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Moriwaki K, Ayani Y, Kuwabara H, Terada T, Higashino M, Kawata R. Differential expression of TRKB tyrosine kinase in the two histological types of parotid salivary duct carcinoma with cancer aggressiveness. Oral Oncol 2024; 151:106751. [PMID: 38479153 DOI: 10.1016/j.oraloncology.2024.106751] [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: 10/18/2023] [Revised: 03/06/2024] [Accepted: 03/06/2024] [Indexed: 04/06/2024]
Abstract
Parotid salivary duct carcinoma (SDC) is a rare and aggressive parotid gland carcinoma (PGC). SDC has two origins: de novo and ex pleomorphic adenoma (SDC ex PA); however, because of its rarity, the clinical and molecular features of the two types of SDC are not sufficiently understood. Here, we studied the differences in their clinicopathological and molecular features using clinical specimens while comparing them to those of adenoid cystic carcinoma (AdCC), an intermediate-grade PGC. Clinicopathological analysis of tissues from patients with PGC revealed significant associations between histological types and malignant phenotypes, including nodal metastasis, recurrence, vascular invasion, and neural invasion, and revealed more malignant phenotypes of de novo SDC than of SDC ex PA. The de novo SDC showed a significantly higher frequency of intra-neural invasion (intra-NI) and vascular invasion than AdCC and SDC ex PA. PGCs with high intra-NI were significantly correlated with malignant phenotypes and survival rates. Recently, we observed the overexpression of tropomyosin receptor kinase B (TRKB), a receptor tyrosine kinase, in PGC cells. Here, immunohistochemical and clinicopathological analyses showed that TRKB was highly expressed in SDC cells, particularly de novo SDC cells, and was significantly associated with poor survival and highly malignant phenotypes, including intra-NI and vascular invasion. Collectively, these data show that TRKB expression is significantly elevated in PGC, particularly in de novo SDC, and can be one of the biomarkers of their aggressiveness.
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Affiliation(s)
- Kazumasa Moriwaki
- Department of Pharmacology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
| | - Yusuke Ayani
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Hiroko Kuwabara
- Department of Pathology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Tetsuya Terada
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Masaaki Higashino
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
| | - Ryo Kawata
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical and Pharmaceutical University, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
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de Santana DA, Braga PR, Camillo-Coutinho CM, Freitas VS, Cury PR, Ribeiro DA, de Araújo IB, de Aquino Xavier FC, Dos Santos JN. E-CADERIN, N-CADERIN, SLUG, SNAIL, and TWIST contribute to epithelial-mesenchymal transition in salivary gland tumors. J Oral Pathol Med 2024; 53:193-200. [PMID: 38351435 DOI: 10.1111/jop.13516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 01/24/2024] [Accepted: 01/30/2024] [Indexed: 03/19/2024]
Abstract
BACKGROUND Transcription factors are important in the epithelial-mesenchymal transition process and are possibly related to the development of a more invasive tumor phenotype. Thus, the objective of this study was to analyze the expression and identify the localization of cellular markers related to the epithelial-mesenchymal transition process in salivary gland tumors. STUDY DESIGN The expression and localization of E-CADERIN, N-CADERIN, SLUG, SNAIL, and TWIST were evaluated, using immunohistochemistry, in 48 salivary gland tumors, being 17 pleomorphic adenomas (PA), 14 adenoid cystic carcinomas (ACC), and 17 mucoepidermoid carcinomas (MEC). these proteins were compared to clinical and histopathologic parameters. normal gland tissues were included for immunohistochemical comparisons. RESULTS ACC and MEC cases showed higher expression of SNAIL compared to PA. MEC showed high expression of SLUG and TWIST. Low expression of N-CADHERIN, SNAIL, and TWIST in ACC was frequent in T3 and T4. High expression of TWIST in MEC was more frequent at age ≥ 40 years A positive correlation was only observed between N-cadherin/SNAIL in ACC, between SNAIL/TWIST in MEC, and between SLUG/TWIST in PA. CONCLUSION This study provided insight into EMT-related proteins (E-cadherin, N-cadherin, SNAIL, SLUG, and TWIST) and their contribution to the maintenance of morphogenesis and the development of the salivary gland tumors and showed a positive correlation among N-CADHERIN/SNAIL in ACC and SNAIL/TWIST in MEC.
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Affiliation(s)
- Dandara Andrade de Santana
- Dentistry and Health Postgraduate Program, School of Dentistry, Federal University of Bahia, Salvador, Brazil
- Laboratory of Oral and Maxillofacial Pathology, School of Dentistry, Federal University of Bahia, Salvador, Brazil
| | - Poliana Ramos Braga
- Dentistry and Health Postgraduate Program, School of Dentistry, Federal University of Bahia, Salvador, Brazil
| | | | - Valéria Souza Freitas
- Department of Health, School of Dentistry, State University of Feira de Santana, Feira de Santana, Brazil
| | | | - Daniel Araki Ribeiro
- Department of Bioscience, Institute of Health and Society, Federal University of São Paulo, São Paulo, Brazil
| | | | - Flávia Caló de Aquino Xavier
- Dentistry and Health Postgraduate Program, School of Dentistry, Federal University of Bahia, Salvador, Brazil
- Laboratory of Oral and Maxillofacial Pathology, School of Dentistry, Federal University of Bahia, Salvador, Brazil
| | - Jean Nunes Dos Santos
- Dentistry and Health Postgraduate Program, School of Dentistry, Federal University of Bahia, Salvador, Brazil
- Laboratory of Oral and Maxillofacial Pathology, School of Dentistry, Federal University of Bahia, Salvador, Brazil
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Goncharov AP, Vashakidze N, Kharaishvili G. Epithelial-Mesenchymal Transition: A Fundamental Cellular and Microenvironmental Process in Benign and Malignant Prostate Pathologies. Biomedicines 2024; 12:418. [PMID: 38398019 PMCID: PMC10886988 DOI: 10.3390/biomedicines12020418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/01/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a crucial and fundamental mechanism in many cellular processes, beginning with embryogenesis via tissue remodulation and wound healing, and plays a vital role in tumorigenesis and metastasis formation. EMT is a complex process that involves many transcription factors and genes that enable the tumor cell to leave the primary location, invade the basement membrane, and send metastasis to other tissues. Moreover, it may help the tumor avoid the immune system and establish radioresistance and chemoresistance. It may also change the normal microenvironment, thus promoting other key factors for tumor survival, such as hypoxia-induced factor-1 (HIF-1) and promoting neoangiogenesis. In this review, we will focus mainly on the role of EMT in benign prostate disease and especially in the process of establishment of malignant prostate tumors, their invasiveness, and aggressive behavior. We will discuss relevant study methods for EMT evaluation and possible clinical implications. We will also introduce clinical trials conducted according to CONSORT 2010 that try to harness EMT properties in the form of circulating tumor cells to predict aggressive patterns of prostate cancer. This review will provide the most up-to-date information to establish a keen understanding of the cellular and microenvironmental processes for developing novel treatment lines by modifying or blocking the pathways.
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Affiliation(s)
- Aviv Philip Goncharov
- Department of Clinical and Molecular Pathology, Palacky University, University Hospital, 779 00 Olomouc, Czech Republic; (A.P.G.); (N.V.)
| | - Nino Vashakidze
- Department of Clinical and Molecular Pathology, Palacky University, University Hospital, 779 00 Olomouc, Czech Republic; (A.P.G.); (N.V.)
| | - Gvantsa Kharaishvili
- Department of Clinical and Molecular Pathology, Palacky University, University Hospital, 779 00 Olomouc, Czech Republic; (A.P.G.); (N.V.)
- Department of Human Morphology and Pathology, Medical Faculty, David Tvildiani Medical University, Tbilisi 0159, Georgia
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Wang Y, Liang J, Xu B, Yang J, Wu Z, Cheng L. TrkB/BDNF signaling pathway and its small molecular agonists in CNS injury. Life Sci 2024; 336:122282. [PMID: 38008209 DOI: 10.1016/j.lfs.2023.122282] [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: 02/18/2023] [Revised: 10/19/2023] [Accepted: 11/18/2023] [Indexed: 11/28/2023]
Abstract
As one of the most prevalent neurotrophic factors in the central nervous system (CNS), brain-derived neurotrophic factor (BDNF) plays a significant role in CNS injury by binding to its specific receptor Tropomyosin-related kinase receptor B (TrkB). The BDNF/TrkB signaling pathway is crucial for neuronal survival, structural changes, and plasticity. BDNF acts as an axonal growth and extension factor, a pro-survival factor, and a synaptic modulator in the CNS. BDNF also plays an important role in the maintenance and plasticity of neuronal circuits. Several studies have demonstrated the importance of BDNF in the treatment and recovery of neurodegenerative and neurotraumatic disorders. By undertaking in-depth study on the mechanism of BDNF/TrkB function, important novel therapeutic strategies for treating neuropsychiatric disorders have been discovered. In this review, we discuss the expression patterns and mechanisms of the TrkB/BDNF signaling pathway in CNS damage and introduce several intriguing small molecule TrkB receptor agonists produced over the previous several decades.
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Affiliation(s)
- Yujin Wang
- Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Medical School, Tongji University, Shanghai 200433, China
| | - Jing Liang
- Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; School of Stomatology, Tongji University, Shanghai 200072, China
| | - Boyu Xu
- Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Medical School, Tongji University, Shanghai 200433, China
| | - Jin Yang
- Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China; Medical School, Tongji University, Shanghai 200433, China
| | - Zhourui Wu
- Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China.
| | - Liming Cheng
- Division of Spine, Department of Orthopedics, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Spine and Spinal cord Injury Repair and Regeneration (Tongji University), Ministry of Education, Shanghai 200072, China.
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Nowroozzadeh MH, Ghazanfari S, Sanie-Jahromi F. Human Wharton's Jelly Mesenchymal Stem Cell Secretome Modifies the Processes of Neuroprotection and Epithelial-Mesenchymal Transition in Retinal Pigment Epithelium at Transcriptional Level. Mol Biol Rep 2023:10.1007/s11033-023-08496-0. [PMID: 37217618 DOI: 10.1007/s11033-023-08496-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 04/28/2023] [Indexed: 05/24/2023]
Abstract
BACKGROUND Retinal pigment epithelium (RPE) cells are potential targets for treating retinal detachment (RD) and proliferative vitreoretinopathy (PVR), considering the importance of neuroprotection and epithelial-mesenchymal transition (EMT) of RPE in these conditions. This study investigated the effect of human Wharton's jelly mesenchymal stem cell secretome (WJMSC-S) on the expression of genes involved in both neuroprotection and EMT in RPE cells in vitro (TRKB, MAPK, PI3K, BDNF, and NGF). METHODS RPE cells from passages 5-7 were treated with WJMSC-S (or the vehicle culture medium as control) for 24 h at 37◦C and subsequently subjected to RNA extraction and cDNA synthesis. Gene expression level was evaluated using real-time PCR in the treated versus control cells. RESULTS The results of our study showed that WJMSC-S led to a significant downregulation in three out of five studied gene expression (MAPK, TRKB, and NGF), and simultaneously, remarkably upregulated the expression of the BDNF gene. CONCLUSIONS According to the present data, WJMSC-S can affect the EMT and neuroprotection processes at the mRNA level by suppressing EMT and promoting neuroprotection in RPE cells. This finding may have positive clinical implications in the context of RD and PVR.
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Affiliation(s)
- M Hossein Nowroozzadeh
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Zand Boulevard, Poostchi Street, Shiraz, Iran
| | - Shiva Ghazanfari
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Zand Boulevard, Poostchi Street, Shiraz, Iran
| | - Fatemeh Sanie-Jahromi
- Poostchi Ophthalmology Research Center, Department of Ophthalmology, School of Medicine, Shiraz University of Medical Sciences, Zand Boulevard, Poostchi Street, Shiraz, Iran.
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Chen D, Yi R, Hong W, Wang K, Chen Y. Anoikis resistance of small airway epithelium is involved in the progression of chronic obstructive pulmonary disease. Front Immunol 2023; 14:1155478. [PMID: 37090717 PMCID: PMC10113535 DOI: 10.3389/fimmu.2023.1155478] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 03/27/2023] [Indexed: 04/07/2023] Open
Abstract
BackgroundAnoikis resistance is recognized as a crucial step in the metastasis of cancer cells. Most epithelial tumors are distinguished by the ability of epithelial cells to abscond anoikis when detached from the extracellular matrix. However, no study has investigated the involvement of anoikis in the small airway epithelium (SAE) of chronic obstructive pulmonary disease (COPD).MethodsAnoikis-related genes (ANRGs) exhibiting differential expression in COPD were identified using microarray datasets obtained from the Gene Expression Omnibus (GEO) database. Unsupervised clustering was performed to classify COPD patients into anoikis-related subtypes. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) were used to annotate the functions between different subtypes. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were leveraged to identify key molecules. The relative proportion of infiltrating immune cells in the SAE was quantified using the CIBERSORT and ssGSEA computational algorithms, and the correlation between key molecules and immune cell abundance was analyzed. The expression of key molecules in BEAS-2B cells exposed to cigarette smoke extract (CSE) was validated using qRT-PCR.ResultsA total of 25 ANRGs exhibited differential expression in the SAE of COPD patients, based on which two subtypes of COPD patients with distinct anoikis patterns were identified. COPD patients with anoikis resistance had more advanced GOLD stages and cigarette consumption. Functional annotations revealed a different immune status between COPD patients with pro-anoikis and anoikis resistance. Tenomodulin (TNMD) and long intergenic non-protein coding RNA 656 (LINC00656) were subsequently identified as key molecules involved in this process, and a close correlation between TNMD and the infiltrating immune cells was observed, such as activated CD4+ memory T cells, M1 macrophages, and activated NK cells. Further enrichment analyses clarified the relationship between TNMD and the inflammatory and apoptotic signaling pathway as the potential mechanism for regulating anoikis. In vitro experiments showed a dramatic upregulation of TNMD and LINC00656 in BEAS-2B cells when exposed to 3% CSE for 48 hours.ConclusionTNMD contributes to the progression of COPD by inducing anoikis resistance in SAE, which is intimately associated with the immune microenvironment.
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Affiliation(s)
- Dian Chen
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - Rongbing Yi
- Department of Emergency Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Weifeng Hong
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Kai Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Yahong Chen
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing, China
- Research Center for Chronic Airway Diseases, Peking University Health Science Center, Beijing, China
- *Correspondence: Yahong Chen,
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Chen H, Tao X, Cao H, Li B, Sun Q, Wang W, Zou Y, Mu M, Tao H, Zhao Y, Ge D. Nicotine exposure exacerbates silica-induced pulmonary fibrosis via STAT3-BDNF-TrkB-mediated epithelial-mesenchymal transition in alveolar type II cells. Food Chem Toxicol 2023; 175:113694. [PMID: 36868510 DOI: 10.1016/j.fct.2023.113694] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 02/20/2023] [Accepted: 02/23/2023] [Indexed: 03/05/2023]
Abstract
The addictive substance nicotine, found in cigarettes and some e-cigarettes, plays a vital role in pro-inflammatory and fibrotic processes. However, the part played by nicotine in the progression of silica-induced pulmonary fibrosis is poorly understood. We used mice exposed to both silica and nicotine to investigate whether nicotine synergizes with silica particles to worsen lung fibrosis. The results revealed that nicotine accelerated the development of pulmonary fibrosis in silica-injured mice by activating STAT3-BDNF-TrkB signalling. Mice with a history of exposure to nicotine showed an increase in Fgf7 expression and alveolar type II cell proliferation if they were also exposed to silica. However, newborn AT2 cells could not regenerate the alveolar structure and release pro-fibrotic factor IL-33. Moreover, activated TrkB induced the expression of p-AKT, which promotes the expression of epithelial-mesenchymal transcription factor Twist, but no Snail. In vitro assessment confirmed activation of the STAT3-BDNF-TrkB pathway in AT2 cells, exposed to nicotine plus silica. In addition, TrkB inhibitor K252a downregulated p-TrkB and the downstream p-AKT and restricted the epithelial-mesenchymal transition caused by nicotine plus silica. In conclusion, nicotine activates the STAT3-BDNF-TrkB pathway, which promotes epithelial-mesenchymal transition and exacerbates pulmonary fibrosis in mice with combined exposure to silica particles and nicotine.
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Affiliation(s)
- Haoming Chen
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Department of Medical Frontier Experimental Center, Anhui University of Science and Technology, Huainan, China
| | - Xinrong Tao
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Department of Medical Frontier Experimental Center, Anhui University of Science and Technology, Huainan, China.
| | - Hangbing Cao
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Department of Medical Frontier Experimental Center, Anhui University of Science and Technology, Huainan, China
| | - Bing Li
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Department of Medical Frontier Experimental Center, Anhui University of Science and Technology, Huainan, China
| | - Qixian Sun
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Department of Medical Frontier Experimental Center, Anhui University of Science and Technology, Huainan, China
| | - Wenyang Wang
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Department of Medical Frontier Experimental Center, Anhui University of Science and Technology, Huainan, China
| | - Yuanjie Zou
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Department of Medical Frontier Experimental Center, Anhui University of Science and Technology, Huainan, China
| | - Min Mu
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Department of Medical Frontier Experimental Center, Anhui University of Science and Technology, Huainan, China
| | - Huihui Tao
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Department of Medical Frontier Experimental Center, Anhui University of Science and Technology, Huainan, China
| | - Yehong Zhao
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Department of Medical Frontier Experimental Center, Anhui University of Science and Technology, Huainan, China
| | - Deyong Ge
- Key Laboratory of Industrial Dust Control and Occupational Health of the Ministry of Education, Anhui University of Science and Technology, Huainan, China; Key Laboratory of Industrial Dust Deep Reduction and Occupational Health and Safety of Anhui Higher Education Institutes, Anhui University of Science and Technology, Huainan, China; Anhui Province Engineering Laboratory of Occupational Health and Safety, Huainan, China; School of Medicine, Department of Medical Frontier Experimental Center, Anhui University of Science and Technology, Huainan, China
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Dukel M. Combination of naringenin and epicatechin sensitizes colon carcinoma cells to anoikis via regulation of the epithelial–mesenchymal transition (EMT). Mol Cell Toxicol 2022. [DOI: 10.1007/s13273-022-00317-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Poonaki E, Kahlert UD, Meuth SG, Gorji A. The role of the ZEB1–neuroinflammation axis in CNS disorders. J Neuroinflammation 2022; 19:275. [PMCID: PMC9675144 DOI: 10.1186/s12974-022-02636-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/31/2022] [Indexed: 11/21/2022] Open
Abstract
Zinc finger E-box binding homeobox 1 (ZEB1) is a master modulator of the epithelial–mesenchymal transition (EMT), a process whereby epithelial cells undergo a series of molecular changes and express certain characteristics of mesenchymal cells. ZEB1, in association with other EMT transcription factors, promotes neuroinflammation through changes in the production of inflammatory mediators, the morphology and function of immune cells, and multiple signaling pathways that mediate the inflammatory response. The ZEB1–neuroinflammation axis plays a pivotal role in the pathogenesis of different CNS disorders, such as brain tumors, multiple sclerosis, cerebrovascular diseases, and neuropathic pain, by promoting tumor cell proliferation and invasiveness, formation of the hostile inflammatory micromilieu surrounding neuronal tissues, dysfunction of microglia and astrocytes, impairment of angiogenesis, and dysfunction of the blood–brain barrier. Future studies are needed to elucidate whether the ZEB1–neuroinflammation axis could serve as a diagnostic, prognostic, and/or therapeutic target for CNS disorders.
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Affiliation(s)
- Elham Poonaki
- grid.411327.20000 0001 2176 9917Department of Neurology, Faculty of Medicine, Heinrich-Heine-University, Düsseldorf, Germany ,grid.5949.10000 0001 2172 9288Epilepsy Research Center, Department of Neurosurgery, Westfälische Wilhelms-Universität Münster, Domagkstr. 11, 48149 Münster, Germany
| | - Ulf Dietrich Kahlert
- grid.5807.a0000 0001 1018 4307Molecular and Experimental Surgery, Faculty of Medicine, University Clinic for General-, Visceral-, Vascular- and Transplantation Surgery, Otto-Von-Guericke-University, Magdeburg, Germany
| | - Sven G. Meuth
- grid.411327.20000 0001 2176 9917Department of Neurology, Faculty of Medicine, Heinrich-Heine-University, Düsseldorf, Germany
| | - Ali Gorji
- grid.5949.10000 0001 2172 9288Epilepsy Research Center, Department of Neurosurgery, Westfälische Wilhelms-Universität Münster, Domagkstr. 11, 48149 Münster, Germany ,grid.512981.60000 0004 0612 1380Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran ,grid.411583.a0000 0001 2198 6209Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Phetphoung T, Malla A, Rattanapisit K, Pisuttinusart N, Damrongyot N, Joyjamras K, Chanvorachote P, Phakham T, Wongtangprasert T, Strasser R, Chaotham C, Phoolcharoen W. Expression of plant-produced anti-PD-L1 antibody with anoikis sensitizing activity in human lung cancer cells via., suppression on epithelial-mesenchymal transition. PLoS One 2022; 17:e0274737. [PMID: 36367857 PMCID: PMC9651560 DOI: 10.1371/journal.pone.0274737] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 09/06/2022] [Indexed: 11/13/2022] Open
Abstract
Immune checkpoint antibodies in cancer treatment are receptor-ligand pairs that modulate cancer immunity. PD-1/PD-L1 pathway has emerged as one of the major targets in cancer immunotherapy. Atezolizumab, the first anti-PD-L1 antibody approved for the treatment of metastatic urothelial, non-small cell lung, small cell lung and triple-negative breast cancers, is produced in Chinese Hamster Ovary (CHO) cells with several limitations i.e., high-production costs, low-capacity yields, and contamination risks. Due to the rapid scalability and low production costs, the transient expression in Nicotiana benthamiana leaves was investigated by co-infiltration of Agrobacterium tumefaciens GV3101 cultures harboring the nucleic acid sequences encoding for Atezolizumab heavy chain and light chain in this study. The transient expression of Atezolizumab in transformed N. benthamiana accumulated up to 86.76 μg/g fresh leaf weight after 6 days of agroinfiltration (OD 600 nm: 0.4) with 1:1 ratio of heavy chain to light chain. The structural and functional characteristics of plant-produced Atezolizumab was compared with commercially available Tecentriq® from CHO cells with similar binding efficacies to PD-L1 receptor. The direct anti-cancer effect of plant-produced anti-PD-L1 was further performed in human lung metastatic cancer cells H460 cultured under detachment condition, demonstrating the activity of anti-PD-L1-antibody on sensitizing anoikis as well as the suppression on anti-apoptosis proteins (Bcl-2 and Mcl-1) and modulation of epithelial to mesenchymal regulating proteins (E-cadherin, N-cadherin, Snail and Slug). In conclusion, this study manifests plants as an alternative cost-effective platform for the production of functional monoclonal antibodies for use in cancer therapy.
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Affiliation(s)
- Thareeya Phetphoung
- Graduate Program of Pharmaceutical Sciences and Technology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Plant-produced Pharmaceuticals, Chulalongkorn University, Bangkok, Thailand
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | | | | | - Nuttapat Pisuttinusart
- Graduate Program of Pharmaceutical Sciences and Technology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Plant-produced Pharmaceuticals, Chulalongkorn University, Bangkok, Thailand
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Naruechai Damrongyot
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Keerati Joyjamras
- Pharmacology and Toxicology Unit, Department of Medical Science, Faculty of Science, Rangsit University, Pathum Thani, Thailand
| | - Pithi Chanvorachote
- Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Tanapati Phakham
- Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Excellence Center for Cancer Immunotherapy, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Tossapon Wongtangprasert
- Center of Excellence in Systems Biology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Excellence Center for Cancer Immunotherapy, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
- Excellence Chulalongkorn Comprehensive Cancer Center, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Richard Strasser
- Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, Vienna, Austria
| | - Chatchai Chaotham
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
- * E-mail: (CC); (WP)
| | - Waranyoo Phoolcharoen
- Center of Excellence in Plant-produced Pharmaceuticals, Chulalongkorn University, Bangkok, Thailand
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
- * E-mail: (CC); (WP)
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11
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BDNF/TRKB axis provokes EMT progression to induce cell aggressiveness via crosstalk with cancer-associated fibroblasts in human parotid gland cancer. Sci Rep 2022; 12:17553. [PMID: 36266462 PMCID: PMC9584965 DOI: 10.1038/s41598-022-22377-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 10/13/2022] [Indexed: 01/13/2023] Open
Abstract
Parotid gland cancer (PGC) is a rare malignancy and its molecular characteristics remain poorly understood, which has precluded the development of effective drug therapies. Given the poor prognosis of many human cancers in which tropomyosin receptor kinase B (TRKB) is highly expressed, we investigated the involvement of brain-derived neurotrophic factor (BDNF)/TRKB pathway in PGC cells using clinical specimens and observed upregulation of TRKB and BDNF. In primary culture systems of patient-derived PGC cells and cancer-associated fibroblasts (CAFs), PGC cells co-cultured with CAFs exhibited significant upregulation of BDNF and epithelial-mesenchymal transition (EMT). Similar results were observed in PGC cells treated with conditioned medium from co-cultures of PGC cells with CAFs. Administration of TRK inhibitors suppressed BDNF-induced cell migration in PGC cells. Immunohistochemical and clinicopathological analyses of tumors from patients with PGC revealed that BDNF and TRKB were highly expressed in both tumor cells and stromal cells such as CAFs, and TRKB expression levels in PGC cells were significantly correlated with aggressive features, including vascular invasion, nodal metastasis, and poor prognosis. Collectively, these data suggest that the BDNF/TRKB pathway regulates PGC cell aggressiveness via crosstalk with CAFs and is a potential therapeutic target for PGC harboring invasive and metastatic features.
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12
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Wang J, Luo Z, Lin L, Sui X, Yu L, Xu C, Zhang R, Zhao Z, Zhu Q, An B, Wang Q, Chen B, Leung ELH, Wu Q. Anoikis-Associated Lung Cancer Metastasis: Mechanisms and Therapies. Cancers (Basel) 2022; 14:cancers14194791. [PMID: 36230714 PMCID: PMC9564242 DOI: 10.3390/cancers14194791] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 09/25/2022] [Accepted: 09/27/2022] [Indexed: 12/08/2022] Open
Abstract
Simple Summary Anoikis is a programmed cell death process resulting from the loss of interaction between cells and the extracellular matrix. Therefore, it is necessary to overcome anoikis when tumor cells acquire metastatic potential. In lung cancer, the composition of the extracellular matrix, cell adhesion-related membrane proteins, cytoskeletal regulators, and epithelial–mesenchymal transition are involved in the process of anoikis, and the initiation of apoptosis signals is a critical step in anoikis. Inversely, activation of growth signals counteracts anoikis. This review summarizes the regulators of lung cancer-related anoikis and explores potential drug applications targeting anoikis. Abstract Tumor metastasis occurs in lung cancer, resulting in tumor progression and therapy failure. Anoikis is a mechanism of apoptosis that combats tumor metastasis; it inhibits the escape of tumor cells from the native extracellular matrix to other organs. Deciphering the regulators and mechanisms of anoikis in cancer metastasis is urgently needed to treat lung cancer. Several natural and synthetic products exhibit the pro-anoikis potential in lung cancer cells and in vivo models. These products include artonin E, imperatorin, oroxylin A, lupalbigenin, sulforaphane, renieramycin M, avicequinone B, and carbenoxolone. This review summarizes the current understanding of the molecular mechanisms of anoikis regulation and relevant regulators involved in lung cancer metastasis and discusses the therapeutic potential of targeting anoikis in the treatment of lung cancer metastasis.
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Affiliation(s)
- Jing Wang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
- Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Zhijie Luo
- The First Clinical Medical College, The First Hospital Affiliated, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Lizhu Lin
- The First Clinical Medical College, The First Hospital Affiliated, Guangzhou University of Chinese Medicine, Guangzhou 510405, China
| | - Xinbing Sui
- School of Pharmacy, Department of Medical Oncology, Hangzhou Normal University, Hangzhou 311121, China
| | - Lili Yu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Cong Xu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Ruonan Zhang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Ziming Zhao
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Qianru Zhu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Bo An
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Qiao Wang
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Bi Chen
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Elaine Lai-Han Leung
- Cancer Center, Faculty of Health Science, MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau 999078, China
- Correspondence: (E.L.-H.L.); (Q.W.)
| | - Qibiao Wu
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
- Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong University of Technology, Guangzhou 510006, China
- Zhuhai MUST Science and Technology Research Institute, Zhuhai 519031, China
- Correspondence: (E.L.-H.L.); (Q.W.)
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13
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Basu B, Ghosh MK. Ubiquitination and deubiquitination in the regulation of epithelial-mesenchymal transition in cancer: Shifting gears at the molecular level. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119261. [PMID: 35307468 DOI: 10.1016/j.bbamcr.2022.119261] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/03/2022] [Accepted: 03/14/2022] [Indexed: 06/14/2023]
Abstract
The process of conversion of non-motile epithelial cells to their motile mesenchymal counterparts is known as epithelial-mesenchymal transition (EMT), which is a fundamental event during embryonic development, tissue repair, and for the maintenance of stemness. However, this crucial process is hijacked in cancer and becomes the means by which cancer cells acquire further malignant properties such as increased invasiveness, acquisition of stem cell-like properties, increased chemoresistance, and immune evasion ability. The switch from epithelial to mesenchymal phenotype is mediated by a wide variety of effector molecules such as transcription factors, epigenetic modifiers, post-transcriptional and post-translational modifiers. Ubiquitination and de-ubiquitination are two post-translational processes that are fundamental to the ubiquitin-proteasome system (UPS) of the cell, and the shift in equilibrium between these two processes during cancer dictates the suppression or activation of different intracellular processes, including EMT. Here, we discuss the complex and dynamic relationship between components of the UPS and EMT in cancer.
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Affiliation(s)
- Bhaskar Basu
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata- 700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
| | - Mrinal K Ghosh
- Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector-V, Salt Lake, Kolkata- 700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India.
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14
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Beyond Genetics: Metastasis as an Adaptive Response in Breast Cancer. Int J Mol Sci 2022; 23:ijms23116271. [PMID: 35682953 PMCID: PMC9181003 DOI: 10.3390/ijms23116271] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/26/2022] [Accepted: 06/01/2022] [Indexed: 01/27/2023] Open
Abstract
Metastatic disease represents the primary cause of breast cancer (BC) mortality, yet it is still one of the most enigmatic processes in the biology of this tumor. Metastatic progression includes distinct phases: invasion, intravasation, hematogenous dissemination, extravasation and seeding at distant sites, micro-metastasis formation and metastatic outgrowth. Whole-genome sequencing analyses of primary BC and metastases revealed that BC metastatization is a non-genetically selected trait, rather the result of transcriptional and metabolic adaptation to the unfavorable microenvironmental conditions which cancer cells are exposed to (e.g., hypoxia, low nutrients, endoplasmic reticulum stress and chemotherapy administration). In this regard, the latest multi-omics analyses unveiled intra-tumor phenotypic heterogeneity, which determines the polyclonal nature of breast tumors and constitutes a challenge for clinicians, correlating with patient poor prognosis. The present work reviews BC classification and epidemiology, focusing on the impact of metastatic disease on patient prognosis and survival, while describing general principles and current in vitro/in vivo models of the BC metastatic cascade. The authors address here both genetic and phenotypic intrinsic heterogeneity of breast tumors, reporting the latest studies that support the role of the latter in metastatic spreading. Finally, the review illustrates the mechanisms underlying adaptive stress responses during BC metastatic progression.
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15
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Ghatak S, Mehrabi SF, Mehdawi LM, Satapathy SR, Sjölander A. Identification of a Novel Five-Gene Signature as a Prognostic and Diagnostic Biomarker in Colorectal Cancers. Int J Mol Sci 2022; 23:ijms23020793. [PMID: 35054980 PMCID: PMC8776147 DOI: 10.3390/ijms23020793] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/03/2022] [Accepted: 01/08/2022] [Indexed: 01/05/2023] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The current TNM (Tumor, Node, and Metastasis) classification approach is suboptimal in determining the prognosis of CRC patients. The prognosis for CRC is affected by a variety of features that are present at the initial diagnosis. Herein, we performed a systematic exploration and established a novel five-panel gene signature as a prognostic and early diagnosis biomarker after performing differential gene expression analyses in five independent in silico CRCs cohort and independently validating it in one clinical cohort, using immunohistochemistry. Four genes (BDNF, PTGS2, GSK3B, and CTNNB1) were significantly upregulated and one gene (HPGD) was significantly downregulated in primary tumor tissues compared with adjacent normal tissues throughout all the five in silico datasets. The univariate CoxPH analysis yielded a five-gene signature that accurately predicted overall survival (OS) and recurrence-free survival (RFS) in the in silico training (AUC = 0.73 and 0.69, respectively) and one independent in silico validation cohort (AUC = 0.69 and 0.74, respectively). This five-gene signature demonstrated significant associations with poor OS in independent clinical validation cohorts of colon cancer (CC) patients (AUC = 0.82). Intriguingly, a risk stratification model comprising of the five-gene signature together with TNM stage and gender status achieved an even superior AUC of 0.89 in the clinical cohorts. On the other hand, the circulating mRNA expression of the upregulated four-gene signature achieved a robust AUC = 0.83 with high sensitivity and specificity as a diagnosis marker in plasma from CRC patients. We have identified a novel, five-gene signature as an independent predictor of OS, which in combination with TNM stage and gender offers an easy-to-translate and facile assay for the personalized risk-assessment in CRC patients.
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16
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Epigenetic Regulation and Post-Translational Modifications of SNAI1 in Cancer Metastasis. Int J Mol Sci 2021; 22:ijms222011062. [PMID: 34681726 PMCID: PMC8538584 DOI: 10.3390/ijms222011062] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/05/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022] Open
Abstract
SNAI1, a zinc finger transcription factor, not only acts as the master regulator of epithelial-mesenchymal transition (EMT) but also functions as a driver of cancer progression, including cell invasion, survival, immune regulation, stem cell properties, and metabolic regulation. The regulation of SNAI1 occurs at the transcriptional, translational, and predominant post-translational levels including phosphorylation, acetylation, and ubiquitination. Here, we discuss the regulation and role of SNAI1 in cancer metastasis, with a particular emphasis on epigenetic regulation and post-translational modifications. Understanding how signaling networks integrate with SNAI1 in cancer progression will shed new light on the mechanism of tumor metastasis and help develop novel therapeutic strategies against cancer metastasis.
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17
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Peng T, Huang Y, Feng X, Zhu C, Yin S, Wang X, Bai X, Pan X, Wu C. TPGS/hyaluronic acid dual-functionalized PLGA nanoparticles delivered through dissolving microneedles for markedly improved chemo-photothermal combined therapy of superficial tumor. Acta Pharm Sin B 2021; 11:3297-3309. [PMID: 34729317 PMCID: PMC8546669 DOI: 10.1016/j.apsb.2020.11.013] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 08/21/2020] [Accepted: 08/28/2020] [Indexed: 12/18/2022] Open
Abstract
Nanoparticles (NPs) have shown potential in cancer therapy, while a single administration conferring a satisfactory outcome is still unavailable. To address this issue, the dissolving microneedles (DMNs) were developed to locally deliver functionalized NPs with combined chemotherapy and photothermal therapy (PTT). α-Tocopheryl polyethylene glycol succinate (TPGS)/hyaluronic acid (HA) dual-functionalized PLGA NPs (HD10 NPs) were fabricated to co-load paclitaxel and indocyanine green. HD10 NPs significantly enhanced the cytotoxicity of low-dose paclitaxel because of active and mitochondrial targeting by HA and TPGS, respectively. PTT could further sensitize tumor cells toward chemotherapy by promoting apoptosis into the advanced period, highly activating caspase 3 enzyme, and significantly reducing the expression of survivin and MMP-9 proteins. Further, the anti-tumor effects of HD10 NPs delivered through different administration routes were conducted on the 4T1 tumor-bearing mice. After a single administration, HD10 NPs delivered with DMNs showed the best anti-tumor effect when giving chemotherapy alone. As expected, the anti-tumor effect was profoundly enhanced after combined therapy, and complete tumor ablation was achieved in the mice treated with DMNs and intra-tumor injection. Moreover, DMNs showed better safety due to moderate hyperthermia. Therefore, the DMNs along with combined chemo-photothermal therapy provide a viable treatment option for superficial tumors.
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Affiliation(s)
- Tingting Peng
- College of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Yao Huang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Xiaoqian Feng
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Chune Zhu
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Shi Yin
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Xinyi Wang
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510055, China
| | - Xuequn Bai
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Xin Pan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
- Corresponding authors.
| | - Chuanbin Wu
- College of Pharmacy, Jinan University, Guangzhou 510632, China
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
- Corresponding authors.
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18
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Ristescu AI, Tiron CE, Tiron A, Grigoras I. Exploring Hyperoxia Effects in Cancer-From Perioperative Clinical Data to Potential Molecular Mechanisms. Biomedicines 2021; 9:1213. [PMID: 34572400 PMCID: PMC8470547 DOI: 10.3390/biomedicines9091213] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/06/2021] [Accepted: 09/10/2021] [Indexed: 12/15/2022] Open
Abstract
Increased inspiratory oxygen concentration is constantly used during the perioperative period of cancer patients to prevent the potential development of hypoxemia and to provide an adequate oxygen transport to the organs, tissues and cells. Although the primary tumours are surgically removed, the effects of perioperative hyperoxia exposure on distal micro-metastases and on circulating cancer cells can potentially play a role in cancer progression or recurrence. In clinical trials, hyperoxia seems to increase the rate of postoperative complications and, by delaying postoperative recovery, it can alter the return to intended oncological treatment. The effects of supplemental oxygen on the long-term mortality of surgical cancer patients offer, at this point, conflicting results. In experimental studies, hyperoxia effects on cancer biology were explored following multiple pathways. In cancer cell cultures and animal models, hyperoxia increases the production of reactive oxygen species (ROS) and increases the oxidative stress. These can be followed by the induction of the expression of Brain-derived neurotrophic factor (BDNF) and other molecules involved in angiogenesis and by the promotion of various degrees of epithelial mesenchymal transition (EMT).
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Affiliation(s)
- Anca Irina Ristescu
- Department of Anaesthesia and Intensive Care, School of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.I.R.); (I.G.)
- Department of Anaesthesia and Intensive Care, Regional Institute of Oncology, 700483 Iasi, Romania
| | - Crina Elena Tiron
- TRANSCEND Research Centre, Regional Institute of Oncology, 700483 Iasi, Romania;
| | - Adrian Tiron
- TRANSCEND Research Centre, Regional Institute of Oncology, 700483 Iasi, Romania;
| | - Ioana Grigoras
- Department of Anaesthesia and Intensive Care, School of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.I.R.); (I.G.)
- Department of Anaesthesia and Intensive Care, Regional Institute of Oncology, 700483 Iasi, Romania
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19
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Lin CW, Zheng T, Grande G, Nanna AR, Rader C, Lerner RA. A new immunochemical strategy for triple-negative breast cancer therapy. Sci Rep 2021; 11:14875. [PMID: 34290315 PMCID: PMC8295383 DOI: 10.1038/s41598-021-94230-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 07/05/2021] [Indexed: 01/17/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly diverse group of malignant neoplasms which tend to have poor outcomes, and the development of new targets and strategies to treat these cancers is sorely needed. Antibody-drug conjugate (ADC) therapy has been shown to be a promising targeted therapy for treating many cancers, but has only rarely been tried in patients with TNBC. A major reason the efficacy of ADC therapy in the setting of TNBC has not been more fully investigated is the lack of appropriate target molecules. In this work we were able to identify an effective TNBC target for use in immunotherapy. We were guided by our previous observation that in some breast cancer patients the protein tropomyosin receptor kinase B cell surface protein (TrkB) had become immunogenic, suggesting that it was somehow sufficiently chemically different enough (presumably by mutation) to escaped immune tolerance. We postulated that this difference might well offer a means for selective targeting by antibodies. We engineered site-specific ADCs using a dual variable domain (DVD) format which combines anti-TrkB antibody with the h38C2 catalytic antibody. This format enables rapid, one-step, and homogeneous conjugation of β-lactam-derivatized drugs. Following conjugation to β-lactam-derivatized monomethyl auristatin F, the TrkB-targeting DVD-ADCs showed potency against multiple breast cancer cell lines, including TNBC cell lines. In addition, our isolation of antibody that specifically recognized the breast cancer-associated mutant form of TrkB, but not the wild type TrkB, indicates the possibility of further refining the selectivity of anti-TrkB DVD-ADCs, which should enhance their therapeutic index. These results confirmed our supposition that TrkB is a potential target for immunotherapy for TNBC, as well as for other cancers with mutated cell surface proteins.
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Affiliation(s)
- Chih-Wei Lin
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Tianqing Zheng
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Geramie Grande
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037, USA
| | - Alex R Nanna
- Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, 33458, USA
| | - Christoph Rader
- Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, 33458, USA
| | - Richard A Lerner
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037, USA.
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Tuli HS, Aggarwal V, Tuorkey M, Aggarwal D, Parashar NC, Varol M, Savla R, Kaur G, Mittal S, Sak K. Emodin: A metabolite that exhibits anti-neoplastic activities by modulating multiple oncogenic targets. Toxicol In Vitro 2021; 73:105142. [PMID: 33722736 DOI: 10.1016/j.tiv.2021.105142] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/11/2021] [Accepted: 03/09/2021] [Indexed: 12/19/2022]
Abstract
Oncogenic transformation has been the major cause of global mortality since decades. Despite established therapeutic regimes, majority of cancer patients either present with tumor relapse, refractory disease or therapeutic resistance. Numerous drug candidates are being explored to tap the key reason being poor tumor remission rates, from novel chemotherapy agents to immunotherapy to exploring natural compound derivatives with effective anti-cancer potential. One of these natural product metabolites, emodin has present with significant potential to target tumor oncogenic processes: induction of apoptosis and cell cycle arrest, tumor angiogenesis, and metastasis to chemoresistance in malignant cells. Based on the present scientific excerpts on safety and effectiveness of emodin in targeting hallmarks of tumor progression, emodin is being promisingly explored using nanotechnology platforms for long-term sustained treatment and management of cancer patients. In this review, we summarize the up-to-date scientific literature supporting the anti-neoplastic potential of emodin. We also provide an insight into toxicity and safety profile of emodin and how emodin has emerged as an effective therapeutic alternative in synergism with established conventional chemotherapeutic regimes for management and treatment of tumor progression.
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Affiliation(s)
- Hardeep Singh Tuli
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana 133207, India.
| | - Vaishali Aggarwal
- Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, USA
| | - Muobarak Tuorkey
- Division of Physiology, Zoology Department, Faculty of Science, Damanhour University, Damanhour, Egypt
| | - Diwakar Aggarwal
- Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana 133207, India
| | | | - Mehmet Varol
- Department of Molecular Biology and Genetics, Faculty of Science, Kotekli Campus, Mugla Sitki Kocman University, Mugla TR48000, Turkey
| | - Raj Savla
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's NMIMS, Mumbai 56, Maharashtra, India
| | - Ginpreet Kaur
- Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's NMIMS, Mumbai 56, Maharashtra, India
| | - Sonam Mittal
- School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
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21
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Addison JB, Voronkova MA, Fugett JH, Lin CC, Linville NC, Trinh B, Livengood RH, Smolkin MB, Schaller MD, Ruppert JM, Pugacheva EN, Creighton CJ, Ivanov AV. Functional Hierarchy and Cooperation of EMT Master Transcription Factors in Breast Cancer Metastasis. Mol Cancer Res 2021; 19:784-798. [PMID: 33500360 PMCID: PMC8137545 DOI: 10.1158/1541-7786.mcr-20-0532] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 11/23/2020] [Accepted: 01/21/2021] [Indexed: 11/16/2022]
Abstract
Several master transcription factors (TF) can activate the epithelial-to-mesenchymal transition (EMT). However, their individual and combinatorial contributions to EMT in breast cancer are not defined. We show that overexpression of EMT-TFs individually in epithelial cells upregulated endogenous SNAI2, ZEB1/2, TCF4, and TWIST1/2 as a result of positive feedback mediated in part by suppression of their negative regulator miRNAs miR200s/203/205. We identified TCF4 as a potential new target of miR200s. Expression of ZEB1/2 strongly correlated with the mesenchymal phenotype in breast cancer cells, with the CD24-/CD44+ stemness profile, and with lower expression of core epithelial genes in human breast tumors. Knockdown of EMT-TFs identified the key role of ZEB1 and its functional cooperation with other EMT-TFs in the maintenance of the mesenchymal state. Inducible ZEB1+2 knockdown in xenograft models inhibited pulmonary metastasis, emphasizing their critical role in dissemination from primary site and in extravasation. However, ZEB1+2 depletion one-week after intravenous injection did not inhibit lung colonization, suggesting that ZEB1/2 and EMT are not essential for macrometastatic outgrowth. These results provide strong evidence that EMT is orchestrated by coordinated expression of several EMT-TFs and establish ZEB1 as a key master regulator of EMT and metastasis in breast cancer. IMPLICATIONS: The EMT program is orchestrated by coordinated expression of multiple EMT transcription factors, whereas ZEB1 integrates the EMT master regulatory network and plays the major role in promoting EMT and metastasis.
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Affiliation(s)
- Joseph B Addison
- WVU Cancer Institute and Department of Biochemistry, West Virginia University, Morgantown, West Virginia
| | - Maria A Voronkova
- WVU Cancer Institute and Department of Biochemistry, West Virginia University, Morgantown, West Virginia
| | - James H Fugett
- WVU Cancer Institute and Department of Biochemistry, West Virginia University, Morgantown, West Virginia
| | - Chen-Chung Lin
- WVU Cancer Institute and Department of Biochemistry, West Virginia University, Morgantown, West Virginia
| | - Nathaniel C Linville
- WVU Cancer Institute and Department of Biochemistry, West Virginia University, Morgantown, West Virginia
| | - Brandon Trinh
- WVU Cancer Institute and Department of Biochemistry, West Virginia University, Morgantown, West Virginia
| | - Ryan H Livengood
- Department of Pathology, West Virginia University, Morgantown, West Virginia
| | - Matthew B Smolkin
- Department of Pathology, West Virginia University, Morgantown, West Virginia
| | - Michael D Schaller
- WVU Cancer Institute and Department of Biochemistry, West Virginia University, Morgantown, West Virginia
| | - J Michael Ruppert
- WVU Cancer Institute and Department of Biochemistry, West Virginia University, Morgantown, West Virginia
| | - Elena N Pugacheva
- WVU Cancer Institute and Department of Biochemistry, West Virginia University, Morgantown, West Virginia
| | - Chad J Creighton
- Department of Medicine and Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, Texas
| | - Alexey V Ivanov
- WVU Cancer Institute and Department of Biochemistry, West Virginia University, Morgantown, West Virginia.
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22
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Clinical Relevance of Mesenchymal- and Stem-Associated Phenotypes in Circulating Tumor Cells Isolated from Lung Cancer Patients. Cancers (Basel) 2021; 13:cancers13092158. [PMID: 33947159 PMCID: PMC8124761 DOI: 10.3390/cancers13092158] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/16/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Lung cancer is the most frequent malignancy in the world. Most lung cancer patients are diagnosed at an advanced stage. To make matters worse, the survival of patients is very poor. Circulating tumor cells (CTCs), albeit rare, have been portrayed as essential players in the progression of lung cancer. It is definitely not easy being a CTC. First, they escape from the primary tumor, then they travel in the bloodstream, have to survive really harsh conditions, and finally, they form metastases. The adoption of epithelial-to-mesenchymal transition as well as cancer stem cell features has been suggested to allow CTCs to survive and metastasize. This review will focus on how these features can be used to estimate the prognosis of lung cancer patients. Abstract Lung cancer is the leading cause of cancer-related mortality globally. Among the types of lung cancer, non-small-cell lung cancer (NSCLC) is more common, while small-cell lung cancer (SCLC) is less frequent yet more aggressive. Circulating tumor cells (CTCs), albeit rare, have been portrayed as essential players in the progression of lung cancer. CTCs are considered to adopt an epithelial-to-mesenchymal transition (EMT) phenotype and characteristics of cancer stem cells (CSCs). This EMT (or partial) phenotype affords these cells the ability to escape from the primary tumor, travel into the bloodstream, and survive extremely adverse conditions, before colonizing distant foci. Acquisition of CSC features, such as self-renewal, differentiation, and migratory potential, further reflect CTCs’ invasive potential. CSCs have been identified in lung cancer, and expression of EMT markers has previously been correlated with poor clinical outcomes. Thus far, a vast majority of studies have concentrated on CTC detection and enumeration as a prognostic tools of patients’ survival or for monitoring treatment efficacy. In this review, we highlight EMT and CSC markers in CTCs and focus on the clinical significance of these phenotypes in the progression of both non-small- and small-cell lung cancer.
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Fatemipour M, Nahand JS, Fard Azar ME, Baghi HB, Taghizadieh M, Sorayyayi S, Hussen BM, Mirzaei H, Moghoofei M, Bokharaei-Salim F. Human papillomavirus and prostate cancer: The role of viral expressed proteins in the inhibition of anoikis and induction of metastasis. Microb Pathog 2021; 152:104576. [PMID: 33086103 DOI: 10.1016/j.micpath.2020.104576] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND The aim of this study is to address the role of HPV in prostate cancer (PCa) development through the inducement of resistance to anoikis. METHODS In this case-control study, prostate tissues and blood samples were collected from 116 individuals, including 72 cases with PCa and 44 non-malignant prostate tissue samples as a control group. The expression level of HPV genes (E2, E6, and E7) and cellular genes including anti-apoptotic mediators (Bcl-2 and survivin), tumor suppressor proteins (Rb and p53), and some mediators involved in anoikis resistance and invasiveness (E-cadherin, N-cadherin, Twist, PTPN13 and SLUG) were evaluated. RESULTS HPV genome was identified in 36.1% cases and 15.9% control samples, additionally there was found to be a statistic significant association between the presence of HPV and PCa (OR = 1.64, 95% C.I = 0.8-1.8, P-value = 0.023). HPV genotype 16 and 18 were the most prevalent genotype in both in the PCa group and the control group. The expression level of the tumor suppressor proteins (Rb and p53) and anti-apoptotic mediators (Bcl-2 and Survivin) were significantly decreased and increased, respectively, in the HPV-positive specimens compared to the HPV-negative specimens. Furthermore, the mean expression level of N-cadherin, SLUG, and TWIST in the HPV-positive specimens was higher than HPV-negative specimens while the mean expression level of PTPN-13 and E-cadherin genes in the HPV-positive specimens was lower than HPV-negative specimens. CONCLUSION Our study suggests that HPV infection may be involved in the development of PCa metastases by modulating anoikis resistance related genes.
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Affiliation(s)
- Maryam Fatemipour
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Javid Sadri Nahand
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women's Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saba Sorayyayi
- Department of Clinical Biochemistry, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohsen Moghoofei
- Department of Microbiology, Faculty of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Farah Bokharaei-Salim
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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24
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Wan X, Hou J, Liu S, Zhang Y, Li W, Zhang Y, Ding Y. Estrogen Receptor α Mediates Doxorubicin Sensitivity in Breast Cancer Cells by Regulating E-Cadherin. Front Cell Dev Biol 2021; 9:583572. [PMID: 33614637 PMCID: PMC7889969 DOI: 10.3389/fcell.2021.583572] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 01/11/2021] [Indexed: 12/31/2022] Open
Abstract
Anthracyclines resistance is commonly seen in patients with estrogen receptor α (ERα) positive breast cancer. Epithelial-mesenchymal transition (EMT), which is characterized with the loss of epithelial cell polarity, cell adhesion and acquisition of new invasive property, is considered as one of the mechanisms of chemotherapy-induced drug resistance. In order to identify factors that associated with doxorubicin resistance, we performed in vitro and in vivo experiments using human and mouse breast cancer cell lines with different ERα status. Cell survival experiments revealed that ERα-positive cells (MCF-7 and MCF-7/ADR cell lines), were less sensitive to doxorubicin than ERα-negative (MDA-MB-231, MDA-MB-468) cells, and mouse mammary carcinoma cells (4T-1). The expression of E-cadherin reduced in low-invasive ERα-positive MCF-7 cells after treatment with doxorubicin, indicating epithelial mesenchymal transition. In contrast, the expression of E-cadherin was upregulated in high-invasive ERα-negative cells, showing mesenchymal-epithelial transition (MET). Moreover, it was found that the growth inhibition of 4T-1 cells by doxorubicin was positively correlated with the expression of E-cadherin. In a mouse breast cancer xenograft model, E-cadherin was overexpressed in the primary tumor tissues of the doxorubicin-treated mice. In ERα-positive MCF-7 cells, doxorubicin treatment upregulated the expression of EMT-related transcription factors Snail and Twist, that regulate the expression of E-cadherin. Following overexpression of ERα in ERα-negative cells (MDA-MB-231 and MDA-MB-468), doxorubicin enhanced the upregulation of Snail and Twist, decreased expression of E-cadherin, and decreased the sensitivity of cells to doxorubicin. In contrast, inhibition of ERα activity increased the sensitivity to doxorubicin in ERα-positive MCF-7 cells. These data suggest that the regulation of Snail and/or Twist varies depends on different ERα status. Therefore, doxorubicin combined with anti-estrogen receptor α therapy could improve the treatment efficacy of doxorubicin in ERα-positive breast cancer.
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Affiliation(s)
- Xiaoqing Wan
- Laboratory of Molecular Oncology, Weifang Medical University, Weifang, China.,Department of Pathophysiology, Weifang Medical University, Weifang, China
| | - Jiaxin Hou
- School of Physical Education & Sports Science, Qufu Normal University, Qufu, China
| | - Shurong Liu
- Laboratory of Molecular Oncology, Weifang Medical University, Weifang, China
| | - Yanli Zhang
- Department of Pathophysiology, Weifang Medical University, Weifang, China
| | - Wenqing Li
- Laboratory of Molecular Oncology, Weifang Medical University, Weifang, China
| | - Yanru Zhang
- Laboratory of Molecular Oncology, Weifang Medical University, Weifang, China
| | - Yi Ding
- Department of Pathophysiology, Weifang Medical University, Weifang, China.,Key Laboratory of Applied Pharmacology, Weifang Medical University, Weifang, China
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25
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Ghafouri-Fard S, Abak A, Bahroudi Z, Shoorei H, Abbas Raza SH, Taheri M. The interplay between non-coding RNAs and Twist1 signaling contribute to human disorders. Biomed Pharmacother 2021; 135:111220. [PMID: 33433357 DOI: 10.1016/j.biopha.2021.111220] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 12/23/2020] [Accepted: 12/31/2020] [Indexed: 12/14/2022] Open
Abstract
Twist-related protein 1 (Twist1) is a basic helix-loop-helix (bHLH) transcription factor (TF) being coded by the TWIST1 gene. This TF has a fundamental effect on the normal development and in the pathogenesis of various diseases especially cancer. Twist1 has interactions with some long non-coding RNAs and miRNAs. The interactions between this TF and various miRNAs such as miR-16, miR-26b-5p, miR-1271, miR-539, miR-214, miR-200b/c, miR-335, miR-10b, and miR-381 are implicated in the carcinogenic processes. TP73-AS1, LINC01638, ATB, NONHSAT101069, CASC15, H19, PVT1, LINC00339, LINC01385, TANAR, SNHG5, DANCR, CHRF, and TUG1 are among long non-coding RNAs which interact with Twist1 and participate in the carcinogenesis. This review aims at depicting the interaction between these non-coding transcripts and Twist1 and the consequence of these interactions in human neoplasms.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atefe Abak
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Bahroudi
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Biranjd University of Medical Sciences, Birjand, Iran
| | - Sayed Haidar Abbas Raza
- College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang, China
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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26
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Xu S, Zhou Y, Biekemitoufu H, Wang H, Li C, Zhang W, Ma Y. Expression of Twist, Slug and Snail in esophageal squamous cell carcinoma and their prognostic significance. Oncol Lett 2021; 21:184. [PMID: 33574923 PMCID: PMC7816285 DOI: 10.3892/ol.2021.12445] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 12/08/2020] [Indexed: 12/24/2022] Open
Abstract
Esophageal cancer is one of the most common types of malignancy worldwide. At present, surgical resection is the main treatment for esophageal cancer, but recurrence and distant metastasis are the main causes of mortality. The transcription factors Twist, Slug and Snail regulate epithelial-mesenchymal transition and thereby participate in tumor invasion and metastasis. The aim of the present study was to investigate the expression of Twist, Slug and Snail in esophageal squamous cell carcinoma (ESCC) and their prognostic significance. The expression of Twist, Slug and Snail in 229 paraffin-embedded ESCC and matched normal mucosal tissues was detected by immunohistochemistry. The expression differences of Twist, Slug and Snail in the ESCC and normal tissues were compared by χ2 test, and the associations between the three proteins and the clinicopathological parameters of ESCC were analyzed. The expression levels of Twist, Slug and Snail in 29 fresh frozen ESCC and matched normal mucosal tissues were detected by reverse transcription-quantitative PCR. The correlations among Twist, Slug and Snail in ESCC were examined by Pearson's correlation analyses. In addition, single factor and multivariate Cox regression analyses were used to analyze the influence of Twist, Slug and Snail on the prognosis of ESCC. Twist was found to be highly expressed in ESCC. The difference of Slug expression in ESCC was associated with differentiation degree, TNM stage and vascular invasion, but no significant association was observed between Snail expression and any clinicopathological parameters. In ESCC, there were significant differences in protein expression between Twist and Snail, and Slug and Snail. The mRNA expression level of Twist in ESCC was significantly higher than that in normal esophageal mucosa. However, the mRNA expression of Slug in normal esophageal mucosa was higher than that in ESCC, and the mRNA expression levels of Twist and Snail were positively correlated in ESCC. Kaplan-Meier analysis of 229 patients with ESCC revealed that Snail influenced the overall survival, as did the co-expression of Twist and Snail. Nerve invasion was also identified as an independent factor affecting the progression-free survival of ESCC. The results indicate that Twist is highly expressed, Slug may be a tumor suppressor, and Snail is an independent prognostic factor in ESCC. Twist and Snail are positively correlated, and the simultaneous inhibition of Twist and Snail protein expression may be beneficial for prolonging the overall survival of patients with ESCC.
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Affiliation(s)
- Shanshan Xu
- Department of Pathology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Yaxing Zhou
- Department of Pathology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Hadeti Biekemitoufu
- Department of Pathology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Hui Wang
- Department of Pathology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Chao Li
- Department of Respiratory Intensive Care Unit, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Wenjing Zhang
- Department of Pathology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
| | - Yuqing Ma
- Department of Pathology, The First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China
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Stock C. Circulating Tumor Cells: Does Ion Transport Contribute to Intravascular Survival, Adhesion, Extravasation, and Metastatic Organotropism? Rev Physiol Biochem Pharmacol 2021; 182:139-175. [DOI: 10.1007/112_2021_68] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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28
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Peyre L, Meyer M, Hofman P, Roux J. TRAIL receptor-induced features of epithelial-to-mesenchymal transition increase tumour phenotypic heterogeneity: potential cell survival mechanisms. Br J Cancer 2021; 124:91-101. [PMID: 33257838 PMCID: PMC7782794 DOI: 10.1038/s41416-020-01177-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 02/07/2023] Open
Abstract
The continuing efforts to exploit the death receptor agonists, such as the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), for cancer therapy, have largely been impaired by the anti-apoptotic and pro-survival signalling pathways leading to drug resistance. Cell migration, invasion, differentiation, immune evasion and anoikis resistance are plastic processes sharing features of the epithelial-to-mesenchymal transition (EMT) that have been shown to give cancer cells the ability to escape cell death upon cytotoxic treatments. EMT has recently been suggested to drive a heterogeneous cellular environment that appears favourable for tumour progression. Recent studies have highlighted a link between EMT and cell sensitivity to TRAIL, whereas others have highlighted their effects on the induction of EMT. This review aims to explore the molecular mechanisms by which death signals can elicit an increase in response heterogeneity in the metastasis context, and to evaluate the impact of these processes on cell responses to cancer therapeutics.
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Affiliation(s)
- Ludovic Peyre
- Université Côte d'Azur, CNRS UMR 7284, Inserm U 1081, Institut de Recherche sur le Cancer et le Vieillissement de Nice (IRCAN), Centre Antoine Lacassagne, 06107, Nice, France
| | - Mickael Meyer
- Université Côte d'Azur, CNRS UMR 7284, Inserm U 1081, Institut de Recherche sur le Cancer et le Vieillissement de Nice (IRCAN), Centre Antoine Lacassagne, 06107, Nice, France
| | - Paul Hofman
- Université Côte d'Azur, CNRS UMR 7284, Inserm U 1081, Institut de Recherche sur le Cancer et le Vieillissement de Nice (IRCAN), Centre Antoine Lacassagne, 06107, Nice, France
| | - Jérémie Roux
- Université Côte d'Azur, CNRS UMR 7284, Inserm U 1081, Institut de Recherche sur le Cancer et le Vieillissement de Nice (IRCAN), Centre Antoine Lacassagne, 06107, Nice, France.
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Okabe T, Togo S, Fujimoto Y, Watanabe J, Sumiyoshi I, Orimo A, Takahashi K. Mesenchymal Characteristics and Predictive Biomarkers on Circulating Tumor Cells for Therapeutic Strategy. Cancers (Basel) 2020; 12:E3588. [PMID: 33266262 PMCID: PMC7761066 DOI: 10.3390/cancers12123588] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 12/22/2022] Open
Abstract
Metastasis-related events are the primary cause of cancer-related deaths, and circulating tumor cells (CTCs) have a pivotal role in metastatic relapse. CTCs include a variety of subtypes with different functional characteristics. Interestingly, the epithelial-mesenchymal transition (EMT) markers expressed in CTCs are strongly associated with poor clinical outcome and related to the acquisition of circulating tumor stem cell (CTSC) features. Recent studies have revealed the existence of CTC clusters, also called circulating tumor microemboli (CTM), which have a high metastatic potential. In this review, we present current opinions regarding the clinical significance of CTCs and CTM with a mesenchymal phenotype as clinical surrogate markers, and we summarize the therapeutic strategy according to phenotype characterization of CTCs in various types of cancers for future precision medicine.
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Affiliation(s)
- Takahiro Okabe
- Leading Center for the Development and Research of Cancer Medicine, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan;
| | - Shinsaku Togo
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Yuichi Fujimoto
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Junko Watanabe
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Issei Sumiyoshi
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Akira Orimo
- Departments of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan;
| | - Kazuhisa Takahashi
- Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; (Y.F.); (J.W.); (I.S.); (K.T.)
- Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
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SNAIL Transctiption factor in prostate cancer cells promotes neurite outgrowth. Biochimie 2020; 180:1-9. [PMID: 33132158 DOI: 10.1016/j.biochi.2020.10.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 10/19/2020] [Accepted: 10/22/2020] [Indexed: 01/22/2023]
Abstract
Neurite outgrowth involves reciprocal signaling interactions between tumor cells and nerves where invading tumor cells have acquired the ability to respond to pro-invasive signals within the nerve environment. Neurite outgrowth could serve as a mechanism leading to invasion of cancer cells into the nerve sheath and subsequent metastasis. Snail transcription factor can promote migration and invasion of prostate cancer cells. We hypothesized that prostate cancer cell interaction with nerve cells will be mediated by Snail expression within prostate cancer cells. For this study we utilized various prostate cancer cell lines: C4-2 non-silencing (NS, control); C4-2 Snail shRNA, (stable Snail knockdown); LNCaP Neo (empty vector control) and LNCaP Snail (stably over-expressing Snail). Cancer cell adhesion and migration towards nerve cells (snF96.2 or NS20Y) was examined by co-culture assays. Conditioned media (CM) collected from C4-2 cells was cultured with nerve cells (PC-12 or NS20Y) for 48 h followed by qualitative or quantitative neurite outgrowth assay. Our results showed that cancer cells expressing high levels of Snail (LNCaP Snail/C4-2 NS) displayed significantly higher migration adherence to nerve cells, compared to cells with lower levels of Snail (LNCaP Neo/C4-2 Snail shRNA). Additionally, LNCaP Snail or C4-2 NS (Snail-high) CM led to a higher neurite outgrowth compared to the LNCaP Neo or C4-2 Snail shRNA (Snail-low). In conclusion, Snail promotes migration and adhesion to nerve cells, as well as neurite outgrowth via secretion of soluble factors. Therefore, targeting cancer cell interaction with nerves may contribute to halting prostate cancer progression/metastasis.
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Hu Q, Masuda T, Kuramitsu S, Tobo T, Sato K, Kidogami S, Nambara S, Ueda M, Tsuruda Y, Kuroda Y, Ito S, Oki E, Mori M, Mimori K. Potential association of LOXL1 with peritoneal dissemination in gastric cancer possibly via promotion of EMT. PLoS One 2020; 15:e0241140. [PMID: 33095806 PMCID: PMC7584171 DOI: 10.1371/journal.pone.0241140] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 10/08/2020] [Indexed: 12/27/2022] Open
Abstract
Background Peritoneal dissemination (PD) frequently occurs in gastric cancer (GC) and is incurable. In this study, we aimed to identify novel PD-associated genes and clarify their clinical and biological significance in GC. Materials and methods We identified LOXL1 as a PD-associated candidate gene by in silico analysis of GC datasets (highly disseminated peritoneal GC cell line and two freely available GC datasets, GSE15459 and TCGA). Next, we evaluated the clinical significance of LOXL1 expression using RT-qPCR and immunohistochemistry staining (IHC) in a validation cohort (Kyushu cohort). Moreover, we performed gene expression analysis, including gene set enrichment analysis (GSEA) with GSE15459 and TCGA datasets. Finally, we performed a series of in vitro experiments using GC cells. Results In silico analysis showed that LOXL1 was overexpressed in tumor tissues of GC patients with PD and in highly disseminated peritoneal GC cells, relative to that in the control GC patients and cells, respectively. High expression of LOXL1 was a poor prognostic factor in the TCGA dataset. Next, IHC showed that LOXL1 was highly expressed in GC cells. High LOXL1 mRNA expression was associated with poorly differentiated histological type, lymph node metastasis, and was an independent poor prognostic factor in the Kyushu validation cohort. Moreover, LOXL1 expression was positively correlated with the EMT (epithelial-mesenchymal transition) gene set in GSEA. Finally, LOXL1-overexpressing GC cells changed their morphology to a spindle-like form. LOXL1 overexpression reduced CDH1 expression; increased the expression of VIM, CDH2, SNAI2, and PLS3; and promoted the migration capacity of GC cells. Conclusions LOXL1 is associated with PD in GC, possibly through the induction of EMT.
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Affiliation(s)
- Qingjiang Hu
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
- Department of Surgery and Science, Kyushu University Hospital, Fukuoka, Japan
| | - Takaaki Masuda
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Shotaro Kuramitsu
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Taro Tobo
- Department of Clinical Laboratory Medicine, Kyushu University Beppu Hospital, Beppu, Japan
| | - Kuniaki Sato
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Shinya Kidogami
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Sho Nambara
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Masami Ueda
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Yusuke Tsuruda
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Yosuke Kuroda
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Shuhei Ito
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
| | - Eiji Oki
- Department of Surgery and Science, Kyushu University Hospital, Fukuoka, Japan
| | - Masaki Mori
- Department of Surgery and Science, Kyushu University Hospital, Fukuoka, Japan
| | - Koshi Mimori
- Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan
- * E-mail:
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Tasdemir N, Ding K, Savariau L, Levine KM, Du T, Elangovan A, Bossart EA, Lee AV, Davidson NE, Oesterreich S. Proteomic and transcriptomic profiling identifies mediators of anchorage-independent growth and roles of inhibitor of differentiation proteins in invasive lobular carcinoma. Sci Rep 2020; 10:11487. [PMID: 32661241 PMCID: PMC7359337 DOI: 10.1038/s41598-020-68141-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 06/19/2020] [Indexed: 12/11/2022] Open
Abstract
Invasive lobular carcinoma (ILC) is a histological subtype of breast cancer with distinct molecular and clinical features from the more common subtype invasive ductal carcinoma (IDC). ILC cells exhibit anchorage-independent growth in ultra-low attachment (ULA) suspension cultures, which is largely attributed to the loss of E-cadherin. In addition to anoikis resistance, herein we show that human ILC cell lines exhibit enhanced cell proliferation in ULA cultures as compared to IDC cells. Proteomic comparison of ILC and IDC cell lines identified induction of PI3K/Akt and p90-RSK pathways specifically in ULA culture in ILC cells. Further transcriptional profiling uncovered unique upregulation of the inhibitors of differentiation family transcription factors ID1 and ID3 in ILC ULA culture, the knockdown of which diminished the anchorage-independent growth of ILC cell lines through cell cycle arrest. We find that ID1 and ID3 expression is higher in human ILC tumors as compared to IDC, correlated with worse prognosis uniquely in patients with ILC and associated with upregulation of angiogenesis and matrisome-related genes. Altogether, our comprehensive study of anchorage independence in human ILC cell lines provides mechanistic insights and clinical implications for metastatic dissemination of ILC and implicates ID1 and ID3 as novel drivers and therapeutic targets for lobular breast cancer.
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Affiliation(s)
- Nilgun Tasdemir
- Women's Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Kai Ding
- Women's Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA
- Integrative Systems Biology Program, University of Pittsburgh, Pittsburgh, PA, USA
| | - Laura Savariau
- Women's Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA
- Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, 15261, USA
| | - Kevin M Levine
- Women's Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA
| | - Tian Du
- Women's Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA
- School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Ashuvinee Elangovan
- Women's Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA
- Molecular Genetics and Developmental Biology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Emily A Bossart
- Women's Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Adrian V Lee
- Women's Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Nancy E Davidson
- Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
- University of Washington, Seattle, WA, 98195, USA
| | - Steffi Oesterreich
- Women's Cancer Research Center, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center (HCC), Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, PA, 15213, USA.
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
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Pierce CJ, Simmons JL, Broit N, Karunarathne D, Ng MF, Boyle GM. BRN2 expression increases anoikis resistance in melanoma. Oncogenesis 2020; 9:64. [PMID: 32632141 PMCID: PMC7338542 DOI: 10.1038/s41389-020-00247-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 06/11/2020] [Accepted: 06/16/2020] [Indexed: 11/08/2022] Open
Abstract
Melanoma tumors are highly heterogeneous, comprising of many cell populations that vary in their potential for growth and invasion. Differential transcription factor expression contributes to these phenotypic traits. BRN2, a member of the POU domain family of transcription factors is thought to play important roles in melanoma invasion and metastasis. However, the function of BRN2 during the metastatic process of melanoma remains largely unknown. We therefore investigated the effect of BRN2 expression in melanoma cells with no or low constitutive expression using a doxycycline-inducible system. Induction of BRN2 expression led to reduced proliferation and partial resistance to an inhibitor of mutated BRAF. Whole-genome profiling analysis revealed novel targets and signaling pathway changes related to prevention of cell death induced by detachment from the extracellular matrix, known as anoikis resistance. Further investigation confirmed increased survival of BRN2-expressing cell lines in non-adherent conditions. Functionally, expression of BRN2 promoted induction of c-MET levels as well as increased phosphorylation of STAT3. Treatment with crizotinib, a c-MET inhibitor, decreased cellular viability of BRN2-expressing cells under non-adherent conditions to death by anoikis. Alternative inhibitors of c-MET showed similar results. These results highlight the importance of a largely overlooked transcription factor in the progression and metastasis of melanoma, and may suggest a strategy to target BRN2-expressing cells resistant to therapy and cell death by anoikis.
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Affiliation(s)
- Carly J Pierce
- Cancer Drug Mechanisms Group, Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Jacinta L Simmons
- Cancer Drug Mechanisms Group, Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Natasa Broit
- Cancer Drug Mechanisms Group, Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Deshapriya Karunarathne
- Molecular Immunology Group, Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Mei Fong Ng
- Cancer Drug Mechanisms Group, Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - Glen M Boyle
- Cancer Drug Mechanisms Group, Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
- School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
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34
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Kim MS, Jin W. TrkB-Induced Inhibition of R-SMAD/SMAD4 Activation is Essential for TGF-β-Mediated Tumor Suppressor Activity. Cancers (Basel) 2020; 12:cancers12041048. [PMID: 32340410 PMCID: PMC7226331 DOI: 10.3390/cancers12041048] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 04/08/2020] [Accepted: 04/13/2020] [Indexed: 12/24/2022] Open
Abstract
TrkB-mediated activation of the IL6/JAK2/STAT3 signaling pathway is associated with the induction of the epithelial–mesenchymal transition (EMT) program and the acquisition of metastatic potential by tumors. Conversely, the transforming of growth factor-β (TGF-β) is implicated in tumor suppression through the canonical SMAD-dependent signaling pathway. Hence, TrkB could play a role in disrupting the potent TGF-β-mediated growth inhibition, a concept that has not been fully explored. Here, we identified TrkB to be a crucial regulator of the TGF-β signaling pathway as it inhibits the TGF-β-mediated tumor suppression and the activation of TrkB kinase. We further show that the interactions between TrkB and SMADs inhibit TGF-β-mediated R-SMAD/SMAD4 complex formation and suppress TGF-β-induced nuclear translocation and target gene expression. Additionally, the knockdown of TrkB restored the tumor inhibitory activity of TGF-β signaling. These observations suggest that interactions between TrkB and SMADs are critical for the inhibition of TGF-β tumor suppressor activity in cancer cells.
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35
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Bhatia S, Wang P, Toh A, Thompson EW. New Insights Into the Role of Phenotypic Plasticity and EMT in Driving Cancer Progression. Front Mol Biosci 2020; 7:71. [PMID: 32391381 PMCID: PMC7190792 DOI: 10.3389/fmolb.2020.00071] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Accepted: 03/30/2020] [Indexed: 12/14/2022] Open
Abstract
Tumor cells demonstrate substantial plasticity in their genotypic and phenotypic characteristics. Epithelial-mesenchymal plasticity (EMP) can be characterized into dynamic intermediate states and can be orchestrated by many factors, either intercellularly via epigenetic reprograming, or extracellularly via growth factors, inflammation and/or hypoxia generated by the tumor stromal microenvironment. EMP has the capability to alter phenotype and produce heterogeneity, and thus by changing the whole cancer landscape can attenuate oncogenic signaling networks, invoke anti-apoptotic features, defend against chemotherapeutics and reprogram angiogenic and immune recognition functions. We discuss here the role of phenotypic plasticity in tumor initiation, progression and metastasis and provide an update of the modalities utilized for the molecular characterization of the EMT states and attributes of cellular behavior, including cellular metabolism, in the context of EMP. We also summarize recent findings in dynamic EMP studies that provide new insights into the phenotypic plasticity of EMP flux in cancer and propose therapeutic strategies to impede the metastatic outgrowth of phenotypically heterogeneous tumors.
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Affiliation(s)
- Sugandha Bhatia
- Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.,Translational Research Institute, Brisbane, QLD, Australia
| | - Peiyu Wang
- Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.,Translational Research Institute, Brisbane, QLD, Australia
| | - Alan Toh
- Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.,Translational Research Institute, Brisbane, QLD, Australia
| | - Erik W Thompson
- Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.,Translational Research Institute, Brisbane, QLD, Australia
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36
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Tiron A, Ristescu I, Postu PA, Tiron CE, Zugun-Eloae F, Grigoras I. Long-Term Deleterious Effects of Short-term Hyperoxia on Cancer Progression-Is Brain-Derived Neurotrophic Factor an Important Mediator? An Experimental Study. Cancers (Basel) 2020; 12:cancers12030688. [PMID: 32183322 PMCID: PMC7140073 DOI: 10.3390/cancers12030688] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/11/2020] [Accepted: 03/11/2020] [Indexed: 12/28/2022] Open
Abstract
Perioperative factors promoting cancer recurrence and metastasis are under scrutiny. While oxygen toxicity is documented in several acute circumstances, its implication in tumor evolution is poorly understood. We investigated hyperoxia long-term effects on cancer progression and some underlying mechanisms using both in vitro and in vivo models of triple negative breast cancer (TNBC). We hypothesized that high oxygen exposure, even of short duration, may have long-term effects on cancer growth. Considering that hyperoxic exposure results in reactive oxygen species (ROS) formation, increased oxidative stress and increased Brain-Derived Neurotrophic Factor (BDNF) expression, BDNF may mediate hyperoxia effects offering cancer cells a survival advantage by increased angiogenesis and epithelial mesenchymal transition (EMT). Human breast epithelial MCF10A, human MDA-MB-231 and murine 4T1 TNBC were investigated in 2D in vitro system. Cells were exposed to normoxia or hyperoxia (40%, 60%, 80% O2) for 6 h. We evaluated ROS levels, cell viability and the expression of BDNF, HIF-1α, VEGF-R2, Vimentin and E-Cadherin by immunofluorescence. The in vivo model consisted of 4T1 inoculation in Balb/c mice and tumor resection 2 weeks after and 6 h exposure to normoxia or hyperoxia (40%, 80% O2). We measured lung metastases and the same molecular markers, immediately and 4 weeks after surgery. The in vitro study showed that short-term hyperoxia exposure (80% O2) of TNBC cells increases ROS, increases BDNF expression and that promotes EMT and angiogenesis. The in vivo data indicates that perioperative hyperoxia enhances metastatic disease and this effect could be BDNF mediated.
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Affiliation(s)
- Adrian Tiron
- TRANSCEND Research Centre, Regional Institute of Oncology, 700483 Iasi, Romania; (A.T.); (P.A.P.); (F.Z.-E.)
| | - Irina Ristescu
- Department of Anaesthesia and Intensive Care, School of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.R.); (I.G.)
- Department of Anaesthesia and Intensive Care, Regional Institute of Oncology, 700483 Iasi, Romania
| | - Paula A. Postu
- TRANSCEND Research Centre, Regional Institute of Oncology, 700483 Iasi, Romania; (A.T.); (P.A.P.); (F.Z.-E.)
| | - Crina E. Tiron
- TRANSCEND Research Centre, Regional Institute of Oncology, 700483 Iasi, Romania; (A.T.); (P.A.P.); (F.Z.-E.)
- Correspondence:
| | - Florin Zugun-Eloae
- TRANSCEND Research Centre, Regional Institute of Oncology, 700483 Iasi, Romania; (A.T.); (P.A.P.); (F.Z.-E.)
- Department of Immunology, School of Medicine, “Grigore T Popa” University of Medicine and Pharmacy, 700400 Iasi, Romania
| | - Ioana Grigoras
- Department of Anaesthesia and Intensive Care, School of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (I.R.); (I.G.)
- Department of Anaesthesia and Intensive Care, Regional Institute of Oncology, 700483 Iasi, Romania
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Li XY, Dong M, Zang XY, Li MY, Zhou JY, Ma JJ, Wang GY. The emerging role of circulating tumor cells in cancer management. Am J Transl Res 2020; 12:332-342. [PMID: 32194887 PMCID: PMC7061830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 01/28/2020] [Indexed: 06/10/2023]
Abstract
Circulating tumor cells (CTCs) are cells that are shed from the primary tumor and circulate in the blood, and their metastasis and formation of a secondary tumor are closely associated with cancer-related death. Therefore, regulating tumor metastasis through CTCs can be a novel strategy to fight cancer. It has been demonstrated that CTCs can reflect the profile of the primary tumor and provide valuable information about intratumoral heterogeneity and their evolution over time. Moreover, the revelation of the relationship between metastasis and CTCs suggests that CTC regulation represents a promising novel anticancer strategy. Above all, at the molecular level, genetic analysis might be vital in the new era of gene-targeted cancer therapies and contribute to personalized anti-metastasis tumor treatments. In this review, we will focus on the biological significance of CTCs in the peripheral blood and discuss their potential clinical implications in cancer management.
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Affiliation(s)
- Xue-Yao Li
- Human Anatomy Laboratory, School of Basic Medicine, Xinxiang Medical University Xinxiang 453003, Henan, China
| | - Man Dong
- The Third Affiliated Hospital of Xinxiang Medical University Xinxiang 453003, Henan, China
| | - Xiang-Yang Zang
- Human Anatomy Laboratory, School of Basic Medicine, Xinxiang Medical University Xinxiang 453003, Henan, China
| | - Miao-Ya Li
- Human Anatomy Laboratory, School of Basic Medicine, Xinxiang Medical University Xinxiang 453003, Henan, China
| | - Jing-Yi Zhou
- Human Anatomy Laboratory, School of Basic Medicine, Xinxiang Medical University Xinxiang 453003, Henan, China
| | - Jian-Jun Ma
- Human Anatomy Laboratory, School of Basic Medicine, Xinxiang Medical University Xinxiang 453003, Henan, China
| | - Gang-Yang Wang
- Department of Orthopaedics, Shanghai Bone Tumor Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200080, China
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Maffeis V, Cappellesso R, Galuppini F, Guzzardo V, Zanon A, Cazzador D, Emanuelli E, Ventura L, Martini A, Fassina A. Tumor budding is an adverse prognostic marker in intestinal-type sinonasal adenocarcinoma and seems to be unrelated to epithelial-mesenchymal transition. Virchows Arch 2020; 477:241-248. [PMID: 31980958 DOI: 10.1007/s00428-020-02748-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/23/2019] [Accepted: 01/08/2020] [Indexed: 12/26/2022]
Abstract
Intestinal-type adenocarcinoma (ITAC) of sinonasal tract is a rare malignant tumor with strong morphological, immunophenotypical, and molecular similarities to colorectal adenocarcinoma (CRC). Tumor budding (TB) is a well-established adverse prognostic marker in CRC and some head and neck tumors, with features of epithelial-mesenchymal transition (EMT). The aim of this study was to assess TB in ITAC and to evaluate its possible association with EMT markers in this setting. We selected 32 surgically resected specimens of non-mucinous/non-signet ring ITAC and evaluated them for TB according to the international recommendations developed for CRC. The expression of the EMT markers E-cadherin, ZEB1, ZEB2, SLUG, and SNAIL was evaluated by immunohistochemistry (IHC). Results were stratified using clinical and follow-up data (2/32 patients had metastatic disease and 4/32 died of disease). We observed TB in 13/32 (40.6%) ITAC cases including the 7 patients with relapse (p = 0.0005) and the 4 patients dead of disease (p = 0.02). Lymphovascular invasion was associated with TB (p = 0.008). Absence of TB was associated with low ZEB2 expression (p = 0.003). No other association with EMT markers emerged. Occupational exposure to wood and leather dust was not related to the presence of TB. TB interobserver concordance was substantial (proportion of agreement = 87%; Cohen's kappa = 0.73). This work suggests that TB is associated with a worse prognosis in ITAC, but our findings do not seem to support the involvement of EMT in this specific setting. Further larger studies are needed to address this point.
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Affiliation(s)
- Valeria Maffeis
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Via Aristide Gabelli, 61, 35121, Padua, Italy.
| | - Rocco Cappellesso
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Via Aristide Gabelli, 61, 35121, Padua, Italy
| | - Francesca Galuppini
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Via Aristide Gabelli, 61, 35121, Padua, Italy
| | - Vincenza Guzzardo
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Via Aristide Gabelli, 61, 35121, Padua, Italy
| | - Alessia Zanon
- Department of Neurosciences, Otorhinolaryngology Section, University of Padova, Padua, Italy
| | - Diego Cazzador
- Department of Neurosciences, Otorhinolaryngology Section, University of Padova, Padua, Italy.,Department of Neurosciences, Section of Human Anatomy, University of Padova, Padua, Italy
| | - Enzo Emanuelli
- Department of Neurosciences, Otorhinolaryngology Section, University of Padova, Padua, Italy
| | - Laura Ventura
- Department of Statistics, University of Padova, Padua, Italy
| | - Alessandro Martini
- Department of Neurosciences, Otorhinolaryngology Section, University of Padova, Padua, Italy
| | - Ambrogio Fassina
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Via Aristide Gabelli, 61, 35121, Padua, Italy
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Licochalcone A Inhibits BDNF and TrkB Gene Expression and Hypoxic Growth of Human Tumor Cell Lines. Int J Mol Sci 2020; 21:ijms21020506. [PMID: 31941116 PMCID: PMC7014326 DOI: 10.3390/ijms21020506] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 01/07/2020] [Accepted: 01/10/2020] [Indexed: 12/17/2022] Open
Abstract
Hypoxic cellular proliferation is a common feature of tumor cells and is associated with tumor progression. Therefore, the inhibition of hypoxic cellular proliferation is expected to regulate malignancy processes. Licochalcone A (LicA) is known to show inhibitory effects on cell growth in normoxia, but it is unclear whether LicA exerts similar effects in hypoxia. Here, we studied the inhibitory activity of LicA in the hypoxic cellular proliferation of tumor cells and its molecular mechanism using human cell lines derived from various tumors including neuroblastoma and colorectal cancer. LicA inhibited cell growth at a 50% inhibitory concentration between 7.0 and 31.1 µM in hypoxia. LicA significantly suppressed hypoxic induction of tropomyosin receptor kinase B (TrkB) gene expression at the transcription level. LicA also downregulated mRNA levels of the TrkB high-affinity ligand brain-derived neurotrophic factor, but not neurotrophin-4, another TrkB ligand, or glyceraldehyde-3-phosphate dehydrogenase, indicating that the inhibitory activity of LicA is selective. Since both LicA-treatment and TrkB-knockdown decreased activation of protein kinase B in hypoxia, LicA exerts its inhibitory effect against hypoxic cell growth through inhibition of the TrkB-AKT axis. These results suggest that LicA has therapeutic potential for malignant tumors including neuroblastoma and colorectal cancer.
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40
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Yang WH, Huang Z, Wu J, Ding CKC, Murphy SK, Chi JT. A TAZ-ANGPTL4-NOX2 Axis Regulates Ferroptotic Cell Death and Chemoresistance in Epithelial Ovarian Cancer. Mol Cancer Res 2020; 18:79-90. [PMID: 31641008 PMCID: PMC6942206 DOI: 10.1158/1541-7786.mcr-19-0691] [Citation(s) in RCA: 205] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 09/17/2019] [Accepted: 10/17/2019] [Indexed: 01/10/2023]
Abstract
Ovarian cancer is the deadliest gynecologic cancer. Despite recent advances, clinical outcomes remain poor, necessitating novel therapeutic approaches. To investigate metabolic susceptibility, we performed nutrigenetic screens on a panel of clear cell and serous ovarian cancer cells and identified cystine addiction and vulnerability to ferroptosis, a novel form of regulated cell death. Our results may have therapeutic potential, but little is known about the determinants of ferroptosis susceptibility in ovarian cancer. We found that vulnerability to ferroptosis in ovarian cancer cells is enhanced by lower cell confluency. Because the Hippo pathway effectors Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) are recognized as sensors of cell density, and TAZ is the predominant effector in the tested ovarian cancer cell lines, we investigated the role of TAZ in ferroptosis of ovarian cancer. TAZ removal confers ferroptosis resistance, while TAZS89A overexpression sensitizes cells to ferroptosis. In addition, we found that lower TAZ level in chemo-resistant recurrent ovarian cancer is responsible for reduced ferroptosis susceptibility. The integrative genomic analysis identified ANGPTL4 as a direct TAZ-regulated target gene that sensitizes ferroptosis by activating NOX2. Collectively, cell density-regulated ferroptosis in ovarian cancer is mediated by TAZ through the regulation of the ANGPTL4-NOX2 axis, suggesting therapeutic potentials for ovarian cancers and other TAZ-activated tumors. IMPLICATIONS: This study reveals that TAZ promotes ferroptosis in ovarian cancers by regulating ANGPTL4 and NOX, offering a novel therapeutic potential for ovarian tumors with TAZ activation.
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Affiliation(s)
- Wen-Hsuan Yang
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina
- Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, North Carolina
- Department of Biochemistry, Duke University School of Medicine, Durham, North Carolina
| | - Zhiqing Huang
- Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Duke University School of Medicine, Durham, North Carolina
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Jianli Wu
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina
- Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, North Carolina
| | - Chien-Kuang C Ding
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina
- Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, North Carolina
| | - Susan K Murphy
- Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Duke University School of Medicine, Durham, North Carolina
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University School of Medicine, Durham, North Carolina
| | - Jen-Tsan Chi
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina.
- Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, North Carolina
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Immunity against cancer cells may promote their proliferation and metastasis. Proc Natl Acad Sci U S A 2019; 117:426-431. [PMID: 31871166 DOI: 10.1073/pnas.1916833117] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Herein we present a concept in cancer where an immune response is detrimental rather than helpful. In the cancer setting, the immune system is generally considered to be helpful in curtailing the initiation and progression of tumors. In this work we show that a patient's immune response to their tumor can, in fact, either enhance or inhibit tumor cell growth. Two closely related autoantibodies to the growth factor receptor TrkB were isolated from cancer patients' B cells. Although highly similar in sequence, one antibody was an agonist while the other was an antagonist. The agonist antibody was shown to increase breast cancer cell growth both in vitro and in vivo, whereas the antagonist antibody inhibited growth. From a mechanistic point of view, we showed that binding of the agonist antibody to the TrkB receptor was functional in that it initiated downstream signaling identical to its natural growth factor ligand, brain-derived neurotrophic factor (BDNF). Our study shows that individual autoantibodies may play a role in cancer patients.
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Triaca V, Carito V, Fico E, Rosso P, Fiore M, Ralli M, Lambiase A, Greco A, Tirassa P. Cancer stem cells-driven tumor growth and immune escape: the Janus face of neurotrophins. Aging (Albany NY) 2019; 11:11770-11792. [PMID: 31812953 PMCID: PMC6932930 DOI: 10.18632/aging.102499] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 11/17/2019] [Indexed: 05/12/2023]
Abstract
Cancer Stem Cells (CSCs) are self-renewing cancer cells responsible for expansion of the malignant mass in a dynamic process shaping the tumor microenvironment. CSCs may hijack the host immune surveillance resulting in typically aggressive tumors with poor prognosis.In this review, we focus on neurotrophic control of cellular substrates and molecular mechanisms involved in CSC-driven tumor growth as well as in host immune surveillance. Neurotrophins have been demonstrated to be key tumor promoting signaling platforms. Particularly, Nerve Growth Factor (NGF) and its specific receptor Tropomyosin related kinase A (TrkA) have been implicated in initiation and progression of many aggressive cancers. On the other hand, an active NGF pathway has been recently proven to be critical to oncogenic inflammation control and in promoting immune response against cancer, pinpointing possible pro-tumoral effects of NGF/TrkA-inhibitory therapy.A better understanding of the molecular mechanisms involved in the control of tumor growth/immunoediting is essential to identify new predictive and prognostic intervention and to design more effective therapies. Fine and timely modulation of CSCs-driven tumor growth and of peripheral lymph nodes activation by the immune system will possibly open the way to precision medicine in neurotrophic therapy and improve patient's prognosis in both TrkA- dependent and independent cancers.
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Affiliation(s)
- Viviana Triaca
- Institute of Biochemistry and Cell Biology, National Research Council (CNR), International Campus A. Buzzati-Traverso, Monterotondo Scalo, Rome, Italy
| | - Valentina Carito
- Institute of Biochemistry and Cell Biology, National Research Council (CNR), at Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
| | - Elena Fico
- Institute of Biochemistry and Cell Biology, National Research Council (CNR), at Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
| | - Pamela Rosso
- Institute of Biochemistry and Cell Biology, National Research Council (CNR), at Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology, National Research Council (CNR), at Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
| | - Massimo Ralli
- Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
| | | | - Antonio Greco
- Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
| | - Paola Tirassa
- Institute of Biochemistry and Cell Biology, National Research Council (CNR), at Department of Sense Organs, University of Rome La Sapienza, Rome, Italy
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Maffeis V, Nicolè L, Cappellesso R. RAS, Cellular Plasticity, and Tumor Budding in Colorectal Cancer. Front Oncol 2019; 9:1255. [PMID: 31803624 PMCID: PMC6877753 DOI: 10.3389/fonc.2019.01255] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 10/30/2019] [Indexed: 12/14/2022] Open
Abstract
The high morbidity and mortality of colorectal cancer (CRC) remain a worldwide challenge, despite the advances in prevention, diagnosis, and treatment. RAS alterations have a central role in the pathogenesis of CRC universally recognized both in the canonical mutation-based classification and in the recent transcriptome-based classification. About 40% of CRCs are KRAS mutated, 5% NRAS mutated, and only rare cases are HRAS mutated. Morphological and molecular correlations demonstrated the involvement of RAS in cellular plasticity, which is related to invasive and migration properties of neoplastic cells. RAS signaling has been involved in the initiation of epithelial to mesenchymal transition (EMT) in CRC leading to tumor spreading. Tumor budding is the morphological surrogate of EMT and features cellular plasticity. Tumor budding is clinically relevant for CRC patients in three different contexts: (i) in pT1 CRC the presence of tumor buds is associated with nodal metastasis, (ii) in stage II CRC identifies the cases with a prognosis similar to metastatic disease, and (iii) intratumoral budding could be useful in patient selection for neoadjuvant therapy. This review is focused on the current knowledge on RAS in CRC and its link with cellular plasticity and related clinicopathological features.
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Affiliation(s)
- Valeria Maffeis
- Department of Medicine, Surgical Pathology and Cytopathology Unit, University of Padova, Padova, Italy
| | - Lorenzo Nicolè
- Department of Medicine, Surgical Pathology and Cytopathology Unit, University of Padova, Padova, Italy
| | - Rocco Cappellesso
- Pathological Anatomy Unit, Padova University Hospital, Padova, Italy
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Neurotrophins and their involvement in digestive cancers. Cell Death Dis 2019; 10:123. [PMID: 30741921 PMCID: PMC6370832 DOI: 10.1038/s41419-019-1385-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 01/21/2019] [Accepted: 01/22/2019] [Indexed: 12/18/2022]
Abstract
Cancers of the digestive system, including esophageal, gastric, pancreatic, hepatic, and colorectal cancers, have a high incidence and mortality worldwide. Efficient therapies have improved patient care; however, many challenges remain including late diagnosis, disease recurrence, and resistance to therapies. Mechanisms responsible for these aforementioned challenges are numerous. This review focuses on neurotrophins, including NGF, BDNF, and NT3, and their specific tyrosine kinase receptors called tropomyosin receptor kinase (Trk A, B, C, respectively), associated with sortilin and the p75 neurotrophin receptor (p75NTR), and their implication in digestive cancers. Globally, p75NTR is a frequently downregulated tumor suppressor. On the contrary, Trk and their ligands are considered oncogenic factors. New therapies which target NT and/or their receptors, or use them as diagnosis biomarkers could help us to combat digestive cancers.
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Zhao GX, Xu YY, Weng SQ, Zhang S, Chen Y, Shen XZ, Dong L, Chen S. CAPS1 promotes colorectal cancer metastasis via Snail mediated epithelial mesenchymal transformation. Oncogene 2019; 38:4574-4589. [PMID: 30742066 DOI: 10.1038/s41388-019-0740-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 12/26/2018] [Accepted: 01/15/2019] [Indexed: 01/02/2023]
Abstract
Colorectal cancer (CRC) is a common gastrointestinal cancer with high mortality rate mostly due to metastasis. Ca2+-dependent activator protein for secretion 1 (CAPS1) was originally identified as a soluble factor that reconstitutes Ca2+-dependent secretion. In this study, we discovered a novel role of CAPS1 in CRC metastasis. CAPS1 is frequently up-regulated in CRC tissues. Increased CAPS1 expression is associated with frequent metastasis and poor prognosis of CRC patients. Overexpression of CAPS1 promotes CRC cell migration and invasion in vitro, as well as liver metastasis in vivo, without affecting cell proliferation. CAPS1 induces epithelial-mesenchymal transition (EMT), including decreased E-cadherin and ZO-1, epithelial marker expression, and increased N-cadherin and Snail, mesenchymal marker expression. Snail knockdown reversed CAPS1-induced EMT, cell migration and invasion. This result indicates that Snail is required for CAPS1-mediated EMT process and metastasis in CRC. Furthermore, CAPS1 can bind with Septin2 and p85 (subunit of PI3K). LY294002 and wortmanin, PI3K/Akt inhibitors, can abolish CAPS1-induced increase of Akt/GSK3β activity, as well as increase of Snail protein level. Taken together, CAPS1 promotes colorectal cancer metastasis through PI3K/Akt/GSK3β/Snail signal pathway-mediated EMT process.
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Affiliation(s)
- Guang-Xi Zhao
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.,Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Ying-Ying Xu
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Shu-Qiang Weng
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, 200032, China
| | - Si Zhang
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Ying Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Xi-Zhong Shen
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.
| | - Ling Dong
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.
| | - She Chen
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
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Meng L, Liu B, Ji R, Jiang X, Yan X, Xin Y. Targeting the BDNF/TrkB pathway for the treatment of tumors. Oncol Lett 2018; 17:2031-2039. [PMID: 30675270 DOI: 10.3892/ol.2018.9854] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 12/12/2018] [Indexed: 12/12/2022] Open
Abstract
Neurotrophins are a family of growth factors that regulate neural survival, development, function and plasticity in the central and the peripheral nervous system. There are four neurotrophins: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and NT-4. Among them, BDNF is the most studied due to its high expression in the brain. Over the past two decades, BDNF and its receptor tropomyosin receptor kinase B (TrkB) have been reported to be upregulated in a wide range of tumors. This activated signal stimulates a series of downstream pathways, including phosphoinositide 3-kinase/protein kinase B, Ras-Raf-mitogen activated protein kinase kinase-extracellular signal-regulated kinases, the phospholipase-C-γ pathway and the transactivation of epidermal growth factor receptor. Activation of these signaling pathways induces oncogenic effects by increasing cancer cell growth, proliferation, survival, migration and epithelial to mesenchymal transition, and decreasing anoikis, relapse and chemotherapeutic sensitivity. The present review summarizes recent findings to discuss the role of BDNF in tumors, the underlying molecular mechanism, targeting Trk receptors for treatment of cancers and its potential risk.
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Affiliation(s)
- Lingbin Meng
- Department of Internal Medicine, Florida Hospital, Orlando, FL 32803, USA
| | - Baoqiong Liu
- Department of Internal Medicine, Florida Hospital, Orlando, FL 32803, USA
| | - Rui Ji
- Department of Biology, Valencia College, Orlando, FL 32825, USA
| | - Xin Jiang
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Xuebo Yan
- Department of Respiratory Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230000, P.R. China
| | - Ying Xin
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin 130021, P.R. China
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Li Q, Zhang Y, Jiang Q. MFAP5 suppression inhibits migration/invasion, regulates cell cycle and induces apoptosis via promoting ROS production in cervical cancer. Biochem Biophys Res Commun 2018; 507:51-58. [PMID: 30454902 DOI: 10.1016/j.bbrc.2018.10.146] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 10/23/2018] [Indexed: 01/01/2023]
Abstract
Cervical cancer is one of the most lethal types of cancer among female. Microfibrillar-associated protein 5 (MFAP5) is an extracellular matrix (ECM) glycoprotein, and is confirmed to be involved in cell signaling during microfibril assembly, elastinogenesis and cell survival. However, the role of MFAP5 in cervical cancer development and progression remains poorly understood. In the study, MFAP5 was over-expressed in human cervical cancers, and in different cervical cancer cell lines. Patients suffering from cervical cancer with low MFAP5 expression exhibited better survival rate. Suppressing MFAP5 in cervical cancer cells markedly reduced the cell proliferation, migration and invasion by modulating epithelial-mesenchymal transition (EMT)-related signaling pathway. In addition, MFAP5 knockdown induced large number of cells distributed in G2/M phase, along with reduced Cyclin B1, Cyclin D1 and cyclin-dependent kinase 4 (CDK4) expressions, and enhanced p21 and p53 levels. Moreover, apoptosis was highly induced by MFAP5 silence through reducing Bcl-xl and Bcl-2 expressions, and promoting Bax, cleaved Caspase-3 and poly (ADP-Ribose) polymerase (PARP) expressions in cervical cancer cells. Reactive oxygen species (ROS) production levels were also higher in MFAP5-knockdown cells, along with Jun-N-terminal kinase (JNK) activation. Importantly, we found that MFAP5 knockdown-inhibited cervical cancer cell growth was dependent on ROS production. Finally, the depletion of MFAP5 prevented cervical cancer progression in vivo. In summary, our study identified a critical role played by MFAP5 in the progression of cervical cancer and the potential mechanisms by which exerted its effects, indicating that targeting MFAP5-related pathways could be conducive to the therapies for cervical cancer.
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Affiliation(s)
- Qingmei Li
- 2nd Area of Obstetrics, The People's Hospital of Pingyi County, No. 7, Jinhua Road, Pingyi Street, Linyi, 273300, China
| | - Yanqin Zhang
- Department of Nursing, Yulin Traditional Chinese Medicine Hospital, No. 131 Xinjian South Road, Yuyang District, Yulin, 719000, China
| | - Qiuli Jiang
- Department of Gynecology, Hanzhong Central Hospital, No.22, Kangfu Road, Hantai District, Hanzhomg, 723000, China.
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48
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Sorensen EP, Dietert JB, Hurst EA. Cells to Surgery Quiz: September 2018. J Invest Dermatol 2018. [DOI: 10.1016/j.jid.2018.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Zacharias M, Brcic L, Eidenhammer S, Popper H. Bulk tumour cell migration in lung carcinomas might be more common than epithelial-mesenchymal transition and be differently regulated. BMC Cancer 2018; 18:717. [PMID: 29976164 PMCID: PMC6034257 DOI: 10.1186/s12885-018-4640-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 06/27/2018] [Indexed: 11/26/2022] Open
Abstract
Background Epithelial-to-mesenchymal transition (EMT) is one mechanism of carcinoma migration, while complex tumour migration or bulk migration is another - best demontrated by tumour cells invading blood vessels. Methods Thirty cases of non-small cell lung carcinomas were used for identifying genes responsible for bulk cell migration, 232 squamous cell and adenocarcinomas to identify bulk migration rates. Genes expressed differently in the primary tumour and in the invasion front were regarded as relevant in migration and further validated in 528 NSCLC cases represented on tissue microarrays (TMAs) and metastasis TMAs. Results Markers relevant for bulk cancer cell migration were regulated differently when compared with EMT: Twist expressed in primary tumour, invasion front, and metastasis was not associated with TGFβ1 and canonical Wnt, as Slug, Snail, and Smads were negative and β-Catenin expressed membraneously. In the majority of tumours, E-Cadherin was downregulated at the invasive front, but not absent, but, coexpressed with N-Cadherin. Vimentin was coexpressed with cytokeratins at the invasion site in few cases, whereas fascin expression was seen in a majority. Expression of ERK1/2 was downregulated, PLCγ was only expressed at the invasive front and in metastasis. Brk and Mad, genes identified in Drosophila border cell migration, might be important for bulk migration and metastasis, together with invadipodia proteins Tks5 and Rab40B, which were only upregulated at the invasive front and in metastasis. CXCR1 was expressed equally in all carcinomas, as opposed to CXCR2 and 4, which were only expressed in few tumours. Conclusion Bulk cancer cell migration seems predominant in AC and SCC. Twist, vimentin, fascin, Mad, Brk, Tsk5, Rab40B, ERK1/2 and PLCγ are associated with bulk cancer cell migration. This type of migration requires an orchestrated activation of proteins to keep the cells bound to each other and to coordinate movement. This hypothesis needs to be proven experimentally. Electronic supplementary material The online version of this article (10.1186/s12885-018-4640-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Martin Zacharias
- Diagnostic and Research Center, Institute of Pathology, Medical University of Graz, Neue Stiftingtalstraße 6, Graz, 8036, Austria
| | - Luka Brcic
- Diagnostic and Research Center, Institute of Pathology, Medical University of Graz, Neue Stiftingtalstraße 6, Graz, 8036, Austria
| | - Sylvia Eidenhammer
- Diagnostic and Research Center, Institute of Pathology, Medical University of Graz, Neue Stiftingtalstraße 6, Graz, 8036, Austria
| | - Helmut Popper
- Diagnostic and Research Center, Institute of Pathology, Medical University of Graz, Neue Stiftingtalstraße 6, Graz, 8036, Austria.
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50
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Moriwaki K, Ayani Y, Kuwabara H, Terada T, Kawata R, Asahi M. TRKB tyrosine kinase receptor is a potential therapeutic target for poorly differentiated oral squamous cell carcinoma. Oncotarget 2018; 9:25225-25243. [PMID: 29861866 PMCID: PMC5982746 DOI: 10.18632/oncotarget.25396] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 04/26/2018] [Indexed: 12/20/2022] Open
Abstract
It has been reported that one of the neurotrophin receptors, tropomyosin receptor kinase B (TRKB), is frequently overexpressed in various tumor tissues including oral squamous cell carcinoma (OSCC), and that its upregulation promotes tumor progression in human cancers. However, the correlation between TRKB overexpression and clinicopathological characteristics is not fully elucidated. Here, we present the correlation between the expression levels of TRKB and/or its secreted ligand, brain-derived neurotrophic factor (BDNF), and clinicopathological characteristics, especially regarding tumor differentiation, tissue invasion, and disease-free survival in patients with OSCC. The results obtained through immunohistochemical analysis of human OSCC tumor specimens showed that the expression levels of TRKB and/or BDNF, were significantly higher in moderately and poorly differentiated OSCC (MD/PD-OSCC) tumor cells than in well differentiated cells (WD-OSCC). Moreover, the OSCC tumors highly expressing TRKB and/or BDNF exhibited promotion in tissue invasion and reduction in disease-free survival in the patients. In an orthotopic transplantation mouse model of human OSCC cell lines, administration of a TRKB-specific inhibitor significantly suppressed the tumor growth and invasion in PD-OSCC-derived tumor cells, but not in WD-OSCC-derived tumor cells. Moreover, the TRKB inhibitor selectively blocked BDNF-induced tumor cell proliferation and migration accompanied with the suppression of TRKB phosphorylation in PD-OSCC but not in WD-OSCC in vitro. Taken together, these data suggest that the BDNF/TRKB signaling pathway may regulate tumor progression in poorly differentiated OSCC. Expression levels of signal molecules may be an accurate prognosis marker for tumor aggressiveness, and the molecules may be an attractive target for new OSCC therapies.
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Affiliation(s)
- Kazumasa Moriwaki
- Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
| | - Yusuke Ayani
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan
| | - Hiroko Kuwabara
- Department of Pathology, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan
| | - Tetsuya Terada
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan
| | - Ryo Kawata
- Department of Otolaryngology-Head and Neck Surgery, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan
| | - Michio Asahi
- Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
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