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1
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Wang JF, Wang MC, Jiang LL, Lin NM. The neuroscience in breast cancer: Current insights and clinical opportunities. Heliyon 2025; 11:e42293. [PMID: 39975839 PMCID: PMC11835589 DOI: 10.1016/j.heliyon.2025.e42293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 01/25/2025] [Accepted: 01/25/2025] [Indexed: 02/21/2025] Open
Abstract
The involvement of nerves in the development of breast cancer has emerged as a significant factor. Interaction between the nervous system and breast cancer can influence tumor initiation, growth, invasion, metastasis, reverse resistance to drugs, promote inflammation in tumors, and impair the immune system's ability to combat cancer. This review examined the intricate relationship linking the nervous system with breast cancer, emphasizing both central and peripheral aspects of the nervous system. Moreover, we reviewed neural cell factors and their impact on breast cancer progression, alongside the interactions between nerves and immunology, microbiota in breast cancer. Furthermore, the study discussed the potential of nerves as biomarkers for diagnosing and prognosticating breast cancer, and evaluated prospects for improving chemotherapy and immunotherapy therapeutic outcomes in breast cancer treatment. We hope to provide a deeper understanding of the neurobiological underpinnings of breast cancer and pave the way for the discovery of innovative therapeutic targets and prognostic markers.
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Affiliation(s)
- Jia-feng Wang
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
| | - Meng-chuan Wang
- Affiliated Cixi Hospital, Wenzhou Medical University, Ningbo, 315300, China
| | - Lei-lei Jiang
- The First Affiliated Hospital of Anhui University of Chinese Medicine,Hefei, 230031, China
| | - Neng-ming Lin
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, China
- Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, 310024, China
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Liao S, Kang K, Yao Z, Lu Y. Nervous system contributions to small cell lung cancer: Lessons from diverse oncological studies. Biochim Biophys Acta Rev Cancer 2025; 1880:189252. [PMID: 39725176 DOI: 10.1016/j.bbcan.2024.189252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 12/05/2024] [Accepted: 12/19/2024] [Indexed: 12/28/2024]
Abstract
The nervous system plays a vital role throughout the entire lifecycle and it may regulate the formation, development and metastasis of tumors. Small cell lung cancer is a typical neuroendocrine tumor, and it is naturally equipped with neurotropism. In this review, we firstly summarize current preclinical and clinical evidence to demonstrate the reciprocal crosstalk among the nervous system, tumor, and tumor microenvironment in various ways, including neurotransmitter-receptor pathways, innervations of nerve fibers, different types of synapse formation by neurons, astrocytes, and cancer cells, neoneurogenesis. Futherly, we emphasize how the nervous system interacts with small cell lung cancer and discuss the limitations of current research methods for examining the interactions. We propose that integrating neuroscience, development biology, and tumor biology can be a promising direction to provide new insights into development and metastasis of small cell lung cancer and raise some novel treatment strategies.
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Affiliation(s)
- Shuangsi Liao
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Kai Kang
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhuoran Yao
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China.
| | - You Lu
- Thoracic Oncology Ward, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Department of Radiotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China; Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China.
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3
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Dąbkowska M, Stukan I, Kowalski B, Donerowicz W, Wasilewska M, Szatanik A, Stańczyk-Dunaj M, Michna A. BDNF-loaded PDADMAC-heparin multilayers: a novel approach for neuroblastoma cell study. Sci Rep 2023; 13:17939. [PMID: 37864014 PMCID: PMC10589271 DOI: 10.1038/s41598-023-45045-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 10/15/2023] [Indexed: 10/22/2023] Open
Abstract
Biomaterial science has contributed tremendously to developing nanoscale materials for delivering biologically active compounds, enhancing protein stability, and enabling its therapeutic use. This paper presents a process of formation of polyelectrolyte multilayer (PEM) prepared by sequential adsorption of positively charged polydiallyldimethylammonium chloride (PDADMAC) and negatively charged heparin sodium salt (HP), from low polyelectrolyte concentration, on a solid substrate. PEM was further applied as a platform for the adsorption of a brain-derived growth factor (BDNF), which is a protein capable of regulating neuronal cell development. The multilayers containing BDNF were thoroughly characterized by electrokinetic (streaming potential measurements, SPM) and optical (optical waveguide lightmode spectroscopy, OWLS) techniques. It was found that BDNF was significantly adsorbed onto polyelectrolyte multilayers terminated by HP under physiological conditions. We further explore the effect of established PEMs in vitro on the neuroblastoma SH-SY5Y cell line. An enzyme-linked immunosorbent assay (ELISA) confirmed that BDNF was released from multilayers, and the use of the PEMs intensified its cellular uptake. Compared to the control, PEMs with adsorbed BDNF significantly reduced cell viability and mitochondrial membrane polarization to as low as 72% and 58%, respectively. HPLC analysis showed that both PDADMAC-terminated and HP-terminated multilayers have antioxidative properties as they almost by half decreased lipid peroxidation in SH-SY5Y cells. Finally, enhanced formation of spheroid-like, 3D structures was observed by light microscopy. We offer a well-characterized PEM with antioxidant properties acting as a BDNF carrier, stabilizing BDNF and making it more accessible to cells in an inhomogeneous, dynamic, and transient in vitro environment. Described multilayers can be utilized in future biomedical applications, such as boosting the effect of treatment by selective anticancer as adjuvant therapy, and in biomedical research for future development of more precise neurodegenerative disease models, as they enhance cellular 3D structure formation.
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Affiliation(s)
- Maria Dąbkowska
- Independent Laboratory of Pharmacokinetic and Clinical Pharmacy, Pomeranian Medical University, Rybacka 1, 70-204, Szczecin, Poland.
| | - Iga Stukan
- Department of General Pathology, Pomeranian Medical University, Rybacka 1, 70-204, Szczecin, Poland
| | - Bogusław Kowalski
- Independent Laboratory of Pharmacokinetic and Clinical Pharmacy, Pomeranian Medical University, Rybacka 1, 70-204, Szczecin, Poland
| | - Wiktoria Donerowicz
- Independent Laboratory of Pharmacokinetic and Clinical Pharmacy, Pomeranian Medical University, Rybacka 1, 70-204, Szczecin, Poland
| | - Monika Wasilewska
- Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, 30-239, Kraków, Poland
| | - Alicja Szatanik
- Independent Laboratory of Pharmacokinetic and Clinical Pharmacy, Pomeranian Medical University, Rybacka 1, 70-204, Szczecin, Poland
| | | | - Aneta Michna
- Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, 30-239, Kraków, Poland
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Xiong X, Zeng M, Peng X, Feng C, Li C, Weng W, Li Y. Serum brain-derived neurotrophic factor (BDNF) as predictors of childhood neuroblastoma relapse. BMC Cancer 2023; 23:670. [PMID: 37460933 PMCID: PMC10351183 DOI: 10.1186/s12885-023-11159-9] [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: 09/12/2022] [Accepted: 07/07/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Neuroblastoma (NB) is a childhood malignant tumor,50% of high-risk NB children still have recurrence, and the long-term survival rate is very low. NB tumors expressing high levels of BDNF/TrkB are associated with poor survival outcomes.In this study, we show that the trends of serum concentration of BDNF at different growth stages after birth, and explore the relationship with NB replase. METHODS In experiment 1, 87 subjects were enrolled and divided into four groups, neonates group、 children group、adults group and NB patients. The distribution of serum concentration of BDNF by ELISA. In experiment 2, we studied BDNF in stage 4 NB patients to determine their frequency, correlation with clinical parameters, and prognostic impact. RESULTS First, we identified that serum BDNF concentration decreased from the newborn to childhood in healthy subjects, while it was relatively high in children(age > 1 year) with NB. In the second phase our studies showed no significant increase in serum BDNF concentration in these NB patients, with adverse pathologic features, large tumor maximum diameter, and MYCN amplification. After comprehensive treatment, levels of BDNF gradually increased in children with recurrence and decreased in the remission group. High serum BDNF concentration was associated with relapse. Of 21 stage 4 neuroblastoma patients, adopted a comprehensive treatment approach including ATO-basic modified chemotherapy, traditional radiotherapy,stem cell transplatation and immunotherapy. 76% of alive patients having > 3 years follow-up. CONCLUSION The aim is to show that BDNF is a predictor of recurrence risk of NB.
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Affiliation(s)
- Xilin Xiong
- Department of Oncology, Medical Centre of Pediatric, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No 107 Yanjiang Road, Guangzhou, Guangdong, 510120, China
| | - Meiling Zeng
- Department of Oncology, Medical Centre of Pediatric, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No 107 Yanjiang Road, Guangzhou, Guangdong, 510120, China
| | - Xiaomin Peng
- Department of Oncology, Medical Centre of Pediatric, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No 107 Yanjiang Road, Guangzhou, Guangdong, 510120, China
| | - Chuchu Feng
- Department of Oncology, Medical Centre of Pediatric, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No 107 Yanjiang Road, Guangzhou, Guangdong, 510120, China
| | - Chunmou Li
- Department of Oncology, Medical Centre of Pediatric, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No 107 Yanjiang Road, Guangzhou, Guangdong, 510120, China
| | - Wenjun Weng
- Department of Oncology, Medical Centre of Pediatric, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No 107 Yanjiang Road, Guangzhou, Guangdong, 510120, China
| | - Yang Li
- Department of Oncology, Medical Centre of Pediatric, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No 107 Yanjiang Road, Guangzhou, Guangdong, 510120, China.
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Cui Q, Jiang D, Zhang Y, Chen C. The tumor-nerve circuit in breast cancer. Cancer Metastasis Rev 2023; 42:543-574. [PMID: 36997828 PMCID: PMC10349033 DOI: 10.1007/s10555-023-10095-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 02/16/2023] [Indexed: 04/01/2023]
Abstract
It is well established that innervation is one of the updated hallmarks of cancer and that psychological stress promotes the initiation and progression of cancer. The breast tumor environment includes not only fibroblasts, adipocytes, endothelial cells, and lymphocytes but also neurons, which is increasingly discovered important in breast cancer progression. Peripheral nerves, especially sympathetic, parasympathetic, and sensory nerves, have been reported to play important but different roles in breast cancer. However, their roles in the breast cancer progression and treatment are still controversial. In addition, the brain is one of the favorite sites of breast cancer metastasis. In this review, we first summarize the innervation of breast cancer and its mechanism in regulating cancer growth and metastasis. Next, we summarize the neural-related molecular markers in breast cancer diagnosis and treatment. In addition, we review drugs and emerging technologies used to block the interactions between nerves and breast cancer. Finally, we discuss future research directions in this field. In conclusion, the further research in breast cancer and its interactions with innervated neurons or neurotransmitters is promising in the clinical management of breast cancer.
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Affiliation(s)
- Qiuxia Cui
- Affiliated Hospital of Guangdong Medical University Science & Technology of China, Zhanjiang, 524000, China
- Department of Breast Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Dewei Jiang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
| | - Yuanqi Zhang
- Affiliated Hospital of Guangdong Medical University Science & Technology of China, Zhanjiang, 524000, China.
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
- Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China.
- The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China.
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Hu J, Chen W, Shen L, Chen Z, Huang J. Crosstalk between the peripheral nervous system and breast cancer influences tumor progression. Biochim Biophys Acta Rev Cancer 2022; 1877:188828. [PMID: 36283598 DOI: 10.1016/j.bbcan.2022.188828] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/17/2022] [Accepted: 10/19/2022] [Indexed: 11/18/2022]
Abstract
Recent studies have shown that peripheral nerves play an important role in the progression of breast cancer. Breast cancer cells (BCCs) promote local peripheral nerve growth and branching by secreting neuroactive molecules, including neurotrophins and axon guidance molecules (AGMs). Sympathetic nerves promote breast cancer progression, while parasympathetic and sensory nerves mainly have anti-tumor effects in the progression of breast cancer. Specifically, peripheral nerves can influence the progression of breast cancer by secreting neurotransmitters not only directly binding to the corresponding receptors of BCCs, but also indirectly acting on immune cells to modulate anti-tumor immunity. In this review, we summarize the crosstalk between breast cancer and peripheral nerves and the roles of important neuroactive molecules in the progression of breast cancer. In addition, we summarize indicators, including nerve fiber density and perineural invasion (PNI), that may help determine the prognosis of breast cancer based on current research results, as well as potential therapeutic approaches, such as β-blockers and retroviral-mediated genetic neuroengineering techniques, that may enhance the prognosis of breast cancer. In addition, we propose suggestions for future research priorities based on a current lack of knowledge in this area.
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Affiliation(s)
- Jianming Hu
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Wuzhen Chen
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lesang Shen
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Zhigang Chen
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China..
| | - Jian Huang
- Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China..
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7
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Stravodimou A, Voutsadakis IA. Neurotrophic receptor tyrosine kinase family members in secretory and non-secretory breast carcinomas. World J Clin Oncol 2022; 13:135-146. [PMID: 35316931 PMCID: PMC8894271 DOI: 10.5306/wjco.v13.i2.135] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 07/11/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Breast cancer is the most common female cancer and a major cause of morbidity and mortality. Progress in breast cancer therapeutics has been attained with the introduction of targeted therapies for specific sub-sets. However, other subsets lack targeted interventions and thus there is persisting need for identification and characterization of molecular targets in order to advance breast cancer therapeutics.
AIM To analyze the role of lesions in neurotrophic receptor tyrosine kinase (NTRK) genes in breast cancers.
METHODS Analysis of publicly available genomic breast cancer datasets was performed for identification and characterization of cases with fusions and other molecular abnormalities involving NTRK1, NTRK2 and NTRK3 genes.
RESULTS NTRK fusions are present in a small number of breast cancers at the extensive GENIE project data set which contains more than 10000 breast cancers. These cases are not identified as secretory in the database, suggesting that the histologic characterization is not always evident. In the breast cancer The Cancer Genome Atlas (TCGA) cohort the more common molecular lesion in NTRK genes is amplification of NTRK1 observed in 7.9% of breast cancers.
CONCLUSION Neurotrophin receptors molecular lesions other than fusions are observed more often than fusions. However, currently available NTRK inhibitors are effective mainly for fusion lesions. Amplifications of NTRK1, being more frequent in breast cancers, could be a viable therapeutic target if inhibitors efficacious for them become available.
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Affiliation(s)
| | - Ioannis A Voutsadakis
- Department of Medical Oncology, Sault Area Hospital, Sault Ste Marie P6B0A8, Ontario, Canada
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8
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Ha CT, Cheng CY, Zheng MY, Hsu TH, Miao CC, Lee CJ, Wang HD, Pan ST, Chou YT. ID4 predicts poor prognosis and promotes BDNF-mediated oncogenesis of colorectal cancer. Carcinogenesis 2021; 42:951-960. [PMID: 33993270 DOI: 10.1093/carcin/bgab037] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/19/2021] [Accepted: 05/06/2021] [Indexed: 11/14/2022] Open
Abstract
Inhibitors of DNA binding and cell differentiation (ID) proteins regulate cellular differentiation and tumor progression. Whether ID family proteins serve as a linkage between pathological differentiation and cancer stemness in colorectal cancer is largely unknown. Here, the expression of ID4, but not other ID family proteins, was enriched in LGR5-high colon cancer stem cells. Its high expression was associated with poor pathological differentiation of colorectal tumors and shorter survival in patients. Knockdown of ID4 inhibited the growth and dissemination of colon cancer cells, while enhancing chemosensitivity. Through gene expression profiling analysis, brain-derived neurotrophic factor (BDNF) was identified as a downstream target of ID4 expression in colorectal cancer. BDNF knockdown decreased the growth and migration of colon cancer cells, and its expression enhanced dissemination, anoikis resistance and chemoresistance. ID4 silencing attenuated the epithelial-to-mesenchymal transition pattern in colon cancer cells. Gene cluster analysis revealed that ID4 and BDNF expression was clustered with mesenchymal markers and distant from epithelial genes. BDNF silencing decreased the expression of mesenchymal markers Vimentin, CDH2 and SNAI1. These findings demonstrated that ID4-BDNF signaling regulates colorectal cancer survival, with the potential to serve as a prognostic marker in colorectal cancer.
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Affiliation(s)
- Cam-Thu Ha
- Institute of Biotechnology, National Tsing Hua University, Hsinchu,Taiwan
| | | | - Ming-Yi Zheng
- Institute of Biotechnology, National Tsing Hua University, Hsinchu,Taiwan
| | - Tang-Hui Hsu
- Institute of Biotechnology, National Tsing Hua University, Hsinchu,Taiwan
| | - Chia-Cheng Miao
- Institute of Biotechnology, National Tsing Hua University, Hsinchu,Taiwan
| | - Chang-Jung Lee
- Institute of Biotechnology, National Tsing Hua University, Hsinchu,Taiwan
| | - Horng-Dar Wang
- Institute of Biotechnology, National Tsing Hua University, Hsinchu,Taiwan
| | - Shien-Tung Pan
- Department of Pathology, China Medical University Hsinchu Hospital, Hsinchu County, Taiwan
| | - Yu-Ting Chou
- Institute of Biotechnology, National Tsing Hua University, Hsinchu,Taiwan
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Borgi M, Collacchi B, Ortona E, Cirulli F. Stress and coping in women with breast cancer:unravelling the mechanisms to improve resilience. Neurosci Biobehav Rev 2020; 119:406-421. [PMID: 33086128 DOI: 10.1016/j.neubiorev.2020.10.011] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 10/01/2020] [Accepted: 10/13/2020] [Indexed: 12/15/2022]
Abstract
Breast cancer diagnosis, surgery, adjuvant therapies and survivorship can all be extremely stressful. In women, concerns about body image are common as a result of the disease and can affect interpersonal relationships, possibly leading to social isolation, increasing the likelihood for mood disorders. This is particularly relevant as women are at greater risk to develop anxiety and depressive symptoms in response to highly stressful situations. Here we address the mechanisms and the pathways activated as a result of stress and contributing to changes in the pathophysiology of breast cancer, as well as the potential of stress management factors and interventions in buffering the deleterious effects of chronic stress in a gender perspective. An improved understanding of the biological mechanisms linking stress-management resources to health-relevant biological processes in breast cancer patients could reveal novel therapeutic targets and help clarifying which psychosocial interventions can improve cancer outcomes, ultimately offering a unique opportunity to improve contemporary cancer treatments.
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Affiliation(s)
- Marta Borgi
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Barbara Collacchi
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Elena Ortona
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
| | - Francesca Cirulli
- Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
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10
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Liu X, Yang X, Zhan C, Zhang Y, Hou J, Yin X. Perineural Invasion in Adenoid Cystic Carcinoma of the Salivary Glands: Where We Are and Where We Need to Go. Front Oncol 2020; 10:1493. [PMID: 33014792 PMCID: PMC7461905 DOI: 10.3389/fonc.2020.01493] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 07/13/2020] [Indexed: 12/25/2022] Open
Abstract
Adenoid cystic carcinoma of the salivary gland (SACC) is a rare malignant tumors of the head and neck region, but it is one of the most common malignant tumors that are prone to perineural invasion (PNI) of the head and neck. The prognosis of patients with SACC is strongly associated with the presence of perineural spread (PNS). Although many contributing factors have been reported, the mechanisms underlying the preferential destruction of the blood-nerve barrier (BNB) by tumors and the infiltration of the tumor microenvironment by nerve fibers in SACC, have received little research attention. This review summarizes the current knowledge concerning the characteristics of SACC in relation to the PNI, and then highlights the interplay between components of the tumor microenvironment and perineural niche, as well as their contributions to the PNI. Finally, we provide new insights into the possible mechanisms underlying the pathogenesis of PNI, with particular emphasis on the role of extracellular vesicles that may serve as an attractive entry point in future studies.
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Affiliation(s)
- Xiaohao Liu
- Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaojun Yang
- Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chaoning Zhan
- Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yan Zhang
- Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jin Hou
- Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuemin Yin
- Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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11
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Song Y, Wang G, Zhuang J, Ni J, Zhang S, Ye Y, Xia W. MicroRNA‑584 prohibits hepatocellular carcinoma cell proliferation and invasion by directly targeting BDNF. Mol Med Rep 2019; 20:1994-2001. [PMID: 31257521 DOI: 10.3892/mmr.2019.10424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Accepted: 05/22/2019] [Indexed: 11/05/2022] Open
Abstract
In recent decades, an increasing number of studies have demonstrated that numerous microRNAs (miRNAs) are dysregulated in hepatocellular carcinoma (HCC); these aberrantly expressed miRNAs are contributing regulators of HCC formation and progression. Thus, revealing the biological roles of miRNAs in HCC may provide novel information on the identification of effective therapeutic targets and valuable diagnosis methods. Herein, reverse transcription‑quantitative PCR was performed to determine the expression profile of miRNA‑584 (miR‑584) in HCC tissues and cell lines. Cell Counting Kit‑8 and cell invasion assays were utilized to evaluate the influence of mIR‑584 overexpression on HCC cell proliferation and invasion, respectively. The present study demonstrated that miR‑584 expression was reduced in HCC tissues and cell lines compared with normal controls. Clinical analysis indicated that decreased miR‑584 expression was significantly associated with tumor size, TNM stage and lymph node metastasis of patients with HCC. Additionally, resumption of miR‑584 expression inhibited proliferation and invasion of HCC cells. Mechanistically, it was demonstrated that miR‑584 can directly interact with the 3'‑untranslated regions of brain‑derived neurotrophic factor (BDNF) mRNA, and reduce its mRNA and protein levels in HCC cells. Furthermore, BDNF was upregulated in HCC tissues, and its level was inversely correlated with miR‑584 expression. Notably, restored BDNF expression antagonized the inhibitory effects of miR‑584 overexpression on HCC cells. In conclusion, miR‑584 may serve tumor‑suppressive roles in HCC by directly targeting BDNF, thus suggesting that miR‑584 may serve as a potential candidate for treatment of patients with this disease.
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Affiliation(s)
- Yanan Song
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Guoyu Wang
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Juhua Zhuang
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Jing Ni
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Suiliang Zhang
- Department of Oncology, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Ying Ye
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
| | - Wei Xia
- Department of Nuclear Medicine, The Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, P.R. China
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12
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Di YZ, Han BS, Di JM, Liu WY, Tang Q. Role of the brain-gut axis in gastrointestinal cancer. World J Clin Cases 2019; 7:1554-1570. [PMID: 31367615 PMCID: PMC6658366 DOI: 10.12998/wjcc.v7.i13.1554] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Revised: 04/04/2019] [Accepted: 05/02/2019] [Indexed: 02/05/2023] Open
Abstract
Several studies have largely focused on the significant role of the nervous and immune systems in the process of tumorigenesis, including tumor growth, proliferation, apoptosis, and metastasis. The brain-gut-axis is a new paradigm in neuroscience, which describes the biochemical signaling between the gastrointestinal (GI) tract and the central nervous system. This axis may play a critical role in the tumorigenesis and development of GI cancers. Mechanistically, the bidirectional signal transmission of the brain-gut-axis is complex and remains to be elucidated. In this article, we review the current findings concerning the relationship between the brain-gut axis and GI cancer cells, focusing on the significant role of the brain-gut axis in the processes of tumor proliferation, invasion, apoptosis, autophagy, and metastasis. It appears that the brain might modulate GI cancer by two pathways: the anatomical nerve pathway and the neuroendocrine route. The simulation and inactivation of the central nervous, sympathetic, and parasympathetic nervous systems, or changes in the innervation of the GI tract might contribute to a higher incidence of GI cancers. In addition, neurotransmitters and neurotrophic factors can produce stimulatory or inhibitory effects in the progression of GI cancers. Insights into these mechanisms may lead to the discovery of potential prognostic and therapeutic targets.
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Affiliation(s)
- Yang-Zi Di
- Department of General Surgery, Shiyan Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
| | - Bo-Sheng Han
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 443000, Hubei Province, China
| | - Jun-Mao Di
- Department of General Surgery, Shiyan Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
| | - Wei-Yan Liu
- Department of General Surgery, Shiyan Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
| | - Qiang Tang
- Department of General Surgery, Shiyan Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
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Khosla R, Banik A, Kaushal S, Battu P, Gupta D, Anand A. Is Brain-Derived Neurotrophic Factor: A Common Link Between Neurodegenerative Disorders and Cancer? Curr Alzheimer Res 2019; 16:344-352. [PMID: 30961497 DOI: 10.2174/1567205016666190408123947] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 03/06/2019] [Accepted: 03/08/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Cancer is a common disease caused by the excessive proliferation of cells, and neurodegenerative diseases are the disorders caused due to the degeneration of neurons. Both can be considered as diseases caused by the dysregulation of cell cycle events. A recent data suggests that there is a strong inverse association between cancer and neurodegenerative disorders. There is indirect evidence to postulate Brain-derived Neurotrophic Factor (BDNF) as a potential molecular link in this association. DISCUSSION The BDNF levels are found to be downregulated in many neurodegenerative disorders and are found to be upregulated in various kinds of cancers. The lower level of BDNF in Alzheimer's and Parkinson's disease has been found to be related to cognitive and other neuropsychological impairments, whereas, its higher levels are associated with the tumour growth and metastasis and poor survival rate in the cancer patients. CONCLUSION In this review, we propose that variance in BDNF levels is critical in determining the course of cellular pathophysiology and the development of cancer or neurodegenerative disorder. We further propose that an alternative therapeutic strategy that can modulate BDNF expression, can rescue or prevent above said pathophysiological course. Larger studies that examine this link through animal studies are imperative to understand the putative biochemical and molecular link to wellness and disease.
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Affiliation(s)
- Radhika Khosla
- Neuroscience Research Lab, Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, Chandigarh, India
| | - Avijit Banik
- Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, United States
| | - Sushant Kaushal
- Neuroscience Research Lab, Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, Chandigarh, India
| | - Priya Battu
- Neuroscience Research Lab, Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, Chandigarh, India
| | - Deepti Gupta
- Department of English and Cultural Studies, Panjab University, Chandigarh, India
| | - Akshay Anand
- Neuroscience Research Lab, Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, Chandigarh, India
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14
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Expression of brain-derived neurotrophic factor (BDNF) and its naturally occurring antisense in breast cancer samples. Meta Gene 2019. [DOI: 10.1016/j.mgene.2018.10.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
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15
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Song D, Diao J, Yang Y, Chen Y. MicroRNA‑382 inhibits cell proliferation and invasion of retinoblastoma by targeting BDNF‑mediated PI3K/AKT signalling pathway. Mol Med Rep 2017; 16:6428-6436. [PMID: 28901408 DOI: 10.3892/mmr.2017.7396] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 08/16/2017] [Indexed: 11/06/2022] Open
Abstract
It has previously been demonstrated that multiple microRNAs (miRNAs or miRs) are aberrantly expressed in retinoblastoma (RB) and contribute to RB initiation and progression. miR‑382 has been revealed to be aberrantly expressed and therefore exhibits a key role in the progression of various types of cancer. However, the expression pattern, functional roles and underlying molecular mechanism of miR‑382 in RB remain unknown. The present study investigated the expression levels of miR‑382 and its effects on RB cells and the underlying regulatory mechanism of its action. It was demonstrated that miR‑382 was downregulated in RB tissues and cell lines. Upregulation of miR‑382 inhibited RB cell proliferation and invasion in vitro. Additionally, brain‑derived neurotrophic factor (BDNF) was identified as a novel target of miR‑382 in RB. BDNF was upregulated in RB tissues and negatively associated with miR‑382 expression levels. Furthermore, BDNF overexpression rescued the tumour‑suppressing effects on RB cells induced by miR‑382. miR‑382 inactivated the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signalling pathway in RB. These findings suggested that miR‑382 serves as a tumour suppressor in RB, in part, by targeting the BDNF‑mediated PI3K/AKT signalling pathway. The results of the present study suggest a potential therapeutic strategy for treating RB patients in the future.
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Affiliation(s)
- Dan Song
- Department of Ophthalmology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, P.R. China
| | - Jiandong Diao
- Department of Oncology and Hematology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Yongjing Yang
- Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, Jilin 130012, P.R. China
| | - Yahong Chen
- Department of Colorectal Surgery, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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16
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Chiu JH, Chen FP, Tsai YF, Lin MT, Tseng LM, Shyr YM. Effects of Chinese medicinal herbs on expression of brain-derived Neurotrophic factor (BDNF) and its interaction with human breast cancer MDA-MB-231 cells and endothelial HUVECs. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2017; 17:401. [PMID: 28800782 PMCID: PMC5554408 DOI: 10.1186/s12906-017-1909-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 08/03/2017] [Indexed: 11/10/2022]
Abstract
BACKGROUND Our previous study demonstrated that an up-regulation of the Brain-Derived Neurotrophic Factor (BDNF) signaling pathway is involved the mechanism causing the recurrence of triple negative breast cancer. The aim of this study is to investigate the effects of commonly used Chinese medicinal herbs on MDA-MB-231 and HUVEC cells and how they interact with BDNF. METHODS Human TNBC MDA-MB-231 cells and human endothelial HUVEC cells were used to explore the effect of commonly used Chinese herbal medicines on cancer cells alone, on endothelial cells alone and on cancer cell/endothelial cell interactions; this was done via functional studies, including migration and invasion assays. Furthermore, Western blot analysis and real-time PCR investigations were also used to investigate migration signal transduction, invasion signal transduction, and angiogenic signal transduction in these systems. Finally, the effect of the Chinese medicinal herbs on cancer cell/endothelial cell interactions was assessed using co-culture and ELISA. RESULTS In terms of autoregulation, BDNF up-regulated TrkB gene expression in both MDA-MB-231 and HUVEC cells. Furthermore, BDNF enhanced migration by MDA-MB-231 cells via Rac, Cdc42 and MMP, while also increasing the migration of HUVEC cells via MMP and COX-2 expression. As measured by ELISA, the Chinese herbal medicinal herbs A. membranaceus, P. lactiflora, L. chuanxiong, P. suffruticosa and L. lucidum increased BDNF secretion by MDA-MB-231 cells. Similarly, using a co-culture system with MDA-MB-231 cells, A. membranaceus and L. lucidum modulated BDNF-TrkB signaling by HUVEC cells. CONCLUSION We conclude that BDNF plays an important role in the metastatic interaction between MDA-MB-231 and HUVEC cells. Some Chinese medicinal herbs are able to enhance the BDNF-related metastatic potential of the interaction between cancer cells and endothelial cells. These findings provide important information that should help with the development of integrated medical therapies for breast cancer patients.
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Affiliation(s)
- Jen-Hwey Chiu
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Republic of China
- Comprehensive Breast Health Center & Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan Republic of China
- Division of General Surgery, Department of Surgery, Cheng-Hsin General Hospital, Taipei, Taiwan Republic of China
| | - Fang-Pey Chen
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Republic of China
- Center of Traditional Medicine, Taipei Veterans General Hospital, Taipei, Taiwan Republic of China
| | - Yi-Fang Tsai
- Comprehensive Breast Health Center & Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan Republic of China
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Republic of China
| | - Man-Ting Lin
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Republic of China
| | - Ling-Ming Tseng
- Comprehensive Breast Health Center & Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan Republic of China
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Republic of China
| | - Yi-Ming Shyr
- Comprehensive Breast Health Center & Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan Republic of China
- Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan Republic of China
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17
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Sharma S, Nagpal N, Ghosh PC, Kulshreshtha R. P53-miR-191- SOX4 regulatory loop affects apoptosis in breast cancer. RNA (NEW YORK, N.Y.) 2017; 23:1237-1246. [PMID: 28450532 PMCID: PMC5513068 DOI: 10.1261/rna.060657.117] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 04/22/2017] [Indexed: 06/07/2023]
Abstract
miRNAs have emerged as key participants of p53 signaling pathways because they regulate or are regulated by p53. Here, we provide the first study demonstrating direct regulation of an oncogenic miRNA, miR-191-5p, by p53 and existence of a regulatory feedback loop. Using a combination of qRT-PCR, promoter-luciferase, and chromatin-immunoprecipitation assays, we show that p53 brings about down-regulation of miR-191-5p in breast cancer. miR-191-5p overexpression brought about inhibition of apoptosis in breast cancer cell lines (MCF7 and ZR-75) as demonstrated by reduction in annexin-V stained cells and caspase 3/7 activity, whereas miR-191-5p down-regulation showed the opposite. We further unveiled that SOX4 was a direct target of miR-191-5p. SOX4 overexpression was shown to increase p53 protein levels in MCF7 cells. miR-191-5p overexpression brought about down-regulation of SOX4 and thus p53 levels, suggesting the existence of a regulatory feedback loop. Breast cancer treatment by doxorubicin, an anti-cancer drug, involves induction of apoptosis by p53; we thus wanted to check whether miR-191-5p affects doxorubicin sensitivity. Interestingly, Anti-miR-191 treatment significantly decreased the IC50 of the doxorubicin drug and thus sensitized breast cancer cells to doxorubicin treatment by promoting apoptosis. Overall, this work highlights the importance of the p53-miR-191-SOX4 axis in the regulation of apoptosis and drug resistance in breast cancer and offers a preclinical proof-of-concept for use of an Anti-miR-191 and doxorubicin combination as a rational approach to pursue for better breast cancer treatment.
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Affiliation(s)
- Shivani Sharma
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Delhi, New Delhi 110016, India
- Department of Biochemistry, University of Delhi South Campus, New Delhi 110021, India
| | - Neha Nagpal
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Delhi, New Delhi 110016, India
- Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA
| | - Prahlad C Ghosh
- Department of Biochemistry, University of Delhi South Campus, New Delhi 110021, India
| | - Ritu Kulshreshtha
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Delhi, New Delhi 110016, India
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Tajbakhsh A, Mokhtari-Zaer A, Rezaee M, Afzaljavan F, Rivandi M, Hassanian SM, Ferns GA, Pasdar A, Avan A. Therapeutic Potentials of BDNF/TrkB in Breast Cancer; Current Status and Perspectives. J Cell Biochem 2017; 118:2502-2515. [PMID: 28230291 DOI: 10.1002/jcb.25943] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 02/21/2017] [Indexed: 12/14/2022]
Abstract
Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to stimulate breast cancer cell growth and metastasis via tyrosine kinase receptors TrkA, TrkB, and the p75NTR death receptor. The aberrant activation of BDNF/TrkB pathways can modulate several signaling pathways, including Akt/PI3K, Jak/STAT, NF-kB, UPAR/UPA, Wnt/β-catenin, and VEGF pathways as well as the ER receptor. Several microRNAs have been identified that are involved in the modulation of BDNF/TrkB pathways. These include miR-206, miR-204, MiR-200a/c, MiR-210, MiR-134, and MiR-191; and these may be of value as prognostic and predictive biomarkers for detecting patients at high risk of developing breast cancer. It has been also been demonstrated that a high expression of genes involved in the BDNF pathway in breast cancer is associated with poor clinical outcome and reduced survival of patients. Several approaches have been developed for targeting this pathway, for example TKr inhibitors (AZD6918, CEP-701) and RNA interference. The aim of the current review was to provide an overview of the role of BDNF/TrkB pathways in the pathogenesis of breast cancer and its value as a potential therapeutic target. J. Cell. Biochem. 118: 2502-2515, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Amir Tajbakhsh
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amin Mokhtari-Zaer
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Neurogenic Inflammation Research Centre and Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Rezaee
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fahimeh Afzaljavan
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehdi Rivandi
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Department of Medical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, UK
| | - Alireza Pasdar
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Division of Applied Medicine, Medical School, University of Aberdeen, Foresterhill, Aberdeen, UK.,Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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19
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Shan C, Wei J, Hou R, Wu B, Yang Z, Wang L, Lei D, Yang X. Schwann cells promote EMT and the Schwann-like differentiation of salivary adenoid cystic carcinoma cells via the BDNF/TrkB axis. Oncol Rep 2015; 35:427-35. [PMID: 26530352 DOI: 10.3892/or.2015.4366] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Accepted: 09/23/2015] [Indexed: 11/06/2022] Open
Abstract
Perineural invasion (PNI) is a striking biological behavior observed in salivary adenoid cystic carcinoma (SACC). The present study was designed to establish a co-culture model of SACC cells with Schwann cells (SCs), and then study epithelial-mesenchymal transition (EMT) and the Schwann-like differentiation of SACC cells to investigate the likely molecular mechanism of PNI. The co-culture models of SCs with tumor cells (SACC-83, SACC-LM and MEC-1) were established using a Transwell system. An elevated concentration of brain-derived neurotrophic factor (BDNF) was detected by ELISA assay in the co-cultured medium of the SACC-83 group and SACC-LM group rather than the MEC-1 group. The EMT process and Schwann-like differentiation in SACC-83 cells were analyzed by RT-PCR, western blotting, immunofluorescence, photography, and migration and perineural invasion assays. The SACC-83 cells under the co-culture condition with SCs changed to a mesenchymal morphology and had higher migration and invasion capabilities compared with the solely cultured SACC-83 cells, accompanied by the downregulation of E-cadherin and upregulation of N-cadherin and vimentin. The co-cultured SACC-83 cells also developed Schwann-like differentiation with increased expression of SC markers, S100A4 and GFAP. However, inhibition of tropomyosin-related kinase B (TrkB) by K252a markedly blocked these effects. Additionally, the expression and correlation of TrkB, E-cadherin and S100A4 were analyzed by immunohistochemistry in 187 primary SACC cases. The levels of TrkB and S100A4 expression were both positively associated with PNI in the SACC cases, while E-cadherin expression was negatively associated with PNI. Elevated expression of TrkB was significantly correlated with the downregulated expression of E-cadherin and the upregulated expression of S100A4 in the SACC cases. Our results suggest that SCs play a pivotal role in the PNI process by inducing the EMT process and the Schwann-like differentiation of SACC cells via the BDNF/TrkB axis. Interruption of the interreaction between SACC cells and SCs by targeting the BDNF/TrkB axis may be a potential strategy for anti-PNI therapy in SACC.
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Affiliation(s)
- Chun Shan
- State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Jianhua Wei
- State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Rui Hou
- State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Baolei Wu
- State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Zihui Yang
- State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Lei Wang
- State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Delin Lei
- State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
| | - Xinjie Yang
- State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
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20
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Oh EY, Christensen SM, Ghanta S, Jeong JC, Bucur O, Glass B, Montaser-Kouhsari L, Knoblauch NW, Bertos N, Saleh SM, Haibe-Kains B, Park M, Beck AH. Extensive rewiring of epithelial-stromal co-expression networks in breast cancer. Genome Biol 2015; 16:128. [PMID: 26087699 PMCID: PMC4471934 DOI: 10.1186/s13059-015-0675-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 05/13/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Epithelial-stromal crosstalk plays a critical role in invasive breast cancer pathogenesis; however, little is known on a systems level about how epithelial-stromal interactions evolve during carcinogenesis. RESULTS We develop a framework for building genome-wide epithelial-stromal co-expression networks composed of pairwise co-expression relationships between mRNA levels of genes expressed in the epithelium and stroma across a population of patients. We apply this method to laser capture micro-dissection expression profiling datasets in the setting of breast carcinogenesis. Our analysis shows that epithelial-stromal co-expression networks undergo extensive rewiring during carcinogenesis, with the emergence of distinct network hubs in normal breast, and estrogen receptor-positive and estrogen receptor-negative invasive breast cancer, and the emergence of distinct patterns of functional network enrichment. In contrast to normal breast, the strongest epithelial-stromal co-expression relationships in invasive breast cancer mostly represent self-loops, in which the same gene is co-expressed in epithelial and stromal regions. We validate this observation using an independent laser capture micro-dissection dataset and confirm that self-loop interactions are significantly increased in cancer by performing computational image analysis of epithelial and stromal protein expression using images from the Human Protein Atlas. CONCLUSIONS Epithelial-stromal co-expression network analysis represents a new approach for systems-level analyses of spatially localized transcriptomic data. The analysis provides new biological insights into the rewiring of epithelial-stromal co-expression networks and the emergence of epithelial-stromal co-expression self-loops in breast cancer. The approach may facilitate the development of new diagnostics and therapeutics targeting epithelial-stromal interactions in cancer.
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Affiliation(s)
- Eun-Yeong Oh
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. .,Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. .,Harvard Medical School, Boston, MA, 02215, USA.
| | - Stephen M Christensen
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. .,Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. .,Harvard Medical School, Boston, MA, 02215, USA.
| | - Sindhu Ghanta
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. .,Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. .,Harvard Medical School, Boston, MA, 02215, USA.
| | - Jong Cheol Jeong
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. .,Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. .,Harvard Medical School, Boston, MA, 02215, USA.
| | - Octavian Bucur
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. .,Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. .,Harvard Medical School, Boston, MA, 02215, USA.
| | - Benjamin Glass
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. .,Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. .,Harvard Medical School, Boston, MA, 02215, USA.
| | - Laleh Montaser-Kouhsari
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. .,Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. .,Harvard Medical School, Boston, MA, 02215, USA.
| | - Nicholas W Knoblauch
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. .,Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. .,Harvard Medical School, Boston, MA, 02215, USA.
| | - Nicholas Bertos
- Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
| | - Sadiq Mi Saleh
- Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
| | - Benjamin Haibe-Kains
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada. .,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
| | - Morag Park
- Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
| | - Andrew H Beck
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, 02215, USA. .,Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. .,Harvard Medical School, Boston, MA, 02215, USA.
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21
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Huang SM, Lin C, Lin HY, Chiu CM, Fang CW, Liao KF, Chen DR, Yeh WL. Brain-derived neurotrophic factor regulates cell motility in human colon cancer. Endocr Relat Cancer 2015; 22:455-64. [PMID: 25876647 DOI: 10.1530/erc-15-0007] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/14/2015] [Indexed: 12/13/2022]
Abstract
Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that has been shown to affect cancer cell metastasis and migration. In the present study, we investigated the mechanisms of BDNF-induced cell migration in colon cancer cells. The migratory activities of two colon cancer cell lines, HCT116 and SW480, were found to be increased in the presence of human BDNF. Heme oxygenase-1 (HO)-1 is known to be involved in the development and progression of tumors. However, the molecular mechanisms that underlie HO-1 in the regulation of colon cancer cell migration remain unclear. Expression of HO-1 protein and mRNA increased in response to BDNF stimulation. The BDNF-induced increase in cell migration was antagonized by a HO-1 inhibitor and HO-1 siRNA. Furthermore, the expression of vascular endothelial growth factor (VEGF) also increased in response to BDNF stimulation, as did VEGF mRNA expression and transcriptional activity. The increase in BDNF-induced cancer cell migration was antagonized by a VEGF-neutralizing antibody. Moreover, transfection with HO-1 siRNA effectively reduced the increased VEGF expression induced by BDNF. The BDNF-induced cell migration was regulated by the ERK, p38, and Akt signaling pathways. Furthermore, BDNF-increased HO-1 and VEGF promoter transcriptional activity were inhibited by ERK, p38, and AKT pharmacological inhibitors and dominant-negative mutants in colon cancer cells. These results indicate that BDNF increases the migration of colon cancer cells by regulating VEGF/HO-1 activation through the ERK, p38, and PI3K/Akt signaling pathways. The results of this study may provide a relevant contribution to our understanding of the molecular mechanisms by which BDNF promotes colon cancer cell motility.
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Affiliation(s)
- Ssu-Ming Huang
- Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Ch
| | - Chingju Lin
- Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan
| | - Hsiao-Yun Lin
- Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan
| | - Chien-Ming Chiu
- Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan
| | - Chia-Wei Fang
- Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan
| | - Kuan-Fu Liao
- Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Ch
| | - Dar-Ren Chen
- Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan
| | - Wei-Lan Yeh
- Department of Community MedicinePreventive Medicine CenterDivision of Colon and Rectal SurgeryDepartment of Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanSchool of MedicineTzu Chi University, Hualien, TaiwanDepartment of PhysiologySchool of MedicineGraduate Institute of Neural and Cognitive SciencesChina Medical University, Taichung, TaiwanDepartment of Internal MedicineTaichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, TaiwanDepartment of Chinese MedicineGraduate Institute of Integrated Medicine, China Medical University, Taichung, TaiwanComprehensive Breast Cancer CenterDepartment of Cell and Tissue EngineeringChanghua Christian Hospital, Nanxiao St., Changhua City, Changhua County 500, Taiwan
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Analysis of the expression and polymorphism of APOE, HSP, BDNF, and GRIN2B genes associated with the neurodegeneration process in the pathogenesis of primary open angle glaucoma. BIOMED RESEARCH INTERNATIONAL 2015; 2015:258281. [PMID: 25893192 PMCID: PMC4393917 DOI: 10.1155/2015/258281] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Revised: 03/06/2015] [Accepted: 03/10/2015] [Indexed: 11/25/2022]
Abstract
Glaucoma is characterized by optic neuropathy of the RGC or retinal nerve fiber. The aim of this study was to evaluate a relationship between the neurodegenerative genes' polymorphisms of the APOE (rs449647), BDNF (rs2030324), GRIN2B (rs3764028), and HSP70-1 (rs1043618) and the occurrence risk of POAG and to investigate its effect on allele-specific gene expression. Genomic DNA was extracted from peripheral blood. Analysis of the genes' polymorphisms was performed using PCR-RFLP. The level of mRNA expression was determined by QRT-PCR. We showed a statistically significant association of BDNF and APOE genes' polymorphisms with a risk of POAG occurrence. There was a statistically significant association of the rs2030324 polymorphism with progression of POAG based on cup disc ratio value and rs1043618 polymorphism based on nerve fiber index and rim area. Furthermore, we found that mean HSP70-1 mRNA expression was significantly lower in the case of individuals with the G/G genotype than in the case of minor allele carriers, that is, G/C and C/C. We also found that BDNF and HSP70-1 expression level are associated with the progression of POAG based on rim area value. In conclusion, our results suggest that BDNF, APOE, and HSP70-1 genes might be associated with a risk of POAG occurrence in the Polish population.
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Huth L, Rose M, Kloubert V, Winkens W, Schlensog M, Hartmann A, Knüchel R, Dahl E. BDNF is associated with SFRP1 expression in luminal and basal-like breast cancer cell lines and primary breast cancer tissues: a novel role in tumor suppression? PLoS One 2014; 9:e102558. [PMID: 25036590 PMCID: PMC4103839 DOI: 10.1371/journal.pone.0102558] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 06/19/2014] [Indexed: 01/08/2023] Open
Abstract
Secreted frizzled related protein 1 (SFRP1) functions as an important inhibitor of the Wnt pathway and is a known tumor suppressor gene, which is epigenetically silenced in a variety of tumors e.g. in breast cancer. However, it is still unclear how SFRP1 exactly affects the Wnt pathway. Our aim was to decipher SFRP1 involvement in biochemical signaling in dependency of different breast cancer subtypes and to identify novel SFRP1-regulated genes. We generated SFRP1 over-expressing in vitro breast cancer models, reflecting the two major subtypes by using basal-like BT20 and luminal-like HER2-positive SKBR3 cells. DNA microarray expression profiling of these models revealed that SFRP1 expression potentially modulates Bone morphogenetic protein- and Smoothened signaling (p<0.01), in addition to the known impact on Wnt signaling. Importantly, further statistical analysis revealed that in dependency of the cancer subtype model SFRP1 may affect the canonical and non-canonical Wnt pathway (p<0.01), respectively. While SFRP1 re-expression generally mediated distinct patterns of transcriptionally induced or repressed genes in BT20 and SKBR3 cells, brain derived neurotrophic factor (BDNF) was identified as a SFRP1 induced gene in both cell lines. Although BDNF has been postulated as a putative oncogene, the co-regulation with SFRP1 indicates a potential suppressive function in breast cancer. Indeed, a positive correlation between SFRP1 and BDNF protein expression could be shown (p<0.001) in primary breast cancer samples. Moreover, TCGA dataset based analysis clearly underscores that BDNF mRNA is down-regulated in primary breast cancer samples predicting a poor prognosis of these patients. In line, we functionally provide evidence that stable BDNF re-expression in basal-like BT20 breast cancer cells blocks tumor cell proliferation. Hence, our results suggest that BDNF might rather mediate suppressive than promoting function in human breast cancer whose mode of action should be addressed in future studies.
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Affiliation(s)
- Laura Huth
- Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
| | - Michael Rose
- Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
| | - Veronika Kloubert
- Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
| | - Wiebke Winkens
- Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
| | - Martin Schlensog
- Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Hospital Erlangen, Erlangen, Germany
| | - Ruth Knüchel
- Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
| | - Edgar Dahl
- Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
- * E-mail:
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24
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The TrkB+ cancer stem cells contribute to post-chemotherapy recurrence of triple-negative breast cancers in an orthotopic mouse model. Oncogene 2014; 34:761-70. [DOI: 10.1038/onc.2014.8] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Revised: 12/17/2013] [Accepted: 01/06/2014] [Indexed: 12/21/2022]
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25
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Apoptosis signal-regulating kinase 1 is involved in brain-derived neurotrophic factor (BDNF)-enhanced cell motility and matrix metalloproteinase 1 expression in human chondrosarcoma cells. Int J Mol Sci 2013; 14:15459-78. [PMID: 23892595 PMCID: PMC3759868 DOI: 10.3390/ijms140815459] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Revised: 07/15/2013] [Accepted: 07/15/2013] [Indexed: 12/11/2022] Open
Abstract
Chondrosarcoma is the primary malignancy of bone that is characterized by a potent capacity to invade locally and cause distant metastasis, and is therefore associated with poor prognoses. Chondrosarcoma further shows a predilection for metastasis to the lungs. The brain-derived neurotrophic factor (BDNF) is a small molecule in the neurotrophin family of growth factors that is associated with the disease status and outcome of cancers. However, the effect of BDNF on cell motility in human chondrosarcoma cells is mostly unknown. Here, we found that human chondrosarcoma cell lines had significantly higher cell motility and BDNF expression compared to normal chondrocytes. We also found that BDNF increased cell motility and expression of matrix metalloproteinase-1 (MMP-1) in human chondrosarcoma cells. BDNF-mediated cell motility and MMP-1 up-regulation were attenuated by Trk inhibitor (K252a), ASK1 inhibitor (thioredoxin), JNK inhibitor (SP600125), and p38 inhibitor (SB203580). Furthermore, BDNF also promoted Sp1 activation. Our results indicate that BDNF enhances the migration and invasion activity of chondrosarcoma cells by increasing MMP-1 expression through a signal transduction pathway that involves the TrkB receptor, ASK1, JNK/p38, and Sp1. BDNF thus represents a promising new target for treating chondrosarcoma metastasis.
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Nagpal N, Ahmad HM, Molparia B, Kulshreshtha R. MicroRNA-191, an estrogen-responsive microRNA, functions as an oncogenic regulator in human breast cancer. Carcinogenesis 2013; 34:1889-99. [PMID: 23542418 DOI: 10.1093/carcin/bgt107] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Estrogen- and microRNA-mediated gene regulation play a crucial role in breast cancer biology. However, a functional link between the two major players remains unclear. This study reveals miR-191 as an estrogen-inducible onco-miR in breast cancer, which promotes several hallmarks of cancer including enhanced cell proliferation, migration, chemoresistance and survival in tumor microenvironment. miR-191 is a direct estrogen receptor (ER) target and our results suggest existence of a positive regulatory feedback loop. We show miR-191 as critical mediator of estrogen-mediated cell proliferation. Investigations of mechanistic details of miR-191 functions identify several cancer-related genes like BDNF, CDK6 and SATB1 as miR-191 targets. miR-191 and SATB1 show inverse correlation of expression. miR-191-mediated enhanced cell proliferation and migration are partly dependent on targeted downregulation of SATB1. Further, functional validation of estrogen:miR-191:SATB1 link suggests a cascade initiated by estrogen that induces miR-191 in ER-dependent manner to target SATB1, a global chromatin remodeler, thereby contributing to estrogen-specific gene signature to regulate genes like ANXA1, PIWIL2, CASP4, ESR1/ESR2, PLAC1 and SOCS2 involved in breast cancer progression and migration. Overall, the identification of estrogen/ER/miR-191/SATB1 cascade seems to be a significant pathway in estrogen signaling in breast cancer with miR-191 as oncogenic player.
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Affiliation(s)
- Neha Nagpal
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, New Delhi, India
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