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Lin X, Pan F, Abudoureyimu M, Wang T, Hao L, Wang R. Aurora-A inhibitor synergistically enhances the inhibitory effect of anlotinib on hepatocellular carcinoma. Biochem Biophys Res Commun 2024; 690:149247. [PMID: 38000292 DOI: 10.1016/j.bbrc.2023.149247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 11/07/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant tumor with a global prevalence. In addition to the existing clinical guidelines, the effectiveness of anlotinib and Aurora-A inhibitors in treating HCC has also been demonstrated. However, Anlotinib, as an anti-angiogenesis therapy, has shown significant benefits in clinical trials but is limited by its single-agent treatment and the development of drug resistance. Aurora-A inhibitors are currently being tested in clinical trials but have limited efficacy. Combination therapy may offer clear advantages over monotherapy in this context. METHODS In this study, we used HCC cell lines to investigate whether the combination of the two drugs could enhance their individual strengths and mitigate their weaknesses, thereby providing greater clinical benefits both in vitro and in vivo. RESULTS Our findings confirmed that the Aurora-A inhibitor alisertib and anlotinib exhibited a time-dose-dependent inhibitory effect on HCC cells. In vitro cytological experiments demonstrated that the combination of the two drugs synergistically inhibited cell proliferation, invasion, and metastasis, while promoting cell apoptosis. Furthermore, we identified the underlying molecular mechanism by which the combination of the Aurora-A inhibitor alisertib and anlotinib inhibited HCC through the inhibition of the NF-ĸB signaling pathway. CONCLUSIONS In summary, we have demonstrated the effectiveness of combining anlotinib with an Aurora-A inhibitor, which expands the potential applications of anlotinib in the clinical treatment of HCC in the future.
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Affiliation(s)
- Xinrong Lin
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
| | - Fan Pan
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
| | - Mubalake Abudoureyimu
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
| | - Ting Wang
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
| | - Liping Hao
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
| | - Rui Wang
- Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
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Sokolova O, Naumann M. Matrix Metalloproteinases in Helicobacter pylori-Associated Gastritis and Gastric Cancer. Int J Mol Sci 2022; 23:1883. [PMID: 35163805 PMCID: PMC8836485 DOI: 10.3390/ijms23031883] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer is one of the leading causes of the cancer-related mortality worldwide. The etiology of this disease is complex and involves genetic predisposition and environmental factors, including Helicobacter pylori. Infection of the stomach with H. pylori leads to gastritis and gastric atrophy, which can progress stepwise to gastric cancer. Matrix metalloproteinases (MMPs) actively participate in the pathology development. The further progression of gastric cancer seems to be less dependent on bacteria but of intra-tumor cell dynamics. Bioinformatics data confirmed an important role of the extracellular matrix constituents and specific MMPs in stomach carcinoma invasion and metastasis, and revised their potential as predictors of the disease outcome. In this review, we describe, in detail, the impact of MMPs in H. pylori-associated gastritis and gastric cancer.
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Affiliation(s)
- Olga Sokolova
- Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany
| | - Michael Naumann
- Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany
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Ignatova E, Seriak D, Fedyanin M, Tryakin A, Pokataev I, Menshikova S, Vakhabova Y, Smirnova K, Tjulandin S, Ajani JA. Epstein-Barr virus-associated gastric cancer: disease that requires special approach. Gastric Cancer 2020; 23:951-960. [PMID: 32514646 DOI: 10.1007/s10120-020-01095-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023]
Abstract
Epstein-Barr virus-associated gastric cancer [EBV-associated GC, EBV( +) GC] is a distinct molecular subtype of gastrointestinal (GI) cancers. It accounts for up to 10% of all molecular subtypes of gastric cancer (GC). It has unique genetic and epigenetic features, which determine its definitive phenotype with male and younger age predominance, proximal stomach localization, and diffuse adenocarcinoma histology. EBV( +) GC also has a unique epigenetic profile and mutational status with frequent mutations of PIK3CA, ARID1A and BCOR, and PD-L1 and PD-L2 amplifications, as well. The aim of this review is to highlight clinical significance of EBV( +) GC and prognostic role of EBV infection, and to determine potentially appropriate drug therapy for this disease.
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Affiliation(s)
- Ekaterina Ignatova
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation.
| | - Daria Seriak
- Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation
| | - Mikhail Fedyanin
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Alexey Tryakin
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Ilya Pokataev
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Sofia Menshikova
- Department of Anticancer Drug Treatment, AO K31 City, Moscow, Russian Federation
| | - Yuliya Vakhabova
- Chemotherapy Department of Tumors Drug Treatment, Moscow Scientific Research Oncological Institution N.a. P.A. Herzen, Branch of Federal State Budgetary Institution "National Medical Research Center of Radiology" of Ministry of Healthcare of Russian Federation, Moscow, Russian Federation
| | - Ksenia Smirnova
- Laboratory of Viral Carcinogenesis, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
| | - Sergey Tjulandin
- Department of Clinical Pharmacology and Chemotherapy, Federal State Budgetary Institution «N.N. Blokhin National Medical Research Center of Oncology» of the Ministry of Health of the Russian Federation, 24, Kashirskoye shosse, Moscow, Russian Federation
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
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Alarcón-Millán J, Martínez-Carrillo DN, Peralta-Zaragoza O, Fernández-Tilapa G. Regulation of GKN1 expression in gastric carcinogenesis: A problem to resolve (Review). Int J Oncol 2019; 55:555-569. [PMID: 31322194 DOI: 10.3892/ijo.2019.4843] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 07/04/2019] [Indexed: 11/05/2022] Open
Abstract
Gastrokine 1 (GKN1) is a protein expressed on the surface mucosa cells of the gastric antrum and fundus, which contributes to maintaining gastric homeostasis, inhibits inflammation and is a tumor suppressor. The expression of GKN1 decreases in mucosa that are either inflamed or infected by Helicobacter pylori, and is absent in gastric cancer. The measurement of circulating GKN1 concentration, the protein itself, or the mRNA in gastric tissue may be of use for the early diagnosis of cancer. The mechanisms that modulate the deregulation or silencing of GKN1 expression have not been completely described. The modification of histones, methylation of the GKN1 promoter, or proteasomal degradation of the protein have been detected in some patients; however, these mechanisms do not completely explain the absence of GKN1 or the reduction in GKN1 levels. Only NKX6.3 transcription factor has been shown to be a positive modulator of GKN1 transcription, although others also have an affinity with sequences in the promoter of this gene. While microRNAs (miRNAs) are able to directly or indirectly regulate the expression of genes at the post‑transcriptional level, the involvement of miRNAs in the regulation of GKN1 has not been reported. The present review analyzes the information reported on the determination of GKN1 expression and the regulation of its expression at the transcriptional, post‑transcriptional and post‑translational levels; it proposes an integrated model that incorporates the regulation of GKN1 expression via transcription factors and miRNAs in H. pylori infection.
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Affiliation(s)
- Judit Alarcón-Millán
- Clinical Research Laboratory, Faculty of Biological Chemical Sciences, Guerrero Autonomous University, Chilpancingo, Guerrero 39070, México
| | - Dinorah Nashely Martínez-Carrillo
- Clinical Research Laboratory, Faculty of Biological Chemical Sciences, Guerrero Autonomous University, Chilpancingo, Guerrero 39070, México
| | - Oscar Peralta-Zaragoza
- Direction of Chronic Infections and Cancer, Research Center in Infection Diseases, National Institute of Public Health, Cuernavaca, Morelos 62100, México
| | - Gloria Fernández-Tilapa
- Clinical Research Laboratory, Faculty of Biological Chemical Sciences, Guerrero Autonomous University, Chilpancingo, Guerrero 39070, México
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Pandey A, Tripathi SC, Shukla S, Mahata S, Vishnoi K, Misra SP, Misra V, Mitra S, Dwivedi M, Bharti AC. Differentially localized survivin and STAT3 as markers of gastric cancer progression: Association with Helicobacter pylori. Cancer Rep (Hoboken) 2018; 1:e1004. [PMID: 32729225 DOI: 10.1002/cnr2.1004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 03/15/2018] [Accepted: 03/30/2018] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Localization and differential expression of STAT3 and survivin in cancer cells are often related to distinct cellular functions. The involvement of survivin and STAT3 in gastric cancer has been reported in separate studies but without clear understanding of their kinetics in cancer progression. METHODS We examined intracellular distribution of STAT3 and survivin in gastric adenocarcinoma and compared it with normal and precancer tissues using immunoblotting and immunohistochemistry. RESULTS Analysis of a total of 156 gastric samples comprising 61 histologically normal, 30 precancerous tissues (comprising intestinal metaplasia and dysplasia), and 65 adenocarcinomas, collected as endoscopic biopsies from treatment naïve study participants, revealed a significant (P < .001) increase in overall protein levels. Survivin expression was detectable in both cytoplasmic (90.8%) and nuclear (87.7%) compartments in gastric adenocarcinomas lesions. Precancerous dysplastic gastric lesions exhibited a moderate survivin expression (56.7%) localized in cytoplasmic compartment. Similarly, STAT3 and pSTAT3 expression was detected at high level in gastric cancer lesions. The levels of compartmentalized expression of survivin and STAT3/pSTAT3 correlated in precancerous and adenocarcinoma lesions. Although overexpression of these proteins was found associated with the tobacco use and alcohol consumption, their expression invariably and strongly correlated with concurrent Helicobacter pylori infection. Receiver operating characteristic analysis of nuclear survivin, STAT3, and pSTAT3 in different study groups showed acceptable positive and negative predictive values with area under the curve above 0.8 (P < .001). CONCLUSION Overall, our results suggest that overall increase in survivin and STAT3 and their subcellular localization are key determinants of gastric cancer progression, which can be collectively used as potential disease biomarkers and therapeutic targets for gastric cancer.
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Affiliation(s)
- Arvind Pandey
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas, USA.,Division of Molecular Oncology, National Institute of Cancer Prevention and Research (ICMR), Noida, Uttar Pradesh, India
| | | | - Shirish Shukla
- Department of Pathology, University of Michigan Medical School, University of Michigan, Ann Arbor, Michigan, USA
| | - Sutapa Mahata
- Division of Molecular Oncology, National Institute of Cancer Prevention and Research (ICMR), Noida, Uttar Pradesh, India.,Division of Pathology and Cancer Screening, Chittaranjan National Cancer Institute, Kolkata, India
| | - Kanchan Vishnoi
- Division of Molecular Oncology, National Institute of Cancer Prevention and Research (ICMR), Noida, Uttar Pradesh, India.,Department of Surgery, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Sri Prakash Misra
- Department of Gastroenterology, Moti Lal Nehru Medical College, Allahabad, Uttar Pradesh, India
| | - Vatsala Misra
- Department of Pathology, Moti Lal Nehru Medical College, Allahabad, Uttar Pradesh, India
| | - Sankar Mitra
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas, USA
| | - Manisha Dwivedi
- Department of Gastroenterology, Moti Lal Nehru Medical College, Allahabad, Uttar Pradesh, India
| | - Alok C Bharti
- Division of Molecular Oncology, National Institute of Cancer Prevention and Research (ICMR), Noida, Uttar Pradesh, India.,Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
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Kim SH, Yoo HS, Joo MK, Kim T, Park JJ, Lee BJ, Chun HJ, Lee SW, Bak YT. Arsenic trioxide attenuates STAT-3 activity and epithelial-mesenchymal transition through induction of SHP-1 in gastric cancer cells. BMC Cancer 2018; 18:150. [PMID: 29409467 PMCID: PMC5801683 DOI: 10.1186/s12885-018-4071-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 01/29/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND We investigated the effect of arsenic trioxide (ATO) for inhibition of signal transducer and activator of transcription 3 (STAT3) and epithelial-mesenchymal transition (EMT) in gastric cancer cells, and the role of SH2 domain-containing phosphatase-1 (SHP-1) during this process. METHODS We used AGS cells, which showed minimal SHP-1 expression and constitutive STAT3 expression. After treatment of ATO, cellular migration and invasion were assessed by using wound closure assay, Matrigel invasion assay and 3-D culture invasion assay. To validate the role of SHP-1, pervanadate, a pharmacologic phosphatase inhibitor, and SHP-1 siRNA were used. Xenograft tumors were produced, and ATO or pervanadate were administered via intraperitoneal (IP) route. RESULTS Treatment of ATO 5 and 10 μM significantly decreased cellular migration and invasion in a dose-dependent manner. Western blot showed that ATO upregulated SHP-1 expression and downregulated STAT3 expression, and immunofluorescence showed upregulation with E-cadherin (epithelial marker) and downregulation of Snail1 (mesenchymal marker) expression by ATO treatment. Anti-migration and invasion effect and modulation of SHP-1/STAT3 axis by ATO were attenuated by pervanadate or SHP-1 siRNA. IP injection of ATO significantly decreased the xenograft tumor volume and upregulated SHP-1 expression, which were attenuated by co-IP injection of pervanadate. CONCLUSION Our data suggest that ATO inhibits STAT3 activity and EMT process by upregulation of SHP-1 in gastric cancer cells.
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Affiliation(s)
- Sung Ho Kim
- Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul, 152-703, Republic of Korea
| | - Hyo Soon Yoo
- Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul, 152-703, Republic of Korea
| | - Moon Kyung Joo
- Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul, 152-703, Republic of Korea.
| | - Taehyun Kim
- Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul, 152-703, Republic of Korea
| | - Jong-Jae Park
- Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul, 152-703, Republic of Korea
| | - Beom Jae Lee
- Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul, 152-703, Republic of Korea
| | - Hoon Jai Chun
- Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Anam Hospital, 73, Inchon-ro, Seongbuk-gu, Seoul, 136-705, Republic of Korea
| | - Sang Woo Lee
- Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Ansan Hospital, 123, Jeokgeum-ro, Danwon-gu, Ansan-si, Gyeonggi-do, 425-707, Republic of Korea
| | - Young-Tae Bak
- Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul, 152-703, Republic of Korea
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Joo MK, Park JJ, Chun HJ. Recent updates of precision therapy for gastric cancer: Towards optimal tailored management. World J Gastroenterol 2016; 22:4638-4650. [PMID: 27217696 PMCID: PMC4870071 DOI: 10.3748/wjg.v22.i19.4638] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 04/01/2016] [Accepted: 04/20/2016] [Indexed: 02/06/2023] Open
Abstract
Signaling pathways of gastric carcinogenesis and gastric cancer progression are being avidly studied to seek optimal treatment of gastric cancer. Among them, hepatocyte growth factor (HGF)/c-MET, phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathways have been widely investigated. Their aberrant expression or mutation has been significantly associated with advanced stage or poor prognosis of gastric cancer. Recently, aberrations of immune checkpoints including programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) have been suggested as an important step in the formation of a microenvironment favorable for gastric cancer. Accomplishments in basic research have led to the development of novel agents targeting these signaling pathways. However, phase III studies of selective anti-HGF/c-MET antibodies and mTOR inhibitor failed to show significant benefits in terms of overall survival and progression-free survival. Few agents directly targeting STAT3 have been developed. However, this target is still critical issue in terms of chemoresistance, and SH2-containing protein tyrosine phosphatase 1 might be a significant link to effectively inhibit STAT3 activity. Inhibition of PD-1/PD-L1 showed durable efficacy in phase I studies, and phase III evaluation is warranted. Therapeutic strategy to concurrently inhibit multiple tyrosine kinases is a reasonable option, however, lapatinib needs to be further evaluated to identify good responders. Regorafenib has shown promising effectiveness in prolonging progression-free survival in a phase II study. In this topic highlight, we review the biologic roles and outcomes of clinical studies targeting these signaling pathways.
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Gambhir S, Vyas D, Hollis M, Aekka A, Vyas A. Nuclear factor kappa B role in inflammation associated gastrointestinal malignancies. World J Gastroenterol 2015; 21:3174-3183. [PMID: 25805923 PMCID: PMC4363746 DOI: 10.3748/wjg.v21.i11.3174] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2014] [Accepted: 02/12/2015] [Indexed: 02/06/2023] Open
Abstract
Nuclear factor kappa B (NF-κB) has an established role in the regulation of innate immunity and inflammation. NF-κB is also involved in critical mechanisms connecting inflammation and cancer development. Recent investigations suggest that the NF-κB signaling cascade may be the central mediator of gastrointestinal malignancies including esophageal, gastric and colorectal cancers. This review will explore NF-κB’s function in inflammation-associated gastrointestinal malignancies, highlighting its oncogenic contribution to each step of carcinogenesis. NF-κB’s role in the inflammation-to-carcinoma sequence in gastrointestinal malignancies warrants stronger emphasis upon targeting this pathway in achieving greater therapeutic efficacy.
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Wei WY, Yan LH, Wang XT, Li L, Cao WL, Zhang XS, Zhan ZX, Yu H, Xie YB, Xiao Q. E2F-1 overexpression inhibits human gastric cancer MGC-803 cell growth in vivo. World J Gastroenterol 2015; 21:491-501. [PMID: 25593464 PMCID: PMC4292280 DOI: 10.3748/wjg.v21.i2.491] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 05/16/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the influence of E2F-1 on the growth of human gastric cancer (GC) cells in vivo and the mechanism involved.
METHODS: E2F-1 recombinant lentiviral vectors were injected into xenograft tumors of MGC-803 cells in nude mice, and then tumor growth was investigated. Overexpression of transcription factor E2F-1 was assessed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting analysis. Apoptosis rates were determined using a terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay. Expression levels of certain cell cycle regulators and apoptosis-related proteins, such as Bax, survivin, Bcl-2, cyclin D1, S-phase kinase-associated protein 2, and c-Myc were examined by Western blotting and RT-PCR.
RESULTS: Xenograft tumors of MGC-803 cells in nude mice injected with E2F-1 recombinant lentiviral vectors stably overexpressed the E2F-1 gene as measured by semi-quantitative RT-PCR (relative mRNA expression: 0.10 ± 0.02 vs 0.05 ± 0.02 for control vector and 0.06 ± 0.03 for no infection; both P < 0.01) and Western blotting (relative protein expression: 1.90 ± 0.05 vs 1.10 ± 0.03 in control vector infected and 1.11 ± 0.02 for no infection; both P < 0.01). The growth-curve of tumor volumes revealed that infection with E2F-1 recombinant lentiviral vectors significantly inhibited the growth of human GC xenografts (2.81 ± 1.02 vs 6.18 ± 1.15 in control vector infected and 5.87 ± 1.23 with no infection; both P < 0.05) at 15 d after treatment. TUNEL analysis demonstrated that E2F-1 overexpression promoted tumor cell apoptosis (18.6% ± 2.3% vs 6.7% ± 1.2% in control vector infected 6.3% ± 1.2% for no infection; both P < 0.05). Furthermore, lentiviral vector-mediated E2F-1 overexpression increased the expression of Bax and suppressed survivin, Bcl-2, cyclin D1, Skp2, and c-Myc expression in tumor tissue.
CONCLUSION: E2F-1 inhibits growth of GC cells via regulating multiple signaling pathways, and may play an important role in targeted therapy for GC.
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Embryonic stem cells conditioned medium enhances Wharton's jelly-derived mesenchymal stem cells expansion under hypoxic condition. Cytotechnology 2014; 67:493-505. [PMID: 25326788 DOI: 10.1007/s10616-014-9708-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Accepted: 02/19/2014] [Indexed: 12/22/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are accepted as a promising tool for therapeutic purposes. However, low proliferation and early senescence are still main obstacles of MSCs expansion for using as cell-based therapy. Thus, clinical scale of cell expansion is needed to obtain a large number of cells serving for further applications. In this study, we investigated the value of embryonic stem cells conditioned medium (ESCM) for in vitro expansion of Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) as compared to typical culture medium for MSCs, Dulbecco's modified Eagle's medium with 1.0 g/l glucose (DMEM-LG) supplemented with 10 % FBS, under hypoxic condition. The expanded cells from ESCM (ESCM-MSCs) and DMEM-LG (DMEM-MSCs) were characterized for both phenotype and biological activities including proliferation rate, population doubling time, cell cycle distribution and MSCs characteristics. ESCM and DMEM-LG could enhance WJ-MSCs proliferation as 204.66 ± 10.39 and 113.77 ± 7.89 fold increase at day 12, respectively. ESCM-MSCs could express pluripotency genes including Oct-4, Oct-3/4, Nanog, Klf-4, C-Myc and Sox-2 both in early and late passages whereas the downregulations of Oct-4 and Nanog were detected in late passage cells of DMEM-MSCs. The 2 cell populations also showed common MSCs characteristics including normal cell cycle, fibroblastic morphology, cell surface markers expressions (CD29(+), CD44(+), CD90(+), CD34(-), CD45(-)) and differentiation capacities into adipogenic, chondrogenic and osteogenic lineages. Moreover, our results revealed that ESCM exhibited as a rich source of several factors which are required for supportive WJ-MSCs proliferation. In conclusion, ESCM under hypoxic condition could accelerate WJ-MSCs expansion while maintaining their pluripotency properties. Our knowledge provide short term and cost-saving in WJ-MSCs expansion which has benefit to overcome insufficient cell numbers for clinical applications by reusing the discarded cell culture supernates from human ES culture system. Moreover, these findings can also apply for stem cell banking, regenerative medicine and pharmacological applications.
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Abstract
INTRODUCTION STAT3 is a key transcription factor for many regulatory factors that modulate gene transcription. Particularly important are cytokines and growth factors that maintain homeostasis by regulating immunocytes, stromal and epithelial cells. Dysregulation of STAT3 by constitutive activation plays an important role in the initiation of inflammation and cellular transformation in numerous cancers, especially of epithelial origin. This review focuses on STAT3 drive in gastric cancer initiation and progression, with emphasis on its activation by cytokines, and how targeting the primary drivers or gastric STAT3 therapeutically may prevent or slow stomach cancer development. AREAS COVERED This review will discuss the mechanics of STAT3 signalling, how constitutive STAT3 activation promotes gastric tumourigenesis in both human adenocarcinomas and mouse models, the nature of the upstream regulators of STAT3, and their association with chronic Helicobacter pylori infection, STAT3-activated genes that promote transformation and progression, and finally the development and use of STAT3 and upstream cytokine inhibitors as therapeutics. EXPERT OPINION Chronic STAT3 activation is a key event in gastric cancer induction and progression. Specific targeting of stomach epithelial STAT3 or blocking IL-11Rα/gp130 and/or EGFR signal transduction in chronic gastric inflammation and metaplasia may be therapeutically effective in preventing gastric carcinogenesis.
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Affiliation(s)
- Andrew S Giraud
- Murdoch Childrens Research Institute, Royal Childrens Hospital, Parkville, Australia.
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12
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Silva TCR, Leal MF, Calcagno DQ, de Souza CRT, Khayat AS, dos Santos NPC, Montenegro RC, Rabenhorst SHB, Nascimento MQ, Assumpção PP, de Arruda Cardoso Smith M, Burbano RR. hTERT, MYC and TP53 deregulation in gastric preneoplastic lesions. BMC Gastroenterol 2012; 12:85. [PMID: 22768805 PMCID: PMC3482568 DOI: 10.1186/1471-230x-12-85] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Accepted: 06/28/2012] [Indexed: 11/20/2022] Open
Abstract
Background Gastric cancer is a serious public health problem in Northern Brazil and in the world due to its high incidence and mortality. Despite the severity of the disease, more research is needed to better understand the molecular events involved in this intestinal-type gastric carcinogenesis process. Since precancerous lesions precede intestinal-type gastric cancer, here, we evaluated the hTERT, MYC, and TP53 mRNA and protein expression, as well as TP33 copy number, in gastric preneoplastic lesions. Methods We evaluated 19 superficial gastritis, 18 atrophic gastritis, and 18 intestinal metaplasia from cancer-free individuals of Northern Brazil. Quantitative reverse transcription PCR was used to analyze the mRNA expression and immunohistochemical methods were used to assess protein immunoreactivity in tissue samples. The number of TP53 gene copies was investigated in gastric diseases by quantitative PCR. Results We observed hTERT, MYC, and p53 immunoreactivity only in intestinal metaplasia samples. The immunoreactivity of these proteins was strongly associated with each other. A significantly higher MYC mRNA expression was observed in intestinal metaplasia compared to gastritis samples. Loss of TP53 was also only detected in intestinal metaplasia specimens. Conclusions We demonstrated that hTERT, MYC, and TP53 are deregulated in intestinal metaplasia of individuals from Northern Brazil and these alterations may facilitate tumor initiation.
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Affiliation(s)
- Tanielly Cristina Raiol Silva
- Laboratório de Citogenética Humana, Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém, PA, Brazil
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Abstract
Gastric cancer is a main cause of cancer death worldwide. Despite the knowledge that Helicobacter pylori constitutes the main cause of gastric cancer, the mechanisms for gastric carcinogenesis are still elucidated. Cancer development and progression depend on the balance between cell survival and death signals. Common cell survival signaling pathways are activated by carcinogens as well as by inflammatory cytokines, which contribute substantially to tumorigenesis. Nuclear factor-kappaB (NF-κB) is a major cell survival signal. Recent studies with cell culture systems and animal models have certified the links between NF-κB and gastric carcinogenesis and resistance to chemotherapy. Inhibition of NF-κB activation can enhance the sensitivity of cancer cells to chemotherapeutic drugs. In this review, we summarize recent progress in understanding the role of the NF-κB pathway in gastric cancer development as well as in modulating NF-κB for gastric cancer prevention and therapy.
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Chen J, Li T, Wu Y, He L, Zhang L, Shi T, Yi Z, Liu M, Pang X. Prognostic significance of vascular endothelial growth factor expression in gastric carcinoma: a meta-analysis. J Cancer Res Clin Oncol 2011; 137:1799-812. [PMID: 21918901 DOI: 10.1007/s00432-011-1057-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Accepted: 08/30/2011] [Indexed: 01/12/2023]
Abstract
PURPOSE The purpose of this study was to comprehensively and quantitatively summarize available evidences for the use of VEGF protein to evaluate the clinicopathological and prognostic role of VEGF expression in Asian patients with gastric cancer. METHOD Searches were applied to MEDLINE, EMBASE, and the Cochrane Library databases until June 2010, without language restrictions. A meta-analysis was performed to clarify the impact of VEGF expression on clinicopathological parameters or over survival (OS) in gastric cancer. RESULTS Our combined results showed that VEGF expression in Asian patients with gastric cancer was significantly higher in the case-control studies (1,194 patients and 1,618 controls) (odds ratio [OR] = 112.41, 95% confidence interval [CI] = 64.12-197.06). All the analyses estimated favored a stronger link between the high VEGF expression and the poor 5-year overall survival (1,236 patients) (risk ratio [RR] = 2.45, 95% CI = 2.11-2.83, P = 0.000). When stratifying the studies by the pathological variables, the depth of invasion (3,094 patients) (OR = 1.95, 95% CI = 1.40-2.71, P = 0.000), lymph node metastasis (3,240 patients) (OR = 1.82, 95% CI = 1.29-2.57, P = 0.001), distant metastasis (1,980 patients) (OR = 2.76, 95% CI = 1.22-6.25, P = 0.015), vascular invasion (1,803 patients) (OR = 2.61, 95% CI = 2.09-3.27, P = 0.000), and TNM stage (1,819 patients) (OR = 1.92, 95% CI = 1.57-2.36, P = 0.000) provided significant prognostic information. CONCLUSION Our results indicate that VEGF can potently predict the overall survival in Asian patients with gastric cancer. Importantly, VEGF may be converted from candidate to the routine clinical setting for clinicians to predict the outcome of single patient with gastric carcinoma.
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Affiliation(s)
- Jing Chen
- The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China
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Sun Y, Gao X, Liu J, Kong QY, Wang XW, Chen XY, Wang Q, Cheng YF, Qu XX, Li H. Differential Notch1 and Notch2 expression and frequent activation of Notch signaling in gastric cancers. Arch Pathol Lab Med 2011; 135:451-8. [PMID: 21466361 DOI: 10.5858/2009-0665-oa.1] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT The biologic effects of Notch1 and Notch2 vary with cancer types and their potential role(s) in gastric cancers (GCs) remains largely unknown. OBJECTIVES This study aimed to address the previously mentioned issue by checking the expression of Notch1, Notch2, and Notch target gene Hes1 in GCs, premalignant gastric lesions, and noncancerous endoscopic gastric mucosa and by inhibiting Notch signal transduction in GC cells. DESIGN The status of Notch1, Notch2, and Hes1 expression in 74 GC surgical specimens, 10 endoscopic samples, and 4 human GC cell lines was evaluated by tissue microarray-based immunohistochemical staining, Western blotting, and reverse transcription-polymerase chain reaction, and the importance of Notch signaling was elucidated by treating 2 GC cell lines with 2 γ-secretase inhibitors. RESULTS Notch1 was undetectable in noncancerous gastric mucosa but was expressed with nuclear translocation in 16.7% (4 of 24) of chronic gastritis, 50.0% (9 of 18) of intestinal metaplasia, 54.2% (26 of 48) of intestinal GC, and 23.1% (6 of 26) of diffuse GC, showing distinct differences of Notch1 detection rates between either intestinal metaplasia and chronic gastritis or intestinal GCs and diffuse GCs (P = .03; P = .005, respectively). Notch2 nuclear translocation frequencies were 10.0% (1 of 10) in noncancerous endoscopic mucosa, 71.4% (30 of 42) in premalignant lesions, and 97.3% (72 of 74) in GC tissues, demonstrating a correlation of Notch2 expression with both intestinal GC and diffuse GC formation (P < .001). The rates of nuclear-Hes1 labeling were 1 of 10 among noncancerous, 42.9% premalignant, and 81.1% cancer tissues, which were closely correlated with Notch2 (P < .001) rather than Notch1 (P = .42) nuclear translocation. Only Notch2 was expressed accompanied with Hes1 nuclear labeling in the 4 GC cell lines established from diffuse GC cases. Inhibition of Notch signaling with γ-secretase inhibitors, L-685,458 and DAPT, prevented Hes1 nuclear translocation but neither suppressed growth nor induced cell death. CONCLUSIONS This study demonstrated a close correlation of Notch2 expression with GC formation and the potential link of Notch1 upregulation with intestinal-like phenotypes of gastric lesions. Although inhibition of Notch activity failed to achieve anti-GC effects, the activated Notch signaling may reflect a potential GC risk.
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Affiliation(s)
- Yuan Sun
- Liaoning Laboratory of Cancer Genomics and Department of Cell Biology, Dalian Medical University, Dalian, China
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Teimoori-Toolabi L, Azadmanesh K, Zeinali S. Selective suicide gene therapy of colon cancer cell lines exploiting fibroblast growth factor 18 promoter. Cancer Biother Radiopharm 2010; 25:105-16. [PMID: 20187803 DOI: 10.1089/cbr.2009.0643] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Fibroblast growth factor 18 (FGF18) is one of the genes downstream of Wnt, one of the most important signaling pathways activated in colon cancer. An FGF18 promoter containing a single T-cell factor/lymphocyte enhancing factor 1 (TCF/LEF1) binding site was inserted upstream of a thymidine kinase (TK) suicide gene module, while a bacterial beta-Gal (LacZ) element served as the reporter gene. Following transient transfection with pUCFGF18LacZ, beta-Gal staining showed that 5% of SW480, 10% of HCT116, 0% of human umbilical vein endothelial cells (HUVECs) and 0% of normal colon cells (NCCs) had expressed LacZ. beta-Gal enzyme-linked immunosorbent assay revealed that the ratio of pUCFGF18LacZ activity to that of positive control was 0.09 and 0.25 in SW480 and HCT116, respectively (significantly higher than mock plasmid), while there were no significant changes in the beta-Gal expression in HUVEC and NCC cells transfected with pUCFGF18LacZ or mock plasmid. Following transfection with pUCFGF18TK and pUCCMVTK (positive control), cytotoxicity analysis of transfected cells showed that treatment with ganciclovir (GCV) significantly decreased SW480 and HCT116 cell survival at GCV concentrations above 20 microg/mL. An inverse correlation between GCV concentration and cell viability was evident in both colon cancer cell lines following transfection with these suicide plasmids. pUCFGF18TK and pUCCMVTK induced apoptosis after the administration of GCV in HCT116, but not in SW480, as demonstrated by M30 cytodeath antibody. This discrepancy may stem from differences in the mechanisms of TK/GCV-induced apoptosis in p53-proficient (HCT116) and -deficient (SW480) cells. The specific activity of the FGF18 promoter in HCT116 and SW480 may reflect the advantage of this promoter over artificial promoters containing artificial TCF/LEF binding sites.
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Affiliation(s)
- Ladan Teimoori-Toolabi
- Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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CD45+/CD133+positive cells expanded from umbilical cord blood expressing PDX-1 and markers of pluripotency. Cell Biol Int 2010; 34:783-90. [DOI: 10.1042/cbi20090236] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Cytokine signalling via gp130 in gastric cancer. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2009; 1793:1623-33. [PMID: 19665497 DOI: 10.1016/j.bbamcr.2009.07.009] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/02/2009] [Revised: 07/29/2009] [Accepted: 07/30/2009] [Indexed: 12/17/2022]
Abstract
Cytokine signalling pathways that depend on gp130 are dysregulated in several epithelial cancers including gastric cancer. It has been established that blockade of SHP2 activation of MAPK signalling results in hyperactivation of STAT3 resulting in increased cell proliferation, angiogenesis, inflammation and inhibition of both immunocyte and epithelial cell apoptosis. Additionally, key genes regulated downstream of gp130 via MAPK activation such as the stomach-specific tumor suppressor gene tff1 are suppressed, contributing to the oncogenic outcome. The main cytokine driver of gp130 signalling in the stomach is IL-11, with IL-6 having little activity in the antral stomach in which most pathology initiates. IL-11 is up-regulated in both mouse and human gastric cancer and in pre-neoplastic mucosa. A characteristic gene signature specifically associated with IL-11 drive has been observed, although the prognostic value of the signature has not yet been assessed. Infection of human or mouse stomach with Helicobacter pylori, especially that expressing the CagA cytotoxin, produces constitutive MAPK activation, but also activated STAT3 and increases IL-11 expression. The possibility of designing and utilising small molecule inhibitors of either IL-11 or STAT3 activation may be worthwhile in developing new cancer therapeutics.
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Okayama T, Kokura S, Ishikawa T, Adachi S, Hattori T, Takagi T, Handa O, Naito Y, Yoshikawa T. Antitumor effect of pretreatment for colon cancer cells with hyperthermia plus geranylgeranylacetone in experimental metastasis models and a subcutaneous tumor model of colon cancer in mice. Int J Hyperthermia 2009; 25:141-9. [PMID: 19337914 DOI: 10.1080/02656730802631783] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
PURPOSE We examined whether hyperthermia attenuated the metastatic potential of colon cancer through the induction of heat shock protein 70 (Hsp70). MATERIALS AND METHODS Colon26 cells were separated into four groups: (1) no pretreatment, (2) hyperthermia at 42 degrees C for 1 hour, (3) pretreatment with geranylgeranylacetone (GGA) 10(-6) M for 2 hours, and (4) hyperthermia after GGA treatment. We measured cell viabilities and the contents of Hsp70. We assessed nuclear factor-kappa-B (NF-kappa-B) status with and without tumor necrosis factor-alpha (TNF-alpha) stimulation. For in vivo study, colon26 cells were injected via the tail vein or into a subcutaneous area of mice and the numbers of lung metastatic nodules or the volumes of subcutaneous tumors were assessed. Untreated cells were incubated with PKH26. Experimental metastasis models were then generated and used to assess the fixed cancer cells. RESULTS Tumor development in the subcutaneous tumor models and cell viabilities were similar among the four groups. However, the GGA plus hyperthermia group had fewer lung metastatic nodules in the experimental lung metastasis model and higher Hsp70 induction than the other cell groups. The GGA plus hyperthermia pretreatment group also showed a lower number of fixed cells in lungs and lower activation of NF-kappa-B by TNF-alpha than the other cell groups. CONCLUSIONS It is suggested the metastatic potential but not the proliferation potency of cancer cells is inhibited by the transient induction of Hsp70.
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Affiliation(s)
- Tetsuya Okayama
- Department of Inflammation and Immunology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Sherbet GV. Metastasis promoter S100A4 is a potentially valuable molecular target for cancer therapy. Cancer Lett 2008; 280:15-30. [PMID: 19059703 DOI: 10.1016/j.canlet.2008.10.037] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2008] [Revised: 09/30/2008] [Accepted: 10/27/2008] [Indexed: 11/25/2022]
Abstract
The growth, invasion and metastatic spread of cancer have been identified with the deregulation of cell proliferation, altered intercellular and cell-substratum adhesion and enhanced motility and the deposition of disseminated cancer cells at distant sites. The identification of therapeutic targets for cancer is crucial to human welfare. Drug development, molecular modelling and design of effective drugs greatly depend upon the identification of suitable therapeutic targets. Several genetic determinants relating to proliferation and growth, invasion and metastasis have been identified. S100A4 appears to be able to activate and integrate pathways to generate the phenotypic responses that are characteristic of cancer. S100A4 signalling can focus on factors associated with normal and aberrant proliferation, apoptosis and growth, and differentiation. It is able to activate signalling pathways leading to the remodelling of the cell membrane and the extracellular matrix; modulation of cytoskeletal dynamics, acquisition of invasiveness and induction of angiogenesis. Therefore S100A4 is arguably a molecular target of considerable potential possessing a wide ranging biological activity that can alter and regulate the major phenotypic features of cancer. The evolution of an appropriate strategy that permits the identification of therapeutic targets most likely to be effective in the disease process without unduly affecting normal biological processes and function is an incontrovertible imperative. By virtue of its ability to activate interacting and multi-functional signalling systems, S100A4 appears to offer suitable targets for developing new therapeutic procedures. Some effectors of the S100A4-activated pathways might also lend themselves as foci of therapeutic interest.
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Affiliation(s)
- G V Sherbet
- School of Electrical, Electronic and Computer Engineering, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK.
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Stairs DB, Nakagawa H, Klein-Szanto A, Mitchell SD, Silberg DG, Tobias JW, Lynch JP, Rustgi AK. Cdx1 and c-Myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett's esophagus. PLoS One 2008; 3:e3534. [PMID: 18953412 PMCID: PMC2568822 DOI: 10.1371/journal.pone.0003534] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2008] [Accepted: 09/28/2008] [Indexed: 01/16/2023] Open
Abstract
Background Barrett's esophagus is a premalignant condition whereby the normal stratified squamous esophageal epithelium undergoes a transdifferentiation program resulting in a simple columnar epithelium reminiscent of the small intestine. These changes are typically associated with the stratified squamous epithelium chronically exposed to acid and bile salts as a result of gastroesophageal reflux disease (GERD). Despite this well-defined epidemiologic association between acid reflux and Barrett's esophagus, the genetic changes that induce this transdifferentiation process in esophageal keratinocytes have remained undefined. Methodology/Principal Findings To begin to identify the genetic changes responsible for transdifferentiaiton in Barrett's esophagus, we performed a microarray analysis of normal esophageal, Barrett's esophagus and small intestinal biopsy specimens to identify candidate signaling pathways and transcription factors that may be involved. Through this screen we identified the Cdx1 homeodomain transcription factor and the c-myc pathway as possible candidates. Cdx1 and c-myc were then tested for their ability to induce transdifferentiation in immortalized human esophageal keratinocytes using organotypic culturing methods. Analyses of these cultures reveal that c-myc and cdx1 cooperate to induce mucin production and changes in keratin expression that are observed in the epithelium of Barrett's esophagus. Conclusions/Significance These data demonstrate the ability of Cdx1 and c-myc to initiate the earliest stages of transdifferentiation of esophageal keratinocytes toward a cell fate characteristic of Barrett's esophagus.
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Affiliation(s)
- Douglas B Stairs
- Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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