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Ullah MA, Tabassum T, Farzana M, Moin AT, Zohora US, Rahman MS. Expression analysis, molecular characterization and prognostic evaluation on TMED4 and TMED9 gene expression in glioma. Biomed Signal Process Control 2022. [DOI: 10.1016/j.bspc.2022.103922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
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Ullah MA, Islam NN, Moin AT, Park SH, Kim B. Evaluating the Prognostic and Therapeutic Potentials of the Proteasome 26S Subunit, ATPase ( PSMC) Family of Genes in Lung Adenocarcinoma: A Database Mining Approach. Front Genet 2022; 13:935286. [PMID: 35938038 PMCID: PMC9353525 DOI: 10.3389/fgene.2022.935286] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 06/10/2022] [Indexed: 11/30/2022] Open
Abstract
This study explored the prognostic and therapeutic potentials of multiple Proteasome 26S Subunit, ATPase (PSMC) family of genes (PSMC1-5) in lung adenocarcinoma (LUAD) diagnosis and treatment. All the PSMCs were found to be differentially expressed (upregulated) at the mRNA and protein levels in LUAD tissues. The promoter and multiple coding regions of PSMCs were reported to be differentially and distinctly methylated, which may serve in the methylation-sensitive diagnosis of LUAD patients. Multiple somatic mutations (alteration frequency: 0.6-2%) were observed along the PSMC coding regions in LUAD tissues that could assist in the high-throughput screening of LUAD patients. A significant association between the PSMC overexpression and LUAD patients' poor overall and relapse-free survival (p < 0.05; HR: >1.3) and individual cancer stages (p < 0.001) was discovered, which justifies PSMCs as the ideal targets for LUAD diagnosis. Multiple immune cells and modulators (i.e., CD274 and IDO1) were found to be associated with the expression levels of PSMCs in LUAD tissues that could aid in formulating PSMC-based diagnostic measures and therapeutic interventions for LUAD. Functional enrichment analysis of neighbor genes of PSMCs in LUAD tissues revealed different genes (i.e., SLIRP, PSMA2, and NUDSF3) previously known to be involved in oncogenic processes and metastasis are co-expressed with PSMCs, which could also be investigated further. Overall, this study recommends that PSMCs and their transcriptional and translational products are potential candidates for LUAD diagnostic and therapeutic measure discovery.
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Affiliation(s)
- Md. Asad Ullah
- Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Jahangirnagar University, Dhaka, Bangladesh
| | - Nafisa Nawal Islam
- Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Jahangirnagar University, Dhaka, Bangladesh
| | - Abu Tayab Moin
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chattogram, Bangladesh
| | - Su Hyun Park
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, Korea
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul, Korea
- Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Korea
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Ullah MA, Alam S, Farzana M, Tayab Moin A, Binte Sayed Prapty CN, Zohora US, Rahman MS. Prognostic and therapeutic value of LSM5 gene in human brain cancer Glioma: An omics database exploration approach. INFORMATICS IN MEDICINE UNLOCKED 2022. [DOI: 10.1016/j.imu.2022.101114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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Zhang XL, Wu ZZ, Xu Y, Wang JG, Wang YQ, Cao MQ, Wang CH. Saliva proteomic analysis reveals possible biomarkers of renal cell carcinoma. OPEN CHEM 2020. [DOI: 10.1515/chem-2020-0048] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
AbstractEarly diagnosis is a key to improve the prognosis of renal cell carcinoma (RCC); however, reliable RCC biomarkers are lacking in clinical practice. In this study, we used isobaric tags for relative and absolute quantification-based mass spectrometry to identify salivary proteins as biomarkers for the diagnosis of RCC. The objective of this study is to discover biomarkers from saliva by utilizing high-throughput quantitative proteomics approaches. Saliva proteins from 124 RCC patients and healthy individuals were identified and quantified. RCC putative biomarkers were verified by real-time polymerase chain reaction or enzyme-linked immunosorbent assay in a prevalidation sample set. Seventy-one differentially expressed salivary proteins were identified. Serotransferrin, haptoglobin, KRT9, and S100A9, which in previous studies were found to be most closely related to cancers, were selected as putative RCC biomarkers. Haptoglobin and S100A9 were significantly elevated in RCC compared with healthy control samples, although the expression of serotransferrin and KRT9 did not differ between the groups. Furthermore, receiver operating characteristic curves with a cut-off value of 75.49 ng/mL for S100A9 revealed a sensitivity of 87.10% and a specificity of 91.94% for discriminating RCC patients from healthy individuals. Salivary haptoglobin differentiated RCC patients from healthy controls with a sensitivity of 85.48% and specificity of 80.65% (cut-off value 43.02 µg/mL). These results provide experimental evidence to support S100A9 and haptoglobin as potential novel, noninvasive biomarkers for the diagnosis of RCC.
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Affiliation(s)
- Xiao Li Zhang
- Central Laboratory, The ShenZhen Second People’s Hospital, 3002 Sunggang W Road, Futian District, Shenzhen 518035, P. R. China
| | - Zheng Zhi Wu
- Geriatrics Department, The ShenZhen Second People's Hospital, 3002 Sunggang W Road, Futian District, Shenzhen 518035, P. R. China
| | - Yun Xu
- Central Laboratory, The ShenZhen Second People’s Hospital, 3002 Sunggang W Road, Futian District, Shenzhen 518035, P. R. China
| | - Ji Guo Wang
- Oncology Department, Chinese Medicine Hospital of Baoan District, Shenzhen 518113, P. R. China
| | - Yong Qiang Wang
- Central Laboratory, The ShenZhen Second People’s Hospital, 3002 Sunggang W Road, Futian District, Shenzhen 518035, P. R. China
| | - Mei Qun Cao
- Central Laboratory, The ShenZhen Second People’s Hospital, 3002 Sunggang W Road, Futian District, Shenzhen 518035, P. R. China
| | - Chang Hao Wang
- Central Laboratory, The ShenZhen Second People’s Hospital, 3002 Sunggang W Road, Futian District, Shenzhen 518035, P. R. China
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Liu ZY, Zhang WG, Pang SW. Traversing behavior of tumor cells in three-dimensional platforms with different topography. PLoS One 2020; 15:e0234482. [PMID: 32520967 PMCID: PMC7286507 DOI: 10.1371/journal.pone.0234482] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Accepted: 05/27/2020] [Indexed: 12/19/2022] Open
Abstract
Three-dimensional polydimethylsiloxane platforms were developed to mimic the extracellular matrix with blood vessels by having scaffolds with micropatterns, porous membrane and trenches. Precisely controlled physical dimensions, layouts, and topography as well as different surface chemical treatments were applied to study their influences on nasopharyngeal carcinoma cell (10-15 μm in diameter) migration in mimicked platforms over 15-hour of time-lapse imaging. By placing the pores at different distance from the edges of the trenches, pores with different trench sidewall exposures and effective sizes were generated. Pores right next to the trench sidewalls showed the highest cell traversing probability, most likely related to the larger surface contact area with cells along the sidewalls. Straight grating oriented perpendicular to trenches below the top layer increased cell traversing probability. Pore shape as well as pore size influenced the cell traversing probability and cells could not traverse through pores that were 6 μm or less in diameter, which is much smaller than the cell size. Trench depth of 15 μm could induce more cells to traverse through the porous membrane, while shallower trenches impeded cell traversing and longer time was needed for cells to traverse because 3 and 6 μm deep trenches were much smaller than cell size which required large cell deformation. Hydrophobic surface coating on the top layer and fibronectin in pores and trenches increased the cell traversing probability and reduced the pore size that cells could traverse from 8 to 6 μm, which indicated that cells could have larger deformation with certain surface coatings.
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Affiliation(s)
- Z. Y. Liu
- Department of Electrical Engineering, City University of Hong Kong, Hong Kong, China
- Center for Biosystems, Neuroscience, and Nanotechnology, City University of Hong Kong, Hong Kong, China
| | - W. G. Zhang
- Department of Electrical Engineering, City University of Hong Kong, Hong Kong, China
- Center for Biosystems, Neuroscience, and Nanotechnology, City University of Hong Kong, Hong Kong, China
| | - S. W. Pang
- Department of Electrical Engineering, City University of Hong Kong, Hong Kong, China
- Center for Biosystems, Neuroscience, and Nanotechnology, City University of Hong Kong, Hong Kong, China
- * E-mail:
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Khan A, Fan K, Sun N, Yin W, Sun Y, Sun P, Jahejo AR, Li H. Recombinant porcine NK-lysin inhibits the invasion of hepatocellular carcinoma cells in vitro. Int J Biol Macromol 2019; 140:1249-1259. [PMID: 31465800 DOI: 10.1016/j.ijbiomac.2019.08.212] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 08/23/2019] [Accepted: 08/24/2019] [Indexed: 02/07/2023]
Abstract
The therapeutics having ability to target cancer cells specifically and exhibit nominal cytopathic effect on normal healthy cells are highly significant for cancer therapeutic applications. Recombinant porcine natural killer lysin (rpNK-lysin) has proven cationic anti-bacterial and anti-tumor peptide. Herein, we report its anti-invasion and anti-metastasis effects on hepatocellular carcinoma (HCC) cells in vitro. We first investigate the maximum non-toxic concentration (MNTC) of rpNK-lysin for the normal hepato cells (L-02). Using MNTC rpNK-lysin, we explore anti-proliferative, anti-adhesive, anti-invasive and anti-metastatic effect of rpNK-lysin on three different HCC cells lines (SMMC-7721, 97-H and HepG2) through MTT, wound-healing, adhesion and invasion assay along with mRNA and protein expression. The results reveal that rpNK-lysin has potential to specifically inhibit HCC cells growth in a dose and time-dependent manner with a little cytopathic effect on the L-02 cells, effectively reduce migration, adhesion and invasion ability of HCC cells. rpNK-lysin significantly reduce Fascin1 expression, which subsequently decrease β-catenin expression and metaloproteinases (MMP-2 and MMP9). This study suggest that MNTC rpNK-lysin has an anti-invasion and anti-metastasis effect on HCC cells in vitro through inhibition of Fascin 1 expression which regulates Wnt/β-catenin signaling pathway by inducing β-catenin degradation and subsequently results in suppression of MMP-2 and MMP9 expression.
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Affiliation(s)
- Ajab Khan
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, PR China
| | - Kuohai Fan
- Laboratory Animal Center, Shanxi Agricultural University, Taigu, Shanxi 030801, PR China
| | - Na Sun
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, PR China
| | - Wei Yin
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, PR China
| | - Yaogui Sun
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, PR China
| | - Panpan Sun
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, PR China
| | - Ali Raza Jahejo
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, PR China
| | - Hongquan Li
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi 030801, PR China.
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Pinel C, Prainsack B, McKevitt C. Markers as mediators: A review and synthesis of epigenetics literature. BIOSOCIETIES 2019; 13:276-303. [PMID: 31105763 PMCID: PMC6520226 DOI: 10.1057/s41292-017-0068-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Epigenetics, the study of the processes that control gene expression without a change in DNA sequence, highlights the importance of environmental factors in gene regulation. This paper maps the terrain of epigenetics and identifies four main research subfields: gene expression; molecular epigenetics; clinical epigenetics and epigenetic epidemiology. Within and across these fields, we analyse of what is conceptualised as environment and demonstrate the variable ways authors understand epigenetics environments. Then, following an analysis of the discursive strategies employed by epigenetics researchers, we demonstrate how authors portray the interactions between genes, epigenetics, and environment as relationships linking the outside (where the environment is located) with the inside (where the genes are located). We argue that authors assign specific roles to each actor: the environment as the active player initiating the relationship, the genes as recipients, and epigenetics as mediators between environment and genes. Framed as mediators, epigenetic markers can be understood as enablers of communication between environment and genome, capable of processing and organising signals so as to regulate the interactions between the actors of epigenetic relationships. This finding complicates the observation by social science scholars that the interactions between environment and genes can be understood through the concept of signal.
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Affiliation(s)
- Clémence Pinel
- School of Population Sciences and Health Services Research, King’s College London, UK
| | - Barbara Prainsack
- Department of Political Science, University of Vienna, Austria
- Department of Global Health & Social Medicine, King’s College London, UK
| | - Christopher McKevitt
- School of Population Sciences and Health Services Research, King’s College London, UK
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Gonzalez-Reyes C, Marcial-Medina C, Cervantes-Anaya N, Cortes-Reynosa P, Salazar EP. Migration and invasion induced by linoleic acid are mediated through fascin in MDA-MB-231 breast cancer cells. Mol Cell Biochem 2017; 443:1-10. [PMID: 29052029 DOI: 10.1007/s11010-017-3205-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 10/14/2017] [Indexed: 12/12/2022]
Abstract
Epidemiological studies strongly suggest an association between high levels of dietary fat intake and an increased risk of developing breast cancer. Linoleic acid (LA) is an essential omega-6 PUFA and the major fatty acid in occidental diets. In breast cancer cells, LA induces expression of plasminogen activator inhibitor-1, proliferation, migration, and invasion. Fascin is an actin crosslinker globular protein that generates actin bundles made of parallel actin filaments, which mediate formation and stability of microspikes, stress fibers, membrane ruffles, and filopodia. However, the role of fascin in migration and invasion induced by LA in MDA-MB-231 breast cancer cells remains to be studied. We demonstrate here that LA induces an increase of fascin expression in MDA-MB-231 and MCF12A mammary epithelial cells. Particularly, LA induces the formation of filopodia and lamellipodia and the localization of fascin in these actin structures in MDA-MB-231 breast cancer cells. However, LA only induces formation of microspikes and the localization of fascin in these actin structures in mammary non-tumorigenic epithelial cells MCF12A. In addition, LA induces migration, invasion, and matrix metalloproteinase-9 secretion through a fascin-dependent pathway in MDA-MB-231 cells. In summary, our findings demonstrate that fascin is required for migration and invasion induced by LA in MDA-MB-231 breast cancer cells.
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Affiliation(s)
- Christian Gonzalez-Reyes
- Departamento de Biologia Celular, Cinvestav-IPN, Av IPN # 2508, San Pedro Zacatenco, 07360, Mexico City, Mexico
| | - Cleofas Marcial-Medina
- Departamento de Biologia Celular, Cinvestav-IPN, Av IPN # 2508, San Pedro Zacatenco, 07360, Mexico City, Mexico
| | - Nancy Cervantes-Anaya
- Departamento de Biologia Celular, Cinvestav-IPN, Av IPN # 2508, San Pedro Zacatenco, 07360, Mexico City, Mexico
| | - Pedro Cortes-Reynosa
- Departamento de Biologia Celular, Cinvestav-IPN, Av IPN # 2508, San Pedro Zacatenco, 07360, Mexico City, Mexico
| | - Eduardo Perez Salazar
- Departamento de Biologia Celular, Cinvestav-IPN, Av IPN # 2508, San Pedro Zacatenco, 07360, Mexico City, Mexico.
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Cao X, Zou H, Cao J, Cui Y, Sun S, Ren K, Song Z, Li D, Quan M. A candidate Chinese medicine preparation-Fructus Viticis Total Flavonoids inhibits stem-like characteristics of lung cancer stem-like cells. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 16:364. [PMID: 27633248 PMCID: PMC5024514 DOI: 10.1186/s12906-016-1341-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 09/07/2016] [Indexed: 01/26/2023]
Abstract
Background Cancer stem cells (CSCs) are considered as the origin of tumor relapse. Here, we investigated the effects of Fructus Viticis total flavonoids (FVTF) on the characteristics of lung cancer stem-like cells (LCSLCs) derived from human small cell lung cancer NCI-H446 cell line and its potential mechanism. Methods Human small cell lung cancer NCI-H446 cell line was cultured in vitro. The CD133+ cells were sorted from NCI-H446 cell line by magnetic separation. The suspended culture with stem cell-conditioned medium was used to amplify CD133+ sphere-forming cells (SFCs). The stem cell characteristics of CD133+ SFCs were evaluated using cell self-renewal capacity by tumor sphere formation assay, migration and invasion capacity by Transwell assay, tumorigenicity by xenograft model in nude mouse and cancer stem cell markers expression levels by western blot. The effects of FVTF on the properties of LCSLCs were examined by tumorsphere formation assay and transwell chamber assay. The expression level of p-Akt was determined by western blot analysis. Result CD133+ SFCs derived from human small cell lung cancer NCI-H446 cells exhibited stemness properties of tumorsphere formation and tumorigenesis capacity comparing to the parental cells. FVTF relative selectively inhibited the proliferation of LCSLCs, suppressed tumor sphere forming capacity and migration and invasion of LCSLCs, and down-regulated the protein expression of stem cell markers (CD133, CD44 and ALDH1), self-renewal associated transcription factors (Bmi1, Nanog and OCT4) and invasion associated transcription factors (Twist1 and Snail1) in a dose-dependent manner. Moreover, we found that FVTF treatment could significantly decrease the phosphorylation level of Akt in LCSLCs. Meanwhile, LY294002 and FVTF synergistically inhibited the characteristics of LCSLCs. Conclusion FVTF inhibits the characteristics of LCSLCs through down-regulating expression of p-Akt.
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Affiliation(s)
- Xiaocheng Cao
- College of Life Science, Hunan Normal University, Changsha, China.,Laboratory of Medicine Engineering, College of Medicine, Hunan Normal University, Changsha, China
| | - Hui Zou
- Laboratory of Medicine Engineering, College of Medicine, Hunan Normal University, Changsha, China
| | - Jianguo Cao
- Laboratory of Medicine Engineering, College of Medicine, Hunan Normal University, Changsha, China
| | - Yinghong Cui
- Laboratory of Medicine Engineering, College of Medicine, Hunan Normal University, Changsha, China
| | - Shuwen Sun
- Laboratory of Medicine Engineering, College of Medicine, Hunan Normal University, Changsha, China
| | - Kaiqun Ren
- Laboratory of Medicine Engineering, College of Medicine, Hunan Normal University, Changsha, China
| | - Zhenwei Song
- Laboratory of Medicine Engineering, College of Medicine, Hunan Normal University, Changsha, China
| | - Duo Li
- Laboratory of Medicine Engineering, College of Medicine, Hunan Normal University, Changsha, China
| | - Meifang Quan
- Laboratory of Medicine Engineering, College of Medicine, Hunan Normal University, Changsha, China.
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[Bone metastasis by renal cell carcinoma. Importance of calcium and calcium-sensing receptor]. Urologe A 2016; 54:839-43. [PMID: 25503898 DOI: 10.1007/s00120-014-3716-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Bone tissue is one of the main locations of metastases in renal cell carcinoma (RCC). In bone tissue the concentration of calcium ions is very high. Cells recognize extracellular calcium by the calcium-sensing receptor (CaSR). To investigate the role of calcium in bone metastases, the CaSR was quantified in tumor tissue and primary tumor cells of patients who were free of metastases or developed bone or lung metastases during a time period of 5 years after nephrectomy. In tissue specimens and primary cells of patients developing bone metastases, CaSR expression was clearly enhanced. Functionally, analyses showed a higher sensitivity in bone metastasizing cells concerning proliferation and chemotactical migration. These effects were caused by enhanced activity of the downstream targets of CaSR, namely AKT, PLCg, JNK and p38, analyzed in a phospho-kinase array and western blot analysis. The extent to which CaSR is suitable as a new marker for bone-specific metastases from renal cancer must be examined further.
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Ma H, Cai H, Zhang Y, Wu J, Liu X, Zuo J, Jiang W, Ji G, Zhang Y, Liu C, Zhu W, Yu L. Membrane palmitoylated protein 3 promotes hepatocellular carcinoma cell migration and invasion via up-regulating matrix metalloproteinase 1. Cancer Lett 2014; 344:74-81. [PMID: 24513266 DOI: 10.1016/j.canlet.2013.10.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Revised: 09/29/2013] [Accepted: 10/18/2013] [Indexed: 12/31/2022]
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Béduer A, Vaysse L, Loubinoux I, Vieu C. [Micro/nano-engineering to control growth of neuronal cells and tissue engineering applied to the central nervous system]. Biol Aujourdhui 2013; 207:291-307. [PMID: 24594577 DOI: 10.1051/jbio/2013019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Indexed: 11/14/2022]
Abstract
Central nervous system pathologies are often characterized by the loss of cell populations. A promising therapy now being developed consists in using bioactive materials, associating grafted cells to biopolymers which provide a scaffold for the in vitro building of new tissues, to be implanted in vivo. In the present article, the state of the art of this field, at crossroads between microtechnology and neuroscience, is described in detail; thereafter our own approach and results about interactions between adult human neural stem cells and microstructured polymers are summarized and discussed. In a second part, some central nervous system repair strategies, based on cerebral tissue engineering, are presented. We will report the main results of our studies to work out and characterize in vivo a cerebral bioprosthesis.
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Affiliation(s)
- Amélie Béduer
- LAAS, CNRS & Université de Toulouse (UPS, INSA, IAES), 7 avenue du Colonel Roche, 31077 Toulouse, France
| | - Laurence Vaysse
- INSERM, Imagerie Cérébrale et Handicaps Neurologiques UMR 825, 31059 Toulouse, France
| | - Isabelle Loubinoux
- INSERM, Imagerie Cérébrale et Handicaps Neurologiques UMR 825, 31059 Toulouse, France
| | - Christophe Vieu
- LAAS, CNRS & Université de Toulouse (UPS, INSA, IAES), 7 avenue du Colonel Roche, 31077 Toulouse, France
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Fu Y, Chin LK, Bourouina T, Liu AQ, VanDongen AMJ. Nuclear deformation during breast cancer cell transmigration. LAB ON A CHIP 2012; 12:3774-8. [PMID: 22864314 DOI: 10.1039/c2lc40477j] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Metastasis is the main cause of cancer mortality. During this process, cancer cells dislodge from a primary tumor, enter the circulation and form secondary tumors in distal organs. It is poorly understood how these cells manage to cross the tight syncytium of endothelial cells that lines the capillaries. Such capillary transmigration would require a drastic change in cell shape. We have therefore developed a microfluidic platform to study the transmigration of cancer cells. The device consists of an array of microchannels mimicking the confined spaces encountered. A thin glass coverslip bottom allows high resolution imaging of cell dynamics. We show that nuclear deformation is a critical and rate-limiting step for transmigration of highly metastatic human breast cancer cells. Transmigration was significantly reduced following the treatment with a protein methyltransferase inhibitor, suggesting that chromatin condensation might play an important role. Since transmigration is critical for cancer metastasis, this new platform may be useful for developing improved cancer therapies.
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Affiliation(s)
- Yi Fu
- School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore, 639798
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Nikkhah M, Edalat F, Manoucheri S, Khademhosseini A. Engineering microscale topographies to control the cell-substrate interface. Biomaterials 2012; 33:5230-46. [PMID: 22521491 PMCID: PMC3619386 DOI: 10.1016/j.biomaterials.2012.03.079] [Citation(s) in RCA: 437] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Accepted: 03/27/2012] [Indexed: 01/12/2023]
Abstract
Cells in their in vivo microenvironment constantly encounter and respond to a multitude of signals. While the role of biochemical signals has long been appreciated, the importance of biophysical signals has only recently been investigated. Biophysical cues are presented in different forms including topography and mechanical stiffness imparted by the extracellular matrix and adjoining cells. Microfabrication technologies have allowed for the generation of biomaterials with microscale topographies to study the effect of biophysical cues on cellular function at the cell-substrate interface. Topographies of different geometries and with varying microscale dimensions have been used to better understand cell adhesion, migration, and differentiation at the cellular and sub-cellular scales. Furthermore, quantification of cell-generated forces has been illustrated with micropillar topographies to shed light on the process of mechanotransduction. In this review, we highlight recent advances made in these areas and how they have been utilized for neural, cardiac, and musculoskeletal tissue engineering application.
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Affiliation(s)
- Mehdi Nikkhah
- Center for Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Faramarz Edalat
- Center for Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Sam Manoucheri
- Center for Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Ali Khademhosseini
- Center for Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
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Al-Alwan M, Olabi S, Ghebeh H, Barhoush E, Tulbah A, Al-Tweigeri T, Ajarim D, Adra C. Fascin is a key regulator of breast cancer invasion that acts via the modification of metastasis-associated molecules. PLoS One 2011; 6:e27339. [PMID: 22076152 PMCID: PMC3208623 DOI: 10.1371/journal.pone.0027339] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Accepted: 10/13/2011] [Indexed: 12/21/2022] Open
Abstract
The actin-bundling protein, fascin, is a member of the cytoskeletal protein family that has restricted expression in specialized normal cells. However, many studies have reported the induction of this protein in various transformed cells including breast cancer cells. While the role of fascin in the regulation of breast cancer cell migration has been previously shown, the underlying molecular mechanism remained poorly defined. We have used variety of immunological and functional assays to study whether fascin regulates breast cancer metastasis-associated molecules. In this report we found a direct relationship between fascin expression in breast cancer patients and; metastasis and shorter disease-free survival. Most importantly, in vitro interference with fascin expression by loss or gain of function demonstrates a central role for this protein in regulating the cell morphology, migration and invasion potential. Our results show that fascin regulation of invasion is mediated via modulating several metastasis-associated genes. We show for the first time that fascin down-regulates the expression and nuclear translocation of a key metastasis suppressor protein known as breast cancer metastasis suppressor-1 (BRMS1). In addition, fascin up-regulates NF-kappa B activity, which is essential for metastasis. Importantly, fascin up-regulates other proteins that are known to be critical for the execution of metastasis such as urokinase-type plasminogen activator (uPA) and the matrix metalloproteases (MMP)-2 and MMP-9. This study demonstrates that fascin expression in breast cancer cells establishes a gene expression profile consistent with metastatic tumors and offers a potential therapeutic intervention in metastatic breast cancer treatment through fascin targeting.
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Affiliation(s)
- Monther Al-Alwan
- Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
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16
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Zhang D, Pan X, Ohno S, Osuga T, Sawada S, Sato K. No effects of pulsed electromagnetic fields on expression of cell adhesion molecules (integrin, CD44) and matrix metalloproteinase-2/9 in osteosarcoma cell lines. Bioelectromagnetics 2011; 32:463-73. [DOI: 10.1002/bem.20647] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2010] [Accepted: 12/20/2010] [Indexed: 11/09/2022]
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17
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Lai CH, Chang NW, Lin CF, Lin CD, Lin YJ, Wan L, Sheu JJC, Chen SY, Huang YP, Sing YT, Tao TW, Lai CK, Tsai MH, Chan HL, Jou YJ, Lin CW. Proteomics-based identification of haptoglobin as a novel plasma biomarker in oral squamous cell carcinoma. Clin Chim Acta 2010; 411:984-91. [DOI: 10.1016/j.cca.2010.03.028] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2009] [Revised: 02/24/2010] [Accepted: 03/22/2010] [Indexed: 10/19/2022]
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18
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Screening and cloning of multi-drug resistant genes in HL-60/MDR cells. Leuk Res 2009; 33:1120-3. [DOI: 10.1016/j.leukres.2008.11.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2008] [Revised: 11/09/2008] [Accepted: 11/10/2008] [Indexed: 11/20/2022]
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19
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EphB6 receptor significantly alters invasiveness and other phenotypic characteristics of human breast carcinoma cells. Oncogene 2009; 28:1706-13. [PMID: 19234485 DOI: 10.1038/onc.2009.18] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Breast cancer mortality in women is largely attributed to the metastasis of primary breast tumors. We have analysed the function of EphB6, a kinase-deficient receptor, in the invasive phenotype of breast cancer cell lines. We have demonstrated the loss of EphB6 protein in invasive breast carcinoma cell lines and absence of EphB6 transcript in a metastatic breast tumor specimen. The function of EphB6 in invasiveness was confirmed by the ability of EphB6 protein to decrease the in vitro invasiveness of MDA-MB-231, MDA-MB-435 and BT549 cells transfected with an EphB6 expression construct. In MDA-MB-231 cells, the decreased invasiveness appeared to be mediated by decreased transcript levels of matrix metalloproteinase (MMP)7 and MMP19, and increased transcript levels of tissue inhibitors of metalloproteinase 2. In addition to affecting invasiveness phenotype, EphB6 overexpression was also responsible for altering the growth rate and colony-forming efficiency of MCF-7 and MDA-MB-231 cells in a cell-line-specific manner. We suggest that the significant decrease in the invasiveness of MDA-MB-231 and other cell lines transfected with EphB6 is likely occurring by the ability of EphB6 to transduce signals to the nucleus and altering relevant gene expression.
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20
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Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis. Oncogene 2008; 28:219-30. [PMID: 18836481 DOI: 10.1038/onc.2008.379] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Transgenic mice expressing the Notch 4 intracellular domain (ICD) (Int3) in the mammary gland have two phenotypes: arrest of mammary alveolar/lobular development and mammary tumorigenesis. Notch4 signaling is mediated primarily through the interaction of Int3 with the transcription repressor/activator Rbpj. We have conditionally ablated the Rbpj gene in the mammary glands of mice expressing whey acidic protein (Wap)-Int3. Interestingly, Rbpj knockout mice (Wap-Cre(+)/Rbpj(-/-)/Wap-Int3) have normal mammary gland development, suggesting that the effect of endogenous Notch signaling on mammary gland development is complete by day 15 of pregnancy. RBP-J heterozygous (Wap-Cre(+)/Rbpj(-/+)/Wap-Int3) and Rbpj control (Rbpj(flox/flox)/Wap-Int3) mice are phenotypically the same as Wap-Int3 mice with respect to mammary gland development and tumorigenesis. In addition, the Wap-Cre(+)/Rbpj(-/-)/Wap-Int3-knockout mice also developed mammary tumors at a frequency similar to Rbpj heterozygous and Wap-Int3 control mice but with a slightly longer latency. Thus, the effect on mammary gland development is dependent on the interaction of the Notch ICD with the transcription repressor/activator Rbpj, and Notch-induced mammary tumor development is independent of this interaction.
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22
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Chaw KC, Manimaran M, Tay FEH, Swaminathan S. Matrigel coated polydimethylsiloxane based microfluidic devices for studying metastatic and non-metastatic cancer cell invasion and migration. Biomed Microdevices 2007; 9:597-602. [PMID: 17505887 DOI: 10.1007/s10544-007-9071-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Three-dimensional (3-D) extracellular matrices (ECM) allow complex biochemical and biophysical interactions between cells and matrices. Unlike 2-D systems, 3-D models provide a better representation of the micro and local environments in living tissues for facilitating the physiological study of cell migration. Here, we report a microfluidic device based on polydimethylsiloxane (PDMS) for monitoring 3-D cell migration across ECM-coated microgaps with real-time light microscopy. We tracked the migration of the invasive MDA-MB-231 (mammary carcinoma) cells and mapped out their migration paths. It enabled us to quantify the percentage of migrated cells as well as migration information of individual cells. This wide spectrum of data acquisition is vital for elucidating the migration capabilities of different type of cells and to understand the basic mechanism involved in cancer metastasis.
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Affiliation(s)
- K C Chaw
- NUS Graduate School for Integrative Sciences and Engineering, 12 Medical Drive, Singapore, 117598, Singapore
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23
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24
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Yoder BJ, Wilkinson EJ, Massoll NA. Molecular and Morphologic Distinctions between Infiltrating Ductal and Lobular Carcinoma of the Breast. Breast J 2007; 13:172-9. [PMID: 17319859 DOI: 10.1111/j.1524-4741.2007.00393.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Histopathologic distinction between ductal and lobular carcinomas of the breast has been made since 1941. Together, these two subtypes account for >95% of all mammary carcinomas. With the recent advances in molecular techniques, our understanding of the biology behind these carcinomas has greatly expanded. The genomic aberrations in mammary carcinoma are highly complex and appear to be more associated with tumor grade rather than any histopathologic subtype. Protein and RNA expression profiling reveals a classification of mammary carcinoma that has some overlap with traditional histopathology and can at least partially explain clinical behavior. The goal of this review is to present what is currently known about the molecular profiles of infiltrating ductal and lobular carcinoma and how they relate to conventional histopathology and biologic behavior.
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MESH Headings
- Antigens, CD
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Cadherins/genetics
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/metabolism
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Lobular/genetics
- Carcinoma, Lobular/metabolism
- Carcinoma, Lobular/pathology
- Chromosome Aberrations
- Female
- Gene Expression Profiling
- Genes, erbB-2/genetics
- Genomic Instability
- Humans
- Mutation
- Receptor, ErbB-2/metabolism
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Affiliation(s)
- Brian J Yoder
- Department of Pathology, University of Florida, Gainesville, Florida 33805, USA.
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25
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Roth JM, Caunt M, Cretu A, Akalu A, Policarpio D, Li X, Gagne P, Formenti S, Brooks PC. Inhibition of experimental metastasis by targeting the HUIV26 cryptic epitope in collagen. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 168:1576-86. [PMID: 16651624 PMCID: PMC1606585 DOI: 10.2353/ajpath.2006.050176] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Metastasis from the primary tumor to distant sites involves an array of molecules that function in an integrated manner. Proteolytic remodeling and subsequent tumor cell interactions with the extracellular matrix regulate tumor invasion. In previous studies, we have identified a cryptic epitope (HUIV26) that is specifically exposed after alterations in the triple helical structure of type IV collagen. Exposure of this cryptic epitope plays a fundamental role in the regulation of angiogenesis in vivo. However, little is known concerning the ability of tumor cells to interact with this cryptic site or whether this site regulates tumor cell metastasis in vivo. In this regard, many of the same cellular processes that regulate angiogenesis also contribute to tumor metastasis. Here we provide evidence that tumor cells such as B16F10 melanoma interact with denatured collagen type IV in part by recognizing the HUIV26 cryptic site. Systemic administration of a HUIV26 monoclonal antibody inhibited experimental metastasis of B16F10 melanoma in vivo. Taken together, our findings suggest that tumor cell interactions with the HUIV26 cryptic epitope play an important role in regulating experimental metastasis and that this cryptic element may represent a therapeutic target for controlling the spread of tumor cells to distant sites.
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Affiliation(s)
- Jennifer M Roth
- Department of Radiation Oncology, The New York University Cancer Institute, New York University School of Medicine, New York 10016, USA
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26
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Modlin IM, Kidd M, Latich I, Zikusoka MN, Eick GN, Mane SM, Camp RL. Genetic differentiation of appendiceal tumor malignancy: a guide for the perplexed. Ann Surg 2006; 244:52-60. [PMID: 16794389 PMCID: PMC1570599 DOI: 10.1097/01.sla.0000217617.06782.d5] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVE To use differential gene expression of candidate markers to discriminate benign appendiceal carcinoids (APCs) from malignant and mixed cell APCs. SUMMARY BACKGROUND DATA Controversy exists in regard to the appropriate surgical management of APCs since it is sometimes difficult to predict tumor behavior using traditional pathologic criteria. We have identified 5 differentially expressed genes (a mitosis-regulatory gene NAP1L1, an adhesin MAGE-D2, an estrogen-antagonist, the metastasis marker MTA1, the apoptotic marker NALP, and chromogranin A) that define gut neuroendocrine cell behavior. METHODS Total RNA was isolated using TRIzol reagent from 42 appendiceal samples, including appendiceal carcinoids identified at exploration for appendicitis (no evidence of metastasis; n = 16), appendicitis specimens (n = 11), malignant appendiceal tumors (> 1.5 cm, evidence of metastatic invasion; n = 7), and mixed (goblet) cell appendiceal adenocarcinoids (n = 3), normal appendiceal tissue (n = 5), and 5 colorectal cancers. Gene expression (CgA, NAP1L1, MAGE-D2, MTA1, and NALP1) was examined by Q-RT PCR (Applied Biosystems) and quantified against GAPDH. RESULTS CgA message was elevated (> 1000-fold, P < 0.05) in all tumor types. NAP1L1 was elevated (> 10-fold, P < 0.03) in both malignant and goblet cell adenocarcinoids compared with normal and incidental lesions (P < 0.006). MAGE-D2 and MTA1 message were significantly elevated (> 10-fold, P < 0.01) in the malignant and goblet cell adenocarcinoid tumors but not in the appendicitis-associated carcinoids or normal mucosa. The apoptotic marker, NALP1, was overexpressed (> 50-fold, P < 0.05) in the appendicitis-associated and malignant appendiceal carcinoids but was significantly decreased (> 10-fold, P < 0.05) in the goblet cell adenocarcinoids. Elevated CgA transcript and protein levels indicative of a carcinoid tumor were identified in one acute appendicitis sample with no histologic evidence of a tumor. CONCLUSIONS These data demonstrate that malignant APCs and goblet cell adenocarcinoids have elevated expression of NAP1L1, MAGE-D2, and MTA1 compared with appendiceal carcinoids identified at surgery for appendicitis. This and the differences in NALP1 gene expression (decreased in goblet cell adenocarcinoids) provide a series of molecular signatures that differentiate carcinoids of the appendix. CgA identified all appendiceal tumors as well as covert lesions, which may be more prevalent than previously recognized. The molecular delineation of malignant appendiceal tumor potential provides a scientific basis to define the appropriate surgical management as opposed to morphologic assessment alone.
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Affiliation(s)
- Irvin M Modlin
- Department of Surgery, Yale University School of Medicine, New Haven, CT 06520-8062, USA.
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Frausin F, Scarcia V, Cocchietto M, Furlani A, Serli B, Alessio E, Sava G. Free exchange across cells, and echistatin-sensitive membrane target for the metastasis inhibitor NAMI-A (imidazolium trans-imidazole dimethyl sulfoxide tetrachlororuthenate) on KB tumor cells. J Pharmacol Exp Ther 2005; 313:227-33. [PMID: 15579494 DOI: 10.1124/jpet.104.078352] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The duration of cell proadhesive effects induced by imidazolium trans-imidazole dimethyl sulfoxide tetrachlororuthenate (NAMI-A), a compound endowed with in vivo antimetastatic properties, was tested in vitro on the human epithelial tumor cell line KB. The intensity of proadhesive effects continues to increase up to 48 to 72 h after NAMI-A withdrawal and declines only after 96 h. The proadhesive effect on cells seeded on fibronectin is greater than on plastic, since it already reaches its maximum after 24 h. This effect suggests a role for integrin activation, which is further stressed by the inhibitory activity of the disintegrin molecule echistatin. The intensity and duration of NAMI-A's proadhesive effects are correlated to cell exposure time and to the rapid release of NAMI-A metabolites in the culture medium in the first 5 min after drug withdrawal. These metabolites are probably neutral species with ruthenium-bound bioligands to allow for the rapid exchange between cells and extracellular medium. These data suggest a long-lasting effect of NAMI-A in biological systems, even at very low concentrations, and stress the low and reversible effects on kidney, where it naturally concentrates. These data on proadhesive effects are, further, relevant for in vivo antimetastatic effects, as this adhesion is associated to cell motility and invasion, which in turn are related to tumor malignancy and metastasis.
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Affiliation(s)
- F Frausin
- Department of Biomedical Sciences, University of Trieste, Italy
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28
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Xu Y, Sun HC, Tian B, Li Y, Chen J, Chen J, Gao DM, Xue Q, Tang ZY. Establishment of green fluorescent protein-expressing hepatocellular carcinoma cell lines with different metastatic potential: relevant models for in vivo monitoring of metastasis and angiogenesis. J Cancer Res Clin Oncol 2005; 130:375-82. [PMID: 15133661 DOI: 10.1007/s00432-004-0551-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
PURPOSE To establish stable green fluorescent protein (GFP)-expressing metastatic human hepatocellular carcinoma (HCC) cell lines with different metastatic potential for long-term in vivo studies of metastasis and angiogenesis. METHODS The pIRES2-EGFP vector, which contains an enhanced GFP gene, was transfected into MHCC97-H and MHCC97-L, HCC cell lines with different metastatic potential. The stability of GFP expression, basic biological characteristics, invasion abilities in vitro, and spontaneous metastasis in vivo of the new cell lines (MHCC97-HG and MHCC97-LG) were studied. Microvessel density (MVD) of orthotopic implanted tumors was compared by anti-CD31 immunohistochemical staining, and real-time angiogenesis and metastasis of GFP-transfected tumors were detected by intravital fluorescent microscope. RESULTS The GFP-transfected cell lines stably expressed green fluorescence in the absence of G418 over a 36-day period. Compared with the parental cell lines, they exhibited no distinct differences in biological characteristics. MHCC97-HG showed more aggressive invasion and spontaneous metastatic behavior than MHCC97-LG, and even its parental cell line, MHCC97-H (P<0.01). MVD levels induced by MHCC97-HG orthotopic implanted tumors were significantly higher than MHCC97-LG (P<0.01). Real-time angiogenesis and sequential steps of metastasis could be detected clearly under intravital fluorescent microscope. CONCLUSIONS These two stable GFP-expressing HCC cell lines with the same genetic background and different metastatic potential were established, which could be useful models for monitoring metastasis and angiogenesis of HCC.
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Affiliation(s)
- Yang Xu
- Liver Cancer Institute and Zhong Shan Hospital, Fudan University, 136 Yi Xue Yuan Road, 200032 Shanghai, China
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29
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Yoder BJ, Tso E, Skacel M, Pettay J, Tarr S, Budd T, Tubbs RR, Adams JC, Hicks DG. The Expression of Fascin, an Actin-Bundling Motility Protein, Correlates with Hormone Receptor–Negative Breast Cancer and a More Aggressive Clinical Course. Clin Cancer Res 2005. [DOI: 10.1158/1078-0432.186.11.1] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Abstract
The invasion and metastasis of tumor cells is a major cause of mortality in cancer patients. In the current study, we investigated the expression of fascin, an actin-bundling motility-associated protein, in 210 invasive breast carcinomas with corresponding 5-year clinical follow-up. Fascin expression was compared with hormone receptor (ER/PR) status, HER2 status, cancer grade, cancer stage, metastasis pattern, disease-free survival, and overall survival. Fascin expression was seen in 16% (33/210) of the cases and correlated with ER negativity (22/33, P < 0.001), PR negativity (21/33, P < 0.001), Bloom-Richardson grade 3 (19/29, P < 0.001), and advanced stage (stage 3 or 4, P=0.04).There was no correlation between fascin expression and HER2 status or pattern of metastases. Patients whose tumors were positive for fascin showed both a decreased mean disease-free survival (74.44 versus 100.52 months, P = 0.002) and mean overall survival (77.58 versus 98.98 months, P = 0.002), independent of tumor stage and HER2 status, but not independent of ER/PR status or cancer grade. Given fascin's role in altering cell motility, overexpression may contribute to a more aggressive clinical course in ER/PR-negative breast cancers. If so, then fascin may represent a new molecular target for therapeutic intervention in patients with ER-negative breast cancer.
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Affiliation(s)
- Brian J. Yoder
- 1The Cleveland Clinic Foundation, Department of Anatomic Pathology,
| | | | - Marek Skacel
- 1The Cleveland Clinic Foundation, Department of Anatomic Pathology,
| | - Jim Pettay
- 1The Cleveland Clinic Foundation, Department of Anatomic Pathology,
| | - Shannon Tarr
- 1The Cleveland Clinic Foundation, Department of Anatomic Pathology,
| | | | - Raymond R. Tubbs
- 1The Cleveland Clinic Foundation, Department of Anatomic Pathology,
| | | | - David G. Hicks
- 1The Cleveland Clinic Foundation, Department of Anatomic Pathology,
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Burbach BJ, Ji Y, Rapraeger AC. Syndecan-1 ectodomain regulates matrix-dependent signaling in human breast carcinoma cells. Exp Cell Res 2004; 300:234-47. [PMID: 15383330 DOI: 10.1016/j.yexcr.2004.07.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2004] [Revised: 06/29/2004] [Indexed: 10/26/2022]
Abstract
Syndecan-1 was overexpressed in T47D, MCF-7, or Hs578t human breast carcinoma cell lines, mimicking overexpression observed in carcinomas in vivo. Overexpression of syndecan-1, or its ectodomain alone fused to a glycosylphosphatidylinositol anchor (GPI-mS1ED), promotes cell rounding in 2D culture. Deletions within the syndecan-1 ectodomain (S1ED) implicate an active site within the core protein between the glycosaminoglycan attachment region and the transmembrane domain. Polyclonal antibodies directed against the ectodomain, or treatment with the tyrosine kinase inhibitor genistein, block activity and revert GPI-mS1ED overexpressing cells to a normal morphology. Extracellular matrix (ECM)-dependent signaling appears to be targeted, as GPI-mS1ED cells attach and spread similarly to control cells in response to E-cadherin engagement, but fail to spread on integrin-dependent ligands. However, integrin-dependent cell attachment, and integrin activation and subsequent FAK phosphorylation are unaffected, suggesting that the syndecan regulates the integration of signaling following matrix adhesion. In 3D culture, where syndecan-1 may have a more critical role in cell behavior, the disrupted signaling leads to poorly cohesive, invasive colonies. Thus, altered matrix-dependent signaling due to increased levels of cell surface syndecan-1 may lead to epithelial cell invasion during early stages of tumorigenesis.
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Affiliation(s)
- Brandon J Burbach
- Graduate Program in Molecular Pharmacology, University of Wisconsin-Madison. Madison, Wisconsin 53706, USA
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31
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Sava G, Frausin F, Cocchietto M, Vita F, Podda E, Spessotto P, Furlani A, Scarcia V, Zabucchi G. Actin-dependent tumour cell adhesion after short-term exposure to the antimetastasis ruthenium complex NAMI-A. Eur J Cancer 2004; 40:1383-96. [PMID: 15177498 DOI: 10.1016/j.ejca.2004.01.034] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2003] [Revised: 09/20/2003] [Accepted: 01/16/2004] [Indexed: 11/25/2022]
Abstract
Imidazolium trans-imidazoledimethylsulphoxidetrachlororuthenate (NAMI-A) was tested in vitro on the pro-adhesive properties, evaluated as resistance to trypsin treatment, which is a bona fide measure of adhesion strength, of KB and HeLa carcinoma cell lines and on human polymorphonuclear neutrophils (HPMN). NAMI-A increased the pro-adhesive activity of KB cells at 0.001 mM concentration, after few minutes incubation and this effect was not influenced by the vehicle used for cell challenge, neither did it depend on NAMI-A concentration or on temperature. The same effect occurred on HeLa cells at 0.01 mM NAMI-A. This effect, detected at concentrations up to 100 times lower than those necessary to block cells at the G(2)-M premitotic phase of cell cycle, or to inhibit matrix metalloproteinase release or cell invasion, was not related to ruthenium uptake by tumour cells. HeLa cells and healthy HPMN, following short exposure to 0.1 mM NAMI-A, assumed a different shape, with the extrusion of filopodia (HeLa) and of large lamellopodia (HPMN), which increased their interactions with the substrate. This effect was attributed to stabilisation, altered turnover and sensitivity to cytochalasin D of actin filaments. Provided that adhesion is associated with cell motility and invasion, these data suggest that NAMI-A may exert antimetastatic properties at concentrations lower than those observed in the lungs at the end of a conventional intraperitoneal treatment in vivo.
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Affiliation(s)
- G Sava
- Department of Biomedical Sciences, University of Trieste, Via L. Giorgieri 7, 34127 Trieste, Italy.
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Büchler P, Reber HA, Lavey RS, Tomlinson J, Büchler MW, Friess H, Hines OJ. Tumor hypoxia correlates with metastatic tumor growth of pancreatic cancer in an orthotopic murine model. J Surg Res 2004; 120:295-303. [PMID: 15234226 DOI: 10.1016/j.jss.2004.02.014] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2003] [Indexed: 12/12/2022]
Abstract
BACKGROUND The role of tumor hypoxia has become a major focus in cancer research since it influences both local and systemic tumor growth. Oxygen measurements taken in human pancreatic cancer have shown extremely low oxygen tension. The aim of this study was to develop an orthotopic model for pancreatic cancer that mimics the specific tumor microenvironment and to evaluate the role of tumor oxygenation in local tumor growth and systemic dissemination in this model. MATERIALS AND METHODS We used two established human pancreatic cancer cell lines for xenobiotic tumor induction. After subcutaneous tumor formation one small tumor piece was transplanted into the pancreatic parenchyma of mice of the different study groups. Upon orthotopic tumor induction tumor oxygenation was measured with the Eppendorf histograph. Histological evaluation was performed with pimonidazole, an in vivo marker of hypoxia. RESULTS The tumor take rate was 100% in this model. Metastatic tumor dissemination occurred within the abdominal cavity, and distant metastasis were observed in the lung parenchyma. Oxygen measurements taken in various abdominal organs and xenograft tumor showed a high variation between different organs and xenografted tumors. Tumor oxygenation correlated well with the metastatic score in this model. Furthermore hypoxia was found both in the tumor center and also at the rim of a growing tumor mass. A high number of hypoxic cells were detectable in metastases located in the lung parenchyma. CONCLUSION This study provides experimental evidence that tumor hypoxia influences metastatic disease progression and supports recent assumptions that tumor hypoxia is actively involved in progression of pancreatic cancer. It further demonstrates that tumor hypoxia is not only found in the center of a tumor mass, but also occurs at the invasion front.
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Affiliation(s)
- Peter Büchler
- Department of Surgery, The David Geffen School of Medicine at UCLA, University of California-Los Angeles, Los Angeles, California, USA.
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Wang YF, Chow KC, Chang SY, Chiu JH, Tai SK, Li WY, Wang LS. Prognostic significance of nm23-H1 expression in oral squamous cell carcinoma. Br J Cancer 2004; 90:2186-93. [PMID: 15150613 PMCID: PMC2409489 DOI: 10.1038/sj.bjc.6601808] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Recent studies indicated nm23-H1 played a role in cancer progression. Therefore, we investigated clinical significance of nm23-H1 expression in oral squamous cell carcinoma (OSCC). In total, 86 OSCC specimens were immunohistochemically stained with nm23-H1-specific monoclonal antibodies. Immunohistochemical staining of nm23-H1 was confirmed by immunoblotting. The relations between nm23-H1 expression and clinicopathologic variables were evaluated by chi(2) analysis. As increased size of primary tumour could escalate metastatic potential and the data of patients at the late T stage might confound statistical analyses, we thus paid special attention to 54 patients at the early T stage of OSCC. Statistical difference of survival was compared by a log-rank test. Immunohistochemically, nm23-H1 expression was detected in 48.8% (42 out of 86) of tumorous specimens. It positively correlated with larger primary tumour size (P=0.03) and inversely with cigarette-smoking habit (P=0.042). In patients at the early T stage, decreased nm23 expression was associated with increased incidence of lymph node metastasis (P=0.004) and indicated poor survival (P=0.014). Tumour nm23-H1 expression is a prognostic factor for predicting better survival in OSCC patients at the early T stage, which may reflect antimetastatic potential of nm23. Therefore, modulation of nm23-H1 expression in cancer cells can provide a novel possibility of improving therapeutic strategy at this stage. In addition, our results further indicated cigarette smoking could aggravate the extent of nm23-H1 expression and possibly disease progression of OSCC patients.
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Affiliation(s)
- Y-F Wang
- Department of Otolaryngology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei 112, Taiwan, ROC
- Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan, ROC
| | - K-C Chow
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402, Taiwan, ROC
| | - S-Y Chang
- Department of Otolaryngology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei 112, Taiwan, ROC
| | - J-H Chiu
- Institute of Traditional Medicine, National Yang-Ming University, Taipei 112, Taiwan, ROC
| | - S-K Tai
- Department of Otolaryngology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei 112, Taiwan, ROC
| | - W-Y Li
- Department of Pathology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei 112, Taiwan, ROC
| | - L-S Wang
- Division of Chest Surgery, Department of Surgery, Taipei Veterans General Hospital and National Yang-Ming University, Taipei 112, Taiwan, ROC
- Division of Chest Surgery, Department of Surgery, Taipei Veterans General Hospital and National Yang-Ming University, Taipei 112, Taiwan, ROC. E-mail:
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Wu X, Zeng H, Zhang X, Zhao Y, Sha H, Ge X, Zhang M, Gao X, Xu Q. Phosphatase of regenerating liver-3 promotes motility and metastasis of mouse melanoma cells. THE AMERICAN JOURNAL OF PATHOLOGY 2004; 164:2039-54. [PMID: 15161639 PMCID: PMC1615773 DOI: 10.1016/s0002-9440(10)63763-7] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Recent reports suggested that phosphatase of regenerating liver (PRL)-3 might be involved in colorectal carcinoma metastasis with an unknown mechanism. Here we demonstrated that PRL-3 expression was up-regulated in human liver carcinoma compared with normal liver. PRL-3 was also highly expressed in metastatic melanoma B16-BL6 cells but not in its lowly metastatic parental cell line, B16 cells. B16 cells transfected with PRL-3 cDNA displayed morphological transformation from epithelial-like shape to fibroblast-like shape. PRL-3-overexpressed cells showed much higher migratory ability, which could be reversed by specific anti-sense oligodeoxynucleotide and the phosphatase inhibitors sodium orthovanadate or potassium bisperoxo oxovanadate V. Meanwhile, the expression of the catalytically inactive PRL-3 mutations (D72A or C104S) significantly reduced the cell migratory capability. In addition, PRL-3 transfectants demonstrated altered extracellular matrix adhesive property and up-regulated integrin-mediated cell spreading efficiency. Furthermore, we confirmed that PRL-3 could facilitate lung and liver metastasis of B16 cells in an experimental metastasis model in mice, consistent with accelerated proliferation and growth rate both in vitro and in vivo. Together, these observations provide convincing evidence that PRL-3 truly plays a causal role in tumor metastasis.
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Affiliation(s)
- Xiaopeng Wu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, and the Model Animal Genetics Research Center, Nanjing University, Nanjing, China
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Krasowska M, Grzywna ZJ, Mycielska ME, Djamgoz MBA. Patterning of endocytic vesicles and its control by voltage-gated Na+ channel activity in rat prostate cancer cells: fractal analyses. EUROPEAN BIOPHYSICS JOURNAL: EBJ 2004; 33:535-42. [PMID: 15024523 DOI: 10.1007/s00249-004-0394-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2003] [Revised: 06/02/2003] [Accepted: 01/23/2004] [Indexed: 11/25/2022]
Abstract
Fractal methods were used to analyze quantitative differences in secretory membrane activities of two rat prostate cancer cell lines (Mat-LyLu and AT-2) of strong and weak metastatic potential, respectively. Each cell's endocytic activity was determined by horseradish peroxidase uptake. Digital images of the patterns of vesicular staining were evaluated by multifractal analyses: generalized fractal dimension (Dq) and its Legendre transform f(alpha), as well as partitioned iterated function system -- semifractal (PIFS-SF) analysis. These approaches revealed consistently that, under control conditions, all multifractal parameters and PIFS-SF codes determined had values greater for Mat-LyLu compared with AT-2 cells. This would agree generally with the endocytic/vesicular activity of the strongly metastatic Mat-LyLu cells being more developed than the corresponding weakly metastatic AT-2 cells. All the parameters studied were sensitive to tetrodotoxin (TTX) pre-treatment of the cells, which blocked voltage-gated Na+ channels (VGSCs). Some of the parameters had a "simple" dependence on VGSC activity, whereby pre-treatment with TTX reduced the values for the MAT-LyLu cells and eliminated the differences between the two cell lines. For other parameters, however, there was a "complex" dependence on VGSC activity. The possible physical/physiological meaning of the mathematical parameters studied and the nature of involvement of VGSC activity in control of endocytosis/secretion are discussed.
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Affiliation(s)
- Monika Krasowska
- Neuroscience Solutions to Cancer Research Group, Department of Biological Sciences, Imperial College London, Sir Alexander Fleming Building, South Kensington Campus, London, SW7 2AZ, UK
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Hauser P, Ma L, Agrawal D, Haura E, Cress WD, Pledger WJ. Efficient Down-Regulation of Cyclin A-Associated Activity and Expression in Suspended Primary Keratinocytes Requires p21Cip1. Mol Cancer Res 2004. [DOI: 10.1158/1541-7786.96.2.2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Abstract
When suspended in methylcellulose, primary mouse keratinocytes cease proliferation and differentiate. Suspension also reduces the activity of the cyclin-dependent kinase cdk2, an important cell cycle regulatory enzyme. To determine how suspension modulates these events, we examined its effects on wild-type keratinocytes and keratinocytes nullizygous for the cdk2 inhibitor p21Cip1. After suspension of cycling cells, amounts of cyclin A (a cdk2 partner), cyclin A mRNA, and cyclin A-associated activity decreased much more rapidly in the presence than in the absence of p21Cip1. Neither suspension nor p21Cip1 status affected the stability of cyclin A mRNA. Loss of p21Cip1 reduced the capacity of suspended cells to growth arrest, differentiate, and accumulate p27Kip1 (a second cdk2 inhibitor) and affected the composition of E2F DNA binding complexes. Cyclin A-cdk2 complexes in suspended p21+/+ cells contained p21Cip1 or p27Kip1, whereas most of the cyclin A-cdk2 complexes in p21−/− cells lacked p27Kip1. Ectopic expression of p21Cip1 allowed p21−/− keratinocytes to efficiently down-regulate cyclin A and differentiate when placed in suspension. These findings show that p21Cip1 mediates the effects of suspension on numerous processes in primary keratinocytes including cdk2 activity, cyclin A expression, cell cycle progression, and differentiation.
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Affiliation(s)
| | - Le Ma
- 1Molecular Oncology Program and
| | | | - Eric Haura
- 2Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, University of South Florida School of Medicine, Tampa FL
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Ono M, Shindoh M, Kobayashi M, Higashino F, Kohgo T, Yoshida K, Totsuka Y. E1AF Induces Both Matrix Metalloprotease Transcription and Cell Cycle Arrest that Occurs in the Stage of Cancer Cell Invasion. ACTA ACUST UNITED AC 2004. [DOI: 10.3353/omp.9.19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Li XN, Ding YQ, Liu GB. Transcriptional gene expression profiles of HGF/SF-met signaling pathway in colorectal carcinoma. World J Gastroenterol 2003; 9:1734-8. [PMID: 12918110 PMCID: PMC4611533 DOI: 10.3748/wjg.v9.i8.1734] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the transcriptional gene expression profiles of HGF/SF-met signaling pathway in colorectal carcinoma to understand mechanisms of the signaling pathway at so gene level.
METHODS: Total RNA was isolated from human colorectal carcinoma cell line LoVo treated with HGF/SF (80 ng/L) for 48 h. Fluorescent probes were prepared from RNA labeled with cy3-dUTP for the control groups and with cy5-dUTP for the HGF/SF-treated groups through reverse-transcription. The probes were mixed and hybridized on the microarray at 60 °C for 15-20 h, then the microarray was scanned by laser scanner (GenePix 4000B). The intensity of each spot and ratios of Cy5/Cy3 were analyzed and finally the differentially expressed genes were selected by GenePix Pro 3.0 software. 6 differential expression genes (3 up-regulated genes and 3 down-regulated genes) were selected randomly and analyzed by β-actin semi-quantitative RT-PCR.
RESULTS: The fluorescent intensities of built-in negative control spots were less than 200, and the fluorescent intensities of positive control spots were more than 5000. Of the 4004 human genes analyzed by microarray, 129 genes (holding 3.22% of the investigated genes) revealed differential expression in HGF/SF-treated groups compared with the control groups, of which 61 genes were up-regulated (holding 1.52% of the investigated genes) and 68 genes were down-regulated (holding 1.70% of the investigated genes), which supplied abundant information about target genes of HGF/SF-met signaling.
CONCLUSION: HGF/SF-met signaling may up-regulate oncogenes, signal transduction genes, apoptosis-related genes, metastasis related genes, and down-regulate a number of genes. The complexity of HGF/SF-met signaling to control the gene expression is revealed as a whole by the gene chip technology.
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Affiliation(s)
- Xue-Nong Li
- Department of Pathology, First Military Medical University, Guangzhou 510515, Guangdong Province, China.
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Yang YL, Lai CS, Lin SD, Wang CK, Tsai KB. Intramuscular metastasis of cutaneous squamous cell carcinoma: a case report. Kaohsiung J Med Sci 2003; 19:188-92. [PMID: 12795349 DOI: 10.1016/s1607-551x(09)70470-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Cutaneous squamous cell carcinoma (SCC) is a common cancer. Although most patients with primary cutaneous SCC have an excellent prognosis, for those with metastatic disease, the long-term prognosis is poor. The most common sites of metastasis are regional lymph nodes, lung, liver, brain, skin, and bone. However, metastatic soft tissue SCC from cutaneous lesions is extremely rare, with only two reported cases. We report a case in which the patient had a primary SCC lesion on his left palm in 1986. A second primary SCC on his left forearm was confirmed in 2001, with subsequent metastasis to the proximal muscles and bone invasion in spite of the initial wide excision.
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Affiliation(s)
- Yu-Li Yang
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Smeets MB, Fontijn J, Kavelaars A, Pasterkamp G, De Kleijn DPV. The acute phase protein haptoglobin is locally expressed in arthritic and oncological tissues. Int J Exp Pathol 2003; 84:69-74. [PMID: 12801280 PMCID: PMC2517545 DOI: 10.1046/j.1365-2613.2003.00336.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Haptoglobin is an acute phase protein known to be highly expressed in the liver. Recently, we showed increased local arterial haptoglobin expression after flow-induced arterial remodelling and found that haptoglobin is involved in cell migration and arterial restructuring probably through accumulation of a temporary gelatin matrix. Since cell migration and matrix turnover are important features in the pathology of arthritis and cancer, we hypothesized that haptoglobin is also locally expressed in arthritic and oncological tissues. In this study, we investigated local haptoglobin expression in arthritic rats (n = 12) using semi-quantitative PCR and Western blotting, and we studied haptoglobin mRNA localization in human kidney tumours (n = 3) using in situ hybridization. The arthritic rats demonstrated an increase of haptoglobin mRNA (2.5-fold, P < 0.001) and protein (2.6-fold, P < 0.001) in the arthritic Achilles tendon. Haptoglobin protein was also increased in the arthritic ankle (2.6-fold, P < 0.001) but not in the non-arthritic knee. In human kidney tumours, tumour and stromal cells produced haptoglobin mRNA. This study shows that the liver protein haptoglobin is, in addition to the artery, also expressed in arthritic and oncological tissues that are recognized for enhanced cell migration and matrix turnover.
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Affiliation(s)
- Mirjam B Smeets
- Experimental Cardiology Laboratory, University Medical Centre, Utrecht, the Netherlands
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Affiliation(s)
- Gregory J Tsongalis
- Department of Pathology and Laboratory Medicine, Hartford Hospital, Hartford, CT, USA.
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Wu J, Shi YQ, Wu KC, Zhang DX, Yang JH, Fan DM. Angiostatin up-regulation in gastric cancer cell SGC7901 inhibits tumorigenesis in nude mice. World J Gastroenterol 2003; 9:59-64. [PMID: 12508352 PMCID: PMC4728250 DOI: 10.3748/wjg.v9.i1.59] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the influence of angiostatin up-regulation on the biologic behavior of gastric cancer cells in vitro and in vivo, and the potential of angiostatin gene therapy in the treatment of human gastric cancer.
METHODS: Mouse angiostatin cDNA was subcloned into the eukaryotic expression vector pcDNA3.1(+) and identified by restriction endonucleases digestion and sequencing. The recombinant vector pcDNA3.1(+)-angio was transfected into human gastric cancer cells SGC7901 with liposome and paralleled with the vector control and the mock control. Angiostatin transcription and protein expression were examined by RT-PCR and Western blot in the stable cell lines selected by G418. Cell proliferation and growth in vitro of the three groups were observed respectively under microscope, cell number counting and FACS. The cells overexpressing angiostatin, vector transfected and untreated were respectively implanted subcutaneously into nude mice. After 30 days the size of tumors formed was measured, and microvessel density count (MVD) in the tumor tissues was assessed by immunohistochemistry with the primary anti-vWF antibody.
RESULTS: The recombinant vector pcDNA3.1(+)-angio was confirmed with the correct sequence of mouse angiostatin under the promoter CMV. After 30 d of transfection and selection with G418, macroscopic resistant cell clones were formed in the experimental group transfected with pcDNA 3.1(+)-angio and the vector control. But no untreated cells survived in the mock control. Angiostatin mRNA transcription and protein expression were detected in the experimental group. No significant differences were observed among the three groups in cell morphology, cell growth curves and cell cycle phase distributions in vitro. However, in nude mice model, markedly inhibited tumorigenesis and slowed tumor expansion were observed in the experimental group as compared with the controls, which was paralleled with decreased microvessel density in and around tumor tissues (P < 0.05).
CONCLUSION: Angiostatin does not directly inhibit human gastric cancer cell proliferation and growth in vitro, but exerts its anti-tumor functions through antiangiogenesis in a paracrine way in vivo.
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Affiliation(s)
- Jing Wu
- Institute of Gastrointestinal Diseases Research, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shannxi Province, China.
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Achary PMR, Zhao H, Fan Z, Gogineni S, Pulijaal VR, Herbst L, Mahadevia PS, Jones JG, Klinger HP, Vikram B. A candidate metastasis-associated DNA marker for ductal mammary carcinoma. Breast Cancer Res 2003; 5:R52-8. [PMID: 12631399 PMCID: PMC154149 DOI: 10.1186/bcr571] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2002] [Revised: 12/04/2002] [Accepted: 12/17/2002] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Molecular genetic markers to identify the 13% lymph node-negative mammary carcinomas that are prone to develop metastases would clearly be of considerable value in indicating those cases in need of early aggressive therapy. METHODS Representational difference analysis was used in an attempt to identify genetic alterations related to breast cancer metastasis by comparing genomic DNA from microdissected normal cells and from metastatic cells of ductal breast carcinoma patients. RESULTS Representational difference analysis products yielded 10 unique metastasis-associated DNA sequences (MADS), i.e. products apparently lost in metastatic cell DNA. Of these sequences, MADS-IX was found to be lost in the transition from primary to metastasis in two out of five ductal breast carcinoma cases. This sequence was localized on chromosome 10q21 by radiation hybrid mapping and fluorescence in situ hybridization. The PTEN gene, which is also located on chromosome 10q, was detected to be present by PCR in all five cases. On the contrary, a breast carcinoma cell line, HCC-1937, which has homozygous loss of a region encompassing the PTEN gene, showed the presence of MADS-IX. PCR screening of three additional breast carcinoma cell lines with known losses in specific chromosomal regions also showed the presence of MADS-IX. CONCLUSION These data suggest that MADS-IX possibly is part of a novel candidate metastasis-associated gene located close to the PTEN gene on chromosome 10q. The first set of PCR screening in five patient samples indicates that it could be used as a molecular marker for ductal mammary metastasis.
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Affiliation(s)
- Patnala Mohan R Achary
- Metastasis Laboratory, Department of Radiation Oncology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA.
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Current Awareness on Comparative and Functional Genomics. Comp Funct Genomics 2002. [PMCID: PMC2447335 DOI: 10.1002/cfg.120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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