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Wang YW, Tuan YL, Wang JY, Chang HY, Chu CA, Chen YL, Chen HW, Ho CL, Lee CT, Chow NH. Potential of epithelial membrane protein 3 as a novel therapeutic target for human breast cancer. Oncol Rep 2025; 53:16. [PMID: 39611484 PMCID: PMC11632653 DOI: 10.3892/or.2024.8849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 10/18/2024] [Indexed: 11/30/2024] Open
Abstract
Amplification of human epidermal growth factor 2 receptor (HER2) and overexpression of estrogen receptor (ER) and/or progesterone receptor (PR) are key determinants in the treatment planning for human breast cancer (BC). Currently, targeted therapies for BC are focused mainly on these biomarkers. However, development of resistance to targeted drugs is almost unavoidable, emphasizing the importance of biochemical and pharmaceutical advances to improve treatment outcomes. To the best of our knowledge, the present study is the first to show functional crosstalk in vitro between HER2 and epithelial membrane protein 3 (EMP3), a tetraspan membrane protein, in human BC. EMP3 overexpression significantly promoted BC cell proliferation, invasion and migration by Transwell assays via epithelial-mesenchymal transition and transactivated the HER family, resulting in increased ER and PR expression in vitro. Knocking down EMP3 notably suppressed cell proliferation and migration and was accompanied by decreased expression of HER1‑HER3 and p‑SRC proteins. Suppression of EMP3 expression enhanced sensitivity of BC cells to trastuzumab in vitro. Xenograft experiments revealed decreased expression of HER1 and HER2 in stable EMP3‑knockdown cells, resulting in decreased tumor weight and size. In patients with BC, EMP3 overexpression was detected in 72 of 166 cases (43.4%), with 18 of 43 (41.9%) HER2‑amplified BC samples co‑expressing EMP3. Co‑expression of EMP3 and HER2 was positively associated with ER expression (P=0.028) and tended to be associated with nodal metastasis (P=0.085), however this was not significant. Taken together, the present results supported the potential of targeting EMP3 as a novel therapeutic strategy for human BC via co‑expression of HER2 and EMP3.
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Affiliation(s)
- Yi-Wen Wang
- Department of Food Safety Hygiene and Risk Management, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan, R.O.C
| | - Yih-Lin Tuan
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan, R.O.C
| | - Jiu-Yao Wang
- Center for Allergy, Immunology, and Microbiome, China Medical University Hospital, China Medical University, Taichung 404327, Taiwan, R.O.C
- Department of Allergy, Immunology, and Rheumatology, China Medical University Children's Hospital, China Medical University, Taichung 404327, Taiwan, R.O.C
| | - Hong-Yi Chang
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807378, Taiwan, R.O.C
| | - Chien-An Chu
- Department of Food Safety Hygiene and Risk Management, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan, R.O.C
| | - Yi-Lin Chen
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan, R.O.C
- Department of Pathology, National Cheng Kung University Hospital, Tainan 701401, Taiwan, R.O.C
| | - Hui-Wen Chen
- Department of Pathology, National Cheng Kung University Hospital, Tainan 701401, Taiwan, R.O.C
| | - Chung-Liang Ho
- Department of Food Safety Hygiene and Risk Management, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan, R.O.C
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan, R.O.C
- Department of Pathology, National Cheng Kung University Hospital, Tainan 701401, Taiwan, R.O.C
| | - Chung-Ta Lee
- Department of Food Safety Hygiene and Risk Management, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan, R.O.C
- Department of Pathology, National Cheng Kung University Hospital, Tainan 701401, Taiwan, R.O.C
| | - Nan-Haw Chow
- Department of Food Safety Hygiene and Risk Management, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan, R.O.C
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan, R.O.C
- Center for Precision Medicine, China Medical University Hospital, China Medical University, Taichung 404327, Taiwan, R.O.C
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Goyal A, Murkute SL, Bhowmik S, Prasad CP, Mohapatra P. Belling the "cat": Wnt/β-catenin signaling and its significance in future cancer therapies. Biochim Biophys Acta Rev Cancer 2024; 1879:189195. [PMID: 39413855 DOI: 10.1016/j.bbcan.2024.189195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 09/15/2024] [Accepted: 10/07/2024] [Indexed: 10/18/2024]
Abstract
The WNT/β-catenin is among one of the most extensively studied cellular signaling pathways involved in the initiation and progression of several deadly cancers. It is now understood that the WNT/β-catenin signaling, during tumor progression operates in a very complex fashion beyond the earlier assumed simple WNT 'On' or 'Off' mode as it recruits numerous WNT ligands, receptors, transcriptional factors and also cross-talks with other signaling molecules including the noncanonical WNT regulators. WNT/β-catenin signaling molecules are often mutated in different cancers which makes them very challenging to inhibit and sometimes ranks them among the undruggable targets. Furthermore, due to the evolutionary conservation of this pathway, inhibiting WNT/β-catenin has caused significant toxicity in normal cells. These challenges are reflected in clinical trial data, where the use of WNT/β-catenin inhibitors as standalone treatments remains limited. In this review, we have highlighted the crucial functional associations of diverse WNT/β-catenin signaling regulators with cancer progression and the phenotypic switching of tumor cells. Next, we have shed light on the roles of WNT/β-catenin signaling in drug resistance, clonal evolution, tumor heterogeneity, and immune evasion. The present review also focuses on various classes of routine and novel WNT/β-catenin therapeutic regimes while addressing the challenges associated with targeting the regulators of this complex pathway. In the light of multiple case studies on WNT/β-catenin inhibitors, we also highlighted the challenges and opportunities for future clinical trial strategies involving these treatments. Additionally, we have proposed strategies for future WNT/β-catenin-based drug discovery trials, emphasizing the potential of combination therapies and AI/ML-driven prediction approaches. Overall, here we showcased the opportunities, possibilities, and potentialities of WNT/β-catenin signaling modulatory therapeutic regimes as promising precision cancer medicines for the future.
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Affiliation(s)
- Akansha Goyal
- Department of Biotechnology, NIPER Guwahati, Sila Katamur, Changsari, 781101 Kamrup, Assam, India
| | - Satyajit Laxman Murkute
- Department of Biotechnology, NIPER Guwahati, Sila Katamur, Changsari, 781101 Kamrup, Assam, India
| | - Sujoy Bhowmik
- Department of Biotechnology, NIPER Guwahati, Sila Katamur, Changsari, 781101 Kamrup, Assam, India
| | - Chandra Prakash Prasad
- Department of Medical Oncology Lab, DR BRA-IRCH, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
| | - Purusottam Mohapatra
- Department of Biotechnology, NIPER Guwahati, Sila Katamur, Changsari, 781101 Kamrup, Assam, India.
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Zhu W, Song S, Xu Y, Sheng H, Wang S. EMP3: A promising biomarker for tumor prognosis and targeted cancer therapy. Cancer Biomark 2024; 40:227-239. [PMID: 39213053 PMCID: PMC11380316 DOI: 10.3233/cbm-230504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Epithelial membrane protein 3 (EMP3) belongs to the peripheral myelin protein 22 kDa (PMP22) gene family, characterized by four transmembrane domains and widespread expression across various human tissues and organs. Other members of the PMP22 family, including EMP1, EMP2, and PMP22, have been linked to various cancers, such as glioblastoma, laryngeal cancer, nasopharyngeal cancer, gastric cancer, breast cancer, and endometrial cancer. However, few studies report on the function and relevance of EMP3 in tumorigenicity. Given the significant structural similarities among members of the PMP22 family, there are likely potential functional similarities as well. Previous studies have established the regulatory role of EMP3 in immune cells like T cells and macrophages. Additionally, EMP3 is found to be involved in critical signaling pathways, including HER-2/PI3K/Akt, MAPK/ERK, and TGF-beta/Smad. Furthermore, EMP3 is associated with cell cycle regulation, cellular proliferation, and apoptosis. Hence, it is likely that EMP3 participates in cancer development through these aforementioned pathways and mechanisms. This review aims to systematically examine and summarize the structure and function of EMP3 and its association to various cancers. EMP3 is expected to emerge as a significant biological marker for tumor prognosis and a potential target in cancer therapeutics.
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Affiliation(s)
- Wenjing Zhu
- Department of Dermatology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Shu Song
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Yangchun Xu
- Department of Dermatology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Hanyue Sheng
- Department of Dermatology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Shuang Wang
- Department of Dermatology, The Second Hospital of Jilin University, Changchun, Jilin, China
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Cha YJ, Koo JS. Expression of EMP 1, 2, and 3 in Adrenal Cortical Neoplasm and Pheochromocytoma. Int J Mol Sci 2023; 24:13016. [PMID: 37629198 PMCID: PMC10455306 DOI: 10.3390/ijms241613016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/16/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023] Open
Abstract
The purpose of this study is to investigate the expression of the epithelial membrane proteins (EMP) 1, 2, and 3 in adrenal gland neoplasm and to explore the broader implications of this. Tissue microarrays were constructed for 132 cases of adrenal cortical neoplasms (ACN) (adrenal cortical adenoma (115 cases), and carcinoma (17 cases)) and 189 cases of pheochromocytoma. Immunohistochemical staining was performed to identify EMP 1, 2, and 3, and was compared with clinicopathological parameters. The H-score of EMP 3 (p < 0.001) was higher in pheochromocytoma when compared to that of ACN, and the H-score of EMP 1 (p < 0.001) and EMP 3 (p < 0.001) was higher in adrenal cortical carcinomas when compared to that of adrenal cortical adenomas. A higher EMP 1 H-score was observed in pheochromocytomas with a GAPP score ≥3 (p = 0.018). In univariate analysis, high levels of EMP 1 and EMP 3 expression in ACN were associated with shorter overall survival (p = 0.001). Differences were observed in the expression of EMPs between ACN and pheochromocytoma. EMPs are associated with malignant tumor biology in adrenal cortical neoplasm and pheochromocytoma, suggesting the role of a prognostic and/or predictive factor for EMPs in adrenal tumor.
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Affiliation(s)
| | - Ja Seung Koo
- Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea;
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Chen JY, Chou HH, Lim SC, Huang YJ, Lai KC, Guo CL, Tung CY, Su CT, Wang J, Liu E, Han HF, Yeh PY, Hu CM, Dunn AR, Frank CW, Wu YC, Yang MH, Chang YC. Multiomic characterization and drug testing establish circulating tumor cells as an ex vivo tool for personalized medicine. iScience 2022; 25:105081. [PMID: 36204272 PMCID: PMC9529671 DOI: 10.1016/j.isci.2022.105081] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 07/06/2022] [Accepted: 08/31/2022] [Indexed: 11/19/2022] Open
Abstract
Matching the treatment to an individual patient’s tumor state can increase therapeutic efficacy and reduce tumor recurrence. Circulating tumor cells (CTCs) derived from solid tumors are promising subjects for theragnostic analysis. To analyze how CTCs represent tumor states, we established cell lines from CTCs, primary and metastatic tumors from a mouse model and provided phenotypic and multiomic analyses of these cells. CTCs and metastatic cells, but not primary tumor cells, shared stochastic mutations and similar hypomethylation levels at transcription start sites. CTCs and metastatic tumor cells shared a hybrid epithelial/mesenchymal transcriptome state with reduced adhesive and enhanced mobilization characteristics. We tested anti-cancer drugs on tumor cells from a metastatic breast cancer patient. CTC responses mirrored the impact of drugs on metastatic rather than primary tumors. Our multiomic and clinical anti-cancer drug response results reveal that CTCs resemble metastatic tumors and establish CTCs as an ex vivo tool for personalized medicine.
Primary, CTC and metastatic cell lines from mouse models were directly compared Multiomic and phenotypic data indicate circulating cells resemble metastatic cells CTCs and metastasis tumors from a patient similarly respond to anti-cancer drugs CTCs are thus potentially useful for screening individual patient drug responses
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Affiliation(s)
- Jia-Yang Chen
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei 115, Taiwan
| | - Hsu-Huan Chou
- Department of General Surgery, Chang-Gung Memorial Hospital, Linkou, Taoyuan 333, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Syer Choon Lim
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
| | - Yen-Jang Huang
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei 115, Taiwan
| | - Kuan-Chen Lai
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Chin-Lin Guo
- Institute of Physics, Academia Sinica, Taipei 115, Taiwan
| | - Chien-Yi Tung
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | | | - Jocelyn Wang
- The College, The University of Chicago, Chicago, IL 60637, USA
| | - Edward Liu
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
| | - Hsiao-Fen Han
- Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan
| | - Po-Ying Yeh
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
| | - Chun-Mei Hu
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
| | - Alexander R. Dunn
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
| | - Curtis W. Frank
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
| | - Yi-Chun Wu
- Institute of Molecular and Cellular Biology, National Taiwan University, Taipei 106, Taiwan
- Center for Computational and Systems Biology, National Taiwan University, Taipei 106, Taiwan
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei 106, Taiwan
- Corresponding author
| | - Muh-Hwa Yang
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 112, Taiwan
- Corresponding author
| | - Ying-Chih Chang
- Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
- Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA
- National Laboratory Animal Center, National Applied Research Laboratories, Taipei 115, Taiwan
- Biomedical Translational Research Center, Academia Sinica, Taipei 115, Taiwan
- Precision Health and Integrated Diagnostics Center, Stanford University, Stanford, CA 94305, USA
- Corresponding author
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Hou J, Wang L, Zhao J, Zhuo H, Cheng J, Chen X, Zheng W, Hong Z, Cai J. Inhibition of protein PMP22 enhances etoposide-induced cell apoptosis by p53 signaling pathway in Gastric Cancer. Int J Biol Sci 2021; 17:3145-3157. [PMID: 34421356 PMCID: PMC8375224 DOI: 10.7150/ijbs.59825] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 07/06/2021] [Indexed: 01/03/2023] Open
Abstract
Gastric Cancer (GC) is one of the main causes leading to death. PMP22, as a member of the GAS3 family of tetraspan proteins, it is associated with a variety of neurological diseases. Recently, more and more studies have shown that PMP22 play a great role in the physiological processes such as cells adhesion, migration, proliferation and tumorigenesis, but the involvement and functional mechanisms of PMP22 in Gastric carcinoma are not investigated clearly. In this study, we found that the PMP22 was overexpressed in the GC cells and tissue. Knockdown of PMP22 inhibits cell growth. Over-expressed PMP22 inhibits the etoposide-induced apoptosis, meanwhile knockdown of PMP22 promotes the etoposide-induced proliferation suppression, and increases cell apoptosis in GC cells. Furthermore, PMP22 enhanced the inhibition of the p53 transcriptional activities and down-regulated the p53 targeting genes, including p21, BAX and PUMA with or without treatment of etoposide. Finally, our results showed that PMP22 reduced the etoposide-induced tumor growth suppression in nude mice. Taken together, our research provided an anti-apoptotic properties alternative mechanism for PMP22 in gastric carcinoma and suggested PMP22 can be a potential target for the treatment of gastric cancer.
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Affiliation(s)
- Jingjing Hou
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, China
- Institute of Gastrointestinal Oncology, Medical college of Xiamen University, Xiamen, Fujian 361004, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, Fujian, China
| | - Lin Wang
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, China
- Institute of Gastrointestinal Oncology, Medical college of Xiamen University, Xiamen, Fujian 361004, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, Fujian, China
| | - Jiabao Zhao
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, China
- Institute of Gastrointestinal Oncology, Medical college of Xiamen University, Xiamen, Fujian 361004, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, Fujian, China
| | - Huiqin Zhuo
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, China
- Institute of Gastrointestinal Oncology, Medical college of Xiamen University, Xiamen, Fujian 361004, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, Fujian, China
| | - Jia Cheng
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, China
- Institute of Gastrointestinal Oncology, Medical college of Xiamen University, Xiamen, Fujian 361004, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, Fujian, China
| | - Xin Chen
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, China
- Institute of Gastrointestinal Oncology, Medical college of Xiamen University, Xiamen, Fujian 361004, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, Fujian, China
| | - Wei Zheng
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, China
- Institute of Gastrointestinal Oncology, Medical college of Xiamen University, Xiamen, Fujian 361004, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, Fujian, China
| | - Zhijun Hong
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, China
- Institute of Gastrointestinal Oncology, Medical college of Xiamen University, Xiamen, Fujian 361004, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, Fujian, China
| | - Jianchun Cai
- Department of Gastrointestinal Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, China
- Institute of Gastrointestinal Oncology, Medical college of Xiamen University, Xiamen, Fujian 361004, China
- Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen 361004, Fujian, China
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Cha YJ, Koo JS. Expression and Role of Epithelial Membrane Proteins in Tumorigenesis of Hormone Receptor-Positive Breast Cancer. J Breast Cancer 2020; 23:385-397. [PMID: 32908789 PMCID: PMC7462814 DOI: 10.4048/jbc.2020.23.e42] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 07/22/2020] [Indexed: 12/18/2022] Open
Abstract
PURPOSE Studies on the expression of epithelial membrane proteins (EMPs) in breast cancer have been rare and limited. In the present study, we aimed to evaluate the expression of EMP1, EMP2, and EMP3 in invasive ductal carcinoma (IDC) of the breast, and investigate their clinical implications. METHODS In total, 418 IDC cases were collected, and specimens were used to construct a tissue microarray. Immunohistochemical staining of EMP1, EMP2, and EMP3 was performed and the results were analyzed in combination with the clinical data. RESULTS EMP1 was expressed in > 90% of all IDC subtypes. A decreased expression of EMP2 and EMP3 was observed in triple-negative breast cancer. EMP3 expression was independently associated with human epidermal growth factor receptor 2 (HER2) positivity. HER2-negative cases exhibited a decreased EMP2 expression along with a higher histological grade and an increased proliferative index. No significant difference was found in the overall survival or disease-free survival based on the EMP expression. In HER2-negative breast cancer, EMP2 expression inversely correlated with the histological grade and proliferative index. CONCLUSION EMP2 may be involved in the early stage of tumor development in hormone-positive breast cancer.
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Affiliation(s)
- Yoon Jin Cha
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Ja Seung Koo
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
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Hou J, Zhuo H, Chen X, Cheng J, Zheng W, Zhong M, Cai J. MiR-139-5p negatively regulates PMP22 to repress cell proliferation by targeting the NF-κB signaling pathway in gastric cancer. Int J Biol Sci 2020; 16:1218-1229. [PMID: 32174796 PMCID: PMC7053325 DOI: 10.7150/ijbs.40338] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Accepted: 01/18/2020] [Indexed: 12/28/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors worldwide. Peripheral myelin protein 22 (PMP22) is a 22-kDa tetraspan glycoprotein that is predominantly expressed by myelinating Schwann cells. However, recent studies have shown that PMP22 is closely related to cell proliferation and tumorigenesis in different cancers. In this study, we discovered a new miRNA that regulates PMP22 and gastric cancer cell prolifration. Our bioinformatics analysis suggested that there is a conserved miRNA recognition site for miR-139-5p on the 3' UTR of PMP22. Interestingly, our results showed overexpression of miR-139-5p significantly suppressed growth and prolifration in GC cells and inhibited tumor growth in nude mice xenografted with GC cells. MiR-139-5p suppressed the activity of a luciferase reporter containing the PMP22-3' UTR, and the ectopic expression of PMP22 rescued the miR-139-5p-mediated inhibition of cell proliferation in GC cells. Mechanistically, miR-139-5p may negatively regulate PMP22 to repress cell proliferation by targeting the NF-κB signaling pathway in gastric cancer. Finally, overexpression of miR-139-5p significantly inhibited tumor growth in nude mice xenografted with GC cells.and the miR-139-5p levels were inversely correlated with PMP22 expression in nude mice tumor. Taken together, our data suggest an important regulatory role of miR-139-5p in gastric cancer, suggesting that miR-139-5p and PMP22 might be important diagnostic or therapeutic targets for gastric cancer and other human diseases.
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Affiliation(s)
| | | | | | | | | | | | - Jianchun Cai
- ✉ Corresponding author: Prof. Jian-chun Cai, PhD, Zhongshan Hospital affiliated to Xiamen University, Xiamen, China 361004, Tel/Fax: (86-592) 229-2799,
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Wang YW, Cheng HL, Ding YR, Chou LH, Chow NH. EMP1, EMP 2, and EMP3 as novel therapeutic targets in human cancer. Biochim Biophys Acta Rev Cancer 2017; 1868:199-211. [PMID: 28408326 DOI: 10.1016/j.bbcan.2017.04.004] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 03/15/2017] [Accepted: 04/08/2017] [Indexed: 02/09/2023]
Abstract
The epithelial membrane protein genes 1, 2, and 3 (EMP1, EMP2, and EMP3) belong to the peripheral myelin protein 22-kDa (PMP22) gene family, which consists of at least seven members: PMP22, EMP1, EMP2, EMP3, PERP, brain cell membrane protein 1, and MP20. This review addresses the structural and functional features of EMPs, detailing their tissue distribution and functions in the human body, their expression pattern in a variety of tumors, and highlighting the underlying mechanisms involved in carcinogenesis. The implications in cancer biology, patient prognosis prediction, and potential application in disease therapy are discussed. For example, EMP1 was reported to be a biomarker of gefitinib resistance in lung cancer and contributes to prednisolone resistance in acute lymphoblastic leukemia patients. EMP2 functions as an oncogene in human endometrial and ovarian cancers; however, characteristics of EMP2 in urothelial cancer fulfill the criteria of a suppressor gene. Of particular interest, EMP3 overexpression in breast cancer is significantly related to strong HER-2 expression. Co-expression of HER-2 and EMP3 is the most important indicator of progression-free and metastasis-free survival for patients with urothelial carcinoma of the upper urinary tract. Altogether, discovery of pharmacological inhibitors and/or regulators of EMP protein activity could open novel strategies for enhanced therapy against EMP-mediated human diseases.
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Affiliation(s)
- Yi-Wen Wang
- Department of Pathology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Hong-Ling Cheng
- National Cheng Kung University, College of Medicine, Tainan, Taiwan
| | - Ya-Rou Ding
- Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Lien-Hsuan Chou
- School of Medicine, Fu Jen Catholic University, New Taipei, Taiwan
| | - Nan-Haw Chow
- Department of Pathology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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Huang TL, Mu N, Gu JT, Shu Z, Zhang K, Zhao JK, Zhang C, Hao Q, Li WN, Zhang WQ, Liu NN, Zhang Y, Zhang W, Xue XC, Zhang YQ. DDR2-CYR61-MMP1 Signaling Pathway Promotes Bone Erosion in Rheumatoid Arthritis Through Regulating Migration and Invasion of Fibroblast-Like Synoviocytes. J Bone Miner Res 2017; 32:407-418. [PMID: 27653023 DOI: 10.1002/jbmr.2993] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 09/02/2016] [Accepted: 09/12/2016] [Indexed: 01/07/2023]
Abstract
Regulation of matrix metalloproteinases (MMPs) by collagen in the fibroblast-like synoviocytes (FLSs) plays a critical role in joint destruction in rheumatoid arthritis (RA). Our previous study indicated that discoidin receptor 2 (DDR2) mediated collagen upregulation of MMPs. However, the precise underlying mechanism remains unclear. We report here that CYR61, a secreted, extracellular matrix-associated signaling protein which is capable of regulating a broad range of cellular activities, including cell adhesion, migration, proliferation, and apoptosis, is significantly upregulated in collagen II-stimulated RA FLS. Further studies found that collagen II-activated phosphorylated-DDR2 induces CYR61 through activation of transcription factor activator protein 1 (AP-1). The elevated CYR61, in turn, accelerates MMP1 production via ETS1 (ETS proto-oncogene 1). In addition, CYR61 significantly promotes FLS invasion and migration. Blockade of CYR61 by an adenovirus expressing CYR61 shRNA (Ad-shCYR61) in vivo remarkably ameliorated the severity of arthritis, reduced inflammatory cytokine secretion, and attenuated bone erosion as detected by micro-computed tomography (μCT), in collagen-induced arthritis (CIA) rats. Taken together, we uncovered the Collagen II-DDR2-AP-1-CYR61-ETS1-MMP1 loop in RA FLS. In which, CYR61 acts as a hinge to promote cartilage damage through regulating FLS invasion, migration, and MMP1 production and the inflammatory cascade in RA. Thus, CYR61 may be a promising diagnostic and therapeutic target for RA treatment. © 2016 American Society for Bone and Mineral Research.
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Affiliation(s)
- Tong-Lie Huang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China
| | - Nan Mu
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China
| | - Jin-Tao Gu
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China
| | - Zhen Shu
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China
| | - Kuo Zhang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China
| | - Jin-Kang Zhao
- Department of Clinical Immunology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Cun Zhang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China
| | - Qiang Hao
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China
| | - Wei-Na Li
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China
| | - Wang-Qian Zhang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China
| | - Nan-Nan Liu
- Experiment Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Yong Zhang
- Institute of Orthopedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China
| | - Xiao-Chang Xue
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China
| | - Ying-Qi Zhang
- State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Phamacy, Fourth Military Medical University, Xi'an, China
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11
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Liu F, Gu LN, Shan BE, Geng CZ, Sang MX. Biomarkers for EMT and MET in breast cancer: An update. Oncol Lett 2016; 12:4869-4876. [PMID: 28105194 DOI: 10.3892/ol.2016.5369] [Citation(s) in RCA: 81] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 09/29/2016] [Indexed: 01/11/2023] Open
Abstract
Metastasis and recurrence are the leading cause of mortality due to breast cancer, but the underlying mechanisms are still poorly understood. Understanding the breast cancer metastasis mechanism is important for early diagnosis and treatment of breast cancer. The seeding and growth of breast cancer cells at sites distinct from the primary tumor is a complex and multistage process. Recently, it has been reported that the epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET) are the main mechanisms for breast cancer metastasis. During EMT, carcinoma cells shed their differentiated epithelial characteristics, including cell-cell adhesion, polarity and lack of motility, and acquire mesenchymal traits, including motility and invasiveness. This review has summarized the studies of known EMT biomarkers in the context of breast cancer progression. These biomarkers include EMT-related genes, proteins, microRNAs and kinases. In general, the findings of these studies suggest that EMT markers are associated with the invasion and metastasis of breast cancer. Further studies on the link between EMT markers and breast cancer will contribute to identify biomarkers for predicting early breast cancer metastasis as well as to provide new ideas for the treatment of breast cancer.
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Affiliation(s)
- Fei Liu
- Tumor Research Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China; Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Li-Na Gu
- Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Bao-En Shan
- Tumor Research Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China; Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Cui-Zhi Geng
- Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Mei-Xiang Sang
- Tumor Research Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China; Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
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12
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Gründker C, Bauerschmitz G, Schubert A, Emons G. Invasion and increased expression of S100A4 and CYR61 in mesenchymal transformed breast cancer cells is downregulated by GnRH. Int J Oncol 2016; 48:2713-21. [PMID: 27098123 DOI: 10.3892/ijo.2016.3491] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 03/17/2016] [Indexed: 11/05/2022] Open
Abstract
S100 calcium binding protein A4 (S100A4) and cysteine-rich angiogenic inducer 61 (CYR61) play important roles in epithelial-mesenchymal-transition (EMT), invasion and metastasis by promoting cancer cell motility. Recently we were able to show that invasion of GnRH receptor-positive breast cancer cells is time- and dose-dependently reduced by GnRH analogs. We have now analyzed whether GnRH treatment affects S100A4 and CYR61 in mesenchymal transformed breast cancer cells. S100A4 and CYR61 expression was analyzed using RT-PCR. Invasion was quantified by assessment of breast cancer cell migration rate through an artificial basement membrane. The role of S100A4 and CYR61 in invasion of breast cancer cells was analyzed by neutralizing their biological activity. Expression of S100A4, CYR61 and GnRH receptor in human breast cancers, normal and other non-malignant breast tissues was analyzed by immuno-histochemistry. Invasion and expression of S100A4 and CYR61 in MDA-MB-231 breast cancer cells were significant higher as compared with MCF-7 breast cancer cells. Invasion and expression of S100A4 and CYR61 were significantly increased in mesenchymal transformed MCF-7 cells (MCF-7-EMT). The increased invasion of MCF-7-EMT cells could be reduced by anti-S100A4 and anti-CYR61 antibodies. In addition, invasion of MDA-MB-231 cells was decreased by anti-S100A4 and anti-CYR61 antibodies. Treatment of MCF-7-EMT and MDA-MB-231 cells with GnRH agonist Triptorelin resulted in a significant decrease of invasion and expression of S100A4 and CYR61. Both, S100A4 and CYR61 were found highly expressed in biopsy specimens of breast hyperplasia and malignant breast cancers. GnRH receptor expression was detectable in approximately 71% of malignant breast cancers. Our findings suggest that S100A4 and CYR61 play major roles in breast cancer invasion. Both, invasion and expression of S100A4 and CYR61 can be inhibited by GnRH treatment.
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Affiliation(s)
- Carsten Gründker
- Department of Gynecology and Obstetrics, Georg-August-University, D-37075 Göttingen, Germany
| | - Gerd Bauerschmitz
- Department of Gynecology and Obstetrics, Georg-August-University, D-37075 Göttingen, Germany
| | - Antje Schubert
- Department of Gynecology and Obstetrics, Georg-August-University, D-37075 Göttingen, Germany
| | - Günter Emons
- Department of Gynecology and Obstetrics, Georg-August-University, D-37075 Göttingen, Germany
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13
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Hong XC, Fen YJ, Yan GC, Hong H, Yan CH, Bing LW, Zhong YH. Epithelial membrane protein 3 functions as an oncogene and is regulated by microRNA-765 in primary breast carcinoma. Mol Med Rep 2015; 12:6445-50. [PMID: 26398721 PMCID: PMC4626151 DOI: 10.3892/mmr.2015.4326] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 07/10/2015] [Indexed: 01/11/2023] Open
Abstract
Epithelial membrane protein 3 (EMP3) is a transmembrane signaling molecule, which is important in the regulation of apoptosis, differentiation and invasion of cancer cells. However, the specific function and regulatory mechanism of EMP3 in primary breast carcinoma remain to be elucidated. In the present study, the mRNA and protein levels of EMP3 were observed to be upregulated in primary breast carcinoma tissues, compared with normal tissues. It was hypothesized that the overexpression of EMP3 was correlated with the downregulation of microRNA‑765 (miR‑765), an underexpressed miRNA in primary breast carcinoma tissues. Functional analysis demonstrated that EMP3 was regulated by miR‑765 through binding to its 3'untranslated region. In addition, the knockdown of EMP3 and miR‑765 had similar effects on the inhibition of proliferation and invasion in SK‑BR‑3 cells. These results provided novel insight into the regulatory mechanism of EMP3 in primary breast carcinoma.
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Affiliation(s)
- Xiao Chun Hong
- Department of Clinical Laboratory, Nantong Cancer Hospital, Nantong, Jiangsu 226001, P.R. China
| | - Yuan Jian Fen
- Department of Clinical Laboratory, Traditional Chinese Medicine Hospital, Nantong, Jiangsu 226001, P.R. China
| | - Guo Chun Yan
- Department of Clinical Laboratory, Traditional Chinese Medicine Hospital, Nantong, Jiangsu 226001, P.R. China
| | - Hong Hong
- Department of Clinical Laboratory, Traditional Chinese Medicine Hospital, Nantong, Jiangsu 226001, P.R. China
| | - Cao Hong Yan
- Department of Clinical Laboratory, Traditional Chinese Medicine Hospital, Nantong, Jiangsu 226001, P.R. China
| | - Li Wei Bing
- Department of Clinical Laboratory, Traditional Chinese Medicine Hospital, Nantong, Jiangsu 226001, P.R. China
| | - Yu Hai Zhong
- Department of Clinical Laboratory, Traditional Chinese Medicine Hospital, Nantong, Jiangsu 226001, P.R. China
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14
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Yan Z, Jin S, Wei Z, Huilian H, Zhanhai Y, Yue T, Juan L, Jing L, Libo Y, Xu L. Discoidin domain receptor 2 facilitates prostate cancer bone metastasis via regulating parathyroid hormone-related protein. Biochim Biophys Acta Mol Basis Dis 2014; 1842:1350-63. [DOI: 10.1016/j.bbadis.2014.04.018] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Revised: 03/26/2014] [Accepted: 04/21/2014] [Indexed: 12/26/2022]
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15
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Low stability and a conserved N-glycosylation site are associated with regulation of the discoidin domain receptor family by glucose via post-translational N-glycosylation. Biosci Biotechnol Biochem 2013; 77:1907-16. [PMID: 24018687 DOI: 10.1271/bbb.130351] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cell-surface expression of the discoidin domain receptor (DDR) tyrosine kinase family in high molecular mass form was controlled sensitively by the glucose concentration through a post-translational N-glycosylation process. Cycloheximide time-course experiments revealed that the high-molecular-mass forms of DDR1 and DDR2 were significantly less stable than control receptor tyrosine kinases. Site-directed mutational analysis of the consensus N-glycosylation sites of the DDRs revealed that mutations of asparagine 213 of DDR2 and asparagine 211 of DDR1, a conserved N-glycosylation site among vertebrate DDRs, inhibited the generation of the high-molecular-mass isoform. Taken together, these results suggest a mechanism to control the activity of the DDR family by regulating its cell-surface expression. Due to low stability, the steady-state population of functional DDR proteins in the cell surface depends sensitively on its maturation process via post-translational N-glycosylation, which is controlled by the glucose supply and the presence of a conserved N-glycosylation site.
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16
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Identification of novel candidate oncogenes in chromosome region 17p11.2-p12 in human osteosarcoma. PLoS One 2012; 7:e30907. [PMID: 22292074 PMCID: PMC3266911 DOI: 10.1371/journal.pone.0030907] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 12/29/2011] [Indexed: 11/19/2022] Open
Abstract
Osteosarcoma is the most common primary malignancy of bone. The tumours are characterized by high genomic instability, including the occurrence of multiple regions of amplifications and deletions. Chromosome region 17p11.2–p12 is amplified in about 25% of cases. In previous studies, COPS3 and PMP22 have been identified as candidate oncogenes in this region. Considering the complexity and variation of the amplification profiles for this segment, the involvement of additional causative oncogenes is to be expected. The aim of the present investigation is to identify novel candidate oncogenes in 17p11.2–p12. We selected 26 of in total 85 osteosarcoma samples (31%) with amplification events in 17p11.2–p12, using quantitative PCR for 8 marker genes. These were subjected to high-resolution SNP array analysis and subsequent GISTIC analysis to identify the most significantly amplified regions. Two major amplification peaks were found in the 17p11.2–p12 region. Overexpression as a consequence of gene amplification is a major mechanism for oncogene activation in tumours. Therefore, to identify the causative oncogenes, we next determined expression levels of all genes within the two segments using expression array data that could be generated for 20 of the selected samples. We identified 11 genes that were overexpressed through amplification in at least 50% of cases. Nine of these, c17orf39, RICH2, c17orf45, TOP3A, COPS3, SHMT1, PRPSAP2, PMP22, and RASD1, demonstrated a significant association between copy number and expression level. We conclude that these genes, including COPS3 and PMP22, are candidate oncogenes in 17p11.2–p12 of importance in osteosarcoma tumourigenesis.
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17
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Micutkova L, Diener T, Li C, Rogowska-Wrzesinska A, Mueck C, Huetter E, Weinberger B, Grubeck-Loebenstein B, Roepstorff P, Zeng R, Jansen-Duerr P. Insulin-like growth factor binding protein-6 delays replicative senescence of human fibroblasts. Mech Ageing Dev 2011; 132:468-79. [PMID: 21820463 PMCID: PMC3192261 DOI: 10.1016/j.mad.2011.07.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2010] [Revised: 07/08/2011] [Accepted: 07/15/2011] [Indexed: 01/10/2023]
Abstract
Cellular senescence can be induced by a variety of mechanisms, and recent data suggest a key role for cytokine networks to maintain the senescent state. Here, we have used a proteomic LC-MS/MS approach to identify new extracellular regulators of senescence in human fibroblasts. We identified 26 extracellular proteins with significantly different abundance in conditioned media from young and senescent fibroblasts. Among these was insulin-like growth factor binding protein-6 (IGFBP-6), which was chosen for further analysis. When IGFBP-6 gene expression was downregulated, cell proliferation was inhibited and apoptotic cell death was increased. Furthermore, downregulation of IGFBP-6 led to premature entry into cellular senescence. Since IGFBP-6 overexpression increased cellular lifespan, the data suggest that IGFBP-6, in contrast to other IGF binding proteins, is a negative regulator of cellular senescence in human fibroblasts.
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Affiliation(s)
- Lucia Micutkova
- Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria
| | - Thomas Diener
- Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria
| | - Chen Li
- Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Adelina Rogowska-Wrzesinska
- Protein Research Group, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK 5230 Odense M, Denmark
| | - Christoph Mueck
- Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria
| | - Eveline Huetter
- Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria
| | - Birgit Weinberger
- Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria
| | - Beatrix Grubeck-Loebenstein
- Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria
| | - Peter Roepstorff
- Protein Research Group, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK 5230 Odense M, Denmark
| | - Rong Zeng
- Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Pidder Jansen-Duerr
- Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria
- Corresponding author. Tel.: +43 512 583919 44; fax: +43 512 583919 8.
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18
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Tong D, Heinze G, Pils D, Wolf A, Singer CF, Concin N, Hofstetter G, Schiebel I, Rudas M, Zeillinger R. Gene expression of PMP22 is an independent prognostic factor for disease-free and overall survival in breast cancer patients. BMC Cancer 2010; 10:682. [PMID: 21159173 PMCID: PMC3018461 DOI: 10.1186/1471-2407-10-682] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2010] [Accepted: 12/15/2010] [Indexed: 11/10/2022] Open
Abstract
Background Gene expression of peripheral myelin protein 22 (PMP22) and the epithelial membrane proteins (EMPs) was found to be differentially expressed in invasive and non-invasive breast cell lines in a previous study. We want to evaluate the prognostic impact of the expression of these genes on breast cancer. Methods In a retrospective multicenter study, gene expression of PMP22 and the EMPs was measured in 249 primary breast tumors by real-time PCR. Results were statistically analyzed together with clinical data. Results In univariable Cox regression analyses PMP22 and the EMPs were not associated with disease-free survival or tumor-related mortality. However, multivariable Cox regression revealed that patients with higher than median PMP22 gene expression have a 3.47 times higher risk to die of cancer compared to patients with equal values on clinical covariables but lower PMP22 expression. They also have a 1.77 times higher risk to relapse than those with lower PMP22 expression. The proportion of explained variation in overall survival due to PMP22 gene expression was 6.5% and thus PMP22 contributes equally to prognosis of overall survival as nodal status and estrogen receptor status. Cross validation demonstrates that 5-years survival rates can be refined by incorporating PMP22 into the prediction model. Conclusions PMP22 gene expression is a novel independent prognostic factor for disease-free survival and overall survival for breast cancer patients. Including it into a model with established prognostic factors will increase the accuracy of prognosis.
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Affiliation(s)
- Dan Tong
- Department of Obstetrics and Gynaecology, Medical University of Vienna, EBO 5Q, AKH, Währinger Gürtel 18-20, Vienna 1090, Austria.
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Blick T, Hugo H, Widodo E, Waltham M, Pinto C, Mani SA, Weinberg RA, Neve RM, Lenburg ME, Thompson EW. Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/-) stem cell phenotype in human breast cancer. J Mammary Gland Biol Neoplasia 2010; 15:235-52. [PMID: 20521089 DOI: 10.1007/s10911-010-9175-z] [Citation(s) in RCA: 225] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Accepted: 04/20/2010] [Indexed: 02/06/2023] Open
Abstract
We review here the recently emerging relationship between epithelial-mesenchymal transition (EMT) and breast cancer stem cells (BCSC), and provide analyses of published data on human breast cancer cell lines, supporting their utility as a model for the EMT/BCSC state. Genome-wide transcriptional profiling of these cell lines has confirmed the existence of a subgroup with mesenchymal tendencies and enhanced invasive properties ('Basal B'/Mesenchymal), distinct from subgroups with either predominantly luminal ('Luminal') or mixed basal/luminal ('Basal A') features (Neve et al. Cancer Cell, 2006). A literature-derived EMT gene signature has shown specific enrichment within the Basal B subgroup of cell lines, consistent with their over-expression of various EMT transcriptional drivers. Basal B cell lines are found to resemble BCSC, being CD44(high)CD24(low). Moreover, gene products that distinguish Basal B from Basal A and Luminal cell lines (Basal B Discriminators) showed close concordance with those that define BCSC isolated from clinical material, as reported by Shipitsin et al. (Cancer Cell, 2007). CD24 mRNA levels varied across Basal B cell lines, correlating with other Basal B Discriminators. Many gene products correlating with CD24 status in Basal B cell lines were also differentially expressed in isolated BCSC. These findings confirm and extend the importance of the cellular product of the EMT with Basal B cell lines, and illustrate the value of analysing these cell lines for new leads that may improve breast cancer outcomes. Gene products specific to Basal B cell lines may serve as tools for the detection, quantification, and analysis of BCSC/EMT attributes.
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Affiliation(s)
- Tony Blick
- Invasion and Metastasis Unit, St. Vincent's Institute, 9 Princes St, Fitzroy, Melbourne 3065, Australia
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Abstract
Somatic cells that change from one mature phenotype to another exhibit the property of plasticity. It is increasingly clear that epithelial and endothelial cells enjoy some of this plasticity, which is easily demonstrated by studying the process of epithelial-mesenchymal transition (EMT). Published reports from the literature typically rely on ad hoc criteria for determining EMT events; consequently, there is some uncertainty as to whether the same process occurs under different experimental conditions. As we discuss in this Personal Perspective, we believe that context and various changes in plasticity biomarkers can help identify at least three types of EMT and that using a collection of criteria for EMT increases the likelihood that everyone is studying the same phenomenon - namely, the transition of epithelial and endothelial cells to a motile phenotype.
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Affiliation(s)
- Michael Zeisberg
- Division of Matrix Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
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Fumoto S, Tanimoto K, Hiyama E, Noguchi T, Nishiyama M, Hiyama K. EMP3as a candidate tumor suppressor gene for solid tumors. Expert Opin Ther Targets 2009; 13:811-22. [DOI: 10.1517/14728220902988549] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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22
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Siddiqui K, Kim GW, Lee DH, Shin HR, Yang EG, Lee NT, Yang BS. Actinomycin D identified as an inhibitor of discoidin domain receptor 2 interaction with collagen through an insect cell based screening of a drug compound library. Biol Pharm Bull 2009; 32:136-41. [PMID: 19122296 DOI: 10.1248/bpb.32.136] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Discoidin domain receptors belong to the cell surface receptor tyrosine kinase family and recognize collagens for their activating ligands. They have been implicated for cell growth and migration and their elevated expressions were observed in various human cancers. When we expressed human Discoidin domain receptor 2 (DDR2) in insect cells, the protein was targeted properly into the cell membrane and this could enforce the cells to adhere on culture plate coated with type I collagen. By taking advantage of this, we established a novel insect cell based screening protocol to identify chemicals which inhibit the interaction between DDR2 and collagen. We screened a drug-compound library to select an anti-cancer drug, actinomycin D, as the inhibitory compound. Actinomycin D prevented the activation of DDR2 by type I collagen in human embryonic kidney 293 cells with an IC(50) value of 9 microM, while it did not interfere with the activation of other receptor tyrosine kinases by their ligands. In conclusion we identified a new biological function of actinomycin D and the insect cell based method provides a useful protocol for screening inhibitors against the association of DDR2 with collagen.
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Affiliation(s)
- Kauser Siddiqui
- Biomedical Research Center, Korea Institute of Science and Technology, Seoul
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23
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Zhou W, Jiang Z, Li X, Xu F, Liu Y, Wen P, Kong L, Hou M, Yu J. EMP3 overexpression in primary breast carcinomas is not associated with epigenetic aberrations. J Korean Med Sci 2009; 24:97-103. [PMID: 19270820 PMCID: PMC2650972 DOI: 10.3346/jkms.2009.24.1.97] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2007] [Accepted: 04/15/2008] [Indexed: 11/20/2022] Open
Abstract
Epithelial membrane protein 3 (EMP3) is a trans-membrane signaling molecule with important roles in the regulation of apoptosis, differentiation and invasion of cancer cells, but the detailed is largely still unknown. We analyzed the mRNA levels and methylation statuses of EMP3 in 63 primary breast carcinomas and assessed their correlations with clinicopathologic variables. The expression of EMP3 mRNA in primary breast carcinomas was significantly higher than the expression of 20 normal breast tissues (p<10(-7)). EMP3 overexpression in breast carcinomas was significantly related to histological grade III (p=3.9 x 10(-7)), lymph node metastasis (p=0.003), and strong Her-2 expression (p=3.3 x 10(-6)). Hypermethylation frequencies of EMP3 were detected in 36.5% of breast carcinomas by methylation-specific polymerase chain reaction. However, no significant correlations were found between methylation status of EMP3 and mRNA expression levels as well as other clinical parameters. In conclusion, EMP3 may be a novel marker of tumor aggressiveness. Overexpression of EMP3 in primary breast carcinoma is not associated with DNA methylation.
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Affiliation(s)
- Wei Zhou
- Department of Radiation Oncology, Shandong Tumor Hospital, Shandong University, Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong, China
| | - Zheng Jiang
- Department of Neurosurgery, Qilu Hospital, Shandong University, Shandong, China
| | - Xingang Li
- Department of Neurosurgery, Qilu Hospital, Shandong University, Shandong, China
| | - Fenghua Xu
- Department of Radiation Oncology, Shandong Tumor Hospital, Shandong University, Shandong, China
| | - Yanbing Liu
- Breast Center, Shandong Cancer Hospital and Institute, Shandong, China
| | - Peie Wen
- Department of Immunology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China
| | - Li Kong
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong, China
| | - Ming Hou
- Cancer Center, Qilu Hospital, Shandong University, Shandong, China
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong, China
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Rahman M, Davis SR, Pumphrey JG, Bao J, Nau MM, Meltzer PS, Lipkowitz S. TRAIL induces apoptosis in triple-negative breast cancer cells with a mesenchymal phenotype. Breast Cancer Res Treat 2009; 113:217-30. [PMID: 18266105 PMCID: PMC2615075 DOI: 10.1007/s10549-008-9924-5] [Citation(s) in RCA: 146] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2007] [Accepted: 01/28/2008] [Indexed: 10/22/2022]
Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in some but not all breast cancer cell lines. Breast cancers can be divided into those which express the estrogen (ER) and progesterone (PR) receptors, those with HER-2 amplification, and those without expression of ER, PR, or HER-2 amplification (referred to as basal or triple-negative breast cancer). We tested a panel of 20 breast cancer cell lines representing the different types of breast cancer to evaluate if the molecular phenotype of the breast cancer cells determined their response to TRAIL. The most striking finding was that eight of eleven triple-negative cell lines are sensitive to TRAIL-mediated apoptosis. The eight TRAIL-sensitive triple-negative cell lines have a mesenchymal phenotype while the three TRAIL-resistant triple-negative cell lines have an epithelial phenotype. Two of five cell lines with HER-2 amplification were sensitive to TRAIL and none of the five ER positive cell lines were sensitive. RNAi-mediated knockdown of TRAIL receptor expression demonstrated that TRAIL Receptor 2 (TRAIL-R2) mediates the effects of TRAIL, even when both TRAIL-R1 and TRAIL-R2 are expressed. Finally, inhibition of EGFR, expressed in both TRAIL-sensitive and TRAIL-resistant triple-negative breast cancer cell lines, using a small molecule tyrosine kinase inhibitor (AG1478), enhanced TRAIL-induced apoptosis in TRAIL-sensitive cell lines but did not convert resistant cells into TRAIL-sensitive cells. Together, these findings suggest that a subset of triple-negative breast cancer, those with mesenchymal features, may be the most likely to benefit from TRAIL targeted therapy. These findings could form the basis to select breast cancer patients for clinical trials of TRAIL-R2 ligands.
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Affiliation(s)
- Monzur Rahman
- Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Blg 37, Room 2066, 37 Convent Drive, Bethesda, MD 20892-4256, USA
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25
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Rybak JN, Trachsel E, Scheuermann J, Neri D. Ligand-based vascular targeting of disease. ChemMedChem 2008; 2:22-40. [PMID: 17154429 DOI: 10.1002/cmdc.200600181] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
This review illustrates the basic principles of ligand-based vascular targeting and presents some of the most advanced results obtained in this field, not only in terms of biopharmaceuticals, which are currently being investigated in clinical and preclinical studies, but also in terms of enabling technologies that facilitate target and ligand discovery. Whereas most of the vascular targeting research activities have so far concentrated on tumoral angiogenesis, the development of non-oncological applications has recently gained momentum and is likely to become an important area of modern pharmaceutical research.
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Affiliation(s)
- Jascha-N Rybak
- ETH Zürich, Institute of Pharmaceutical Sciences, Zürich, Switzerland
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26
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Pang EYT, Bai AHC, To KF, Sy SMH, Wong NLY, Lai PBS, Squire JA, Wong N. Identification of PFTAIRE protein kinase 1, a novel cell division cycle-2 related gene, in the motile phenotype of hepatocellular carcinoma cells. Hepatology 2007; 46:436-45. [PMID: 17559150 DOI: 10.1002/hep.21691] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
UNLABELLED Metastasis is a major cause of cancer morbidity and mortality in individuals with hepatocellular carcinoma (HCC), yet little is known about the underlying molecular basis. Using genetic information derived from chromosome-based comparative genomic hybridization, we have reported previously on regional chromosome 7q21-q22 gains in close association with HCC progression. In this study, we undertook cDNA microarray-based comparative genomic hybridization, to examine the 7q21-q22 region for the involved gene(s) in HCC. High-resolution mapping analysis highlighted 7 candidates, namely PFTAIRE protein kinase 1 (PFTK1), ODAG, CDK6, CAS1, PEX1, SLC25A, and PEG10, within the region. Quantitative reverse transcription (RT)-PCR evaluation further indicated upregulation of a single candidate gene, PFTK1, that correlated significantly with both advanced metastatic HCCs (P = 0.032) and tumor microvascular invasion (P = 0.012). Given that little is known about the function(s) of PFTK1, which is a novel cell division cycle (Cdc)2-related gene, we examined its potential role in the motile phenotype of HCC cells by both ectopic expression and knockdown investigations. RNA-interference knockdown of PFTK1 in invasive Hep3B cells resulted in a significant reduction in cell invasion, chemotactic migration, and cell motility (P < 0.001). Conversely, ectopic expression of PFTK1 in noninvasive HKCI-C3 cells induced substantial cellular invasion and migration (P < or = 0.007). In neither cell line was there any effect on cell viability. Immunofluorescence showed marked filamentous actin polymerizations in PFTK1-expressing cells. CONCLUSION In this study, we have thus provided preliminary evidence that overexpression of PFTK1 may confer a motile phenotype in malignant hepatocytes that accounts for the association of upregulation of this gene in metastatic HCC.
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Affiliation(s)
- Etonia Y-T Pang
- Li Ka-Shing Institute of Health, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
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27
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Forbes A, Wadehra M, Mareninov S, Morales S, Shimazaki K, Gordon LK, Braun J. The tetraspan protein EMP2 regulates expression of caveolin-1. J Biol Chem 2007; 282:26542-51. [PMID: 17609206 DOI: 10.1074/jbc.m702117200] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Caveolin-1 is the primary component of caveolae and functions in a variety of intracellular activities, including membrane trafficking and signal transduction. EMP2 (epithelial membrane protein 2) is a tetraspan protein recently identified as a novel regulator of caveolin-1 expression. In this study, we analyzed the mechanism of EMP2-mediated caveolin-1 regulation. In NIH 3T3 cells and in the human retinal pigment epithelium cell line (ARPE-19), EMP2 regulates caveolin-1 transcription and more substantially its protein levels. EMP2-mediated down-regulation of caveolin-1 does not affect caveolin-1 translational efficiency, phosphorylation, or proteasome-mediated degradation. Analysis of caveolin-1 protein half-life indicates the EMP2-mediated loss of caveolin-1 occurs rapidly. Protease inhibition and laser confocal microscopy associates this fate with specific intracellular compartmentalization, including early lysosomal delivery. These findings elucidate a new mechanism of caveolin-1 regulation and define an additional role for EMP2 as a key regulator of cell membrane composition.
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Affiliation(s)
- Ashley Forbes
- Molecular Biology Institute, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
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28
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Chan MM, Lu X, Merchant FM, Iglehart JD, Miron PL. Serial transplantation of NMU-induced rat mammary tumors: A model of human breast cancer progression. Int J Cancer 2007; 121:474-85. [PMID: 17405122 DOI: 10.1002/ijc.22684] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Human breast cancer is a heterogeneous disease that appears to progress from an in situ tumor to invasive cancer. Little is known about the molecular events driving this progression. Although microarray technology has helped us understand the genetic heterogeneity of breast cancer, its application to studying the transition from in situ to invasive disease is limited by the inability to follow the progression of a single patient's tumor. We previously used rat specific microarrays to show that N-methyl-N-nitrosourea induced tumors are similar to low-grade estrogen-receptor positive human breast cancer. Here, we transplanted these tumors through 5 generations of syngeneic hosts, and studied 65 resulting tumors. Most transplanted tumors gradually progressed from a noninvasive, low-grade cancer to a higher-grade invasive disease, losing p63 localization and basement membrane integrity. Invasive cancers frequently demonstrated a more mesenchymal phenotype with increased vimentin expression. Additionally, a unique transplant series is described with a phenotype similar to human basal-like breast cancer. Rat-specific Affymetrix gene arrays containing 15,866 gene probes identified genes that differentiated highly invasive tumors from those of low invasive potential. A linear regression analysis was used to find genes whose change in expression paralleled increasing invasive features independent of the transplant lineage of origin. Genes identified were assigned membership in cell adhesion, signal transduction, cell cycle and extracellular matrix groups, among others. This animal model overcomes the difficulty in studying human breast cancer progression. Our data support a gradual and continuous alteration in programs of gene expression during breast cancer invasion.
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Affiliation(s)
- Maren M Chan
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA
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29
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Noordeen NA, Carafoli F, Hohenester E, Horton MA, Leitinger B. A Transmembrane Leucine Zipper Is Required for Activation of the Dimeric Receptor Tyrosine Kinase DDR1. J Biol Chem 2006; 281:22744-51. [PMID: 16774916 DOI: 10.1074/jbc.m603233200] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Receptor tyrosine kinases of the discoidin domain family, DDR1 and DDR2, are activated by different types of collagen and play important roles in cell adhesion, migration, proliferation, and matrix remodeling. In a previous study, we found that collagen binding by the discoidin domain receptors (DDRs) requires dimerization of their extracellular domains (Leitinger, B. (2003) J. Biol. Chem. 278, 16761-16769), indicating that the paradigm of ligand-induced receptor dimerization may not apply to the DDRs. Using chemical cross-linking and co-immunoprecipitation of differently tagged DDRs, we now show that the DDRs form ligand-independent dimers in the biosynthetic pathway and on the cell surface. We further show that both the extracellular and the cytoplasmic domains are individually dispensable for DDR1 dimerization. The DDR1 transmembrane domain contains two putative dimerization motifs, a leucine zipper and a GXXXG motif. Mutations disrupting the leucine zipper strongly impaired collagen-induced transmembrane signaling, although the mutant DDR1 proteins were still able to dimerize, whereas mutation of the GXXXG motif had no effect. A bacterial reporter assay (named TOXCAT) showed that the DDR1 transmembrane domain has a strong potential for self-association in a biological membrane and that this interaction occurs via the leucine zipper and not the GXXXG motif. Our results demonstrate that the DDRs exist as stable dimers in the absence of ligand and that receptor activation requires specific interactions made by the transmembrane leucine zipper.
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Affiliation(s)
- Nafeesa A Noordeen
- Department of Medicine, University College London, 5 University Street, London WC1E 6JJ, UK
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30
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Vogel WF, Abdulhussein R, Ford CE. Sensing extracellular matrix: an update on discoidin domain receptor function. Cell Signal 2006; 18:1108-16. [PMID: 16626936 DOI: 10.1016/j.cellsig.2006.02.012] [Citation(s) in RCA: 268] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2006] [Accepted: 02/20/2006] [Indexed: 02/06/2023]
Abstract
Discoidin Domain Receptors (DDRs) have recently emerged as non-integrin-type receptors for collagen. The two mammalian gene products Discoidin Domain Receptor 1 and -2 constitute a subfamily of tyrosine kinase receptors that are selectively expressed in a number of different cell types and organs. Upon collagen activation, DDRs regulate cell adhesion, proliferation and extracellular matrix remodeling. Here we review the various signaling pathways and cellular responses evoked by activated DDRs. Additionally, we give an overview of the more recent advances in understanding the role of DDRs in various human diseases, in particular during tumor progression, atherosclerosis, inflammation and tissue fibrosis. Furthermore, we discuss potential roles of genes homologous to mammalian DDRs identified in flies, worms and sponges. We show that the structural organization of these DDR-related genes is highly conserved throughout evolution suggesting that invertebrate DDRs may also function as receptors for collagen. By highlighting current questions about these unusual collagen receptors, we hope to attract new research on DDRs from a variety of different fields.
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Affiliation(s)
- Wolfgang F Vogel
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario Canada, M5S 1A8.
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31
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Yang K, Kim JH, Kim HJ, Park IS, Kim IY, Yang BS. Tyrosine 740 phosphorylation of discoidin domain receptor 2 by Src stimulates intramolecular autophosphorylation and Shc signaling complex formation. J Biol Chem 2005; 280:39058-66. [PMID: 16186108 DOI: 10.1074/jbc.m506921200] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
DDR2 is a receptor tyrosine kinase whose activating ligands are various collagens. DDR2-mediated cellular signaling has been shown to require Src activity. However, the precise mechanism underlying the Src dependence of DDR2 signaling is unknown. Here, using baculoviral co-expression of the DDR2 cytosolic domain and Src, we show that Src targets three tyrosine residues (Tyr-736, Tyr-740, and Tyr-741) in the activation loop of DDR2 for phosphorylation. This phosphorylation by Src stimulates DDR2 cis-autophosphorylation of additional tyrosine residues. In vitro Shc binding assays demonstrate that phosphotyrosines resulting from DDR2 autophosphorylation are involved in Shc binding to the DDR2 cytosolic domain. Mutating tyrosine 740 of DDR2 to phenylalanine stimulates autophosphorylation of DDR2 to an extent similar to that resulting from Src phosphorylation of DDR2. In addition, the DDR2 Y740F mutant protein displays collagen-independent, constitutively activated signaling. These findings suggest that tyrosine 740 inhibits DDR2 autophosphorylation. Collectively, our findings are consistent with the following mechanism for Src-dependent DDR2 activation and signaling: 1) ligand binding promotes phosphorylation of Tyr-740 in the DDR2 activation loop by Src; 2) Tyr-740 phosphorylation stimulates intramolecular autophosphorylation of DDR2; 3) DDR2 autophosphorylation generates cytosolic domain phosphotyrosines that promote the formation of DDR2 cytosolic domain-Shc signaling complexes.
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Affiliation(s)
- Kyungmi Yang
- Biomedical Research Center, Korea Institute of Science and Technology, 39-1, Hawolgok-Dong, Sungbuk-Ku, Seoul 136-791, Korea
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32
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Abstract
Insulin-like growth factor binding protein (IGFBP)-6 is unique among IGFBPs for its IGF-II binding specificity. IGFBP-6 inhibits growth of a number of IGF-II-dependent cancers, including rhabdomyosarcoma, neuroblastoma and colon cancer. Although the major action of IGFBP-6 appears to be inhibition of IGF-II actions, a number of studies suggest that it may also have IGF-independent actions. Gene array studies show regulation of IGFBP-6 in many circumstances that are consistent with antiproliferative actions. However, other studies show the opposite, so that IGFBP-6 may be acting as a counter-regulator in these situations or it may have other as yet undetermined actions. Both the N-terminal and C-terminal domains of IGFBP-6 contribute to high affinity IGF binding, and the C-terminal domain appears to confer its IGF-II specificity. The three-dimensional structure of the C-domain of IGFBP-6 contains a thyroglobulin type 1 fold, and the IGF-II binding site is located in the proximal half of this domain adjacent to the glycosaminoglycan binding site. Future studies are needed to further delineate the putative IGF-independent actions of IGFBP-6 and to build on the structural information to enhance our understanding of this IGFBP. This is particularly significant since IGFBP-6 provides an attractive basis for therapy of IGF-II-dependent tumors.
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Affiliation(s)
- Leon A Bach
- Department of Endocrinology and Diabetes, Alfred Hospital, Melbourne, Vic. 3004, Australia.
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33
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Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Conventional diagnosis and treatment of this malignancy have been dismal and should be complemented by novel tools. The development and progress of HCC are believed to be caused by the accumulation of genetic changes resulting in altered expression of thousands of cancer-related genes, which can be measured by globe genetic analysis. Gene expression profiling of HCC has been employed to elucidate hepatocarcinogenesis and disclose molecular mechanisms underlying complex clinical features. Identifying phenotype-associated genes/profiles has impacts on current diagnosis and management strategy of HCC. In spite of some pitfalls of this technology and challenges in improving the research process, scrutinous validation of profiling data of HCC combined with other approaches will eventually benefit the patients.
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Affiliation(s)
- Lian-Hai Zhang
- Peking University School of Oncology, Beijing Cancer Hospital, Beijing Institute for Cancer Research, Beijing 100034, China
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34
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Rye PD, Rittenhouse H, Stigbrand T. Up close and personal: molecular diagnostics in oncology. Tumour Biol 2004; 25:217-20. [PMID: 15557760 DOI: 10.1159/000081105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2004] [Accepted: 08/06/2004] [Indexed: 11/19/2022] Open
Abstract
The almost overwhelming volume of information and new technological developments that has demanded so much of our scientific attention over the last decade will shortly revolutionize clinical diagnostics. Some of these developments are already affecting the working lives of scientists and clinicians alike, but will eventually require a greater understanding and acceptance from a much wider audience. Therefore it is important in our current scientific endeavor and commercial enthusiasm for molecular diagnostics that we maintain some awareness of the significant obstacles that must be overcome if we are to see an appropriate, timely and widespread adoption of molecular diagnostic testing in oncology. This article presents a brief commentary on the current state of the art in molecular diagnostics in oncology and how this relates to a more personalized approach to treatment.
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