different stages of cancer development, namely tumour initiation, promotion and progression. With both the innate and adaptive arms of the immune system being central to the inflammatory process, we examine the role of a number of immune effectors in contributing to the carcinogenic process. In addition, we highlight the influences of host genetics in altering cancer risk.
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Affiliation(s)
- Stephen G Maher
- Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin and St. James's Hospital, Dublin 8, Ireland.
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Cronin J, McAdam E, Danikas A, Tselepis C, Griffiths P, Baxter J, Thomas L, Manson J, Jenkins G. Epidermal growth factor receptor (EGFR) is overexpressed in high-grade dysplasia and adenocarcinoma of the esophagus and may represent a biomarker of histological progression in Barrett's esophagus (BE). Am J Gastroenterol 2011; 106:46-56. [PMID: 21157443 DOI: 10.1038/ajg.2010.433] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The assessment of cancer risk in patients with Barrett's esophagus (BE) is currently fraught with difficulty. The current gold standard method of assessing cancer risk is histological assessment, with the appearance of high-grade dysplasia (HGD) as the key event monitored. Sampling error during endoscopy limits the usefulness of this approach, and there has been much recent interest in supplementing histological assessment with molecular markers, which may aid in patient stratification. METHODS No molecular marker has been yet validated to accurately correlate with esophageal histological progression. Here, we assessed the suitability of several membranous proteins as biomarkers by correlating their abundance with histological progression. In all, 107 patient samples, from 100 patients, were arranged on a tissue microarray (TMA) and represented the various stages of histological progression in BE. This TMA was probed with antibodies for eight receptor proteins (mostly membranous). RESULTS Epidermal growth factor receptor (EGFR) staining was found to be the most promising biomarker identified with clear increases in staining accompanying histological progression. Further, immunohistochemistry was performed using the full-tissue sections from BE, HGD, and adenocarcinoma tissues, which confirmed the stepwise increase in EGFR abundance. Using a robust H-score analysis, EGFR abundance was shown to increase 13-fold in the adenocarcinoma tissues compared to the BE tissues. EGFR was "overexpressed" in 35% of HGD specimens and 80% of adenocarcinoma specimens when using the H-score of the BE patients (plus 3 s.d.) as the threshold to define overexpression. EGFR staining was also noted to be higher in BE tissues adjacent to HGD/adenocarcinoma. Western blotting, although showing more EGFR protein in the adenocarcinomas compared to the BE tissue, was highly variable. EGFR overexpression was accompanied by aneuploidy (gain) of chromosome 7, plus amplification of the EGFR locus. Finally, the bile acid deoxycholic acid (DCA) (at neutral and acidic pH) and acid alone was capable of upregulating EGFR mRNA in vitro, and in the case of neutral pH DCA, this was NF-κB dependent. CONCLUSIONS EGFR is overexpressed during the histological progression in BE tissues and hence may be useful as a biomarker of histological progression. Furthermore, as EGFR is a membranous protein expressed on the luminal surface of the esophageal mucosa, it may also be a useful target for biopsy guidance during endoscopy.
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Affiliation(s)
- James Cronin
- Institute of Life Science, Swansea School of Medicine, Swansea University, Swansea, UK
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Anticancer activity of a broccoli derivative, sulforaphane, in barrett adenocarcinoma: potential use in chemoprevention and as adjuvant in chemotherapy. Transl Oncol 2010; 3:389-99. [PMID: 21151478 DOI: 10.1593/tlo.10235] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2010] [Revised: 10/06/2010] [Accepted: 10/09/2010] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION The incidence of Barrett esophageal adenocarcinoma (BEAC) has been increasing at an alarming rate in western countries. In this study, we have evaluated the therapeutic potential of sulforaphane (SFN), an antioxidant derived from broccoli, in BEAC. METHODS BEAC cells were treated with SFN, alone or in combination with chemotherapeutic, paclitaxel, or telomerase-inhibiting agents (MST-312, GRN163L), and live cell number determined at various time points. The effect on drug resistance/chemosensitivity was evaluated by rhodamine efflux assay. Apoptosis was detected by annexin V labeling and Western blot analysis of poly(ADP-ribose) polymerase cleavage. Effects on genes implicated in cell cycle and apoptosis were determined by Western blot analyses. To evaluate the efficacy in vivo, BEAC cells were injected subcutaneously in severe combined immunodeficient mice, and after the appearance of palpable tumors, mice were treated with SFN. RESULTS SFN induced both time- and dose-dependent decline in cell survival, cell cycle arrest, and apoptosis. The treatment with SFN also suppressed the expression of multidrug resistance protein, reduced drug efflux, and increased anticancer activity of other antiproliferative agents including paclitaxel. A significant reduction in tumor volume was also observed by SFN in a subcutaneous tumor model of BEAC. Anticancer activity could be attributed to the induction of caspase 8 and p21 and down-regulation of hsp90, a molecular chaperon required for activity of several proliferation-associated proteins. CONCLUSIONS These data indicate that a natural product with antioxidant properties from broccoli has great potential to be used in chemoprevention and treatment of BEAC.
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Pappou EP, Ahuja N. The role of oncogenes in gastrointestinal cancer. GASTROINTESTINAL CANCER RESEARCH : GCR 2010:S2-S15. [PMID: 21472044 PMCID: PMC3047044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Accepted: 07/22/2010] [Indexed: 05/30/2023]
Abstract
Oncogene research over the last century has been one of the major advances in understanding the molecular biology of malignant disease. Oncogenes are a structurally and functionally heterogeneous group of genes, whose protein products act pleiotropically and affect multiple complex regulatory cascades within the cell. They regulate cell proliferation, growth, and differentiation, as well as control of the cell cycle and apoptosis. The products of oncogenes include growth factors, growth factor receptors, signal transducers, transcription factors, and apoptosis regulators, as well as chromatin remodelers. Several distinct mechanisms have been described for the conversion of proto-oncogenes to active oncogenes. Quantitative forms of oncogene activation include multiplication (gene amplification) or translocation to an active chromatin domain that brings a growth-regulatory gene under the control of a different promoter, causing inappropriate expression of the gene. Qualitative forms include either point mutations or the production of a novel product from a chimeric gene. Further understanding of the molecular mechanisms by which oncogenes regulate normal development and tumorigenesis may lead to novel concepts in the diagnosis and treatment of cancer in humans. In this review, we focus on the role of selected oncogenes in gastrointestinal cancer.
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Savarino E, Zentilin P, Frazzoni M, Cuoco DL, Pohl D, Dulbecco P, Marabotto E, Sammito G, Gemignani L, Tutuian R, Savarino V. Characteristics of gastro-esophageal reflux episodes in Barrett's esophagus, erosive esophagitis and healthy volunteers. Neurogastroenterol Motil 2010; 22:1061-e280. [PMID: 20557468 DOI: 10.1111/j.1365-2982.2010.01536.x] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Gastro-esophageal reflux is considered a major culprit in the pathogenesis of Barrett's esophagus (BE). Still, there is controversy on the role of weakly acidic and weakly alkaline reflux in BE. To compare characteristics of reflux episodes patients with BE, erosive esophagitis (EE), and healthy volunteers (HV). METHODS One hundred consecutive patients with BE (75 short-segment BE, 25 long-segment BE), 50 with EE and 48 HV underwent multichannel intraluminal impedance-pH off-therapy. We quantified esophageal acid exposure, characteristics, and proximal extension of reflux episodes. KEY RESULTS Total and acid reflux episodes gradually increased from HV [28 (17.5-43) and 18 (8-31)] to EE [73.5 (54-96) and 52 (39-68)], short-segment BE (SSBE) [83 (73.2-131) and 65 (43.3-95)] and long-segment BE (LSBE) [105 (102-187) and 77 (75-107)]. Weakly acidic reflux episodes were significantly higher (P < 0.05) in LSBE [36 (27.5-50.5)] and SSBE [34 (18.5-41)] compared to EE [21.5 (15-37)] and HV [19 (14-25)]. No differences in terms of proportion of acid, weakly acidic and weakly alkaline reflux were found [HV (49%-49%-2%) vs EE (68%-32%-1%) vs SSBE (65%-34%-1%) vs LSBE (69%-30%-1%); P = ns]. In LSBE, a higher percentage of reflux episodes (P < 0.05) reached the proximal esophagus (59%) compared with SSBE (43%). CONCLUSIONS & INFERENCES Barrett esophagus patients have more severe reflux as shown by the number of acid and weakly acidic reflux episodes, re-reflux episodes and proximal migration. Given that PPI change only the pH of the refluxate, the role of weakly acidic reflux in Barrett's patients on acid suppressive therapy warrants further investigation.
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Affiliation(s)
- E Savarino
- Division of Gastroenterology, Department of Internal Medicine, University of Genoa, Genoa, Italy.
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Genetic profiles of gastroesophageal cancer: combined analysis using expression array and tiling array--comparative genomic hybridization. ACTA ACUST UNITED AC 2010; 200:120-6. [PMID: 20620594 DOI: 10.1016/j.cancergencyto.2010.03.013] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2009] [Revised: 03/03/2010] [Accepted: 03/30/2010] [Indexed: 12/20/2022]
Abstract
We aimed to characterize the genomic profiles of adenocarcinomas in the gastroesophageal junction in relation to cancers in the esophagus and the stomach. Profiles of gains/losses as well as gene expression profiles were obtained from 27 gastroesophageal adenocarcinomas by means of 32k high-resolution array-based comparative genomic hybridization and 27k oligo gene expression arrays, and putative target genes were validated in an extended series. Adenocarcinomas in the distal esophagus and the gastroesophageal junction showed strong similarities with the most common gains at 20q13, 8q24, 1q21-23, 5p15, 13q34, and 12q13, whereas different profiles with gains at 5p15, 7p22, 2q35, and 13q34 characterized gastric cancers. CDK6 and EGFR were identified as putative target genes in cancers of the esophagus and the gastroesophageal junction, with upregulation in one quarter of the tumors. Gains/losses and gene expression profiles show strong similarity between cancers in the distal esophagus and the gastroesophageal junction with frequent upregulation of CDK6 and EGFR, whereas gastric cancer displays distinct genetic changes. These data suggest that molecular diagnostics and targeted therapies can be applied to adenocarcinomas of the distal esophagus and gastroesophageal junction alike.
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Genetic diversity during the development of Barrett's oesophagus-associated adenocarcinoma: how, when and why? Biochem Soc Trans 2010; 38:374-9. [PMID: 20298186 DOI: 10.1042/bst0380374] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Recent investigations into Barrett's oesophagus at the level of individual crypts have found significant genetic heterogeneity within a single lesion. Furthermore, this genetic diversity has been shown to predict cancer development. In the present article, we review the genetic alterations implicated in disease progression in Barrett's oesophagus and discuss how genetic diversity could arise during tumorigenesis. Three arguments are discussed: a high mutation rate coupled with strong selection, clonal interaction driving progression, and a hitherto unidentified alteration that disrupts epithelial cell homoeostasis. Suggestions are made for future research to distinguish which of these theories is the predominant mechanism in Barrett's oesophagus-associated tumorigenesis.
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Wang JS, Canto MI. Predicting Neoplastic Progression in Barrett's Esophagus. ANNALS OF GASTROENTEROLOGY & HEPATOLOGY 2010; 1:1-10. [PMID: 21552467 PMCID: PMC3087308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Patients with Barrett's esophagus have a significantly increased risk of esophageal adenocarcinoma, 40-125 times higher than the general population. Since only a small fraction of Barrett's esophagus patients will actually progress to esophageal adenocarcinoma, there is a need to develop markers that may accurately predict which patients with Barrett's esophagus are likely to have aggressive disease and progress to cancer versus patients who will remain histologically stable and have a benign course. This would allow for better risk stratification of patients with Barrett's esophagus in order to target aggressive surveillance and intervention towards only those patients at highest risk for neoplastic progression. Predictive biomarkers may thus have significant clinical utility in the management of Barrett's esophagus patients. The detection of dysplasia in esophageal biopsies is currently the only standard method used in clinical practice as a marker for increased risk of cancer. However, dysplasia has not been a accurate or reliable marker for predicting malignant progression and suffers from poor interobserver agreement among pathologists and sampling error. A multitude of potential biomarkers have been studied over the years. It is likely that the best model for predicting progression to esophageal adenocarcinoma in Barrett's esophagus patients will ultimately involve a combination of biomarkers, dysplasia grade and other pathological characteristics, as well as clinical and demographic attributes. In this review, we will discuss the most promising biomarkers that have been studied thus far.
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Affiliation(s)
- Jean S. Wang
- Department of Medicine (Gastroenterology), Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Marcia I. Canto
- Department of Medicine (Gastroenterology), Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Stamp D. Bile acids and esophageal cancer the elusive "pulsatile acid or bile acid-induced" proliferation. Med Hypotheses 2010; 75:338-40. [PMID: 20427131 DOI: 10.1016/j.mehy.2010.03.034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2009] [Revised: 03/23/2010] [Accepted: 03/24/2010] [Indexed: 12/12/2022]
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Gadaleta RM, van Mil SWC, Oldenburg B, Siersema PD, Klomp LWJ, van Erpecum KJ. Bile acids and their nuclear receptor FXR: Relevance for hepatobiliary and gastrointestinal disease. Biochim Biophys Acta Mol Cell Biol Lipids 2010; 1801:683-92. [PMID: 20399894 DOI: 10.1016/j.bbalip.2010.04.006] [Citation(s) in RCA: 112] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2010] [Revised: 04/03/2010] [Accepted: 04/09/2010] [Indexed: 12/15/2022]
Abstract
The nuclear receptor Farnesoid X Receptor (FXR) critically regulates nascent bile formation and bile acid enterohepatic circulation. Bile acids and FXR play a pivotal role in regulating hepatic inflammation and regeneration as well as in regulating extent of inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. Recent evidence suggests, that the bile acid-FXR interaction is involved in the pathophysiology of a wide range of diseases of the liver, biliary and gastrointestinal tract, such as cholestatic and inflammatory liver diseases and hepatocellular carcinoma, inflammatory bowel disease and inflammation-associated cancer of the colon and esophagus. In this review we discuss current knowledge of the role the bile acid-FXR interaction has in (patho)physiology of the liver, biliary and gastrointestinal tract, and proposed underlying mechanisms, based on in vitro data and experimental animal models. Given the availability of highly potent synthetic FXR agonists, we focus particularly on potential relevance for human disease.
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Affiliation(s)
- Raffaella M Gadaleta
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands.
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Hong J, Behar J, Wands J, Resnick M, Wang LJ, DeLellis RA, Lambeth D, Souza RF, Spechler SJ, Cao W. Role of a novel bile acid receptor TGR5 in the development of oesophageal adenocarcinoma. Gut 2010; 59:170-80. [PMID: 19926617 PMCID: PMC3049934 DOI: 10.1136/gut.2009.188375] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Mechanisms of the progression from Barrett's oesophagus to oesophageal adenocarcinoma (OA) are not fully understood. Bile acids may have an important role in this progression. This study aimed at examining the role of NADPH oxidase NOX5-S and a novel bile acid receptor TGR5 in taurodeoxycholic acid (TDCA)-induced increase in cell proliferation. METHODS Human Barrett's cell line BAR-T and OA cell line FLO were transfected by the Lipofectamine 2000 or Amaxa-Nucleofector-System. mRNAs were measured by real-time PCR. H(2)O(2) was measured by a fluorescent assay. Cell proliferation was determined by measurement of thymidine incorporation. RESULTS NOX5-S was present in FLO cells. TDCA significantly increased NOX5-S expression, H(2)O(2) production and thymidine incorporation in FLO and BAR-T cells. This increase in thymidine incorporation was significantly reduced by knockdown of NOX5-S. TGR5 mRNA and protein levels were significantly higher in OA tissues than in normal oesophageal mucosa or Barrett's mucosa. Knockdown of TGR5 markedly inhibited TDCA-induced increase in NOX5-S expression, H(2)O(2) production and thymidine incorporation in FLO and BAR-T cells. Overexpression of TGR5 significantly enhanced the effects of TDCA in FLO cells. TGR5 receptors were coupled with Galphaq and Galphai3 proteins, but only Galphaq mediated TDCA-induced increase in NOX5-S expression, H(2)O(2) production and thymidine incorporation in FLO cells. CONCLUSIONS TDCA-induced increase in cell proliferation depends on upregulation of NOX5-S expression in BAR-T and FLO cells. TDCA-induced NOX5-S expression may be mediated by activation of the TGR5 receptor and Galphaq protein. These data may provide potential targets to prevent and/or treat Barrett's OA.
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Affiliation(s)
- Jie Hong
- Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI
| | - Jose Behar
- Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI
| | - Jack Wands
- Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI
| | - Murray Resnick
- Department of Pathology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI
| | - Li Juan Wang
- Department of Pathology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI
| | - Ronald A. DeLellis
- Department of Pathology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI
| | - David Lambeth
- Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322
| | - Rhonda F. Souza
- Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX 75216
| | - Stuart J. Spechler
- Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX 75216
| | - Weibiao Cao
- Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI,Department of Pathology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI
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