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Zhou R, Qin B, Zhuang Z, Li J, Shi Y, Gao T, Wu D, Yuan Y, Tang Y, Lin L. Mechanistic insights into Yifei Sanjie pill's regulation of EMT to enhance gefitinib treatment effect in NSCLC by in silico analysis and experimental validation. JOURNAL OF ETHNOPHARMACOLOGY 2024; 334:118343. [PMID: 38750985 DOI: 10.1016/j.jep.2024.118343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 04/30/2024] [Accepted: 05/13/2024] [Indexed: 07/20/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The Yi-Fei San-Jie pill (YFSJ) is a well-known Chinese medicine that has been used to treat non-small cell lung cancer in China for decades. AIM OF THE STUDY Previous studies have shown that YFSJ combined with gefitinib can effectively inhibit the proliferation of gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines by promoting apoptosis and autophagy, but the molecular biological mechanisms involved and whether YFSJ combined with gefitinib can have synergistic effects still need to be further explored. Thus, the present study aimed to establish an in silico and experimental framework to decipher the underlying mechanism by which YFSJ augments the efficacy of gefitinib in treating NSCLC. MATERIALS AND METHODS Integrated approaches, including microarray analysis, network pharmacology, RNA sequencing, bioinformatics algorithm analysis and in vivo and in vitro experiments, were applied to elucidate the underlying mechanism. RESULTS Analysis of microarray datasets indicated that gefitinib may play a role in the regulation of the epithelial-mesenchymal transition (EMT) of PC9 cells. EMT-related Gene Ontology (GO) terms and the MAPK pathway were found to be enriched in the differentially expressed genes (DEGs), and a decreasing trend was observed in the EMT score. Network pharmacology analysis revealed that the potential NSCLC-related targets of YFSJ also showed enrichment in EMT-related GO terms and the MAPK pathway. Experimental findings demonstrated that combined YFSJ-treated serum and gefitinib treatment significantly inhibited PC9 cell migration and invasion. In addition, the combined treatment dramatically reduced the tumour volume in an animal model. The effectiveness of the combination treatment surpassed that of gefitinib alone in both cell and animal experiments. RNA sequencing analysis revealed significant enrichment of DEGs in EMT-related GO terms for the gefitinib treatment group, YFSJ treatment group, and combination treatment group compared to the control group. Notably, the negative regulation of EMT showed significant enrichment in the DEGs of the combination treatment group. The MAPK pathway was significantly enriched among the different groups. Moreover, combined treatment with YFSJ and gefitinib may exert synergistic anti-NSCLC effects by inhibiting the p-p38 MAPK/GSK3β signalling axis, subsequently suppressing downstream EMT processes. CONCLUSION Combined treatment with YFSJ and gefitinib could enhance the sensitivity of NSCLC cells to gefitinib by suppressing EMT through the EGFR/p-p38 MAPK/GSK3β signalling axis. YFSJ may serve as an important adjunctive medication for NSCLC patients receiving gefitinib treatment in clinical practice.
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Affiliation(s)
- Ruisheng Zhou
- Guangzhou University of Chinese Medicine, Guangzhou, China; The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Binyu Qin
- West China-Frontier PharmaTech Co., Lt, Chengdu, China
| | - Zhenjie Zhuang
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jing Li
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yafei Shi
- School of Fundamental Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Tianqi Gao
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Dailin Wu
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi Yuan
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Tang
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Lizhu Lin
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.
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Wang G, Zhang Z, Tao M, Wei X, Zhou L. Identification of potential crucial genes and mechanisms associated with metastasis of medulloblastoma based on gene expression profile. Neurol Res 2023; 45:260-267. [PMID: 36215435 DOI: 10.1080/01616412.2022.2132457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
OBJECTIVES Medulloblastoma is the most common malignant brain tumor in childhood. Although metastasis constitutes one of the poorest prognostic indicators in this disease, the mechanisms that drive metastasis have received less attention. The aim of our study is to provide valid biological information for the metastasis mechanism of medulloblastoma. METHODS Gene expression profile of GSE468 was downloaded from GEO database and was analyzed using limma R package. Function and enrichment analyses of DEGs were performed based on PANTHER database. PPI network construction, hub gene selection and module analysis were conducted in Cytoscape software. RESULTS Nine upregulated genes and 34 downregulated genes were selected as DEGs. The upregulated genes were mainly enriched in molecular function and cell component, which mainly included protein binding and nucleus respectively. A total of 120 enriched GO terms and 40 KEGG pathways were identified. The main enriched GO terms were the biological process such as apoptosis and MAPK activity. Besides, the enriched KEGG pathways also included MAPK signaling pathway. A PPI network was obtained, and JUN was identified as a hub gene. Also, we firstly investigated the role and regulatory mechanism of JUN in the metastasis of medulloblastoma. CONCLUSIONS Through the bioinformatics analysis of the gene microarray in GEO, we found some crucial genes and pathways associated with the metastasis of medulloblastoma.
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Affiliation(s)
- Guoqing Wang
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, PR China
| | - Zongliang Zhang
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China
| | - Mengying Tao
- Department of Ophthalmology, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, PR China
| | - Xin Wei
- Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Liangxue Zhou
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, PR China
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Kciuk M, Gielecińska A, Budzinska A, Mojzych M, Kontek R. Metastasis and MAPK Pathways. Int J Mol Sci 2022; 23:ijms23073847. [PMID: 35409206 PMCID: PMC8998814 DOI: 10.3390/ijms23073847] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/18/2022] [Accepted: 03/29/2022] [Indexed: 02/07/2023] Open
Abstract
Cancer is a leading cause of death worldwide. In many cases, the treatment of the disease is limited due to the metastasis of cells to distant locations of the body through the blood and lymphatic drainage. Most of the anticancer therapeutic options focus mainly on the inhibition of tumor cell growth or the induction of cell death, and do not consider the molecular basis of metastasis. The aim of this work is to provide a comprehensive review focusing on cancer metastasis and the mitogen-activated protein kinase (MAPK) pathway (ERK/JNK/P38 signaling) as a crucial modulator of this process.
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Affiliation(s)
- Mateusz Kciuk
- Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90-237 Lodz, Poland; (A.G.); (R.K.)
- Correspondence:
| | - Adrianna Gielecińska
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90-237 Lodz, Poland; (A.G.); (R.K.)
| | - Adrianna Budzinska
- Laboratory of Mitochondrial Biochemistry, Department of Bioenergetics, Faculty of Biology, Adam Mickiewicz University, 61-614 Poznan, Poland;
| | - Mariusz Mojzych
- Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3 Maja 54, 08-110 Siedlce, Poland;
| | - Renata Kontek
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 12/16 Banacha St., 90-237 Lodz, Poland; (A.G.); (R.K.)
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Bao CH, Guo L. Retracted: miR-27b-3p Inhibits Invasion, Migration and Epithelial-mesenchymal Transition in Gastric Cancer by Targeting RUNX1 and Activation of the Hippo Signaling Pathway. Anticancer Agents Med Chem 2022; 22:864-873. [PMID: 34238170 DOI: 10.2174/1871520621666210707095833] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/19/2021] [Accepted: 05/04/2021] [Indexed: 11/22/2022]
Abstract
The article entitled “miR-27b-3p Inhibits Invasion, Migration and Epithelial-mesenchymal Transition in Gastric Cancer by Targeting RUNX1 and Activation of the Hippo Signaling Pathway”, by Chen-Hui Bao and Lin Guo, has been retracted on the request of the Author in light of the changes to the University’s promotion policy, due to which the article needs further content. Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused. Kindly see Bentham Science Policy on Article retraction at the link https://benthamscience.com/journals/anti-canceragents-in-medicinal-chemistry/editorial-policies/ Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure, or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.
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Affiliation(s)
- Chen-Hui Bao
- Department of General surgery, ShengJing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang City 110004, Liaoning Province, China
| | - Lin Guo
- Department of General surgery, ShengJing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang City 110004, Liaoning Province, China
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Hou Y, Li S, Du W, Li H, Wen R. The Tumor Suppressor Role of the Ras Association Domain Family 10. Anticancer Agents Med Chem 2021; 20:2207-2215. [PMID: 32664845 DOI: 10.2174/1871520620666200714141906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 04/30/2020] [Accepted: 05/17/2020] [Indexed: 11/22/2022]
Abstract
The Ras association domain family 10(RASSF10), a tumor suppressor gene, is located on human chromosome 11p15.2, which is one of the members homologous to other N-terminal RASSF families obtained through structural prediction. RASSF10 plays an important role in inhibiting proliferation, invasion, and migration, inducing apoptosis, making cancer cells sensitive to docetaxel, and capturing G2/M phase. Some studies have found that RASSF10 may inhibit the occurrence and development of tumors by regulating Wnt/β-catenin, P53, and MMP2. Methylation of tumor suppressor gene promoter is a key factor in the development and progression of many tumors. Various methylation detection methods confirmed that the methylation and downregulation of RASSF10 often occur in various tumors, such as gastric cancer, lung cancer, colon cancer, breast cancer, and leukemia. The status of RASSF10 methylation is positively correlated with tumor size, tumor type, and TNM stage. RASSF10 methylation can be used as a prognostic factor for overall survival and disease-free survival, and is also a sign of tumor diagnosis and sensitivity to docetaxel chemotherapy. In this review, we mainly elucidate the acknowledged structure and progress in the verified functions of RASSF10 and the probably relevant signaling pathways.
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Affiliation(s)
- Yulong Hou
- Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
| | - Shuofeng Li
- Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China
| | - Wei Du
- Xuzhou Medical University, Xuzhou 221002, Jiangsu, China
| | - Hailong Li
- Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China
| | - Rumin Wen
- Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China
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Ryu KJ, Park SM, Park SH, Kim IK, Han H, Kim HJ, Kim SH, Hong KS, Kim H, Kim M, Yoon SJ, Asaithambi K, Lee KH, Park JY, Hah YS, Cho HJ, Yook JI, Yang JW, Ko GH, Lee G, Kang YJ, Hwangbo C, Kim KD, Park YJ, Yoo J. p38 Stabilizes Snail by Suppressing DYRK2-Mediated Phosphorylation That Is Required for GSK3β-βTrCP-Induced Snail Degradation. Cancer Res 2019; 79:4135-4148. [PMID: 31209060 DOI: 10.1158/0008-5472.can-19-0049] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 05/07/2019] [Accepted: 06/11/2019] [Indexed: 11/16/2022]
Abstract
Snail is a key regulator of epithelial-mesenchymal transition (EMT), which is a major step in tumor metastasis. Although the induction of Snail transcription precedes EMT, posttranslational regulation, especially phosphorylation of Snail, is critical for determining Snail protein levels or stability, subcellular localization, and the ability to induce EMT. To date, several kinases are known that enhance the stability of Snail by preventing its ubiquitination; however, the molecular mechanism(s) underlying this are still unclear. Here, we identified p38 MAPK as a crucial posttranslational regulator that enhances the stability of Snail. p38 directly phosphorylated Snail at Ser107, and this effectively suppressed DYRK2-mediated Ser104 phosphorylation, which is critical for GSK3β-dependent Snail phosphorylation and βTrCP-mediated Snail ubiquitination and degradation. Importantly, functional studies and analysis of clinical samples established a crucial role for the p38-Snail axis in regulating ovarian cancer EMT and metastasis. These results indicate the potential therapeutic value of targeting the p38-Snail axis in ovarian cancer. SIGNIFICANCE: These findings identify p38 MAPK as a novel regulator of Snail protein stability and potential therapeutic target in ovarian cancer.
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Affiliation(s)
- Ki-Jun Ryu
- Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea
| | - Sun-Mi Park
- Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea
| | - Seung-Ho Park
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - In-Kyu Kim
- Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea
| | - Hyeontak Han
- Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea
| | - Hyo-Jin Kim
- Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea
| | - Seon-Hee Kim
- Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea
| | - Keun-Seok Hong
- Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea
| | - Hyemin Kim
- Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea
| | - Minju Kim
- Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea
| | - Sung-Jin Yoon
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Killivalavan Asaithambi
- Department of Convergence Medical Science (BK21 Plus), Graduate School Gyeongsang National University, Jinju, Korea
- Department of Microbiology, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Kon Ho Lee
- Department of Convergence Medical Science (BK21 Plus), Graduate School Gyeongsang National University, Jinju, Korea
- Department of Microbiology, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Jae-Yong Park
- School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul, Korea
| | - Young-Sool Hah
- Biomedical Research Institute, Gyeongsang National University Hospital, Jinju, Korea
- Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Hee Jun Cho
- Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Jong In Yook
- Department of Oral Pathology, Oral Cancer Research Institute, College of Dentistry, Yonsei University, Seoul, Korea
| | - Jung Wook Yang
- Department of Pathology, Gyeongsang National University Hospital, Jinju, Korea
| | - Gyung-Hyuck Ko
- Department of Pathology, Gyeongsang National University Hospital, Jinju, Korea
- Department of Pathology, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Gyemin Lee
- Department of Information and Statistics, College of Natural Sciences, Gyeongsang National University, Jinju, Korea
| | - Yang Jae Kang
- Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Korea
| | - Cheol Hwangbo
- Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Korea
| | - Kwang Dong Kim
- Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Korea
| | - Young-Jun Park
- Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea.
| | - Jiyun Yoo
- Division of Applied Life Science (BK21 Plus), Research Institute of Life Sciences, Gyeongsang National University, Jinju, Korea.
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, Korea
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Duan CY, Han J, Zhang CY, Wu K, Lin Y. UA promotes epithelial‑mesenchymal transition in peritoneal mesothelial cells. Mol Med Rep 2019; 20:2396-2402. [PMID: 31322227 DOI: 10.3892/mmr.2019.10476] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 12/06/2018] [Indexed: 11/06/2022] Open
Abstract
Long‑term peritoneal dialysis is often limited or interrupted due to the development and progression of peritoneal fibrosis. Accumulating evidence suggests that epithelial‑mesenchymal transition (EMT) is a major component of peritoneal injury associated with peritoneal fibrosis in the end stage of renal disease; however, at present, the underlying mechanisms remain unclear. Thus, in the present study, uric acid (UA)‑induced EMT of peritoneal mesothelial cells was investigated by western‑blot and immunofluorescence staining. The results revealed that peritoneal mesothelial cells stimulated with UA underwent EMT, as demonstrated by the decreased expression of epithelial markers (E‑cadherin) and an increased expression of mesenchymal markers (α‑smooth muscle actin and vimentin). Additionally, it was reported that UA could facilitate the progression of EMT of peritoneal mesothelial cells via EMT transcription pathways, including transforming growth factor‑β1/mothers against decapentaplegic homolog 3 and P38/mitogen‑activated protein kinase by western‑blot and reverse transcription semi‑quantitative polymerase chain reaction. The results of the present study suggest that UA could promote EMT and may contribute to peritoneal chronic disease. Furthermore, the data obtained suggest that the levels of blood UA may account for the development of EMT; thus, lowering the levels of blood UA may be beneficial to inhibit the occurrence and development of peritoneal fibrosis.
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Affiliation(s)
- Chao-Yang Duan
- Department of Nephrology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Jin Han
- Department of Nephrology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Chong-Yu Zhang
- National and Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Kunyi Wu
- Core Research Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Yan Lin
- Department of Endocrine and Metabolic Diseases, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
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Fan Y, Li M, Ma K, Hu Y, Jing J, Shi Y, Li E, Dong D. Dual-target MDM2/MDMX inhibitor increases the sensitization of doxorubicin and inhibits migration and invasion abilities of triple-negative breast cancer cells through activation of TAB1/TAK1/p38 MAPK pathway. Cancer Biol Ther 2018; 20:617-632. [PMID: 30462562 DOI: 10.1080/15384047.2018.1539290] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Triple-negative breast cancer (TNBC) has a poor prognosis mainly due to insensitivity or resistance to standard anthracycline- and taxane-based chemotherapy, urgently calling for new adjuvants to reverse drug resistance. Dual-target murine double minute 2 (MDM2) and murine double minute X (MDMX) inhibitor has been proved to play a critical part against cancer, particularly focusing on the tremendous potential to enhance the efficacy of doxorubicin (DOX), however little was reported in TNBC. In the present study, we investigated the synergistic antitumor effect of the MDM2/MDMX inhibitor with DOX using three TNBC cell lines, two in situ transplantation tumor models and 214 clinical samples. We observed that the MDM2/MDMX inhibitor combined with DOX could not only inhibit cell vitality and migration and invasion abilities, but also highly inhibit tumor growth in TNBC nude mice. Besides, co-treatment of MDM2/MDMX inhibitor and DOX suppressed epithelial to mesenchymal transition (EMT) through increasing the TAK1-binding protein 1 (TAB1), transforming growth factor β-activated kinase 1 (TAK1) and p38 mitogen-activated protein kinase (MAPK) expression. Small interfering RNA-mediated TAB1 knockdown induced the EMT, desensitized cells to DOX and enhanced the migration and invasion abilities. High MDM2/MDMX expression was positively associated with weak TAB1 expression in 214 TNBC tumor tissues confirmed by immumohistochemical staining and MDM2/MDMX/TAB1 expression was significantly related to TNBC patient survival. These findings indicate that dual-target MDM2/MDMX inhibitor could increase the sensitization of doxorubicin and inhibit migration and invasion abilities in TNBC cells through p38 MAPK pathway activation caused EMT suppression and hence could be useful in TNBC treatments in future.
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Affiliation(s)
- Yangwei Fan
- a Department of Medical Oncology , the First Affiliated Hospital of medical school of Xi'an Jiaotong University , Xi'an , China
| | - Mengya Li
- b Department of Medical Oncology , the First Affiliated Hospital of Henan University , Kaifeng , China
| | - Ke Ma
- c Department of Medical Oncology , the First Affiliated Hospital of Zhengzhou University , Zhengzhou , China
| | - Yuan Hu
- a Department of Medical Oncology , the First Affiliated Hospital of medical school of Xi'an Jiaotong University , Xi'an , China
| | - Jiayu Jing
- a Department of Medical Oncology , the First Affiliated Hospital of medical school of Xi'an Jiaotong University , Xi'an , China
| | - Yu Shi
- a Department of Medical Oncology , the First Affiliated Hospital of medical school of Xi'an Jiaotong University , Xi'an , China
| | - Enxiao Li
- a Department of Medical Oncology , the First Affiliated Hospital of medical school of Xi'an Jiaotong University , Xi'an , China
| | - Danfeng Dong
- a Department of Medical Oncology , the First Affiliated Hospital of medical school of Xi'an Jiaotong University , Xi'an , China
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Li JM, Tseng CW, Lin CC, Law CH, Chien YA, Kuo WH, Chou HC, Wang WC, Chan HL. Upregulation of LGALS1 is associated with oral cancer metastasis. Ther Adv Med Oncol 2018; 10:1758835918794622. [PMID: 30159048 PMCID: PMC6109855 DOI: 10.1177/1758835918794622] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 07/04/2018] [Indexed: 12/12/2022] Open
Abstract
Background Oral cancer metastasis is a devastating process that contributes to poor prognosis and high mortality, yet its detailed underlying mechanisms remain unclear. Here, we aimed to evaluate metastasis-specific markers in oral cancer and to provide comprehensive recognition concerning functional roles of the specific target in oral cancer metastasis. Methods Lectin, galactoside-binding, soluble, 1 (LGALS1) was identified by secretomic analysis. LGALS1 expression of patient samples with oral cancer on the tissue microarray were examined by immunochemical (IHC) staining. Small interfering RNA (siRNA)-mediated knockdown of LGALS1 revealed the role of LGALS1 in oral cancer metastasis in vitro and in vivo. Results LGALS1 was observed to be upregulated in highly invasive oral cancer cells, and elevated LGALS1 expression was correlated with cancer progression and lymph node metastasis in oral cancer tissue specimens. Functionally, silencing LGALS1 resulted in suppressed cell growth, wound healing, cell migration, and cell invasion in oral cancer cells in vitro. Knockdown of LGALS1 in highly invasive oral cancer cells dramatically inhibited lung metastasis in an in vivo mouse model. Mechanistic studies suggested p38 mitogen-activated protein kinase (MAPK) phosphorylation, upregulated MMP-9, and mesenchymal phenotypes of epithelial-mesenchymal transition (EMT) in highly invasive oral cancer cells, whereas siRNA against LGALS1 resulted in the inactivation of p38 MAPK pathway, downregulated MMP-9, and EMT inhibition. Conclusions These findings demonstrate that elevated LGALS1 is strongly correlated with oral cancer progression and metastasis, and that it could potentially serve as a prognostic biomarker and an innovative target for oral cancer therapy.
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Affiliation(s)
- Ji-Min Li
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Chien-Wei Tseng
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan
| | - Chi-Chen Lin
- Department of Life Sciences, Institute of Biomedical Science, National Chung Hsing University, Taichung, Taiwan
| | - Ching-Hsuan Law
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Yu-An Chien
- Department of Applied Sciences, National Tsing Hua University, Hsinchu, Taiwan
| | - Wen-Hung Kuo
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsiu-Chuan Chou
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan
| | - Wen-Ching Wang
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Hong-Lin Chan
- Institute of Bioinformatics and Structural Biology and Department of Medical Sciences, National Tsing Hua University, No. 101, Kuang-Fu Rd. Sec. 2, Hsinchu, 30013, Taiwan
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Zhang C, Liu T, Wang G, Wang H, Che X, Gao X, Liu H. Rac3 Regulates Cell Invasion, Migration and EMT in Lung Adenocarcinoma through p38 MAPK Pathway. J Cancer 2017; 8:2511-2522. [PMID: 28900489 PMCID: PMC5595081 DOI: 10.7150/jca.18161] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 05/18/2017] [Indexed: 12/25/2022] Open
Abstract
Background: The role of Rac3 in cell proliferation in lung adenocarcinoma has been tackled in our previous study. However, the role of Rac3 in cell invasion and migration of lung adenocarcinoma is still not clear. Methods: The expression of Rac3 in lung adenocarcinoma specimens and paired noncancerous normal tissues were evaluated by immunohistochemistry. Lentivirus-mediated RNA interference (RNAi) was employed to silence Rac3 in lung adenocarcinoma cell lines A549 and H1299. A p38 MAPK inhibitor (LY2228820) was employed to inhibit activity of p38 MAPK pathway. Cell invasion and migration in vitro were examined by invasion and migration assays, respectively. PathScan® intracellular signaling array kit and western blot were employed in mechanism investigation. Results: Rac3 expression was frequently higher in lung adenocarcinoma than paired noncancerous normal tissues. Rac3 expression was an independent risk factor for lymphonode metastasis, and was associated with worse survival outcome. Silencing of Rac3 inhibited cell invasion and cell migration in lung adenocarcinoma cell lines. Knockdown of Rac3 decreased activity of p38 MAPK pathway. LY2228820, which was an important p38 MAPK inhibitor, inhibited Rac3-induced cell invasion and migration of lung adenocarcinoma. E-cadherin expression was increased and vimentin expression was decreased after silencing of Rac3 or following the treatment of LY2228820. Conclusions: Our findings suggest that Rac3 regulates cell invasion, migration and EMT via p38 MAPK pathway. Rac3 may be a potential biomarker of invasion and metastasis for lung adenocarcinoma, and knockdown of Rac3 may potentially serve as a promising therapeutic target for lung adenocarcinoma.
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Affiliation(s)
- Chenlei Zhang
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning, P.R. China
| | - Tieqin Liu
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning, P.R. China
| | - Gebang Wang
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning, P.R. China
| | - Huan Wang
- Department of Thoracic Surgery, The First Hospital of China Medical University, NO.155 North Nanjing Street, Heping District, Shenyang 110001, Liaoning, P.R. China
| | - Xiaofang Che
- Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, NO.155 North Nanjing Street, Heping District, Shenyang 110001, Liaoning, P.R. China
| | - Xinghua Gao
- Department of Dermatology, The First Hospital of China Medical University and Key Laboratory of Immunodermatology, Ministry of Education and Ministry of Health, NO.155 North Nanjing Street, Heping District, Shenyang 110001, Liaoning, P.R. China
| | - Hongxu Liu
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, Liaoning, P.R. China
- Department of Thoracic Surgery, The First Hospital of China Medical University, NO.155 North Nanjing Street, Heping District, Shenyang 110001, Liaoning, P.R. China
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11
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p38 MAPK mediates epithelial-mesenchymal transition by regulating p38IP and Snail in head and neck squamous cell carcinoma. Oral Oncol 2016; 60:81-9. [PMID: 27531877 DOI: 10.1016/j.oraloncology.2016.06.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 06/10/2016] [Accepted: 06/13/2016] [Indexed: 12/25/2022]
Abstract
BACKGROUND In the present study, we investigated the role of p38-p38IP signaling in the inflammation-induced promotion of epithelial-to-mesenchymal transition (EMT) in Head and Neck Squamous Cell Carcinoma (HNSCC). METHODS Quantitative RT-PCR, western blot analysis, spheroid modeling and immunohistochemical staining of human HNSCC tissue sections were used. RESULTS p38 inhibitor treated and p38 shRNA HNSCC cell lines demonstrate a significant upregulation in E-cadherin mRNA and a decrease in the mRNA expression of Snail. p38 binds to and stabilizes p38IP, a subunit of histone SPT3-TAF9-GCN5 acetyltransferase (STAGA), resulting in enhanced transcription of Snail. p38 shRNA HNSCC cell lines show a less invasive phenotype in a spheroid model. In clinical HNSCC samples, p38 interacting protein (p38IP) is significantly increased compared to adjacent normal tissue. An inverse relationship between p38, p38IP and E-cadherin is demonstrated. CONCLUSIONS Herein we provide the first report that p38-p38IP is required for the Snail-induced E-cadherin down-regulation and cell invasion in HNSCC.
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12
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Effect of benzophenone-1 and octylphenol on the regulation of epithelial-mesenchymal transition via an estrogen receptor-dependent pathway in estrogen receptor expressing ovarian cancer cells. Food Chem Toxicol 2016; 93:58-65. [DOI: 10.1016/j.fct.2016.04.026] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 04/25/2016] [Accepted: 04/29/2016] [Indexed: 11/24/2022]
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13
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Sharma T, Radosevich JA, Pachori G, Mandal CC. A Molecular View of Pathological Microcalcification in Breast Cancer. J Mammary Gland Biol Neoplasia 2016; 21:25-40. [PMID: 26769216 DOI: 10.1007/s10911-015-9349-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 12/30/2015] [Indexed: 12/11/2022] Open
Abstract
Breast microcalcification is a potential diagnostic indicator for non-palpable breast cancers. Microcalcification type I (calcium oxalate) is restricted to benign tissue, whereas type II (calcium hydroxyapatite) occurs both in benign as well as in malignant lesions. Microcalcification is a pathological complication of the mammary gland. Over the past few decades, much attention has been paid to exploit this property, which forms the basis for advances in diagnostic procedures and imaging techniques. The mechanism of its formation is still poorly understood. Hence, in this paper, we have attempted to address the molecular mechanism of microcalcification in breast cancer. The central theme of this communication is "how a subpopulation of heterogeneous breast tumor cells attains an osteoblast-like phenotype, and what activities drive the process of pathophysiological microcalcification, especially at the invasive or infiltrating front of breast tumors". The role of bone morphogenetic proteins (BMPs) and tumor associated macrophages (TAMs) along with epithelial to mesenchymal transition (EMT) in manipulating this pathological process has been highlighted. Therefore, this review offers a novel insight into the mechanism underlying the development of microcalcification in breast carcinomas.
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Affiliation(s)
- Tanu Sharma
- Department of Biochemistry, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh, Ajmer, Rajasthan, 305817, India
| | - James A Radosevich
- Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Geeta Pachori
- Department of Pathology, J.L.N Medical College, Ajmer, Rajasthan, 305001, India
| | - Chandi C Mandal
- Department of Biochemistry, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh, Ajmer, Rajasthan, 305817, India.
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14
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Yin J, Wang L, Zhu JM, Yu Q, Xue RY, Fang Y, Zhang YA, Chen YJ, Liu TT, Dong L, Shen XZ. Prp19 facilitates invasion of hepatocellular carcinoma via p38 mitogen-activated protein kinase/twist1 pathway. Oncotarget 2016; 7:21939-21951. [PMID: 26959880 PMCID: PMC5008335 DOI: 10.18632/oncotarget.7877] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 02/20/2016] [Indexed: 12/18/2022] Open
Abstract
Pre-mRNA processing factor 19 (Prp19) is involved in many cellular events including pre-mRNA processing and DNA damage response. However, the pathological role of Prp19 in hepatocellular carcinoma (HCC) is still elusive. Here, we reported that Prp19 was increased in most HCC tissues and HCC cell lines, and its overexpression in HCC tissues was positively correlated with vascular invasion, tumor capsule breakthrough and poor prognosis. Prp19 potentiated migratory and invasive abilities of HCC cells in vitro and in vivo. Furthermore Prp19 facilitated Twist1-induced epithelial-mesenchymal transition. Mechanistic insights revealed that Prp19 directly binded with TGF-β-activated kinase1 (TAK1) and promoted the activation of p38 mitogen-activated protein kinase (MAPK), preventing Twist1 from degradation. Finally Prp19/p38 MAPK/Twist1 axis was attested in nude mice xenografts and HCC patient specimens. This work implies that the gain of Prp19 is a critical event during the progression of HCC, making it a promising target for malignancies with aberrant Prp19 expression.
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Affiliation(s)
- Jie Yin
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Lan Wang
- Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Ji-Min Zhu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Qian Yu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Ru-Yi Xue
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Ying Fang
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Yi-An Zhang
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Yan-Jie Chen
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Tao-Tao Liu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Ling Dong
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Xi-Zhong Shen
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
- Key Laboratory of Medical Molecular Virology, Shanghai Medical College of Fudan University, Shanghai, China
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15
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Yang M, Huang CZ. Mitogen-activated protein kinase signaling pathway and invasion and metastasis of gastric cancer. World J Gastroenterol 2015; 21:11673-11679. [PMID: 26556994 PMCID: PMC4631968 DOI: 10.3748/wjg.v21.i41.11673] [Citation(s) in RCA: 117] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 07/11/2015] [Accepted: 09/15/2015] [Indexed: 02/06/2023] Open
Abstract
The mortality rate of gastric cancer worldwide is as high as 70%, despite the development of novel therapeutic strategies. One reason for the high mortality is the rapid and uninhibited spread of the disease, such that the majority of patients are diagnosed at a stage when efficient therapeutic treatment is not available. Therefore, in-depth research is needed to investigate the mechanism of gastric cancer metastasis and invasion to improve outcomes and provide biomarkers for early diagnosis. The mitogen-activated protein kinase (MAPK) signaling pathway is widely expressed in multicellular organisms, with critical roles in multiple biological processes, such as cell proliferation, death, differentiation, migration, and invasion. The MAPK pathway typically responds to extracellular stimulation. However, the MAPK pathway is often involved in the occurrence and progression of cancer when abnormally regulated. Many studies have researched the relationship between the MAPK signaling pathway and cancer metastasis and invasion, but little is known about the important roles that the MAPK signaling pathway plays in gastric cancer. Based on an analysis of published data, this review aims to summarize the important role that the MAP kinases play in the invasion and metastasis of gastric cancer and attempts to provide potential directions for further research and clinical treatment.
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16
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Kwon Y, Song J, Lee H, Kim EY, Lee K, Lee SK, Kim S. Design, Synthesis, and Biological Activity of Sulfonamide Analogues of Antofine and Cryptopleurine as Potent and Orally Active Antitumor Agents. J Med Chem 2015; 58:7749-62. [PMID: 26393416 DOI: 10.1021/acs.jmedchem.5b00764] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Due to their profound antiproliferative activity and unique mode of action, phenanthroindolizidine and phenanthroquinolizidine alkaloids, represented by antofine and cryptopleurine, have attracted attention recently as potential therapeutic agents. We have designed, synthesized, and evaluated the methanesulfonamide analogues of these natural alkaloids with the hope of improving their druglikeness. The analogues showed enhanced growth inhibition of human cancer cells compared with the parent natural products. In particular, a methanesulfonamide analogue of cryptopleurine (5b) exhibited improved bioavailability and significant antitumor activity, which suggests that 5b is a promising new anticancer agent. Our studies suggest that the inhibition of cancer cell growth by 5b is associated with the induction of G0/G1 cell cycle arrest via nicotinamide N-methyltransferase-dependent JNK activation in Caki-1 renal cancer cells. In addition, compound 5b significantly inhibited the migration and invasion of Caki-1 cancer cells by modulating the p38 MAPK signaling pathway.
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Affiliation(s)
- Yongseok Kwon
- Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University , Seoul 151-742, Korea
| | - Jayoung Song
- Natural Products Research Institute, College of Pharmacy, Seoul National University , Seoul 151-742, Korea
| | - Honggu Lee
- Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University , Seoul 151-742, Korea
| | - Eun-Yeong Kim
- College of Pharmacy, Korea University , Sejong 339-700, Korea
| | - Kiho Lee
- College of Pharmacy, Korea University , Sejong 339-700, Korea
| | - Sang Kook Lee
- Natural Products Research Institute, College of Pharmacy, Seoul National University , Seoul 151-742, Korea
| | - Sanghee Kim
- Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University , Seoul 151-742, Korea
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17
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Kim YS, Hwang KA, Hyun SH, Nam KH, Lee CK, Choi KC. Bisphenol A and Nonylphenol Have the Potential to Stimulate the Migration of Ovarian Cancer Cells by Inducing Epithelial–Mesenchymal Transition via an Estrogen Receptor Dependent Pathway. Chem Res Toxicol 2015; 28:662-71. [DOI: 10.1021/tx500443p] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
| | | | | | - Ki-Hoan Nam
- Laboratory Animal Resource
Center, Korea Research Institute of Bioscience and Biotechnology, 30
Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju, Chungbuk, Republic of Korea
| | - Chang-Kyu Lee
- Department of Agricultural Biotechnology, Animal Biotechnology Major,
and Research Institute for Agriculture and Life Science, Seoul National University, Seoul, Republic of Korea
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18
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Yi BR, Kim TH, Kim YS, Choi KC. Alteration of epithelial-mesenchymal transition markers in human normal ovaries and neoplastic ovarian cancers. Int J Oncol 2014; 46:272-80. [PMID: 25310727 DOI: 10.3892/ijo.2014.2695] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 09/19/2014] [Indexed: 11/05/2022] Open
Abstract
Most ovarian cancers originate in the ovarian surface epithelium (OSE). Ovarian cancers might undergo epithelial-mesenchymal transition (EMT) in response to various mediators or regulators such as EMT-inducing factors. In this study, ovarian tumor specimens from patients were analyzed to demonstrate alteration of EMT-related markers according to benign and malignant types of ovarian cancers. In the three ovarian cancer cell lines, OVCAR-3, SKOV-3, and BG-1, the expression of epithelial (E-cadherin) and mesenchymal (vimentin) cell markers was identified by RNA and protein analysis. OVCAR-3 and BG-1 cells strongly expressed E-cadherin as well as morphological features such as epithelial cells, but vimentin was not observed. In contrast to these cancer cells, SKOV-3 showed a phenotype typical of mesenchymal cells. Alteration of EMT markers and EMT-related transcriptional factors were confirmed in clinical ovarian tissue samples obtained from 74 patients. E-cadherin was expressed in 57.1% of benign tumors, while vimentin was expressed in 83.3% of normal ovaries by immunohistochemistry (IHC) analysis of E-cadherin and vimentin revealed the phenomenon in the tissue specimens. Evaluation of the EMT-associated transcriptional factors Snail, Slug, and Twist revealed that Snail was overexpressed by 7.1-fold in malignant ovarian cancer compared to normal ovaries or benign tumors. Although expression levels of other factors were higher in benign and malignant ovarian tumors, they were not closely correlated with the aforementioned ovarian cancer types. Overall, Snail may affect the EMT process in ovarian cancer development and upregulation of Snail expression followed by the downregulation of E-cadherin enhances the invasiveness of ovarian cancer.
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Affiliation(s)
- Bo-Rim Yi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Tae-Hee Kim
- Department of Obstetrics and Gynecology, College of Medicine, Soonchunhyang University, Bucheon, Republic of Korea
| | - Ye-Seul Kim
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea
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19
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Cha JH, Wee HJ, Seo JH, Ahn BJ, Park JH, Yang JM, Lee SW, Lee OH, Lee HJ, Gelman IH, Arai K, Lo EH, Kim KW. Prompt meningeal reconstruction mediated by oxygen-sensitive AKAP12 scaffolding protein after central nervous system injury. Nat Commun 2014; 5:4952. [PMID: 25229625 DOI: 10.1038/ncomms5952] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Accepted: 08/11/2014] [Indexed: 11/09/2022] Open
Abstract
The meninges forms a critical epithelial barrier, which protects the central nervous system (CNS), and therefore its prompt reconstruction after CNS injury is essential for reducing neuronal damage. Meningeal cells migrate into the lesion site after undergoing an epithelial-mesenchymal transition (EMT) and repair the impaired meninges. However, the molecular mechanisms of meningeal EMT remain largely undefined. Here we show that TGF-β1 and retinoic acid (RA) released from the meninges, together with oxygen tension, could constitute the mechanism for rapid meningeal reconstruction. AKAP12 is an effector of this mechanism, and its expression in meningeal cells is regulated by integrated upstream signals composed of TGF-β1, RA and oxygen tension. Functionally, AKAP12 modulates meningeal EMT by regulating the TGF-β1-non-Smad-SNAI1 signalling pathway. Collectively, TGF-β1, RA and oxygen tension can modulate the dynamic change in AKAP12 expression, causing prompt meningeal reconstruction after CNS injury by regulating the transition between the epithelial and mesenchymal states of meningeal cells.
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Affiliation(s)
- Jong-Ho Cha
- SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea
| | - Hee-Jun Wee
- SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea
| | - Ji Hae Seo
- SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea
| | - Bum Ju Ahn
- SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea
| | - Ji-Hyeon Park
- SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea
| | - Jun-Mo Yang
- SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea
| | - Sae-Won Lee
- Department of Internal Medicine, Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul 110-799, Korea
| | - Ok-Hee Lee
- Department of Biomedical Science, CHA University, Seoul 135-081, Korea
| | - Hyo-Jong Lee
- College of Pharmacy, Inje University, Gimhae 621-749, Korea
| | - Irwin H Gelman
- Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
| | - Ken Arai
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA
| | - Eng H Lo
- Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA
| | - Kyu-Won Kim
- 1] SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea [2] Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul 151-742, Korea
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20
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Fan XJ, Wan XB, Fu XH, Wu PH, Chen DK, Wang PN, Jiang L, Wang DH, Chen ZT, Huang Y, Wang JP, Wang L. Phosphorylated p38, a negative prognostic biomarker, complements TNM staging prognostication in colorectal cancer. Tumour Biol 2014; 35:10487-95. [PMID: 25056534 DOI: 10.1007/s13277-014-2320-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 03/22/2013] [Indexed: 12/17/2022] Open
Abstract
Phosphorylated p38 (p-p38) played a pivotal role in the regulation of disease progression and correlated with tumor prognosis. Here, we characterized the prognostic effect of p-p38 in colorectal cancer (CRC). Three hundred and sixteen CRC patients in stages I-III were recruited in this study. P-p38 expression was semi-quantitatively evaluated using tissue microarrays and immunohistochemistry staining. Overall survival (OS), disease-free survival (DFS), local failure-free survival (LFFS), and distant metastasis-free survival (DMFS) of patient subgroups, segregated by p-p38 expression level and clinical stage, were compared using Kaplan-Meier analysis. We found that p-p38 was overexpressed in 48.1 % (152/316) CRC tissues, whereas low or deficiently expressed in normal adjacent epithelia. Overexpression of p-p38 predicted poor OS (P < 0.001), DFS (P = 0.002), LFFS (P = 0.016), and DMFS (P = 0.025) in CRC. Importantly, patient subgroups in the early stage (stages I + II) and with low p-p38 had similar OS, PFS, LFFS, and DMFS probabilities to that of stage I, whereas those with high p-p38 were similar to stage III disease. In addition, for stage III disease, the subgroup with low p-p38 had a similar survival probability to that of stage I, whereas the subgroup with high p-p38 had the worst survival. Multivariate Cox analysis confirmed that p-p38 was indeed a significantly independent factor for death, recurrence, and distant metastases in CRC. Our results demonstrated that p-p38 was a negative independent prognostic factor for CRC. Complementing TNM staging with p-p38 might refine the risk definition more accurately for a subset of patients.
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Affiliation(s)
- Xin-Juan Fan
- Gastrointestinal Institute of Sun Yat-sen University, the Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancunerheng Road, Guangzhou, 510655, Guangdong, China
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21
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Deng B, Tan QY, Wang RW, Jiang YG, Zhou JH, Huang W. P130cas is required for TGF-β1-mediated epithelial-mesenchymal transition in lung cancer. Oncol Lett 2014; 8:454-460. [PMID: 24959295 PMCID: PMC4063590 DOI: 10.3892/ol.2014.2123] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Accepted: 04/16/2014] [Indexed: 12/21/2022] Open
Abstract
In lung cancer A549 cells, the present study evaluated the associations between p130cas expression and the activation of p38 or Smad2, which are components of two of the main signaling pathways of transforming growth factor-β1 (TGF-β1), i.e., epithelial-mesenchymal transition (EMT) and apoptosis, respectively. TGF-β1-induced EMT was investigated by inspecting cell shape and cell migration, and by testing E-Cadherin, N-Cadherin and Vimentin biomarkers in p130cas-RNA interference (RNAi)-A549 cells. The changes in TGF-β1-induced apoptosis, i.e., cleaved Caspase-3 levels, were additionally analyzed following p130cas-RNAi. p130cas-knockdown decreased the phosphorylated (p)-p38 expression level, and blockaded the TGF-β1-induced activation of p-p38 in the A549 cells. p130cas-knockdown arrested cell migration and impaired TGF-β1-induced EMT in the A549 cells, characterized by changes in cell morphology and biomarker levels. However, p130cas-knockdown had no impact on the activation of Smad2 and the cleavage of Caspase-3. These results indicate that p130cas is a novel molecular ‘rheostat’ that alters the function of the TGF-β1 signaling pathway from tumor suppression to tumor promotion in lung cancer cells. The underlying mechanism warrants further study.
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Affiliation(s)
- Bo Deng
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, P.R. China
| | - Qun-You Tan
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, P.R. China
| | - Ru-Wen Wang
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, P.R. China
| | - Yao-Guang Jiang
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, P.R. China
| | - Jing-Hai Zhou
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, P.R. China
| | - Wei Huang
- Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, P.R. China
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22
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Longuespée R, Boyon C, Desmons A, Vinatier D, Leblanc E, Farré I, Wisztorski M, Ly K, D'Anjou F, Day R, Fournier I, Salzet M. Ovarian cancer molecular pathology. Cancer Metastasis Rev 2013; 31:713-32. [PMID: 22729278 DOI: 10.1007/s10555-012-9383-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Ovarian cancer (OVC) is the fourth leading cause of cancer mortality among women in Europe and the United States. Its early detection is difficult due to the lack of specificity of clinical symptoms. Unfortunately, late diagnosis is a major contributor to the poor survival rates for OVC, which can be attributed to the lack of specific sets of markers. Aside from patients sharing a strong family history of ovarian and breast cancer, including the BRCA1 and BRCA2 tumor suppressor genes mutations, the most used biomarker is the Cancer-antigen 125 (CA-125). CA-125 has a sensitivity of 80 % and a specificity of 97 % in epithelial cancer (stage III or IV). However, its sensitivity is 30 % in stage I cancer, as its increase is linked to several physiological phenomena and benign situations. CA-125 is particularly useful for at-risk population diagnosis and to assess response to treatment. It is clear that alone, CA-125 is inadequate as a biomarker for OVC diagnosis. There is an unmet need to identify additional biomarkers. Novel and more sensitive proteomic strategies such as MALDI mass spectrometry imaging studies are well suited to identify better markers for both diagnosis and prognosis. In the present review, we will focus on such proteomic strategies in regards to OVC signaling pathways, OVC development and escape from the immune response.
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Affiliation(s)
- Rémi Longuespée
- Laboratoire de Spectrométrie de Masse Biologique Fondamentale et Appliquée, Université Nord de France, EA 4550, Université de Lille 1, Cité Scientifique, 59650 Villeneuve D'Ascq, France
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Moore HM, Gonzalez ME, Toy KA, Cimino-Mathews A, Argani P, Kleer CG. EZH2 inhibition decreases p38 signaling and suppresses breast cancer motility and metastasis. Breast Cancer Res Treat 2013; 138:741-52. [PMID: 23539298 DOI: 10.1007/s10549-013-2498-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Accepted: 03/21/2013] [Indexed: 01/02/2023]
Abstract
EZH2 is a Polycomb group protein that exerts oncogenic functions in breast cancer, where its overexpression is associated with metastatic disease. While it reportedly acts a transcriptional repressor through trimethylation of histone H3 at lysine 27, EZH2 may exhibit context-dependent activating functions. Despite associations with worse outcome and metastasis in breast cancer, a functional role of EZH2 in breast cancer metastasis in vivo has not been demonstrated. Furthermore, whether EZH2 regulates cancer cell phenotype and motility are unknown. In this study, we discovered that knockdown of EZH2 induces a phenotypic reprogramming from mesenchymal to epithelial, reduces motility, and blocks invasion in breast cancer cell lines. In vivo, EZH2 downregulation in MDA-MB-231 cells decreases spontaneous metastasis to the lungs. We uncover an unexpected role of EZH2 in inducing the p38 mitogen-activated protein kinase signaling pathway, an important regulator of breast cancer invasion and metastasis. In breast cancer cells, EZH2 binds to phosphorylated p38 (p-p38) in association with other core members of the Polycomb repressive complex 2, EED, and SUZ12, and EZH2 overexpression leads to increased levels of p-p38 and of activated, downstream pathway proteins. The effect on p-p38 was confirmed in vivo, where it correlated with decreased spontaneous metastasis. In clinical specimens of matched primary and invasive breast carcinomas, we found that EZH2 expression was upregulated in 100 % of the metastases, and that EZH2 and p-p38 were coexpressed in 63 % of cases, consistent with the functional results. Together our findings reveal a new mechanism by which EZH2 functions in breast cancer, and provide direct evidence that EZH2 inhibition reduces breast cancer metastasis in vivo.
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Affiliation(s)
- Heather M Moore
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
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Kroepil F, Fluegen G, Vallböhmer D, Baldus SE, Dizdar L, Raffel AM, Hafner D, Stoecklein NH, Knoefel WT. Snail1 expression in colorectal cancer and its correlation with clinical and pathological parameters. BMC Cancer 2013; 13:145. [PMID: 23522088 PMCID: PMC3617032 DOI: 10.1186/1471-2407-13-145] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 03/14/2013] [Indexed: 11/14/2022] Open
Abstract
Background Snail1 is a transcription regulator of E-cadherin. The loss of E-cadherin seems to be a crucial step in the process of Epithelial-mesenchymal transition (EMT). EMT initiates invasion and proliferation in many tumours. Overexpression of Snail1 is known to be associated with poor outcome in several solid tumours. The aim of this study was to analyse its expression profile and prognostic significance in colorectal cancer. Methods Tissue microarrays (TMA) containing paraffin-embedded primary colorectal cancer (CRC) tissue samples from 251 patients were used in this study. The expression of Snail1 and E-cadherin was assessed by immunohistochemistry in different tumour compartments, corresponding lymph node metastases and normal colonic mucosa. Intensity of staining was classified according to the Remmele score (standardized scoring system) as well as the semiquantitative score established by Blechschmidt et al. Results Snail1 expression was observed in 76% of the CRC. Loss of E-cadherin was noted in 87% of the CRC. Snail1 positive tumours were significantly correlated with Snail1 positive lymph node metastases (p=0.03). There was no significant correlation between loss of E-cadherin and Snail1 expression, or between N-stage or grading and Snail1 expression. Kaplan-Meier survival analysis identified no prognostic impact of Snail1 expression on overall survival. Conclusion Snail1 expression was detectable in most of the CRC but showed no significant association with E-cadherin loss, clinical pathological characteristics or overall survival. The observed loss of E-cadherin could be explained by effects of other important EMT pathways, such as the Wnt-signalling cascade.
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Affiliation(s)
- Feride Kroepil
- Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Düsseldorf, 40225, Germany.
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Abstract
Reverse phase protein array (RPPA) is a very suitable technique to analyze large numbers of proteins in small samples like for example tumor biopsies. Beside their small size another major hindrance for the analysis of proteins from biopsies is the extraction of proteins from formalin-fixed and paraffin-embedded (FFPE) tissues. Here we describe a protocol, allowing quantitative extraction of large numbers of proteins from FFPE tissues and their subsequent analysis by RPPA. To elucidate the role of epidermal growth factor receptor (EGFR) signalling in ovarian cancer, we analyzed 23 primary tumors and corresponding metastases for the expression of 25 proteins involved in EGFR signalling with special emphasis on epithelial-mesenchymal transition (EMT). We found a significant correlation of Snail with EGFR((Tyr1086)) and p38 MAPK((Thr180/Tyr182)) in primary ovarian carcinoma and with EGFR((Tyr1086)) in their corresponding metastases. Additionally, we showed that high expression levels of the E-cadherin repressor Snail in primary tumors combined with high expression levels of the pp38 MAPK((Thr180/Tyr182)) in metastasis lead to an increased risk for death in ovarian carcinoma patients.
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Gündisch S, Hauck S, Sarioglu H, Schott C, Viertler C, Kap M, Schuster T, Reischauer B, Rosenberg R, Verhoef C, Mischinger HJ, Riegman P, Zatloukal K, Becker KF. Variability of protein and phosphoprotein levels in clinical tissue specimens during the preanalytical phase. J Proteome Res 2012; 11:5748-62. [PMID: 23134551 DOI: 10.1021/pr300560y] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The quality of human tissue specimens can have a significant impact on analytical data sets for biomarker research. The aim of this study was to characterize fluctuations of protein and phosphoprotein levels in human tissue samples during the preanalytical phase. Eleven intestine and 17 liver specimens were surgically resected, aliquoted, and either snap-frozen or fixed in formalin immediately or exposed to different ischemic conditions before preservation. Protein levels in the resultant samples were investigated by reverse phase protein array, Western blot analysis, and liquid chromatography-tandem mass spectrometry. Our data revealed that the degree of sensitivity of proteins and phosphoproteins to delayed preservation varied between different patients and tissue types. For example, up-regulation of phospho-p42/44 MAPK in intestine samples was seen in some patients but not in others. General trends toward up- or down-regulation of most proteins were not evident due to pronounced interpatient variability but signal intensities of only a few proteins, such as cytokeratin 18, were altered from baseline in postresection samples. In contrast, glyceraldehyde 3-phosphate dehydrogenase was found to be stable during periods of cold ischemia. Our study represents a proper approach for studying potential protein fluctuations in tissue specimens for future biomarker development programs.
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Affiliation(s)
- Sibylle Gündisch
- Institute of Pathology, Technische Universität München, Trogerstrasse 18, D-81675 Munich, Germany
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Davidson B, Tropé CG, Reich R. Epithelial-mesenchymal transition in ovarian carcinoma. Front Oncol 2012; 2:33. [PMID: 22655269 PMCID: PMC3356037 DOI: 10.3389/fonc.2012.00033] [Citation(s) in RCA: 127] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2012] [Accepted: 03/21/2012] [Indexed: 12/22/2022] Open
Abstract
Ovarian cancer is the most lethal gynecologic malignancy, with the majority of patients dying within 5 years of diagnosis. This poor survival of patients diagnosed with this malignancy is attributed to diagnosis at advanced stage, when the tumor has metastasized, and to chemotherapy resistance, either primary or developing along tumor progression. However, ovarian carcinomas, constituting the vast majority of ovarian cancers, additionally have unique biology, one aspect of which is the ability to co-express epithelial and mesenchymal determinants. epithelial–mesenchymal transition (EMT), a physiological process by which mesenchymal cells are formed and migrate to target organs during embryogenesis, is involved in cancer cell invasion and metastasis. However, these changes do not fully occur in ovarian carcinoma, and are even reversed in tumor cells present in malignant peritoneal and pleural effusions. This review summarizes current knowledge in this area, including the characteristics of EMT related to adhesion, transcriptional regulation and chemoresistance, and their clinical relevance, as well as the recently observed regulation of EMT by microRNA.
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Affiliation(s)
- Ben Davidson
- Division of Pathology, Norwegian Radium Hospital, Oslo University Hospital Oslo, Norway
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Abstract
Cells from primary tumours need to go through several steps to become fully metastatic. During this process, cancer cells acquire the ability to invade, migrate across the surrounding tissue, enter into the circulation and colonize distant organs. In the present paper, we review recent progress in understanding how the p38 MAPK (mitogen-activated protein kinase) signalling pathway participates in the different steps of metastasis. Experimental evidence suggests that tumour cells need to modulate p38 MAPK activity levels to successfully metastasize.
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