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Dorafshan S, Razmi M, Safaei S, Gentilin E, Madjd Z, Ghods R. Periostin: biology and function in cancer. Cancer Cell Int 2022; 22:315. [PMID: 36224629 PMCID: PMC9555118 DOI: 10.1186/s12935-022-02714-8] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 09/13/2022] [Indexed: 11/24/2022] Open
Abstract
Periostin (POSTN), a member of the matricellular protein family, is a secreted adhesion-related protein produced in the periosteum and periodontal ligaments. Matricellular proteins are a nonstructural family of extracellular matrix (ECM) proteins that regulate a wide range of biological processes in both normal and pathological conditions. Recent studies have demonstrated the key roles of these ECM proteins in the tumor microenvironment. Furthermore, periostin is an essential regulator of bone and tooth formation and maintenance, as well as cardiac development. Also, periostin interacts with multiple cell-surface receptors, especially integrins, and triggers signals that promote tumor growth. According to recent studies, these signals are implicated in cancer cell survival, epithelial-mesenchymal transition (EMT), invasion, and metastasis. In this review, we will summarize the most current data regarding periostin, its structure and isoforms, expressions, functions, and regulation in normal and cancerous tissues. Emphasis is placed on its association with cancer progression, and also future potential for periostin-targeted therapeutic approaches will be explored.
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Affiliation(s)
- Shima Dorafshan
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Mahdieh Razmi
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Sadegh Safaei
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Erica Gentilin
- Bioacoustics Research Laboratory, Department of Neurosciences, University of Padua, via G. Orus, 2b, 35129, Padua, Italy
| | - Zahra Madjd
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.
| | - Roya Ghods
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.
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Morshedi K, Borran S, Ebrahimi MS, Masoud Khooy MJ, Seyedi ZS, Amiri A, Abbasi-Kolli M, Fallah M, Khan H, Sahebkar A, Mirzaei H. Therapeutic effect of curcumin in gastrointestinal cancers: A comprehensive review. Phytother Res 2021; 35:4834-4897. [PMID: 34173992 DOI: 10.1002/ptr.7119] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/18/2021] [Accepted: 03/26/2021] [Indexed: 12/11/2022]
Abstract
Gastrointestinal (GI) cancers with a high global prevalence are a leading cause of morbidity and mortality. Accordingly, there is a great need to develop efficient therapeutic approaches. Curcumin, a naturally occurring agent, is a promising compound with documented safety and anticancer activities. Recent studies have demonstrated the activity of curcumin in the prevention and treatment of different cancers. According to systematic studies on curcumin use in various diseases, it can be particularly effective in GI cancers because of its high bioavailability in the gastrointestinal tract. Nevertheless, the clinical applications of curcumin are largely limited because of its low solubility and low chemical stability in water. These limitations may be addressed by the use of relevant analogues or novel delivery systems. Herein, we summarize the pharmacological effects of curcumin against GI cancers. Moreover, we highlight the application of curcumin's analogues and novel delivery systems in the treatment of GI cancers.
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Affiliation(s)
- Korosh Morshedi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Sarina Borran
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | - Zeynab Sadat Seyedi
- Department of Cell and Molecular Biology, Faculty of Chemistry, University of Kashan, Kashan, Iran
| | - Atefeh Amiri
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Abbasi-Kolli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maryam Fallah
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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The Roles of Osteopontin in the Pathogenesis of West Nile Encephalitis. Vaccines (Basel) 2020; 8:vaccines8040748. [PMID: 33317005 PMCID: PMC7768535 DOI: 10.3390/vaccines8040748] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/03/2020] [Accepted: 12/06/2020] [Indexed: 12/18/2022] Open
Abstract
Osteopontin (OPN), a multifunctional protein encoded by the secreted phosphoprotein-1 (Spp-1) gene in humans, plays important roles in a variety of physiological conditions, such as biomineralization, bone remodeling and immune functions. OPN also has significant roles in the pathogenesis of autoimmune, allergy and inflammatory diseases, as well as bacterial, fungal and viral infections. West Nile virus (WNV), a mosquito-transmitted flavivirus, is the leading agent for viral encephalitis in North America. Recent progress has been made in understanding both the biological functions of OPN and the pathogenesis of WNV. In this review article, we have summarized the current understanding of the biology of OPN and its vital roles in the pathogenesis of WNV encephalitis.
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Mazaheri N, Peymani M, Galehdari H, Ghaedi K, Ghoochani A, Kiani-Esfahani A, Nasr-Esfahani MH. Ameliorating Effect of Osteopontin on H 2O 2-Induced Apoptosis of Human Oligodendrocyte Progenitor Cells. Cell Mol Neurobiol 2018; 38:891-899. [PMID: 29110207 PMCID: PMC11481903 DOI: 10.1007/s10571-017-0563-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Accepted: 10/30/2017] [Indexed: 12/22/2022]
Abstract
Recently our group used oligodendrocyte progenitor cells (OPCs) as appropriate model cells to pinpoint the mechanism of the progress of neurodegenerative disorders. In the present study, we focused on the therapeutic role of osteopontin (OPN), a secreted glycosylated phosphoprotein, involved in a number of physiological events including bone formation and remodeling, immune responses, and tumor progression. Protective role of OPN, as a negative regulator of tumorigenesis, has already been clarified. Human embryonic stem cell-derived OPCs were pretreated with OPN before induction of apoptosis by H2O2. Data indicated that OPN prohibited cell death and enhanced OPC viability. This effect is achieved through reduction of apoptosis and induction of anti-apoptosis markers. In addition OPN induces expression of several integrin subunits, responsible for OPN interaction. Notably, our findings showed that expression of αV β1/β3/β5 and β8 integrins increased in response to OPN, while treatment with H2O2 down-regulated αV β1/β5 and β8 integrins expression significantly. In conclusion, OPN may act via αV integrin signaling and trigger suppression of P53-dependent apoptotic cascades. Therefore OPN therapy may be considered as a feasible process to prevent progress of neurodegenerative diseases in human.
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Affiliation(s)
- Neda Mazaheri
- Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, 816513-1378, Iran
| | - Hamid Galehdari
- Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Kamran Ghaedi
- Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran.
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, 816513-1378, Iran.
| | - Ali Ghoochani
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, 816513-1378, Iran
| | - Abbas Kiani-Esfahani
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, 816513-1378, Iran
| | - Mohammad Hossein Nasr-Esfahani
- Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran.
- Department of Cellular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, 816513-1378, Iran.
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Is Osteopontin a Friend or Foe of Cell Apoptosis in Inflammatory Gastrointestinal and Liver Diseases? Int J Mol Sci 2017; 19:ijms19010007. [PMID: 29267211 PMCID: PMC5795959 DOI: 10.3390/ijms19010007] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 12/11/2017] [Accepted: 12/19/2017] [Indexed: 12/15/2022] Open
Abstract
Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells, and T lymphocytes. OPN plays an important role in the efficient development of T helper 1 immune responses and cell survival by inhibiting apoptosis. The association of OPN with apoptosis has been investigated. In this review, we described the role of OPN in inflammatory gastrointestinal and liver diseases, focusing on the association of OPN with apoptosis. OPN changes its association with apoptosis depending on the type of disease and the phase of disease activity, acting as a promoter or a suppressor of inflammation and inflammatory carcinogenesis. It is essential that the roles of OPN in those diseases are elucidated, and treatments based on its mechanism are developed.
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Liu G, Xiang T, Wu QF, Wang WX. Curcumin suppresses the proliferation of gastric cancer cells by downregulating H19. Oncol Lett 2016; 12:5156-5162. [PMID: 28105222 PMCID: PMC5228417 DOI: 10.3892/ol.2016.5354] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Accepted: 10/18/2016] [Indexed: 01/17/2023] Open
Abstract
Curcumin, a major phytochemical in turmeric, inhibits the proliferation of many types of solid cancer cells by enhancing p53 expression. However, the long non-coding RNA H19 directly inhibits p53 activation and thus promotes gastric cancer progression. The aim of this study was to assess the role of H19 in curcumin-induced proliferative inhibition of gastric cancer. The gastric cancer cell line SGC-7901 was treated with curcumin at different concentrations and time points. The effect of curcumin on proliferation was assessed using cell counting kit-8 assays and flow cytometry with Ki67 staining. In addition, H19 expression was quantified by reverse transcription-quantitative polymerase chain reaction, and apoptosis was evaluated by flow cytometric detection of Annexin V and propidium iodide double staining. The protein expression of p53, B-cell lymphoma (Bcl)-2, Bcl-2-associated X protein (Bax) and c-Myc in curcumin-treated cells was detected by western blotting. The present study demonstrated that curcumin inhibited the proliferation of SGC7901 cells and suppressed H19 expression in a concentration-dependent manner, while p53 expression was enhanced. Ectopic expression of H19 in SGC7901 cells reversed curcumin-induced proliferative inhibition and downregulated p53 expression. Furthermore, while curcumin induced cell apoptosis and enhanced the expression ratio of Bax/Bcl-2, which are downstream molecules of p53, ectopic expression of H19 inhibited curcumin-induced cell apoptosis. In addition, curcumin decreased the expression of the c-Myc oncogene, and exogenous c-Myc protein reversed the curcumin-induced downregulation of H19 expression. These results suggested that curcumin inhibits the proliferation of gastric cancer cells by downregulating the c-Myc/H19 pathway. Therefore, curcumin may be considered a novel therapeutic strategy to inhibit gastric cancer cell growth.
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Affiliation(s)
- Gao Liu
- Department of Gastrointestinal Surgery, Central Hospital of Enshi Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, Hubei 445000, P.R. China
| | - Tian Xiang
- Department of Clinical Laboratory Center, Central Hospital of Enshi Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, Hubei 445000, P.R. China
| | - Quan-Feng Wu
- Department of Gastrointestinal Surgery, Central Hospital of Enshi Autonomous Prefecture, Enshi Clinical College of Wuhan University, Enshi, Hubei 445000, P.R. China
| | - Wei-Xing Wang
- Department of Hepatobiliary and Laparoscopic Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Mohammadi S, Ghaffari SH, Shaiegan M, Zarif MN, Nikbakht M, Akbari Birgani S, Alimoghadam K, Ghavamzadeh A. Acquired expression of osteopontin selectively promotes enrichment of leukemia stem cells through AKT/mTOR/PTEN/β-catenin pathways in AML cells. Life Sci 2016; 152:190-8. [DOI: 10.1016/j.lfs.2016.04.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/31/2016] [Accepted: 04/03/2016] [Indexed: 01/11/2023]
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Nakamura T, Shinriki S, Jono H, Ueda M, Nagata M, Guo J, Hayashi M, Yoshida R, Ota T, Ota K, Kawahara K, Nakagawa Y, Yamashita S, Nakayama H, Hiraki A, Shinohara M, Ando Y. Osteopontin-integrin α(v)β(3) axis is crucial for 5-fluorouracil resistance in oral squamous cell carcinoma. FEBS Lett 2014; 589:231-9. [PMID: 25497015 DOI: 10.1016/j.febslet.2014.12.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 11/19/2014] [Accepted: 12/02/2014] [Indexed: 01/13/2023]
Abstract
Clinical applications of a chemotherapeutic agent, 5-fluorouracil (5-FU) in oral squamous cell carcinoma (OSCC) have been limited because of drug resistance. This study aimed to identify novel mechanisms of 5-FU resistance. Here we found increased osteopontin (OPN) gene expression in OSCC tissues with resistance to 5-FU-based chemoradiotherapy. OPN overexpression in OSCC cells led to 5-FU resistance and abrogated the prosurvival effect of the drug in a mouse xenograft model. OPN-induced 5-FU resistance required integrin αvβ3. Targeting integrin αvβ3 reversed the resistance in a 5-FU-resistant clone highly expressing OPN. Our data suggest that the OPN-integrin αvβ3 axis is crucial for 5-FU resistance in OSCC.
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Affiliation(s)
- Takuya Nakamura
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Satoru Shinriki
- Department of Laboratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan.
| | - Hirofumi Jono
- Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Department of Pharmacy, Kumamoto University Hospital, Japan
| | - Mitsuharu Ueda
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Masashi Nagata
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Jianying Guo
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Mitsuhiro Hayashi
- Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Ryoji Yoshida
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Tomoko Ota
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Kazutoshi Ota
- Department of Oral and Maxillofacial Surgery, Kumamoto City Hospital, Japan
| | - Kenta Kawahara
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Yoshihiro Nakagawa
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Satoshi Yamashita
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Hideki Nakayama
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Akimitsu Hiraki
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Masanori Shinohara
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan
| | - Yukio Ando
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan
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Qian C, Li P, Yan W, Shi L, Zhang J, Wang Y, Liu H, You Y. Downregulation of osteopontin enhances the sensitivity of glioma U251 cells to temozolomide and cisplatin by targeting the NF-κB/Bcl‑2 pathway. Mol Med Rep 2014; 11:1951-5. [PMID: 25405848 DOI: 10.3892/mmr.2014.2951] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Accepted: 02/25/2014] [Indexed: 11/06/2022] Open
Abstract
Glioma is resistant to the apoptotic effects of chemotherapy and the mechanism underlying its chemoresistance is not currently understood. In a previous study, we reported that osteopontin (OPN) was overexpressed in glioma tissues and had an important anti‑apoptotic effect. Furthermore, overexpression of OPN was observed following chemotherapy. To elucidate whether OPN plays a role in chemotherapy resistance and to investigate its downstream signaling pathway, this study used small interfering RNA (siRNA) to silence the expression of OPN in U251 human neuronal glioma astrocytoma cells. OPN downregulation in U251 cells enhanced the apoptotic effects induced by temozolomide (TMZ) and cisplatin (DDP). Furthermore, OPN siRNA suppressed the nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB) activation and B cell lymphoma 2 (Bcl‑2) expression that was induced by chemotherapy. Taken together, these results demonstrated that the expression levels of OPN are involved in glioma chemoresistance. Knockdown of OPN through siRNA enhanced the effects of TMZ and DDP chemotherapy by targeting the NF‑κB/Bcl‑2 pathway.
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Affiliation(s)
- Chunfa Qian
- Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Ping Li
- Department of Neurosurgery, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China
| | - Wei Yan
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Lei Shi
- Department of Neurosurgery, The First People's Hospital of Kunshan Affiliated to Jiangsu University, Suzhou, Jiangsu 215300, P.R. China
| | - Junxia Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Yingyi Wang
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Hongyi Liu
- Department of Neurosurgery, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Yongping You
- Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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Tilli TM, Bellahcène A, Castronovo V, Gimba ERP. Changes in the transcriptional profile in response to overexpression of the osteopontin-c splice isoform in ovarian (OvCar-3) and prostate (PC-3) cancer cell lines. BMC Cancer 2014; 14:433. [PMID: 24928374 PMCID: PMC4075779 DOI: 10.1186/1471-2407-14-433] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 05/23/2014] [Indexed: 12/16/2022] Open
Abstract
Background Especially in human tumor cells, the osteopontin (OPN) primary transcript is subject to alternative splicing, generating three isoforms termed OPNa, OPNb and OPNc. We previously demonstrated that the OPNc splice variant activates several aspects of the progression of ovarian and prostate cancers. The goal of the present study was to develop cell line models to determine the impact of OPNc overexpression on main cancer signaling pathways and thus obtain insights into the mechanisms of OPNc pro-tumorigenic roles. Methods Human ovarian and prostate cancer cell lines, OvCar-3 and PC-3 cells, respectively, were stably transfected to overexpress OPNc. Transcriptomic profiling was performed on these cells and compared to controls, to identify OPNc overexpression-dependent changes in gene expression levels and pathways by qRT-PCR analyses. Results Among 84 genes tested by using a multiplex real-time PCR Cancer Pathway Array approach, 34 and 16, respectively, were differentially expressed between OvCar-3 and PC-3 OPNc-overexpressing cells in relation to control clones. Differentially expressed genes are included in all main hallmarks of cancer, and several interacting proteins have been identified using an interactome network analysis. Based on marked up-regulation of Vegfa transcript in response to OPNc overexpression, we partially validated the array data by demonstrating that conditioned medium (CM) secreted from OvCar-3 and PC-3 OPNc-overexpressing cells significantly induced endothelial cell adhesion, proliferation and migration, compared to CM secreted from control cells. Conclusions Overall, the present study elucidated transcriptional changes of OvCar-3 and PC-3 cancer cell lines in response to OPNc overexpression, which provides an assessment for predicting the molecular mechanisms by which this splice variant promotes tumor progression features.
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Affiliation(s)
| | | | | | - Etel R P Gimba
- Coordenação de Pesquisa, Programa de Carcinogênese Molecular, Instituto Nacional de Câncer (INCa)/Programa de Pós Graduação Stricto Sensu em Oncologia do INCa, Rio de Janeiro, RJ, Brazil.
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Štemberger C, Matušan-Ilijaš K, Avirović M, Bulat-Kardum L, Ivančić A, Jonjić N, Lučin K. Osteopontin is associated with decreased apoptosis and αv integrin expression in lung adenocarcinoma. Acta Histochem 2014; 116:222-9. [PMID: 23992637 DOI: 10.1016/j.acthis.2013.07.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 07/12/2013] [Accepted: 07/14/2013] [Indexed: 01/13/2023]
Abstract
Osteopontin (OPN) is a glycoprotein involved in invasion, progression and metastasis of many carcinomas. It contains several functional domains including binding sites for αv integrins, cell surface molecules playing a major role in mediating cell migration and adhesion. The aim of the study was to evaluate the expression of osteopontin in human non-small cell lung cancer (NSCLC) and to determine its possible prognostic significance as well as relation to apoptosis and αv integrin expression. We analyzed 111 surgically resected NSCLC for immunohistochemical expression of OPN and αv integrin. OPN expression was compared to apoptotic rate and clinicopathological parameters such as tumor size, histological grade, lymph node status, pT, and TNM stage. Apoptotic rate was measured by TUNEL staining method. OPN expression in NSCLC was significantly higher in lung adenocarcinomas (AC) then in squamous cell carcinomas (p<0.001). There was no correlation between OPN expression and clinicopathological parameters. The level of OPN expression in AC was associated with decreased apoptotic activity of tumor cells (p=0.006), and correlated with αv integrin expression (p=0.048), particularly in low stage tumors (p=0.013). Prolonged tumor cell survival in lung AC due to OPN and αv integrin overexpression may have an impact on tumor progression and resistance to therapy.
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Li Y, Dai C, Li J, Wang W, Song G. Bid-overexpression regulates proliferation and phosphorylation of Akt and MAPKs in response to etoposide-induced DNA damage in hepatocellular carcinoma cells. Onco Targets Ther 2012; 5:279-86. [PMID: 23093908 PMCID: PMC3477928 DOI: 10.2147/ott.s36087] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background Growing evidence supports BH3-interacting domain death agonist (Bid) playing a dual role in DNA damage response. However, the effects of Bid on hepatocellular carcinoma (HCC) cell proliferation in response to etoposide-induced DNA damage have not been sufficiently investigated. Methods Using a stable Bid-overexpression HCC cell line, Bid/PLC/PRF/5, overexpression of Bid promoted loss of viability in response to etoposide-induced DNA damage. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]- and BrdU (5′-bromo-2′-deoxyuridine)-labeling assays revealed that etoposide-inhibited HCC cells grew in concentration-and time-dependent manners. The phosphorylations of Akt and mitogen-activated protein kinases (MAPKs) in response to etoposide-induced DNA damage were analyzed by Western blotting. Results The survival rates of 100 μM etoposide on the cells with control vector and Bid/PLC/PRF/5 at 48 hours amounted to 71% ± 0.75% and 59% ± 0.60% with MTT assay, and similar results of 85% ± 0.08% and 63% ± 0.14% with BrdU-labeling assay respectively. Moreover, overexpression of Bid sensitized the cells to apoptosis at a high dose of etoposide (causing irreparable damage). However, it had little effect on the proliferation at a low dose of etoposide (repairable damage). Furthermore, the phosphorylation status of Akt and MAPKs were investigated. Overexpression of Bid suppressed the activation of Akt with respect to etoposide-induced DNA damage. Similar to Akt, the levels of phosphorylated p38 and phosphorylated c-Jun were attenuated by Bid-overexpression. On the contrary, the level of phosphorylated ERK1/2 was sustained at a high level, especially in Bid/PLC/PRF/5 cells. Conclusion Taken together, these results suggest that overexpression of Bid suppressed the activation of Akt, p38, and c-Jun, and promoted the activation of ERK1/2 induced by etoposide, suggesting that the promotion of ERK1/2 activation may have a negative effect on Bid-mediated HCC DNA damage induced by etoposide.
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Affiliation(s)
- Yuanyue Li
- Fisheries College, Jimei University, Fujian, China
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Ma PF, Chen JQ, Wang Z, Liu JL, Li BP. Function of chloride intracellular channel 1 in gastric cancer cells. World J Gastroenterol 2012; 18:3070-3080. [PMID: 22791942 PMCID: PMC3386320 DOI: 10.3748/wjg.v18.i24.3070] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2011] [Revised: 02/28/2012] [Accepted: 04/09/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of chloride intracellular channel 1 (CLIC1) on the cell proliferation, apoptosis, migration and invasion of gastric cancer cells. METHODS CLIC1 expression was evaluated in human gastric cancer cell lines SGC-7901 and MGC-803 by real time polymerase chain reaction (RT-PCR). Four segments of small interference RNA (siRNA) targeting CLIC1 mRNA and a no-sense control segment were designed by bioinformatics technology. CLIC1 siRNA was selected using Lipofectamine 2000 and transfected transiently into human gastric cancer SGC-7901 and MGC-803 cells. The transfected efficiency was observed under fluorescence microscope. After transfection, mRNA expression of CLIC1 was detected with RT-PCR and Western blotting was used to detect the protein expression. Proliferation was examined by methyl thiazolyl tetrazolium and apoptosis was detected with flow cytometry. Polycarbonate membrane transwell chamber and Matrigel were used for the detection of the changes of invasion and migration of the two cell lines. RESULTS In gastric cancer cell lines SGC-7901 and MGC-803, CLIC1 was obviously expressed and CLIC1 siRNA could effectively suppress the expression of CLIC1 protein and mRNA. Proliferation of cells transfected with CLIC1 siRNA3 was enhanced notably, and the highest proliferation rate was 23.3% (P = 0.002) in SGC-7901 and 35.55% (P = 0.001) in MGC-803 cells at 48 h. The G2/M phase proportion increased, while G0/G1 and S phase proportions decreased. The apoptotic rate of the CLIC1 siRNA3 group obviously decreased in both SGC-7901 cells (62.24%, P = 0.000) and MGC-803 cells (52.67%, P = 0.004). Down-regulation of CLIC1 led to the inhibition of invasion and migration by 54.31% (P = 0.000) and 33.62% (P = 0.001) in SGC-7901 and 40.74% (P = 0.000) and 29.26% (P = 0.002) in MGC-803. However, there was no significant difference between the mock group cells and the negative control group cells. CONCLUSION High CLIC1 expression can efficiently inhibit proliferation and enhance apoptosis, migration and invasion of gastric cancer cells in vitro. CLIC1 might be a promising target for the treatment of gastric cancer.
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Boltzen U, Eisenreich A, Antoniak S, Weithaeuser A, Fechner H, Poller W, Schultheiss HP, Mackman N, Rauch U. Alternatively spliced tissue factor and full-length tissue factor protect cardiomyocytes against TNF-α-induced apoptosis. J Mol Cell Cardiol 2012; 52:1056-65. [PMID: 22326437 DOI: 10.1016/j.yjmcc.2012.01.015] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Revised: 12/21/2011] [Accepted: 01/23/2012] [Indexed: 01/04/2023]
Abstract
Tissue Factor (TF) is expressed in various cell types of the heart, such as cardiomyocytes. In addition to its role in the initiation of blood coagulation, the TF:FVIIa complex protects cells from apoptosis. There are two isoforms of Tissue Factor (TF): "full length" (fl)TF--an integral membrane protein, and alternatively spliced (as)TF--a protein that lacks a transmembrane domain and can thus be secreted in a soluble form. Whether asTF or flTF affects apoptosis of cardiomyocytes is unknown. In this study, we examined whether asTF or flTF protects murine cardiomyocytes from TNF-α-induced apoptosis. We used murine cardiomyocytic HL-1 cells and primary murine embryonic cardiomyocytes that overexpressed either murine asTF or murine flTF, and stimulated them with TNF-α to initiate cell death. Apoptosis was assessed by annexin-V assay, propidium iodide assay, as well as activation of caspase-3 and -9. In addition, signaling via integrins, Akt, NFκB and Erk1/2, and gene-expression of Bcl-2 family members were analyzed. We here report that overexpression of asTF reduced phosphatidylserine exposure upon TNF-α-stimulation. asTF overexpression led to an increased expression and phosphorylation of Akt, as well as up-regulation of the anti-apoptotic protein Bcl-x(L). The anti-apoptotic effects of asTF overexpression were mediated via α(V)β(3)/Akt/NFκB signaling and were dependent on Bcl-x(L) expression in HL-1 cells. The anti-apoptotic activity of asTF was also observed using primary cardiomyocytes. Analogous yet less pronounced anti-apoptotic sequelae were observed due to overexpression of flTF. Importantly, cardiomyocytes deficient in TF exhibited increased apoptosis compared to wild type cells. We propose that asTF and flTF protect cardiomyocytes against TNF-α-induced apoptosis via activation of specific signaling pathways, and up-regulation of anti-apoptotic members of the Bcl-2 protein family.
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Affiliation(s)
- U Boltzen
- Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Zentrum für Herz und Kreislaufmedizin, D-12200 Berlin, Germany
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15
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Toward an integrative analysis of the tumor microenvironment in ovarian epithelial carcinoma. CANCER MICROENVIRONMENT 2011; 5:173-83. [PMID: 22109660 DOI: 10.1007/s12307-011-0092-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Accepted: 11/10/2011] [Indexed: 12/11/2022]
Abstract
Ovarian epithelial carcinomas are heterogeneous malignancies exhibiting great diversity in histological phenotypes as well as genetic and epigenetic aberrations. A general early event in tumorigenesis is regional dissemination into the peritoneal cavity. Initial spread to the peritoneum is made possible by cooperative signaling between a wide array of molecules constituting the tissue microenvironment in the coelomic epithelium. Changes in the activity of key microenvironmental components not constitutively expressed in normal tissue, including several disclosed adhesion molecules, growth factors, proteases, and G-protein coupled receptors (GPCRs), coordinate the transition. Remodeling of the extracellular matrix (ECM) and subsequent cell surface interactions enable transformation by promoting chromosomal instability (CIN) and stimulating several common signal transduction cascades to prepare the tissue for harboring and facilitating growth, angiogenesis and metastasis of the developing tumor.
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16
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Luo D, Zheng MY, Huang H. Role of integrins in invasion and metastasis of gastric cancer: potential therapeutic implications. Shijie Huaren Xiaohua Zazhi 2011; 19:2540-2545. [DOI: 10.11569/wcjd.v19.i24.2540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Integrins are a large family of cell adhesion molecules that are involved in many important cellular and pathological functions including cell survival, growth, differentiation, migration, inflammatory responses, platelet aggregation, tissue repair and tumor invasion. Over the past two decades, several integrin-targeted drugs have made their way into clinical practice, many others are increasing each year in clinical trials and still more are showing promising potential for therapeutic development based on preclinical studies. Additionally, the role of integrins in pathological conditions combined with their druggability by means of cell surface accessibility makes them attractive pharmacological targets in cancer research. As such, the identification of key roles of integrins in gastric cancer has revealed their substantial potential as therapeutic targets. This review summarizes recent progress in the study of correlation between integrins and invasion and metastasis of gastric cancer and evaluates their values in developing molecularly targeted therapies for this disease.
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17
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Zhang R, Wang J, Ma S, Huang Z, Zhang G. Requirement of Osteopontin in the migration and protection against Taxol-induced apoptosis via the ATX-LPA axis in SGC7901 cells. BMC Cell Biol 2011; 12:11. [PMID: 21406114 PMCID: PMC3068946 DOI: 10.1186/1471-2121-12-11] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2010] [Accepted: 03/16/2011] [Indexed: 01/28/2023] Open
Abstract
Background Autotaxin (ATX) possesses lysophospholipase D (lyso PLD) activity, which converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation and tumor progression. Osteopontin (OPN) is an important chemokine involved in the survival, proliferation, migration, invasion and metastasis of gastric cancer cells. The focus of the present study was to investigate the relationship between the ATX-LPA axis and OPN. Results In comparison with non-treated cells, we found that the ATX-LPA axis up-regulated OPN expression by 1.92-fold in protein levels and 1.3-fold in mRNA levels. The ATX-LPA axis activates LPA2, Akt, ERK and ELK-1 and also protects SGC7901 cells from apoptosis induced by Taxol treatment. Conclusions This study provides the first evidence that expression of OPN induced by ATX-LPA axis is mediated by the activation of Akt and MAPK/ERK pathways through the LPA2 receptor. In addition, OPN is required for the protective effects of ATX-LPA against Taxol-induced apoptosis and ATX-LPA-induced migration of SGC7901 cells.
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Affiliation(s)
- Rihua Zhang
- Department of Gastroenterology, Nanjing Medical University, Nanjing 210029, China
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18
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Zhang R, Zhang Z, Pan X, Huang X, Huang Z, Zhang G. ATX-LPA Axis Induces Expression of OPN in Hepatic Cancer Cell SMMC7721. Anat Rec (Hoboken) 2010; 294:406-11. [DOI: 10.1002/ar.21324] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2010] [Accepted: 11/09/2010] [Indexed: 01/10/2023]
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Chiang SF, Lin TY, Chow KC, Chiou SH. SARS spike protein induces phenotypic conversion of human B cells to macrophage-like cells. Mol Immunol 2010; 47:2575-86. [PMID: 20667598 PMCID: PMC7112600 DOI: 10.1016/j.molimm.2010.06.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2009] [Revised: 06/28/2010] [Accepted: 06/29/2010] [Indexed: 12/25/2022]
Abstract
Massive aggregations of macrophages are frequently detected in afflicted lungs of patients with severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infection. In vitro, ectopic expression of transcription factors, in particular CCAAT/enhancer-binding protein alpha (C/EBPα) and C/EBPβ, can convert B cells into functional macrophages. However, little is known about the specific ligands responsible for such phenotype conversion. Here, we investigated whether spike protein of SARS-CoV can act as a ligand to trigger the conversion of B cells to macrophages. We transduced SARS-CoV spike protein-displayed recombinant baculovirus (SSDRB), vAtEpGS688, into peripheral B cells and B lymphoma cells. Cell surface expression of CD19 or Mac-1 (CD11b) was determined by flow cytometry. SSDRB-mediated changes in gene expression profiles of B lymphoma cells were analyzed by microarray. In this report, we showed that spike protein of SARS virus could induce phenotypic conversion of human B cells, either from peripheral blood or B lymphoma cells, to macrophage-like cells that were steadily losing the B-cell marker CD19 and in turn expressing the macrophage-specific marker Mac-1. Furthermore, we found that SSDRB enhanced the expression of CD86, hypoxia-inducible factor-1α (HIF1α), suppressor of cytokine signaling (SOCS or STAT-induced STAT inhibitor)-3, C/EBPβ, insulin-like growth factor-binding protein 3 (IGFBP3), Krüpple-like factor (KLF)-5, and CD54, without marked influence on C/EBPα or PU.1 expression in transduced cells. Prolonged exposure to hypoxia could also induce macrophage-like conversion of B cells. These macrophage-like cells were defective in phagocytosis of red fluorescent beads. In conclusion, our results suggest that conversion of B cells to macrophage-like cells, similar to a pathophysiological response, could be mediated by a devastating viral ligand, in particular spike protein of SARS virus, or in combination with severe local hypoxia, which is a condition often observed in afflicted lungs of SARS patients.
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Affiliation(s)
- Shu-Fen Chiang
- Graduate Institute of Microbiology and Public Health, National Chung Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan
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20
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Shevde LA, Das S, Clark DW, Samant RS. Osteopontin: an effector and an effect of tumor metastasis. Curr Mol Med 2010; 10:71-81. [PMID: 20205680 DOI: 10.2174/156652410791065381] [Citation(s) in RCA: 112] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2008] [Accepted: 05/11/2008] [Indexed: 12/12/2022]
Abstract
Osteopontin (OPN) is a matricellular protein that is produced by multiple tissues in our body and is most abundant in bone. It is also produced by cancer cells and plays a determinative role in the growth, progression and metastasis of cancer. Clinically, OPN has been reported to be upregulated in tumor cells per se; this is also reflected by increased levels of OPN in the circulation. Thus, increased OPN levels the plasma are an effect of tumor growth and progression. Functionally, high OPN levels are determinative of higher incidence of bone metastases in mouse models and are clinically correlated with metastatic bone disease and bone resorption in advanced breast cancer patients. Several research efforts have been made to therapeutically target and inhibit the activities of OPN. In this article we have reviewed OPN in its role as an effector of critical steps in tumor progression and metastasis, with a particular emphasis on its role in facilitating bone metastasis of breast cancer. We have also addressed the role of the host-derived OPN in influencing the malignant behavior of the tumor cells.
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Affiliation(s)
- L A Shevde
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
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21
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Shewchuk LJ, Bryan S, Ulanova M, Khaper N. Integrin β3 prevents apoptosis of HL-1 cardiomyocytes under conditions of oxidative stressThis article is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease. Can J Physiol Pharmacol 2010; 88:324-30. [DOI: 10.1139/y09-131] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Integrin receptors are essential in the regulation of vital cardiac functions, and impaired integrin activity has been associated with cardiac remodeling. Oxidative stress is known to be involved in apoptosis and cardiac remodeling and thus may profoundly influence cardiac function via integrin modulation. The aim of this study was to determine the expression pattern and functional role of integrins in HL-1 cardiomyocytes under conditions of oxidative stress. Gene expression was studied by end-point and real-time PCR; surface protein expression was studied by flow cytometry; integrin knockdown was accomplished by siRNA gene silencing; and apoptosis was studied by annexin V staining and active caspase-3/7 using flow cytometry. Among the various subunits under study (αv, α5, α6, and β1, β3, β4, and β5), the expression of β3 integrin was significantly increased at both the mRNA and protein levels in cardiomyocytes exposed to 100 µmol/L hydrogen peroxide for 3 h. Gene silencing of β3 integrin by using siRNA resulted in a 2-fold increase in cardiomyocyte apoptosis upon treatment with hydrogen peroxide. This increase in apoptosis, as measured by annexin V staining, correlated with an increase in active caspase-3/7. Integrin β3 plays a vital role in preventing cardiomyocyte apoptosis under conditions of oxidative stress.
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Affiliation(s)
- Lee J. Shewchuk
- Medical Sciences Division, Northern Ontario School of Medicine, Lakehead University, 955 Oliver Road, Thunder Bay, ON P7B 5E1, Canada
- Department of Biology, Lakehead University, Thunder Bay, ON P7B 5E1, Canada
| | - Sean Bryan
- Medical Sciences Division, Northern Ontario School of Medicine, Lakehead University, 955 Oliver Road, Thunder Bay, ON P7B 5E1, Canada
- Department of Biology, Lakehead University, Thunder Bay, ON P7B 5E1, Canada
| | - Marina Ulanova
- Medical Sciences Division, Northern Ontario School of Medicine, Lakehead University, 955 Oliver Road, Thunder Bay, ON P7B 5E1, Canada
- Department of Biology, Lakehead University, Thunder Bay, ON P7B 5E1, Canada
| | - Neelam Khaper
- Medical Sciences Division, Northern Ontario School of Medicine, Lakehead University, 955 Oliver Road, Thunder Bay, ON P7B 5E1, Canada
- Department of Biology, Lakehead University, Thunder Bay, ON P7B 5E1, Canada
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Abstract
Hypoxia has been recognized as one of the fundamentally important features of solid tumors and plays a critical role in various cellular and physiologic events, including cell proliferation, survival, angiogenesis, immunosurveillance, metabolism, as well as tumor invasion and metastasis. These responses to hypoxia are at least partially orchestrated by activation of the hypoxia-inducible factors (HIFs). HIF-1 is a key regulator of the response of mammalian cells to oxygen deprivation and plays critical roles in the adaptation of tumor cells to a hypoxic microenvironment. Hypoxia and overexpression of HIF-1 have been associated with radiation therapy and chemotherapy resistance, an increased risk of invasion and metastasis, and a poor clinical prognosis of solid tumors. The discovery of HIF-1 signaling has led to a rapidly increasing understanding of the complex mechanisms involved in tumor hypoxia and has helped greatly in screening novel anticancer agents. In this review, we will first introduce the cellular responses to hypoxia and HIF-1 signaling pathway in hypoxia, and then summarize the multifaceted role of hypoxia in the hallmarks of human cancers.
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Affiliation(s)
- Kai Ruan
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005, China
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Yuan XX, Ma XY, Wang FR, Wang Z, Wang X, Wang SH. Significance of osteopontin and hypoxia-inducible factor-α expression in colorectal carcinoma and adenoma. Shijie Huaren Xiaohua Zazhi 2009; 17:3174-3179. [DOI: 10.11569/wcjd.v17.i30.3174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of osteopontin (OPN) and hypoxia-inducible factor-α (HIF-1α) and analyze their correlation with clinical and pathophysiological parameters in colorectal carcinoma and adenoma.
METHODS: The expression of OPN and HIF-1α in 50 colorectal carcinoma specimens, 24 colorectal adenoma specimens and 12 normal colorectal tissues were examined by immunohistochemistry using the streptavidin-peroxidase method.
RESULTS: OPN and HIF-1α expression was not detected in normal colorectal tissues. In contrast, OPN and HIF-1α were highly expressed in colorectal carcinoma and adenoma. Although no significant difference was noted in OPN expression level between colorectal adenoma and carcinoma, significant difference was found in HIF-1α expression level between colorectal adenoma and carcinoma (33.33% vs 62.00%, P < 0.05). Both OPN and HIF-1α expression were positively correlated with lymph node metastasis, depth of tumor invasion and Dukes' stage, but not with patients' gender and age. A significant correlation was noted between the expression of OPN and HIF-1α in colorectal carcinoma (r = 0.700, P < 0.01).
CONCLUSION: OPN and HIF-1α may play an important role in the invasion and metastasis of colorectal carcinoma. Tumors expressing high level of HIF-1α have greater invasive and metastatic capacity.
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Imano M, Satou T, Itoh T, Sakai K, Ishimaru E, Yasuda A, Peng YF, Shinkai M, Akai F, Yasuda T, Imamoto H, Okuno K, Ito H, Shiozaki H, Ohyanagi H. Immunohistochemical expression of osteopontin in gastric cancer. J Gastrointest Surg 2009; 13:1577-82. [PMID: 19582521 DOI: 10.1007/s11605-009-0955-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2009] [Accepted: 06/12/2009] [Indexed: 01/31/2023]
Abstract
BACKGROUND/AIMS Osteopontin (OPN) is significantly overexpressed in a variety of malignancies. However, little is known concerning the significance of OPN expression in human cancers. Thus, the aim of this study was to determine the relationship between the degree of OPN expression, the proliferative activity of cancer cells, and the clinicopathological findings for surgically resected gastric cancer. METHODOLOGY We evaluated the immunohistochemical expression of OPN in 85 specimens of cancer. Additionally, we investigated a cancer cell proliferative index using an anti-MIB-1 antibody and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling staining. Levels of OPN expression in gastric cancers were classified into three groups. To compare the relationship between OPN expression and clinicopathological findings, the features of cancer lesions were classified using the TNM Classification of Malignant Tumors, 6th Edition. RESULTS Immunohistochemical examination of OPN expression in gastric cancer revealed diffuse granular staining in the cytoplasm. High OPN expression was observed in 37 of 85 carcinomas. Strong OPN expression was significantly associated with a low apoptotic index, a high proliferative index, depth of invasion, lymphatic invasion, and venous invasion. Pathologically, intestinal type carcinoma showed strong expression of OPN. CONCLUSIONS These data suggested that OPN may play an important role in the invasiveness and the progressive nature of gastric cancer.
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Affiliation(s)
- Motohiro Imano
- Department of Surgery, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
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Ruan K, Bao S, Ouyang G. The multifaceted role of periostin in tumorigenesis. Cell Mol Life Sci 2009; 66:2219-30. [PMID: 19308325 PMCID: PMC11115806 DOI: 10.1007/s00018-009-0013-7] [Citation(s) in RCA: 265] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2009] [Revised: 02/24/2009] [Accepted: 02/27/2009] [Indexed: 12/18/2022]
Abstract
Periostin, also called osteoblast-specific factor 2 (OSF-2), is a member of the fasciclin family and a disulfide-linked cell adhesion protein that has been shown to be expressed preferentially in the periosteum and periodontal ligaments, where it acts as a critical regulator of bone and tooth formation and maintenance. Furthermore, periostin plays an important role in cardiac development. Recent clinical evidence has also revealed that periostin is involved in the development of various tumors, such as breast, lung, colon, pancreatic, and ovarian cancers. Periostin interacts with multiple cell-surface receptors, most notably integrins, and signals mainly via the PI3-K/Akt and other pathways to promote cancer cell survival, epithelial-mesenchymal transition (EMT), invasion, and metastasis. In this review, aspects related to the function of periostin in tumorigenesis are summarized.
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Affiliation(s)
- Kai Ruan
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, 361005 Xiamen, China
| | - Shideng Bao
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, 361005 Xiamen, China
- Present Address: Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195 USA
| | - Gaoliang Ouyang
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, 361005 Xiamen, China
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26
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Weismann D, Briese J, Niemann J, Grüneberger M, Adam P, Hahner S, Johanssen S, Liu W, Ezzat S, Saeger W, Bamberger AM, Fassnacht M, Schulte HM, Asa SL, Allolio B, Bamberger CM. Osteopontin stimulates invasion of NCI-h295 cells but is not associated with survival in adrenocortical carcinoma. J Pathol 2009; 218:232-40. [PMID: 19326399 DOI: 10.1002/path.2528] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Gene array studies indicated that osteopontin (OPN) mRNA is highly expressed in adrenocortical carcinomas (ACCs). OPN enhances invasiveness, proliferation, and metastasis formation, and is associated with poor survival in some malignant diseases. Integrin alphavbeta3 has been shown to mediate OPN effects on invasion. In this study, we demonstrated OPN and integrin alphavbeta3 expression in normal adrenal glands and benign adenomas, with staining seen exclusively in adrenocortical cells as well as even stronger staining in ACC. Western blot analysis confirmed overexpression of OPN in ACC (p < 0.01). With Matrigel invasion assays, we have shown that OPN greatly stimulates the invasiveness of NCI-h295 cells (>six-fold increase, p < 0.001). Transfection with integrin alphavbeta3 further increased invasiveness after OPN stimulation (p < 0.001). This increase was reversed by the addition of an anti-integrin beta3 antibody, indicating a functional relationship of OPN and integrin alphavbeta3 in ACC. With tissue arrays, we confirmed high OPN expression in 147 ACC samples. However, no association with survival was seen in Kaplan-Meier analysis including 111 patients with primary tumours graded for OPN staining and follow-up data available. In conclusion, our in vitro data indicate that OPN and integrin alphavbeta3 may act as a functional complex facilitating the invasiveness of adrenocortical tumours. This relationship remains of relevance to our understanding of carcinogenesis, but further studies are needed to address the physiological and pathological function of OPN in adrenal tissue.
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Affiliation(s)
- Dirk Weismann
- University Hospital of Würzburg, Department of Internal Medicine I, Endocrine and Diabetes Unit, Würzburg, Germany.
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Ruan K, Fang X, Ouyang G. MicroRNAs: novel regulators in the hallmarks of human cancer. Cancer Lett 2009; 285:116-26. [PMID: 19464788 DOI: 10.1016/j.canlet.2009.04.031] [Citation(s) in RCA: 336] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2009] [Revised: 04/20/2009] [Accepted: 04/23/2009] [Indexed: 12/15/2022]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs of 18-25 nucleotides in length that function as negative regulators. miRNAs post-transcriptionally regulate gene expression by either inhibiting mRNA translation or inducing mRNA degradation, and participate in a wide variety of physiological and pathological cellular processes. Recent reports have revealed that the deregulation of miRNAs correlates with various human cancers and is involved in the initiation and progression of human cancers. miRNAs can act as oncogenes or tumor suppressors to inhibit the expression of cancer-related target genes and to promote or suppress tumorigenesis in various tissues. Therefore, abnormal miRNA expression can be regarded as a common feature of human cancers, and the identification of miRNAs and their respective targets may provide potential diagnostic and prognostic tumor biomarkers and new therapeutic strategies to treat cancers. In the present review, we discuss the emerging roles of miRNAs in the hallmarks of human cancers.
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Affiliation(s)
- Kai Ruan
- Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005, China
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