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Wang M, Pu N, Bo X, Chen F, Zhou Y, Cheng Q. Significance and mechanisms of perineural invasion in malignant tumors. Front Oncol 2025; 15:1572396. [PMID: 40421086 PMCID: PMC12104087 DOI: 10.3389/fonc.2025.1572396] [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: 02/07/2025] [Accepted: 04/18/2025] [Indexed: 05/28/2025] Open
Abstract
Cancer remains the second leading cause of death worldwide. Tumor invasion and metastasis pose significant challenges for clinical management. In addition to the traditional pathways of metastasis such as hematologic or lymphatic transmission, perineural invasion (PNI) has become a unique mechanism of metastasis, which is closely associated with neuropathic pain, motor deficits, and poor prognosis. PNI is often observed in malignant tumors of the pancreas, head and neck, gastrointestinal tract, and lungs, and it reflects a unique neurotropic transfer behavior utilizing neural networks. Despite its clinical significance, targeted therapies for PNI are still lacking. This review synthesizes current evidences regarding PNI, elucidates the clinical significance of PNI in tumor metastasis, prognosis, and neurological dysfunction. By integrating the latest advances in multi-omics, we analyzed the potential key molecular pathways and tumor microenvironment drivers of PNI, and proposed future research directions for developing PNI-specific therapies to improve patient outcomes.
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Affiliation(s)
- Mengyao Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Niu Pu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Xitong Bo
- Department of Surgery, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Fuxiang Chen
- Department of Surgery, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Yilong Zhou
- Department of Surgery, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Medical School of Nantong University, Nantong, China
| | - Qiong Cheng
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
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2
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Wang Y, Gao H, Li X, Li D, Huang F, Sun Y, Liu X, Yang J, Sun F. PRC1 as an independent adverse prognostic factor in Wilms tumor via integrated bioinformatics and experimental validation. Sci Rep 2025; 15:13282. [PMID: 40247060 PMCID: PMC12006549 DOI: 10.1038/s41598-025-98030-y] [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: 12/16/2024] [Accepted: 04/09/2025] [Indexed: 04/19/2025] Open
Abstract
Wilms Tumor (WT), a prevalent pediatric renal malignancy, exhibits marked heterogeneity and variable clinical outcomes. Epithelial-mesenchymal transition (EMT), a biological process enabling epithelial cells to acquire mesenchymal traits associated with enhanced migratory and invasive capacities, plays a crucial role in cancer progression. Protein Regulator of Cytokinesis 1 (PRC1) is a critical protein in cell division, whose overexpression is linked to poor prognosis in various cancers. This study investigates the role of PRC1 as a key prognostic factor in WT and explore the mechanism through comprehensive bioinformatic and experimental approaches. Through bulk RNA-seq data from the TARGET database, we identified PRC1 as significantly up-regulated in WT and associated with poor overall survival. Functional enrichment analyses (GO, KEGG, GSEA) demonstrated PRC1's involvement in cell division, chromatin dynamics, and activation of oncogenic pathways including Wnt/β-catenin, PI3K/AKT/mTOR, and Hedgehog signaling. Immunological analysis showed that elevated PRC1 expression correlates with diminished immune cell activity, particularly in NK cells, suggesting potential immune evasion mechanisms. Single-cell RNA-seq analysis (GSE200256) confirmed PRC1's elevated expression in anaplastic Wilms tumor (AWT) compared to favorable Wilms tumor (FWT), and highlighted its involvement in intercellular communication and metastasis via the EMT process. Genomic analyses identified copy number variations (CNVs) and downregulated PRC1-targeting microRNAs as drivers of its overexpression. In vitro, PRC1 knockdown in WIT-49 cells significantly impaired migratory capacity, invasive potential, EMT progression, and glycolytic metabolism. These findings collectively position PRC1 as a promising therapeutic target and prognostic biomarker in WT.
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Affiliation(s)
- Yanping Wang
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Hongjie Gao
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China
| | - Xuetian Li
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Ding Li
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Fan Huang
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yuqiang Sun
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Xingjian Liu
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Junli Yang
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China.
| | - Fengyin Sun
- Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China.
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Haque M, Shyanti RK, Mishra MK. Targeted therapy approaches for epithelial-mesenchymal transition in triple negative breast cancer. Front Oncol 2024; 14:1431418. [PMID: 39450256 PMCID: PMC11499239 DOI: 10.3389/fonc.2024.1431418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 09/24/2024] [Indexed: 10/26/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is distinguished by negative expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), making it an aggressive subtype of breast cancer and contributes to 15-20% of the total incidence. TNBC is a diverse disease with various genetic variations and molecular subtypes. The tumor microenvironment involves multiple cells, including immune cells, fibroblast cells, extracellular matrix (ECM), and blood vessels that constantly interact with tumor cells and influence each other. The ECM undergoes significant structural changes, leading to induced cell proliferation, migration, adhesion, invasion, and epithelial-to-mesenchymal transition (EMT). The involvement of EMT in the occurrence and development of tumors through invasion and metastasis in TNBC has been a matter of concern. Therefore, EMT markers could be prognostic predictors and potential therapeutic targets in TNBC. Chemotherapy has been one of the primary options for treating patients with TNBC, but its efficacy against TNBC is still limited. Targeted therapy is a critical emerging option with enhanced efficacy and less adverse effects on patients. Various targeted therapy approaches have been developed based on the specific molecules and the signaling pathways involved in TNBC. These include inhibitors of signaling pathways such as TGF-β, Wnt/β-catenin, Notch, TNF-α/NF-κB and EGFR, as well as immune checkpoint inhibitors, such as pembrolizumab, 2laparib, and talazoparib have been widely explored. This article reviews recent developments in EMT in TNBC invasion and metastasis and potential targeted therapy strategies.
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Affiliation(s)
| | | | - Manoj K. Mishra
- Cancer Research Center, Department of Biological Sciences, Alabama State
University, Montgomery, AL, United States
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4
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Strippoli R, Niayesh-Mehr R, Adelipour M, Khosravi A, Cordani M, Zarrabi A, Allameh A. Contribution of Autophagy to Epithelial Mesenchymal Transition Induction during Cancer Progression. Cancers (Basel) 2024; 16:807. [PMID: 38398197 PMCID: PMC10886827 DOI: 10.3390/cancers16040807] [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: 12/15/2023] [Revised: 02/13/2024] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
Epithelial Mesenchymal Transition (EMT) is a dedifferentiation process implicated in many physio-pathological conditions including tumor transformation. EMT is regulated by several extracellular mediators and under certain conditions it can be reversible. Autophagy is a conserved catabolic process in which intracellular components such as protein/DNA aggregates and abnormal organelles are degraded in specific lysosomes. In cancer, autophagy plays a controversial role, acting in different conditions as both a tumor suppressor and a tumor-promoting mechanism. Experimental evidence shows that deep interrelations exist between EMT and autophagy-related pathways. Although this interplay has already been analyzed in previous studies, understanding mechanisms and the translational implications of autophagy/EMT need further study. The role of autophagy in EMT is not limited to morphological changes, but activation of autophagy could be important to DNA repair/damage system, cell adhesion molecules, and cell proliferation and differentiation processes. Based on this, both autophagy and EMT and related pathways are now considered as targets for cancer therapy. In this review article, the contribution of autophagy to EMT and progression of cancer is discussed. This article also describes the multiple connections between EMT and autophagy and their implication in cancer treatment.
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Affiliation(s)
- Raffaele Strippoli
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy;
- National Institute for Infectious Diseases “Lazzaro Spallanzani”, I.R.C.C.S., 00149 Rome, Italy
| | - Reyhaneh Niayesh-Mehr
- Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran P.O. Box 14115-331, Iran;
| | - Maryam Adelipour
- Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 61357-15794, Iran;
| | - Arezoo Khosravi
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, Istanbul 34959, Türkiye;
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain;
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Türkiye;
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai 600077, India
| | - Abdolamir Allameh
- Department of Clinical Biochemistry, Faculty of Medical Science, Tarbiat Modares University, Tehran P.O. Box 14115-331, Iran;
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Abdolahi M, Ghaedi Talkhounche P, Derakhshan Nazari MH, Hosseininia HS, Khoshdel-Rad N, Ebrahimi Sadrabadi A. Functional Enrichment Analysis of Tumor Microenvironment-Driven Molecular Alterations That Facilitate Epithelial-to-Mesenchymal Transition and Distant Metastasis. Bioinform Biol Insights 2024; 18:11779322241227722. [PMID: 38318286 PMCID: PMC10840405 DOI: 10.1177/11779322241227722] [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: 01/06/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024] Open
Abstract
Nowadays, hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths, and identifying the effective factors in causing this disease can play an important role in its prevention and treatment. Tumors provide effective agents for invasion and metastasis to other organs by establishing appropriate communication between cancer cells and the microenvironment. Epithelial-to-mesenchymal transition (EMT) can be mentioned as one of the effective phenomena in tumor invasion and metastasis. Several factors are involved in inducing this phenomenon in the tumor microenvironment, which helps the tumor survive and migrate to other places. It can be effective to identify these factors in the use of appropriate treatment strategies and greater patient survival. This study investigated the molecular differences between tumor border cells and tumor core cells or internal tumor cells in HCC for specific EMT genes. Expression of NOTCH1, ID1, and LST1 genes showed a significant increase at the HCC tumor border. Targeting these genes can be considered as a useful therapeutic strategy to prevent distant metastasis in HCC patients.
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Affiliation(s)
- Mahnaz Abdolahi
- Department of Immunology, Faculty of Medicine, Shahid Beheshti University, Tehran, Iran
| | - Parnian Ghaedi Talkhounche
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mohammad Hossein Derakhshan Nazari
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Haniyeh Sadat Hosseininia
- Department of Cellular and Molecular Biology, Faculty of Advanced Medical Science, Islamic Azad University of Medical Sciences, Tehran, Iran
- Cytotech & Bioinformatics Research Group, Bioinformatics Department, Tehran, Iran
| | - Niloofar Khoshdel-Rad
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Amin Ebrahimi Sadrabadi
- Cytotech & Bioinformatics Research Group, Bioinformatics Department, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran
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Chhabra G, Singh CK, Ndiaye MA, Su S, Shirley CA, Ahmad N. Role of PLK1/NUMB/NOTCH in epithelial-mesenchymal transition in human melanoma. NPJ Precis Oncol 2024; 8:6. [PMID: 38184733 PMCID: PMC10771520 DOI: 10.1038/s41698-023-00493-7] [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: 01/13/2023] [Accepted: 12/02/2023] [Indexed: 01/08/2024] Open
Abstract
Polo-like kinase 1 (PLK1), a serine/threonine kinase, is overexpressed in melanoma and its expression has been associated with poor disease prognosis. PLK1 has been shown to interact with NUMB, a NOTCH antagonist. However, the exact role of PLK1, NUMB, and NOTCH signaling in epithelial-mesenchymal transition (EMT) in melanoma progression is unclear. In this study, Affymetrix microarray analysis was performed to determine differentially expressed genes following shRNA-mediated knockdown of PLK1 in human melanoma cells that showed significant modulations in EMT and metastasis-related genes. Using multiple PLK1-modulated melanoma cell lines, we found that PLK1 is involved in the regulation of cell migration, invasion, and EMT via its kinase activity and NOTCH activation. In vitro kinase assay and mass spectrometry analysis demonstrated a previously unknown PLK1 phosphorylation site (Ser413) on NUMB. Overexpression of non-phosphorylatable (S413A) and phosphomimetic (S413D) mutants of NUMB in melanoma cells implicated the involvement of NUMB-S413 phosphorylation in cell migration and invasion, which was independent of NOTCH activation. To determine the clinical relevance of these findings, immunohistochemistry was performed using melanoma tissue microarray, which indicated a strong positive correlation between PLK1 and N-cadherin, a protein required for successful EMT. These findings were supported by TCGA analysis, where expression of high PLK1 with low NUMB or high NOTCH or N-cadherin showed a significant decrease in survival of melanoma patients. Overall, these results suggest a potential role of PLK1 in EMT, migration, and invasion of melanoma cells. Our findings support the therapeutic targeting of PLK1, NUMB, and NOTCH for melanoma management.
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Affiliation(s)
- Gagan Chhabra
- Department of Dermatology, University of Wisconsin, Madison, WI, 53705, USA
| | - Chandra K Singh
- Department of Dermatology, University of Wisconsin, Madison, WI, 53705, USA
| | - Mary A Ndiaye
- Department of Dermatology, University of Wisconsin, Madison, WI, 53705, USA
| | - Shengqin Su
- Department of Dermatology, University of Wisconsin, Madison, WI, 53705, USA
| | - Carl A Shirley
- Department of Dermatology, University of Wisconsin, Madison, WI, 53705, USA
| | - Nihal Ahmad
- Department of Dermatology, University of Wisconsin, Madison, WI, 53705, USA.
- William S. Middleton Memorial Veterans Hospital, Madison, WI, 53705, USA.
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Ye M, Du J, Wang X, Xiu L, Liu X, Gu Y, Pei B, Sun D, Yue X. Xiaotansanjiefang inhibits the viability of colorectal cancer cells via Jagged 1/Notch 3/Snail signaling pathway. ENVIRONMENTAL TOXICOLOGY 2022; 37:2957-2964. [PMID: 36039874 PMCID: PMC9804677 DOI: 10.1002/tox.23651] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/17/2022] [Accepted: 08/17/2022] [Indexed: 06/15/2023]
Abstract
The purpose of this study is to explore the anti-colorectal cancer of Xiaotansanjiefang, a famous traditional Chinese medicine, and its potential anti-cancer mechanism. In this study, the HCT116 cell spheres were prepared as in vitro study model. We found the Xiaotansanjiefang medication was able to inhibit the proliferation of HCT116 cell spheres in a dose-dependent manner, especially in 3 and 6 mg/ml Xiaotansanjiefang medication treated groups. We also found the high concentration of Xiaotansanjiefang medication could suppress the migration and promote the apoptosis of HCT116 cell spheres. Moreover, we found the expression of Jagged 1, Notch 3, Snail, and Hes 1 were decreased in HCT116 cell spheres treated with Xiaotansanjiefang medication. Furthermore, the proliferation and apoptosis behaviors of HCT116 cell spheres treated with Xiaotansanjiefang medication were reversed with the addition of Jagged 1 Fc chimera protein. The expression of Jagged 1, Notch 3, Snail, and Hes 1 were also increased again in HCT116 cells treated with Xiaotansanjiefang medication plus with Jagged 1 Fc chimera protein. The presented study may provide a promising strategy to treat and prevent colorectal cancer.
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Affiliation(s)
- Min Ye
- Department of Traditional Chinese Medicine, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Jiaqi Du
- Department of Bai's Proctology, Shuguang HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Xiaowei Wang
- Department of Traditional Chinese Medicine, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Lijuan Xiu
- Department of Traditional Chinese Medicine, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Xuan Liu
- Department of Traditional Chinese Medicine, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Yufang Gu
- Department of Traditional Chinese Medicine, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Bei Pei
- Department of Traditional Chinese Medicine, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Dazhi Sun
- Department of Traditional Chinese Medicine, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
| | - Xiaoqiang Yue
- Department of Traditional Chinese Medicine, Changzheng HospitalSecond Military Medical UniversityShanghaiChina
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8
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Li Y, Hung SW, Zhang R, Man GCW, Zhang T, Chung JPW, Fang L, Wang CC. Melatonin in Endometriosis: Mechanistic Understanding and Clinical Insight. Nutrients 2022; 14:nu14194087. [PMID: 36235740 PMCID: PMC9572886 DOI: 10.3390/nu14194087] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/27/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Endometriosis is defined as the development of endometrial glands and stroma outside the uterine cavity. Pathophysiology of this disease includes abnormal hormone profiles, cell survival, migration, invasion, angiogenesis, oxidative stress, immunology, and inflammation. Melatonin is a neuroendocrine hormone that is synthesized and released primarily at night from the mammalian pineal gland. Increasing evidence has revealed that melatonin can be synthesized and secreted from multiple extra-pineal tissues where it regulates immune response, inflammation, and angiogenesis locally. Melatonin receptors are expressed in the uterus, and the therapeutic effects of melatonin on endometriosis and other reproductive disorders have been reported. In this review, key information related to the metabolism of melatonin and its biological effects is summarized. Furthermore, the latest in vitro and in vivo findings are highlighted to evaluate the pleiotropic functions of melatonin, as well as to summarize its physiological and pathological effects and treatment potential in endometriosis. Moreover, the pharmacological and therapeutic benefits derived from the administration of exogenous melatonin on reproductive system-related disease are discussed to support the potential of melatonin supplements toward the development of endometriosis. More clinical trials are needed to confirm its therapeutic effects and safety.
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Affiliation(s)
- Yiran Li
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Sze-Wan Hung
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Ruizhe Zhang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Gene Chi-Wai Man
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Tao Zhang
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Jacqueline Pui-Wah Chung
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Lanlan Fang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Correspondence: (L.F.); (C.-C.W.); Tel.: +86-371-6691-3635 (L.F.); +852-3505-4267 (C.-C.W.)
| | - Chi-Chiu Wang
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
- Laboratory of Reproduction and Development, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
- Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
- Correspondence: (L.F.); (C.-C.W.); Tel.: +86-371-6691-3635 (L.F.); +852-3505-4267 (C.-C.W.)
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Buyuk B, Jin S, Ye K. Epithelial-to-Mesenchymal Transition Signaling Pathways Responsible for Breast Cancer Metastasis. Cell Mol Bioeng 2022; 15:1-13. [PMID: 35096183 PMCID: PMC8761190 DOI: 10.1007/s12195-021-00694-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023] Open
Abstract
Breast carcinoma is highly metastatic and invasive. Tumor metastasis is a convoluted and multistep process involving tumor cell disseminating from their primary site and migrating to the secondary organ. Epithelial-mesenchymal transition (EMT) is one of the crucial steps that initiate cell progression, invasion, and metastasis. During EMT, epithelial cells alter their molecular features and acquire a mesenchymal phenotype. The regulation of EMT is centered by several signaling pathways, including primary mediators TGF-β, Notch, Wnt, TNF-α, Hedgehog, and RTKs. It is also affected by hypoxia and microRNAs (miRNAs). All these pathways are the convergence on the transcriptional factors such as Snail, Slug, Twist, and ZEB1/2. In addition, a line of evidence suggested that EMT and cancer stem like cells (CSCs) are associated. EMT associated cancer stem cells display mesenchymal phenotypes and resist to chemotherapy or targeted therapy. In this review, we highlighted recent discoveries in these signaling pathways and their regulation in breast cancer metastasis and invasion. While the clinical relevance of EMT and breast cancers remains controversial, we speculated a convergent signaling network pivotal to elucidating the transition of epithelial to mesenchymal phenotypes and onset of metastasis of breast cancer cells.
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Affiliation(s)
- Busra Buyuk
- Department of Biomedical Engineering, Watson College of Engineering and Applied Science, Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), PO Box 6000, Binghamton, NY 13902 USA
| | - Sha Jin
- Department of Biomedical Engineering, Watson College of Engineering and Applied Science, Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), PO Box 6000, Binghamton, NY 13902 USA
| | - Kaiming Ye
- Department of Biomedical Engineering, Watson College of Engineering and Applied Science, Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), PO Box 6000, Binghamton, NY 13902 USA
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10
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Crosstalk between non-coding RNAs expression profile, drug resistance and immune response in breast cancer. Pharmacol Res 2021; 176:106041. [PMID: 34952200 DOI: 10.1016/j.phrs.2021.106041] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/15/2021] [Accepted: 12/19/2021] [Indexed: 12/18/2022]
Abstract
Drug resistance is one of the most critical challenges facing researchers in treating breast cancer. Despite numerous treatments for breast cancer, including conventional chemical drugs, monoclonal antibodies, and immunotherapeutic drugs known as immune checkpoint inhibitors (ICI), many patients resist various approaches. In recent years, the relationship between gene expression profiles and drug resistance phenotypes has attracted much attention. Non-coding RNAs (ncRNAs) are regulatory molecules that have been shown to regulate gene expression and cell transcriptome. Two categories, microRNAs and long non-coding RNAs have been more considered and studied among these ncRNAs. Studying the role of different ncRNAs in chemical drug resistance and ICI resistance together can be beneficial in selecting more effective treatments for breast cancer. Changing the expression and action mechanism of these regulatory molecules on drug resistance phenotypes is the main topic of this review article.
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11
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Kim L, Park SA, Yang Y, Kim Y, Heo TH, Kim H. LncRNA SRA mediates cell migration, invasion, and progression of ovarian cancer via NOTCH signaling and epithelial-mesenchymal transition. Biosci Rep 2021; 41:BSR20210565. [PMID: 34402503 PMCID: PMC8421593 DOI: 10.1042/bsr20210565] [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: 03/10/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 01/07/2023] Open
Abstract
Long non-coding RNA (lncRNA) is a newly identified regulator of tumor formation and tumor progression. The function and expression of lncRNAs remain to be fully elucidated, but recent studies have begun to address their importance in human health and disease. The lncRNA, SRA, known as steroid receptor activator, acts as an important modulator of gynecological cancer, and its expression may affect biological functions including proliferation, apoptosis, steroid formation, and muscle development. However, it is still not well known whether SRA is involved in the regulation of ovarian cancer. The present study investigated the molecular function and association between SRA expression and clinicopathological factors. In ovarian cancer cell lines, SRA knockdown and overexpression regulated cell migration, proliferation, and invasion. Both in vivo and in vitro experiments using knockdown and overexpression showed that SRA potently regulated epithelial-mesenchymal transition (EMT) and NOTCH pathway components. Further, clinical data confirmed that SRA was a significant predictor of overall survival (OS) and progression-free survival and patients with ovarian cancer exhibiting high expression of SRA exhibited higher recurrence rates than patients with low SRA expression. In conclusion, the present study indicates that SRA has clinical significance as its expression can predict the prognosis of ovarian cancer patients. High expression of the lncRNA SRA is strongly correlated with recurrence-free survival of ovarian cancer patients.
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Affiliation(s)
- Lee Kyung Kim
- Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences and BK21 FOUR Team for Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi-do 14662, South Korea
| | - Sun-Ae Park
- Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences and BK21 FOUR Team for Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi-do 14662, South Korea
| | - Yoolhee Yang
- Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, South Korea
| | - Young Tae Kim
- Institute of Women's Life Medical Science, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Tae-Hwe Heo
- Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences and BK21 FOUR Team for Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi-do 14662, South Korea
| | - Hee Jung Kim
- Laboratory of Pharmacoimmunology, Integrated Research Institute of Pharmaceutical Sciences and BK21 FOUR Team for Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Bucheon-si, Gyeonggi-do 14662, South Korea
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Zheng K, Han X, Su Y, Wang Q, Ma Q, Zheng K. Effects of targeted Notch1 silencing on the biological processes of the T24 and 5637 cells in vitro. Oncol Lett 2021; 21:305. [PMID: 33732381 PMCID: PMC7905604 DOI: 10.3892/ol.2021.12566] [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: 01/20/2020] [Accepted: 11/26/2020] [Indexed: 11/30/2022] Open
Abstract
The present study aimed to investigate the roles of Notch1 in the biological processes of bladder cancer cells (BCCs) in vitro. Short hairpin (sh)RNA targeting Notch1 was designed and constructed, and the T24 and 5637 BCCs were selected for transfection. The cells were classified into two groups: shRNA negative control (NC) and Notch1 shRNA. MTT and Transwell assays, and flow cytometry were performed to examine the changes in cell proliferation, invasiveness, and apoptosis, respectively. In addition, reverse transcription-quantitative PCR and western blot analysis was used to detect the mRNA and protein expression levels of apoptosis-related proteins (Bax, Bid and Bcl2) and epithelial-mesenchymal transition factors (vimentin and E- and N-cadherin). Compared with that in the shRNA NC group, the Notch1 shRNA group showed significantly decreased cell proliferation rate and invasiveness; increased apoptotic rate; elevated mRNA expression levels of Bad, Bid and E-cadherin; and reduced mRNA expression levels of Bcl2, N-cadherin and vimentin. The trends for protein expression levels were the same as those for mRNA levels. Notch1 silencing inhibited invasion and promoted apoptosis of BCCs.
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Affiliation(s)
- Kewen Zheng
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, The First Clinical College of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiaomin Han
- Blood Conservation Institute, School of Basic and Forensic Medicine, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region 014040, P.R. China
| | - Yan Su
- Blood Conservation Institute, School of Basic and Forensic Medicine, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region 014040, P.R. China
| | - Qinghai Wang
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Qiang Ma
- Blood Conservation Institute, School of Basic and Forensic Medicine, Baotou Medical College, Baotou, Inner Mongolia Autonomous Region 014040, P.R. China
| | - Kesi Zheng
- Department of Thyroid and Breast Surgery, Wenzhou People's Hospital, The Third Clinical College of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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13
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Prognostic Implications of ALDH1 and Notch1 in Different Subtypes of Oral Cancer. JOURNAL OF ONCOLOGY 2021; 2021:6663720. [PMID: 33854547 PMCID: PMC8020805 DOI: 10.1155/2021/6663720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/27/2021] [Accepted: 02/03/2021] [Indexed: 11/18/2022]
Abstract
Background The present study aimed to investigate the clinical significance and prognostic value of the immunoexpression of cancer stem cell markers, ALDH1 and Notch1, in subtypes of oral squamous cell carcinoma. Materials and Methods The expression of ALDH1 and Notch1 in 63 patients with well and poorly differentiated oral squamous cell carcinomas and their subtypes, verrucous carcinoma and basaloid squamous cell carcinoma, was evaluated by immunohistochemistry. The semi-quantitative analysis of the ALDH1 and Notch immunoexpression levels, based on the capture of 10 microscopic fields, at 400X magnification, at the invasive tumor front was performed and associated with clinicopathological variables using the chi-square test or Fisher's exact test. The overall and disease-free survival rates were estimated according to the Kaplan-Meier method and the curves were compared using the log-rank test. The independent effects of variables were calculated using Cox's proportional hazards regression model. Results Strong ALDH1 and Notch1 expression was observed in 16 (25.4%) and 27 (42.9%) oral squamous cell carcinomas including their subtypes, respectively. Most tumors with strong immunoexpression of ALDH1 were basaloid squamous cell carcinoma (56.3%). Statistically significant associations were observed between the strong immunoexpression of Notch1 in poorly differentiated oral squamous cell carcinoma with perineural infiltration (p = 0.011) and lymph node involvement (pN+) (p = 0.034). The strong immunoexpression of ALDH1 was a prognostic factor associated with worse overall survival (p = 0.040) for patients with oral cancer. Conclusion The strong immunoexpression of Notch1 can contribute to identification of patients with poorly differentiated oral squamous cell carcinoma, who have perineural infiltration or lymph node metastasis. In addition, the strong immunoexpression of ALDH1 may help to identify a worse prognosis in patients with oral squamous cell carcinoma and their subtypes.
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14
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Thakur G, Kumar R, Kim SB, Lee SY, Lee SL, Rho GJ. Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma. Biomedicines 2021; 9:biomedicines9020178. [PMID: 33670230 PMCID: PMC7916947 DOI: 10.3390/biomedicines9020178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
One of the most severe and devastating cancer is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the major pancreatic exocrine cancer with a poor prognosis and growing prevalence. It is the most deadly disease, with an overall five-year survival rate of 6% to 10%. According to various reports, it has been demonstrated that pancreatic cancer stem cells (PCSCs) are the main factor responsible for the tumor development, proliferation, resistance to anti-cancer drugs, and recurrence of tumors after surgery. PCSCs have encouraged new therapeutic methods to be explored that can specifically target cancer cells. Furthermore, stem cells, especially mesenchymal stem cells (MSCs), are known as influential anti-cancer agents as they function through anti-inflammatory, paracrine, cytokines, and chemokine's action. The properties of MSCs, such as migration to the site of infection and host immune cell activation by its secretome, seem to control the microenvironment of the pancreatic tumor. MSCs secretome exhibits similar therapeutic advantages as a conventional cell-based therapy. Moreover, the potential for drug delivery could be enhanced by engineered MSCs to increase drug bioactivity and absorption at the tumor site. In this review, we have discussed available therapeutic strategies, treatment hurdles, and the role of different factors such as PCSCs, cysteine, GPCR, PKM2, signaling pathways, immunotherapy, and NK-based therapy in pancreatic cancer.
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Affiliation(s)
- Gitika Thakur
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Raj Kumar
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan 173 234, Himachal Pradesh, India;
| | - Saet-Byul Kim
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sang-Yeob Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sung-Lim Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Gyu-Jin Rho
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
- Correspondence:
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15
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Zhang N, Ji J, Zhou D, Liu X, Zhang X, Liu Y, Xiang W, Wang M, Zhang L, Wang G, Huang B, Lu J, Zhang Y. The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling. Int J Mol Sci 2021; 22:E849. [PMID: 33467780 PMCID: PMC7830992 DOI: 10.3390/ijms22020849] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/06/2021] [Accepted: 01/12/2021] [Indexed: 01/07/2023] Open
Abstract
Chemotherapy is one of the most common strategies for tumor treatment but often associated with post-therapy tumor recurrence. While chemotherapeutic drugs are known to induce tumor cell senescence, the roles and mechanisms of senescence in tumor recurrence remain unclear. In this study, we used doxorubicin to induce senescence in breast cancer cells, followed by culture of breast cancer cells with conditional media of senescent breast cancer cells (indirect co-culture) or directly with senescent breast cancer cells (direct co-culture). We showed that breast cancer cells underwent the epithelial-mesenchymal transition (EMT) to a greater extent and had stronger migration and invasion ability in the direct co-culture compared with that in the indirect co-culture model. Moreover, in the direct co-culture model, non-senescent breast cancer cells facilitated senescent breast cancer cells to escape and re-enter into the cell cycle. Meanwhile, senescent breast cancer cells regained tumor cell characteristics and underwent EMT after direct co-culture. We found that the Notch signaling was activated in both senescent and non-senescent breast cancer cells in the direct co-culture group. Notably, the EMT process of senescent and adjacent breast cancer cells was blocked upon inhibition of Notch signaling with N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester (DAPT) in the direct co-cultures. In addition, DAPT inhibited the lung metastasis of the co-cultured breast cancer cells in vivo. Collectively, data arising from this study suggest that both senescent and adjacent non-senescent breast cancer cells developed EMT through activating Notch signaling under conditions of intratumoral heterogeneity caused by chemotherapy, which infer the possibility that Notch inhibitors used in combination with chemotherapeutic agents may become an effective treatment strategy.
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Affiliation(s)
- Na Zhang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China; (N.Z.); (D.Z.); (X.Z.); (M.W.); (G.W.)
| | - Jiafei Ji
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Dandan Zhou
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China; (N.Z.); (D.Z.); (X.Z.); (M.W.); (G.W.)
| | - Xuan Liu
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Xinglin Zhang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China; (N.Z.); (D.Z.); (X.Z.); (M.W.); (G.W.)
| | - Yingqi Liu
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Weifang Xiang
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Meida Wang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China; (N.Z.); (D.Z.); (X.Z.); (M.W.); (G.W.)
| | - Lian Zhang
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Guannan Wang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China; (N.Z.); (D.Z.); (X.Z.); (M.W.); (G.W.)
| | - Baiqu Huang
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Jun Lu
- The Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China; (J.J.); (X.L.); (Y.L.); (W.X.); (L.Z.); (B.H.); (J.L.)
| | - Yu Zhang
- The Key Laboratory of Molecular Epigenetics of Ministry of Education (MOE), Northeast Normal University, Changchun 130024, China; (N.Z.); (D.Z.); (X.Z.); (M.W.); (G.W.)
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Liu W, Huang G, Yang Y, Gao R, Zhang S, Kou B. Oridonin inhibits epithelial-mesenchymal transition of human nasopharyngeal carcinoma cells by negatively regulating AKT/STAT3 signaling pathway. Int J Med Sci 2021; 18:81-87. [PMID: 33390776 PMCID: PMC7738957 DOI: 10.7150/ijms.48552] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 10/21/2020] [Indexed: 12/30/2022] Open
Abstract
Oridonin, derived from Rabdosia rubescens, has exhibited anticancer activity in a variety of cancers. However, few studies have explored the effect of oridonin (ORI) on migration, invasion and epithelial-mesenchymal transition (EMT) in nasopharyngeal carcinoma. In our study, the results demonstrated that oridonin significantly inhibited migration and invasion of human nasopharyngeal carcinoma CNE-2Z and HNE-1 cell lines, as depicted by wound healing and Transwell assays. In addition, oridonin increased the expression of E-Cadherin while decreased the expressions of vimentin and twist1 at the mRNA and protein levels in a dose-dependent manner. Interestingly, oridonin also decreased cell mobility in nasopharyngeal carcinoma. The subsequent results of western blotting uncovered that the phosphorylation levels of AKT and signal transducer and activator of transcription 3 (STAT3) were decreased upon oridonin treatment. Furthermore, co-treatment with the AKT activator SC-79 attenuated the anti-metastatic effect of oridonin on nasopharyngeal carcinoma and partially abolished the high expression of E-cadherin and the low expression of twist1 mediated by oridonin. In conclusion, the results revealed that oridonin could repress metastatic phenotype and reverse epithelial-mesenchymal transition (EMT) in nasopharyngeal carcinoma by negatively regulating AKT/STAT3 signaling pathway, suggesting that AKT/STAT3 signaling may be the potential therapeutic target of oridonin against nasopharyngeal carcinoma.
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Affiliation(s)
- Wei Liu
- Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, People's Republic of China
| | - Gaobo Huang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, People's Republic of China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, People's Republic of China
| | - Yang Yang
- Department of Cadiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, People's Republic of China
| | - Ruixia Gao
- School of Science, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, People's Republic of China
| | - Shaoqiang Zhang
- Department of Otorhinolaryngology-Head&Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, People's Republic of China
| | - Bo Kou
- Department of Otorhinolaryngology-Head&Neck Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, People's Republic of China
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17
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Wen CX, Tian HL, Chen E, Liu JF, Liu XX. MiRNA-873-5p Acts as a Potential Novel Biomarker and Promotes Cervical Cancer Progression by Regulating ZEB1 via Notch Signaling Pathway. Dose Response 2021; 19:15593258211001255. [PMID: 35185415 PMCID: PMC8851136 DOI: 10.1177/15593258211001255] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 01/24/2021] [Accepted: 02/16/2021] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE Our group aimed to investigate the expression pattern of miRNA-873-5p in cervical cancer (CC) patients and its association with CC progression. METHODS Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied for the examination of the expressions of miRNA-873-5p in both CC specimens and cell lines. The clinical significance of miRNA-873-5p was statistically analyzed. MTT, colony formation, Transwell and flow cytometry assays were used to detect cell proliferation, metastasis, and apoptosis changes of Hela and Siha cell line. Luciferase reporter assays and Western blots were utilized to identify the target genes of miRNA-873-5p. Western blot and RT-PCR were used to judge the dysregulation of Notch signaling. RESULTS Our results indicated that miRNA-873-5p expression was distinctly reduced in CC patients. Low miRNA-873-5p expressions were distinctly correlated with positively distant metastasis, The International Federation of Gynecology and Obstetrics (FIGO) stage and poor prognosis of CC patients. A functional assay using miRNA-873-5p mimics indicated that overexpression of miRNA-873-5p distinctly suppressed CC cells proliferation and metastasis, and promoted apoptosis. Bioinformatic assays revealed that miRNA-873-5p may target the 3'-UTR of ZEB1 and lead to the suppression of its translation, which was verified by the use of luciferase assays. Finally, overexpression of miRNA-873-5p suppressed the expressions of Jag1, Maml2 and Hey1. CONCLUSION Taken together, we firstly provided evidence that miRNA-873-5p expression was a poor favorable factor for CC patients, and the use of miRNA-873-5p may represent a and potential biomarker and promising therapeutic approach for CC.
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Affiliation(s)
- Chen-Xia Wen
- Department of Obstetrics and Gynecology, Dongying People’s Hospital, Dongying, Shandong, China
| | - Hai-Li Tian
- Department of Obstetrics and Gynecology, Dongying People’s Hospital, Dongying, Shandong, China
| | - E Chen
- Department of Oncology, Dongying People’s Hospital, Dongying, Shandong, China
| | - Jin-Fang Liu
- Department of Rongjun, Dongying Rongjun Hospital, Dongying, Shandong, China
| | - Xiao-Xing Liu
- Department of Obstetrics and Gynecology, Dongying People’s Hospital, Dongying, Shandong, China
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E2F8 Induces Cell Proliferation and Invasion through the Epithelial-Mesenchymal Transition and Notch Signaling Pathways in Ovarian Cancer. Int J Mol Sci 2020; 21:ijms21165813. [PMID: 32823614 PMCID: PMC7460858 DOI: 10.3390/ijms21165813] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/02/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022] Open
Abstract
Background: Despite the recent research implicating E2F8 (E2F Transcription Factor 8) in cancer, the role of E2F8 in the progression of ovarian cancer has remained unclear. Hence, we explored the bio-functional effects of E2F8 knockdown on ovarian cancer cell lines in vitro and in vivo. Methods: The expression of E2F8 was compared between ovarian cancer and noncancer tissues, and its association with the progression-free survival of ovarian cancer patients was analyzed. To demonstrate the function of E2F8 in cell proliferation, migration, and invasion, we employed RNA interference to suppress E2F8 expression in ovarian cancer cell lines. Finally, the effect of E2F8 knockdown was investigated in a xenograft mouse model of ovarian cancer. Results: Ovarian cancer tissue exhibited significantly higher E2F8 expression compared to that of normal ovarian tissue. Clinical data showed that E2F8 was a significant predictor of progression-free survival. Moreover, the prognosis of the ovarian cancer patients with high E2F8 expression was poorer than that of the patients with low E2F8 expression. In vitro experiments using E2F8-knockdown ovarian cancer cell lines demonstrated that E2F8 knockdown inhibited cell proliferation, migration, and tumor invasion. Additionally, E2F8 was a potent inducer and modulator of the expression of epithelial–mesenchymal transition and Notch signaling pathway-related markers. We confirmed the function of E2F8 in vivo, signifying that E2F8 knockdown was significantly correlated with reduced tumor size and weight. Conclusions: Our findings indicate that E2F8 is highly correlated with ovarian cancer progression. Hence, E2F8 can be utilized as a prognostic marker and therapeutic target against ovarian malignancy.
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Liu J, Miao X, Xiao B, Huang J, Tao X, Zhang J, Zhao H, Pan Y, Wang H, Gao G, Xiao GG. Obg-Like ATPase 1 Enhances Chemoresistance of Breast Cancer via Activation of TGF-β/Smad Axis Cascades. Front Pharmacol 2020; 11:666. [PMID: 32528278 PMCID: PMC7266972 DOI: 10.3389/fphar.2020.00666] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 04/23/2020] [Indexed: 01/04/2023] Open
Abstract
Understanding the molecular mechanism of drug resistance helps to identify an effective target for breast cancer therapy. In this study we investigated the regulatory role of Obg-like ATPase 1 which is involved in multiple uses of drug resistance against breast cancer. Paclitaxel resistant cell line (MCF-7-PTR) was developed by a continuous increasing paclitaxel concentration. MTT assay was used to validate either acquired resistant or OLA1 modified cell lines. qRT-PCR, western blotting, apoptosis, and cell cycle assays were executed to evaluate gene and protein expression in cell lines. A series of in vitro assays was performed in the cells with RNAi-mediated knockdown to expound the regulatory function of OLA1 in breast cancer. We demonstrated that OLA1 was highly correlated with either acquired or intrinsic resistance of breast cancer. Further study showed that escalated expression of OLA1 promoted the EMT process in tumor cells through TGF-β/Smad signaling cascades, resulting in the enhanced expression of anti-apoptosis-related proteins (cleaved caspase3, Bax, Bcl-2) and the strengthening depolymerization of microtubules in tumor cells. Our findings revealed that OLA1 enhanced the anti-apoptotic ability and elucidated a regulatory role of OLA1 in promoting chemotherapy resistance of breast cancer. Chemo-sensitivity of the disease can be thus enhanced significantly by knocked down OLA1, which led to the inactivation of the TGF-β/Smad signaling cascades, polymerized microtubules, and promoted cell apoptosis. Our data suggest that OLA1 may be developed as a potential target to improve chemotherapy of patients with breast cancer.
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Affiliation(s)
- Jianzhou Liu
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian, China.,School of Bioengineering, Dalian University of Technology, Dalian, China
| | - Xiaoyu Miao
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian, China
| | - Bowen Xiao
- Cardiothoracic Surgery, Changsha Central Hospital Affiliated to Nanhua University, Changsha, China
| | - Jing Huang
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian, China
| | - Xufeng Tao
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian, China
| | - Jiong Zhang
- Beijing Key Lab of Plant Resource Research and Development, Beijing Technology and Business University, Beijing, China
| | - Hua Zhao
- Beijing Key Lab of Plant Resource Research and Development, Beijing Technology and Business University, Beijing, China
| | - Yue Pan
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian, China
| | - Hongwei Wang
- Department of Dermatology, Peking Union Medical College Hospital, Beijing, China
| | - Ge Gao
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Gary Guishan Xiao
- State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian, China.,School of Bioengineering, Dalian University of Technology, Dalian, China.,Functional Genomics and Proteomics Laboratory, Osteoporosis Research Center, Creighton University Medical Center, Omaha, NE, United States
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20
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Cheng C, Huang Z, Zhou R, An H, Cao G, Ye J, Huang C, Wu D. Numb negatively regulates the epithelial-to-mesenchymal transition in colorectal cancer through the Wnt signaling pathway. Am J Physiol Gastrointest Liver Physiol 2020; 318:G841-G853. [PMID: 32146835 DOI: 10.1152/ajpgi.00178.2019] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors and is associated with a high mortality rate due to the lack of specific biomarkers available for early diagnosis, targeted therapies, and prognostic surveillance. In the present study, we investigated the function of Numb and its underlying mechanism in CRC. Immunohistochemical staining and clinicopathological analysis were used to assess the expression of Numb and its clinical significance in patients with CRC. Quantitative real-time polymerase chain reaction, cell proliferation, Western blot, wound healing, Transwell, and TOP/FOP flash reporter assays were used to investigate the function of Numb and its underlying mechanism in CRC. Numb expression was downregulated and negatively correlated with the depth of invasion, tumor size, metastasis, TNM stage, and epithelial-to-mesenchymal transition (EMT) markers in CRC specimens. Numb negatively regulates the EMT, proliferation, invasion, migration, and the Wnt signaling pathway in vitro, as well as tumor growth and metastasis in vivo. Furthermore, activation of the Wnt signaling pathway by Wnt-3A negated the effect of Numb overexpression, whereas inhibition of the Wnt signaling pathway by IWR-1 impaired the effect of the Numb knockdown on the EMT. We concluded that Numb downregulation is a common event in patients with CRC and is closely correlated with cancer progression and a poor prognosis. Numb functions as a tumor suppressor in CRC, and its tumor suppressor function is mediated by negative regulation of the EMT through the Wnt signaling pathway.NEW & NOTEWORTHY We investigate the function of Numb and its underlying mechanism in colorectal cancer through quantitative real-time polymerase chain reaction, cell proliferation, Western blot, wound healing, Transwell, and TOP/FOP flash reporter assays. We conclude that Numb can negatively regulate the epithelial-to-mesenchymal transition through the Wnt signaling pathway to inhibit the development of colorectal cancer.
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Affiliation(s)
- Chi Cheng
- Department of Gastrointestinal Surgery, Ruian People's Hospital, Ruian, Zhejiang, China
| | - Zhenfeng Huang
- Department of Gastrointestinal Surgery, Ruian People's Hospital, Ruian, Zhejiang, China
| | - Ruiyao Zhou
- Department of Gastrointestinal Surgery, Ruian People's Hospital, Ruian, Zhejiang, China
| | - Huimin An
- Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, China
| | - Gaojian Cao
- Department of Gastrointestinal Surgery, Ruian People's Hospital, Ruian, Zhejiang, China
| | - Jun Ye
- Department of Laboratory Medicine, The Second Affiliated Hospital of Guizhou Medical University, Guizhou, China
| | - Chaolin Huang
- Department of Obstetrics and Gynecology, Chengdu First People's Hospital, Chengdu, Sichuan, China
| | - Daoyi Wu
- Department of Gastrointestinal Surgery, Ruian People's Hospital, Ruian, Zhejiang, China
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Forghanifard MM, Azaraz S, Ardalan Khales S, Morshedi Rad D, Abbaszadegan MR. MAML1 promotes ESCC aggressiveness through upregulation of EMT marker TWIST1. Mol Biol Rep 2020; 47:2659-2668. [PMID: 32180088 DOI: 10.1007/s11033-020-05356-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/27/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND Mastermind-like 1 (MAML1) is the main transcriptional co-activator of Notch signaling pathway. It plays essential roles in several pathways including MEF2C, p53, Nf-кB and Wnt/β-catenin. TWIST1 is known as a regulator of epithelial mesenchymal transition (EMT), which is considered as a primary step in promotion of tumor cell metastasis. Since concomitant expression of these genes was observed in tumors, our aim in this study was to elucidate the linkage between MAML1 and TWIST1 co-overexpression in esophageal squamous cell carcinoma (ESCC). RESULTS While MAML1 silencing significantly down-regulated TWIST1, its ectopic expression up-regulated TWIST1 expression in both mRNA and protein levels in KYSE-30 cells. Expression of mesenchymal markers was increased significantly after MAML1 and TWIST1 ectopic expression, while epithelial markers expression was significantly decreased after silencing of both genes. Concomitant protein expression of MAML1 and TWIST1 was significantly observed in ESCC patients. Enforced expression of TWIST1 had no impact on MAML1 gene expression in KYSE-30 cells. CONCLUSION The results clearly suggest transcriptional regulation of TWIST1 by MAML1 transcription factor in ESCC cells KYSE-30. Since TWIST1 is known as an EMT inducing marker, our results may revealed the mastermind behind TWIST1 function and introduced MAML1 as an upstream master regulator of TWIST1 and EMT in KYSE-30 cells.
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Affiliation(s)
| | - Shirin Azaraz
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sima Ardalan Khales
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Dorsa Morshedi Rad
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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22
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Yi Z, Pu Y, Gou R, Chen Y, Ren X, Liu W, Dong P. Silencing of RIPK4 inhibits epithelial‑mesenchymal transition by inactivating the Wnt/β‑catenin signaling pathway in osteosarcoma. Mol Med Rep 2020; 21:1154-1162. [PMID: 32016450 PMCID: PMC7002986 DOI: 10.3892/mmr.2020.10939] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 03/29/2019] [Indexed: 12/17/2022] Open
Abstract
Receptor interacting protein kinase 4 (RIPK4) is a serine/threonine kinase that plays an important role in the regulation of cell proliferation, invasion and metastasis in several malignancies; however, its clinical significance and biological function in osteosarcoma (OS) remains unknown. In the present study, the RIPK4 expression level was significantly upregulated in OS tissues and cell lines. High RIPK4 expression was positively associated with larger sized tumors, advanced Enneking stage and poor prognosis in patients with OS. Furthermore, the results revealed that RIPK4 knockdown in the OS cell lines MG‑63 and U2OS reduced cell migration and invasion via the inhibition of epithelial‑mesenchymal transition (EMT) process, whereby E‑cadherin expression was increased and N‑cadherin and vimentin expression decreased. Mechanistically, RIPK4 knockdown inhibited EMT by inactivating the Wnt/β‑catenin signaling pathway. These findings suggest that RIPK4 may be a novel potential therapeutic target for the treatment of metastases in patients with OS.
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Affiliation(s)
- Zhigang Yi
- Department of Pediatric Orthopedics and Pediatrics, Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Yanchuan Pu
- Department of Orthopedics, Wuwei City People's Hospital, Wuwei, Gansu 733000, P.R. China
| | - Ruoyan Gou
- Department of Pediatric Orthopedics and Pediatrics, Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Yonggang Chen
- Department of Pediatric Orthopedics and Pediatrics, Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Xiaojun Ren
- Department of Pediatric Orthopedics and Pediatrics, Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Wenzhong Liu
- Department of Pediatric Orthopedics and Pediatrics, Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
| | - Ping Dong
- Department of Pediatric Orthopedics and Pediatrics, Second Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China
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23
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Tekpli X, Lien T, Røssevold AH, Nebdal D, Borgen E, Ohnstad HO, Kyte JA, Vallon-Christersson J, Fongaard M, Due EU, Svartdal LG, Sveli MAT, Garred Ø, Frigessi A, Sahlberg KK, Sørlie T, Russnes HG, Naume B, Kristensen VN. An independent poor-prognosis subtype of breast cancer defined by a distinct tumor immune microenvironment. Nat Commun 2019; 10:5499. [PMID: 31796750 PMCID: PMC6890706 DOI: 10.1038/s41467-019-13329-5] [Citation(s) in RCA: 131] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 10/30/2019] [Indexed: 12/14/2022] Open
Abstract
How mixtures of immune cells associate with cancer cell phenotype and affect pathogenesis is still unclear. In 15 breast cancer gene expression datasets, we invariably identify three clusters of patients with gradual levels of immune infiltration. The intermediate immune infiltration cluster (Cluster B) is associated with a worse prognosis independently of known clinicopathological features. Furthermore, immune clusters are associated with response to neoadjuvant chemotherapy. In silico dissection of the immune contexture of the clusters identified Cluster A as immune cold, Cluster C as immune hot while Cluster B has a pro-tumorigenic immune infiltration. Through phenotypical analysis, we find epithelial mesenchymal transition and proliferation associated with the immune clusters and mutually exclusive in breast cancers. Here, we describe immune clusters which improve the prognostic accuracy of immune contexture in breast cancer. Our discovery of a novel independent prognostic factor in breast cancer highlights a correlation between tumor phenotype and immune contexture. In breast cancer, the immune infiltration of the tumour associates with clinical outcome. Here, the authors infer immune context based on gene expression data and identify a new independent subtype linked to pro-tumorigenic immune infiltration.
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Affiliation(s)
- Xavier Tekpli
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Tonje Lien
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Andreas Hagen Røssevold
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Daniel Nebdal
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Elin Borgen
- Department of Pathology, Division of Laboratory Medicine, Oslo University Hospital, Oslo, Norway
| | - Hege Oma Ohnstad
- Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Jon Amund Kyte
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Johan Vallon-Christersson
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Scheelegatan 2, Medicon Village, 22185, Lund, Sweden
| | - Marie Fongaard
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Eldri Undlien Due
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Lisa Gregusson Svartdal
- Department of Pathology, Division of Laboratory Medicine, Oslo University Hospital, Oslo, Norway
| | - My Anh Tu Sveli
- Department of Pathology, Division of Laboratory Medicine, Oslo University Hospital, Oslo, Norway
| | - Øystein Garred
- Department of Pathology, Division of Laboratory Medicine, Oslo University Hospital, Oslo, Norway
| | | | - Arnoldo Frigessi
- Department of Biostatistics, Oslo Centre for Biostatistics and Epidemiology, University of Oslo and Research Support Services, Oslo University Hospital, Oslo, Norway
| | - Kristine Kleivi Sahlberg
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Department of Research, Vestre Viken Hospital Trust, Drammen, Norway
| | - Therese Sørlie
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Centre for Cancer Biomarkers CCBIO, Bergen, Norway
| | - Hege G Russnes
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Department of Pathology, Division of Laboratory Medicine, Oslo University Hospital, Oslo, Norway
| | - Bjørn Naume
- Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Vessela N Kristensen
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. .,Centre for Cancer Biomarkers CCBIO, Bergen, Norway. .,Department of Clinical Molecular Biology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway.
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24
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Das V, Bhattacharya S, Chikkaputtaiah C, Hazra S, Pal M. The basics of epithelial-mesenchymal transition (EMT): A study from a structure, dynamics, and functional perspective. J Cell Physiol 2019; 234:14535-14555. [PMID: 30723913 DOI: 10.1002/jcp.28160] [Citation(s) in RCA: 161] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 12/07/2018] [Indexed: 02/06/2023]
Abstract
Epithelial-mesenchymal transition (EMT) is a key step in transdifferentiation process in solid cancer development. Forthcoming evidence suggest that the stratified program transforms polarized, immotile epithelial cells to migratory mesenchymal cells associated with enhancement of breast cancer stemness, metastasis, and drug resistance. It involves primarily several signaling pathways, such as transforming growth factor-β (TGF-β), cadherin, notch, plasminogen activator protein inhibitor, urokinase plasminogen activator, and WNT/beta catenin pathways. However, current understanding on the crosstalk of multisignaling pathways and assemblies of key transcription factors remain to be explored. In this review, we focus on the crosstalk of signal transduction pathways linked to the current therapeutic and drug development strategies. We have also performed the computational modeling on indepth the structure and conformational dynamic studies of regulatory proteins and analyze molecular interactions with their associate factors to understand the complicated process of EMT in breast cancer progression and metastasis. Electrostatic potential surfaces have been analyzed that help in optimization of electrostatic interactions between the protein and its ligand. Therefore, understanding the biological implications underlying the EMT process through molecular biology with biocomputation and structural biology approaches will enable the development of new therapeutic strategies to sensitize tumors to conventional therapy and suppress their metastatic phenotype.
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Affiliation(s)
- Vishal Das
- Biological Sciences and Technology Division (Biotechnology Group), CSIR-North East Institute of Science and Technology, Academy of Scientific and Innovative Research, Jorhat, Assam, India
| | - Sourya Bhattacharya
- Department of Biotechnology, Centre for Nanotechnology, Indian Institute of Technology Roorkee (IITR), Roorkee, Uttarakhand, India
| | - Channakeshavaiah Chikkaputtaiah
- Biological Sciences and Technology Division (Biotechnology Group), CSIR-North East Institute of Science and Technology, Academy of Scientific and Innovative Research, Jorhat, Assam, India
| | - Saugata Hazra
- Department of Biotechnology, Centre for Nanotechnology, Indian Institute of Technology Roorkee (IITR), Roorkee, Uttarakhand, India
| | - Mintu Pal
- Biological Sciences and Technology Division (Biotechnology Group), CSIR-North East Institute of Science and Technology, Academy of Scientific and Innovative Research, Jorhat, Assam, India
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25
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Du FY, Zhou QF, Sun WJ, Chen GL. Targeting cancer stem cells in drug discovery: Current state and future perspectives. World J Stem Cells 2019; 11:398-420. [PMID: 31396368 PMCID: PMC6682504 DOI: 10.4252/wjsc.v11.i7.398] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/18/2019] [Accepted: 06/27/2019] [Indexed: 02/06/2023] Open
Abstract
In recent decades, cancer stem cells (CSCs) have been increasingly identified in many malignancies. CSC-related signaling pathways and their functions provide new strategies for treating cancer. The aberrant activation of related signaling pathways (e.g., Wnt, Notch, and Hedgehog pathways) has been linked to multiple types of malignant tumors, which makes these pathways attractive targets for cancer therapy. CSCs display many characteristic features, such as self-renewal, differentiation, high tumorigenicity, and drug resistance. Therefore, there is an urgent need to develop new therapeutic strategies to target these pathways to control stem cell replication, survival, and differentiation. Notable crosstalk occurs among different signaling pathways and potentially leads to compensatory escape. Therefore, multitarget inhibitors will be one of the main methods to overcome the drug resistance of CSCs. Many small molecule inhibitors of components of signaling pathways in CSCs have entered clinical trials, and some inhibitors, such as vismodegib, sonidegib, and glasdegib, have been approved. Tumor cells are susceptible to sonidegib and vismodegib resistance due to mutations in the Smo protein. The signal transducers and activators of transcription 3 (STAT3) inhibitor BBI608 is being evaluated in a phase III trial for a variety of cancers. Structural derivatives of BBI608 are the main focus of STAT3 inhibitor development, which is another strategy for CSC therapy. In addition to the potential pharmacological inhibitors targeting CSC-related signaling pathways, other methods of targeting CSCs are available, such as nano-drug delivery systems, mitochondrion targeting, autophagy, hyperthermia, immunotherapy, and CSC microenvironment targeting. In addition, we summarize the latest advances in the clinical development of agents targeting CSC-related signaling pathways and other methods of targeting CSCs.
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Affiliation(s)
- Fang-Yu Du
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
| | - Qi-Fan Zhou
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
| | - Wen-Jiao Sun
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
| | - Guo-Liang Chen
- Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning Province, China
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26
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Taxifolin inhibits breast cancer cells proliferation, migration and invasion by promoting mesenchymal to epithelial transition via β-catenin signaling. Life Sci 2019; 232:116617. [PMID: 31260685 DOI: 10.1016/j.lfs.2019.116617] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 06/26/2019] [Accepted: 06/28/2019] [Indexed: 01/15/2023]
Abstract
AIM To investigate the effects and underlying mechanisms of taxifolin on proliferation, migration and invasion of highly aggressive breast cancer in vitro and in vivo. MAIN METHODS The antineoplastic activity of taxifolin was evaluated in MDA-MB-231 and 4 T1 cells by crystal violet assay and colony formation assay. The effects of taxifolin on migration and invasion were determined by wound healing assay and Transwell assay, respectively. mRNA and protein expression of genes were assayed respectively with qRT-PCR and western blot, and the protein expression and location was also detected by immunofluorescence and immunohistochemistry. β-catenin overexpression was performed with adenovirus infection. The effects of taxifolin on growth and metastasis of breast cancer in vivo were investigated in BALB/c mice bearing 4T1 xenografts. KEY FINDINGS We found that taxifolin had the potential to inhibit proliferation, migration and invasion of highly aggressive breast cancer cells in a dose-dependent manner. In addition, taxifolin promoted the MET process, the reversed process of EMT, as evaluated by EMT markers and EMT-transcriptional factors in breast cancer cell lines. Meanwhile, the protein and mRNA expressions of β-catenin were dose-dependently downregulated by taxifolin, and overexpression of β-catenin by adenoviruses abrogated these beneficial effects of taxifolin above-mentioned. Furthermore, within a 4T1 xenograft mouse model, taxifolin markedly inhibited the growth of primary tumors and reduced lung metastasis of breast cancer. SIGNIFICANCE Our findings provide a theoretical foundation for the possibility of taxifolin used as a promising agent in the clinical treatment of highly aggressive breast cancer patients.
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27
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MicroRNA-34a inhibits epithelial-mesenchymal transition of lens epithelial cells by targeting Notch1. Exp Eye Res 2019; 185:107684. [PMID: 31158382 DOI: 10.1016/j.exer.2019.05.024] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 04/16/2019] [Accepted: 05/28/2019] [Indexed: 01/08/2023]
Abstract
Posterior capsule opacification (PCO) is a common long-term complication of modern cataract surgery. The epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is a crucial process in the development of PCO. The purpose of this study is to investigate the role of microRNA-34a (miR-34a) in the regulation of EMT and its target gene. Human LECs were treated with TGFβ2 to induce EMT as a model for PCO. The mRNA levels of miR-34a and EMT markers were examined by real-time quantitative polymerase chain reaction (qPCR). The expression level of miR-34a was downregulated, whereas that of Notch1 was upregulated in TGFβ2-induced EMT of LECs. Overexpression of miR-34a by transfection with miR-34a inhibited EMT of LECs and reduced the expression of Notch1; while, inhibition of miR-34a upregulated the expression of both Notch1 and its ligand Jagged1 in LECs. Luciferase reporter assays revealed that Notch1 gene was direct target of miR-34a. Moreover, DAPT, a specific inhibitor of Notch signaling pathway, reversed LEC-EMT. In addition, the expression level of miR-34a was downregulated, whereas that of Notch1 was upregulated in capsular opacification from cataract samples. MiR-34a can negatively regulate EMT of LECs by targeting Notch1. Therefore, miR-34a/Notch1 could serve as a potential therapeutic approach for the treatment of PCO.
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28
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Li D, Cheng P, Wang J, Qiu X, Zhang X, Xu L, Liu Y, Qin S. IRF6 Is Directly Regulated by ZEB1 and ELF3, and Predicts a Favorable Prognosis in Gastric Cancer. Front Oncol 2019; 9:220. [PMID: 31019894 PMCID: PMC6458252 DOI: 10.3389/fonc.2019.00220] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 03/12/2019] [Indexed: 01/09/2023] Open
Abstract
Interferon regulatory factor 6 (IRF6) acts as a tumor suppressor and controls cell differentiation in ectodermal and craniofacial tissues by regulating expression of target genes. However, its function in gastric cancer (GC) remains unknown to date. In this study, we found that the IRF6 expression was significantly downregulated in GC. And the decreased expression of IRF6 was clinically correlated with poor prognosis of GC. Moreover, loss-of-function and gain-of-function studies showed that IRF6 was negatively regulated by ZEB1 but positively regulated by ELF3. Additionally, transcription factor ZEB1 and ELF3 could directly bind on IRF6 promoter, which suggested that transcription factor IRF6 is transcriptionally regulated by ZEB1 and ELF3. Nevertheless, we found that IRF6 expression was negatively related to its promoter methylation in TCGA stomach cancer cohorts. The downregulation of IRF6 in GC might be due to the overexpression of ZEB1 and the DNA methylation of IRF6 promoter.
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Affiliation(s)
- Dandan Li
- Institute of Basic Medical Sciences, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.,School of Biomedical Engineering, Hubei University of Medicine, Shiyan, China
| | - Ping Cheng
- Shiyan Hospital of Traditional Chinese Medicine, Shiyan, China
| | - Jingjie Wang
- Institute of Basic Medical Sciences, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.,School of Biomedical Engineering, Hubei University of Medicine, Shiyan, China
| | - Xuemei Qiu
- Institute of Basic Medical Sciences, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.,School of Biomedical Engineering, Hubei University of Medicine, Shiyan, China
| | - Xudong Zhang
- Institute of Basic Medical Sciences, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China
| | - Li Xu
- School of Biomedical Engineering, Hubei University of Medicine, Shiyan, China
| | - Ying Liu
- Institute of Basic Medical Sciences, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.,School of Biomedical Engineering, Hubei University of Medicine, Shiyan, China
| | - Shanshan Qin
- Institute of Basic Medical Sciences, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.,School of Biomedical Engineering, Hubei University of Medicine, Shiyan, China.,Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Shiyan, China
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29
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Ghasemi A, Saeidi J, Azimi-Nejad M, Hashemy SI. Leptin-induced signaling pathways in cancer cell migration and invasion. Cell Oncol (Dordr) 2019; 42:243-260. [PMID: 30877623 DOI: 10.1007/s13402-019-00428-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Increasing evidence indicates that obesity is associated with tumor development and progression. Leptin is an adipocyte-related hormone with a key role in energy metabolism and whose circulating levels are elevated in obesity. The effect of leptin on cancer progression and metastasis and its underlying mechanisms are still unclear. Leptin can impact various steps in tumor metastasis, including epithelial-mesenchymal transition, cell adhesion to the extracellular matrix (ECM), and proteolysis of ECM components. To do so, leptin binds to its receptor (OB-Rb) to activate signaling pathways and downstream effectors that participate in tumor cell invasion as well as distant metastasis. CONCLUSIONS In this review, we describe metastasis steps in detail and characterize metastasis-related molecules activated by leptin, which may help to develop a roadmap that guides future work. In addition, we conclude that a profound understanding of the fundamental molecular processes that contribute to leptin-induced metastasis may pave the way for the development of new prognostic molecules and appropriate approaches to the treatment of obesity-related cancers.
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Affiliation(s)
- Ahmad Ghasemi
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Jafar Saeidi
- Department of Physiology, School of Basic Science, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran
| | - Mohsen Azimi-Nejad
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Genetic, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Isaac Hashemy
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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30
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Su M, Xiao Y, Ma J, Cao D, Zhou Y, Wang H, Liao Q, Wang W. Long non-coding RNAs in esophageal cancer: molecular mechanisms, functions, and potential applications. J Hematol Oncol 2018; 11:118. [PMID: 30223861 PMCID: PMC6142629 DOI: 10.1186/s13045-018-0663-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 09/06/2018] [Indexed: 12/20/2022] Open
Abstract
Esophageal cancer (EC) is the sixth leading cause of cancer-related death worldwide. The lack of early diagnostic biomarkers and effective prognostic indicators for metastasis and recurrence has resulted in the poor prognosis of EC. In addition, the underlying molecular mechanisms of EC development have yet to be elucidated. Accumulating evidence has demonstrated that lncRNAs play a vital role in the pathological progression of EC. LncRNAs may regulate gene expression through the recruitment of histone-modifying complexes to the chromatin and through interactions with RNAs or proteins. Recent evidence has demonstrated that the dysregulation of lncRNAs plays important roles in the proliferation, metastasis, invasion, angiogenesis, apoptosis, chemoradiotherapy resistance, and stemness of EC, which suggests potential clinical implications. In this review, we highlight the emerging roles and regulatory mechanisms of lncRNAs in the context of EC and discuss their potential clinical applications as diagnostic and prognostic biomarkers.
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Affiliation(s)
- Min Su
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China. .,Department of the Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China.
| | - Yuhang Xiao
- Department of Pharmacy, Xiangya Hospital of Xiangya School of Medicine, Central South University, Changsha, 410001, Hunan, People's Republic of China
| | - Junliang Ma
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Deliang Cao
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Yong Zhou
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Hui Wang
- Department of Thoracic Radiotherapy, Key laboratory of Translational Radiation Oncology, Department of Radiation Oncology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China
| | - Qianjin Liao
- Department of the Central Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China.
| | - Wenxiang Wang
- Department of the 2nd Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, People's Republic of China.
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31
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Pazos MC, Sequeira G, Bocchicchio S, May M, Abramovich D, Parborell F, Tesone M, Irusta G. PDGFB as a vascular normalization agent in an ovarian cancer model treated with a gamma-secretase inhibitor. J Cell Physiol 2018; 233:5949-5961. [PMID: 29266203 DOI: 10.1002/jcp.26404] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 12/12/2017] [Indexed: 12/21/2022]
Abstract
Ovarian cancer is the fifth leading cause of cancer-related deaths in women. In the past 20 years, the canonical types of drugs used to treat ovarian cancer have not been replaced and the survival rates have not changed. These facts show the clear need to find new therapeutic strategies for this illness. Thus, the aim of the present study was to investigate the effect of a gamma-secretase inhibitor (DAPT) in combination with the Platelet-derived growth factor B (PDGFB) on an ovarian cancer xenograft model. To achieve this goal, we analyzed the effect of the administration of DAPT alone and the co-administration of DAPT and recombinant PDGFB on parameters associated with tumor growth and angiogenesis in an orthotopic experimental model of ovarian cancer. We observed that the dose of DAPT used was ineffective to reduce ovarian tumor growth, but showed anticancer activity when co-administered with recombinant PDGFB. The administration of PDGFB alone normalized tumor vasculature by increasing periendothelial coverage and vascular functionality. Interestingly, this effect exerted by PDGFB was also observed in the presence of DAPT. Our findings suggest that PDGFB is able to improve tumor vascularity and allows the anticancer action of DAPT in the tumor. We propose that this therapeutic strategy could be a new tool for ovarian cancer treatment and deserves further studies.
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Affiliation(s)
- Maria C Pazos
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado, Buenos Aires, Argentina
| | - Gonzalo Sequeira
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado, Buenos Aires, Argentina
| | - Sebastian Bocchicchio
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado, Buenos Aires, Argentina
| | - Maria May
- Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina
| | - Dalhia Abramovich
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado, Buenos Aires, Argentina
| | - Fernanda Parborell
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado, Buenos Aires, Argentina
| | - Marta Tesone
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado, Buenos Aires, Argentina
| | - Griselda Irusta
- Instituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado, Buenos Aires, Argentina
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Zhang J, Zheng G, Zhou L, Li P, Yun M, Shi Q, Wang T, Wu X. Notch signalling induces epithelial‑mesenchymal transition to promote metastasis in oral squamous cell carcinoma. Int J Mol Med 2018; 42:2276-2284. [PMID: 30015856 DOI: 10.3892/ijmm.2018.3769] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 06/26/2018] [Indexed: 11/06/2022] Open
Abstract
The activation of Notch signalling induces epithelial‑mesenchymal transition (EMT), but this signalling pathway and its association with EMT in the context of cell motility in oral squamous cell carcinoma (OSCC) remains unclear. The present study aimed to investigate the role of the Notch signalling pathway and EMT in the metastatic potential of OSCC using 2 cell lines, Tca8113 and CAL27. The data demonstrated that zinc finger domain SNAI1 (Snail) knockdown by small interfering RNA decreased the expression of vimentin and increased the expression of epithelial cadherin (E‑cadherin). In addition, silencing Snail also significantly inhibited cell migration in the 2 OSCC cell lines. It was also identified that blocking Notch signalling with the g‑secretase inhibitor DAPT decreased the expression of the EMT markers Snail and vimentin and increased E‑cadherin expression, accompanied by a significant inhibition of cell migration in the 2 OSCC cell lines. These data clearly indicate that Notch signalling mediates EMT to promote metastasis in OSCC cells. Therefore, targeting Notch signalling and its association with EMT may provide novel insights into the mechanism of invasion and metastasis in OSCC and potential therapeutic interventions.
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Affiliation(s)
- Jianping Zhang
- School of Clinical Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
| | - Genjian Zheng
- Department of Stomatology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Lan Zhou
- Department of Stomatology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Pengcheng Li
- Department of Stomatology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Man Yun
- Department of Stomatology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
| | - Qi Shi
- School of Clinical Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
| | - Tingli Wang
- School of Clinical Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
| | - Xiaotong Wu
- School of Clinical Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
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33
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Crosstalk between Notch, HIF-1α and GPER in Breast Cancer EMT. Int J Mol Sci 2018; 19:ijms19072011. [PMID: 29996493 PMCID: PMC6073901 DOI: 10.3390/ijms19072011] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 07/04/2018] [Accepted: 07/09/2018] [Indexed: 12/15/2022] Open
Abstract
The Notch signaling pathway acts in both physiological and pathological conditions, including embryonic development and tumorigenesis. In cancer progression, diverse mechanisms are involved in Notch-mediated biological responses, including angiogenesis and epithelial-mesenchymal-transition (EMT). During EMT, the activation of cellular programs facilitated by transcriptional repressors results in epithelial cells losing their differentiated features, like cell–cell adhesion and apical–basal polarity, whereas they gain motility. As it concerns cancer epithelial cells, EMT may be consequent to the evolution of genetic/epigenetic instability, or triggered by factors that can act within the tumor microenvironment. Following a description of the Notch signaling pathway and its major regulatory nodes, we focus on studies that have given insights into the functional interaction between Notch signaling and either hypoxia or estrogen in breast cancer cells, with a particular focus on EMT. Furthermore, we describe the role of hypoxia signaling in breast cancer cells and discuss recent evidence regarding a functional interaction between HIF-1α and GPER in both breast cancer cells and cancer-associated fibroblasts (CAFs). On the basis of these studies, we propose that a functional network between HIF-1α, GPER and Notch may integrate tumor microenvironmental cues to induce robust EMT in cancer cells. Further investigations are required in order to better understand how hypoxia and estrogen signaling may converge on Notch-mediated EMT within the context of the stroma and tumor cells interaction. However, the data discussed here may anticipate the potential benefits of further pharmacological strategies targeting breast cancer progression.
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34
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Jeon MK, Kaemmerer E, Schneider U, Schiffer M, Klaus C, Hennings J, Clahsen T, Ackerstaff T, Niggemann M, Schippers A, Longerich T, Sellge G, Trautwein C, Wagner N, Liedtke C, Gassler N. Notch inhibition counteracts Paneth cell death in absence of caspase-8. Virchows Arch 2018; 473:71-83. [PMID: 29770852 DOI: 10.1007/s00428-018-2368-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 04/09/2018] [Accepted: 04/29/2018] [Indexed: 02/07/2023]
Abstract
Opposing activities of Notch and Wnt signaling regulate mucosal barrier homeostasis and differentiation of intestinal epithelial cells. Specifically, Wnt activity is essential for differentiation of secretory cells including Wnt3-producing Paneth cells, whereas Notch signaling strongly promotes generation of absorptive cells. Loss of caspase-8 in intestinal epithelium (casp8∆int) is associated with fulminant epithelial necroptosis, severe Paneth cell death, secondary intestinal inflammation, and an increase in Notch activity. Here, we found that pharmacological Notch inhibition with dibenzazepine (DBZ) is able to essentially rescue the loss of Paneth cells, deescalate the inflammatory phenotype, and reduce intestinal permeability in casp8∆int mice. The secretory cell metaplasia in DBZ-treated casp8∆int animals is proliferative, indicating for Notch activities partially insensitive to gamma-secretase inhibition in a casp8∆int background. Our data suggest that casp8 acts in the intestinal Notch network.
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Affiliation(s)
- M K Jeon
- Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - E Kaemmerer
- Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
- Department of Pediatrics, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - U Schneider
- Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - M Schiffer
- Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - C Klaus
- Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - J Hennings
- Department of Medicine III, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - T Clahsen
- Department of Pediatrics, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - T Ackerstaff
- Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - M Niggemann
- Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056, Aachen, Germany
| | - A Schippers
- Department of Pediatrics, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - T Longerich
- Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - G Sellge
- Department of Medicine III, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - C Trautwein
- Department of Medicine III, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - N Wagner
- Department of Pediatrics, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - C Liedtke
- Department of Medicine III, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - N Gassler
- Institute of Pathology, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany.
- Klinikum Braunschweig, Institute of Pathology, Celler Strasse 28, 38114, Braunschweig, Germany.
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35
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Yuan CL, Liang R, Liu ZH, Li YQ, Luo XL, Ye JZ, Lin Y. Bone morphogenetic protein and activin membrane-bound inhibitor overexpression inhibits gastric tumor cell invasion via the transforming growth factor-β/epithelial-mesenchymal transition signaling pathway. Exp Ther Med 2018; 15:5422-5430. [PMID: 29805551 PMCID: PMC5958702 DOI: 10.3892/etm.2018.6083] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 01/22/2018] [Indexed: 12/15/2022] Open
Abstract
Gastric carcinoma is one of the most common human malignancies and remains the second leading cause of cancer-associated mortality worldwide. Gastric carcinoma is characterized by early-stage metastasis and is typically diagnosed in the advanced stage. Previous results have indicated that bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) overexpression has been demonstrated to inhibit growth and metastasis of gastric cancer cells. However, the molecular mechanisms of the BAMBI-mediated signaling pathway in the progression of gastric cancer are poorly understood. In the present study, to assess whether BAMBI overexpression inhibited the growth and aggressiveness of gastric carcinoma cells through regulation of transforming growth factor (TGF)-β/epithelial-mesenchymal transition (EMT) signaling pathway, the growth and metastasis of gastric carcinoma cells were analyzed following BAMBI overexpression and knockdown in vitro and in vivo. Molecular changes in the TGF-β/EMT signaling pathway were studied in gastric carcinoma cells following BAMBI overexpression and knockdown. DNA methylation of the gene regions encoding the TGF-β/EMT signaling pathway was investigated in gastric carcinoma cells. Tumor growth in tumor-bearing mice was analyzed after mice were subjected to endogenous overexpression of BAMBI. Results indicated that BAMBI overexpression significantly inhibited gastric carcinoma cell growth and aggressiveness, whereas knockdown of BAMBI significantly promoted its growth and metastasis compared with the control (P<0.01). The TGF-β/EMT signaling pathway was downregulated in BAMBI-overexpressed gastric carcinoma cells; however, signaling was promoted following BAMBI knockdown. In addition, it was observed that BAMBI overexpression significantly downregulated the DNA methylation of the gene regions encoding the TGF-β/EMT signaling pathway (P<0.01). Furthermore, RNA interference-mediated BAMBI overexpression also promoted apoptosis in gastric cancer cells and significantly inhibited growth of gastric tumors in murine xenografts (P<0.01). In conclusion, the present findings suggest that BAMBI overexpression inhibited the TGF-β/EMT signaling pathway and suppressed the invasiveness of gastric tumors, suggesting BAMBI may be a potential target for the treatment of gastric carcinoma via regulation of the TGF-β/EMT signaling pathway.
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Affiliation(s)
- Chun-Ling Yuan
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Rong Liang
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhi-Hui Liu
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yong-Qiang Li
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xiao-Ling Luo
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jia-Zhou Ye
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yan Lin
- First Department of Chemotherapy, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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36
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Jiang Y, Wang Y, Ma P, An D, Zhao J, Liang S, Ye Y, Lu Y, Zhang P, Liu X, Han H, Qin H. Myeloid-specific targeting of Notch ameliorates murine renal fibrosis via reduced infiltration and activation of bone marrow-derived macrophage. Protein Cell 2018; 10:196-210. [PMID: 29644573 PMCID: PMC6338623 DOI: 10.1007/s13238-018-0527-6] [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: 11/28/2017] [Accepted: 02/28/2018] [Indexed: 12/25/2022] Open
Abstract
Macrophages play critical roles in renal fibrosis. However, macrophages exhibit ontogenic and functional heterogeneities, and which population of macrophages contributes to renal fibrosis and the underlying mechanisms remain unclear. In this study, we genetically targeted Notch signaling by disrupting the transcription factor recombination signal binding protein-Jκ (RBP-J), to reveal its role in regulation of macrophages during the unilateral ureteral obstruction (UUO)-induced murine renal fibrosis. Myeloid-specific disruption of RBP-J attenuated renal fibrosis with reduced extracellular matrix deposition and myofibroblast activation, as well as attenuated epithelial-mesenchymal transition, likely owing to the reduced expression of TGF-β. Meanwhile, RBP-J deletion significantly hampered macrophage infiltration and activation in fibrotic kidney, although their proliferation appeared unaltered. By using macrophage clearance experiment, we found that kidney resident macrophages made negligible contribution, but bone marrow (BM)-derived macrophages played a major role in renal fibrogenesis. Further mechanistic analyses showed that Notch blockade reduced monocyte emigration from BM by down-regulating CCR2 expression. Finally, we found that myeloid-specific Notch activation aggravated renal fibrosis, which was mediated by CCR2+ macrophages infiltration. In summary, our data have unveiled that myeloid-specific targeting of Notch could ameliorate renal fibrosis by regulating BM-derived macrophages recruitment and activation, providing a novel strategy for intervention of this disease.
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Affiliation(s)
- Yali Jiang
- State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.,Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #15, Xi'an, 710032, China
| | - Yuanyuan Wang
- State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.,Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #15, Xi'an, 710032, China
| | - Pengfei Ma
- State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Dongjie An
- State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Junlong Zhao
- State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Shiqian Liang
- State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Yuchen Ye
- State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China
| | - Yingying Lu
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #15, Xi'an, 710032, China
| | - Peng Zhang
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #15, Xi'an, 710032, China
| | - Xiaowei Liu
- Department of Nephrology, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #15, Xi'an, 710032, China.
| | - Hua Han
- State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.
| | - Hongyan Qin
- State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, 710032, China.
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37
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García-Heredia JM, Verdugo Sivianes EM, Lucena-Cacace A, Molina-Pinelo S, Carnero A. Numb-like (NumbL) downregulation increases tumorigenicity, cancer stem cell-like properties and resistance to chemotherapy. Oncotarget 2018; 7:63611-63628. [PMID: 27613838 PMCID: PMC5325389 DOI: 10.18632/oncotarget.11553] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 08/12/2016] [Indexed: 12/23/2022] Open
Abstract
NumbL, or Numb-like, is a close homologue of Numb, and is part of an evolutionary conserved protein family implicated in some important cellular processes. Numb is a protein involved in cell development, in cell adhesion and migration, in asymmetric cell division, and in targeting proteins for endocytosis and ubiquitination. NumbL exhibits some overlapping functions with Numb, but its role in tumorigenesis is not fully known. Here we showed that the downregulation of NumbL alone is sufficient to increase NICD nuclear translocation and induce Notch pathway activation. Furthermore, NumbL downregulation increases epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-related gene transcripts and CSC-like phenotypes, including an increase in the CSC-like pool. These data suggest that NumbL can act independently as a tumor suppressor gene. Furthermore, an absence of NumbL induces chemoresistance in tumor cells. An analysis of human tumors indicates that NumbL is downregulated in a variable percentage of human tumors, with lower levels of this gene correlated with worse prognosis in colon, breast and lung tumors. Therefore, NumbL can act as an independent tumor suppressor inhibiting the Notch pathway and regulating the cancer stem cell pool.
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Affiliation(s)
- José M García-Heredia
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio, Universidad de Sevilla, Consejo Superior de Investigaciones Cientificas, Seville, Spain.,Department of Vegetal Biochemistry and Molecular Biology, University of Seville, Seville, Spain
| | - Eva M Verdugo Sivianes
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio, Universidad de Sevilla, Consejo Superior de Investigaciones Cientificas, Seville, Spain
| | - Antonio Lucena-Cacace
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio, Universidad de Sevilla, Consejo Superior de Investigaciones Cientificas, Seville, Spain
| | - Sonia Molina-Pinelo
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio, Universidad de Sevilla, Consejo Superior de Investigaciones Cientificas, Seville, Spain.,Present address: Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio, Universidad de Sevilla, Consejo Superior de Investigaciones Cientificas, Seville, Spain
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38
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Wang MH, Zhou XM, Zhang MY, Shi L, Xiao RW, Zeng LS, Yang XZ, Zheng XFS, Wang HY, Mai SJ. BMP2 promotes proliferation and invasion of nasopharyngeal carcinoma cells via mTORC1 pathway. Aging (Albany NY) 2018; 9:1326-1340. [PMID: 28455969 PMCID: PMC5425130 DOI: 10.18632/aging.101230] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 04/23/2017] [Indexed: 12/11/2022]
Abstract
Bone morphogenetic protein-2 (BMP2) is a secreted protein that highly expressed in a variety of cancers and contributes to cell proliferation, migration, invasiveness, mobility, metastasis and EMT. However, its clinical significance and biological function in nasopharyngeal carcinoma (NPC) remain unknown up to now. Up-regulation of BMP2 was first observed in NPC cell lines by a genome-wide transcriptome analysis in our previous study. In this study, BMP2 mRNA was detected by qRT-PCR and data showed that it was upregulated in NPC compared with non-cancerous nasopharynx samples. Immunohistochemistry (IHC) analysis in NPC specimens revealed that high BMP2 expression was significantly associated with clinical stage, distant metastasis and shorter survival of NPC patients. Moreover, overexpression of BMP2 in NPC cells promoted cell proliferation, migration, invasiveness and epithelial-mesenchymal transition (EMT). Mechanistically, BMP2 overexpression increase phosphorylated protein level of mTOR, S6K and 4EBP1. Correspondingly, mTORC1 inhibitor rapamycin blocked the effect of BMP2 on NPC cell proliferation and invasion. In conclusion, our results suggest that BMP2 overexpression in NPC enhances proliferation, invasion and EMT of tumor cells through the mTORC1 signaling pathway.
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Affiliation(s)
- Meng-He Wang
- State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.,Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Xiao-Min Zhou
- Zhoukou Hospital of Traditional Chinese Medicine, Zhoukou, China
| | - Mei-Yin Zhang
- State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.,Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Lu Shi
- State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.,Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Ruo-Wen Xiao
- State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.,Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Li-Si Zeng
- Cancer Center of Guangzhou Medical University, Guangzhou, China
| | - Xian-Zi Yang
- Cancer Center of Guangzhou Medical University, Guangzhou, China
| | - X F Steven Zheng
- State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.,Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901, USA
| | - Hui-Yun Wang
- State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.,Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
| | - Shi-Juan Mai
- State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.,Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China
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39
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Weng J, Xiao J, Mi Y, Fang X, Sun Y, Li S, Qin Z, Li X, Liu T, Zhao S, Zhou L, Wen Y. PCDHGA9 acts as a tumor suppressor to induce tumor cell apoptosis and autophagy and inhibit the EMT process in human gastric cancer. Cell Death Dis 2018; 9:27. [PMID: 29348665 PMCID: PMC5833845 DOI: 10.1038/s41419-017-0189-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 11/18/2017] [Accepted: 11/27/2017] [Indexed: 12/14/2022]
Abstract
The results of a cDNA array revealed that protocadherin gamma subfamily A, 9 (PCDHGA9) was significantly decreased in SGC-7901 gastric cancer (GC) cells compared with GES-1 normal gastric cells and was strongly associated with the Wnt/β-catenin and transforming growth factor-β (TGF-β)/Smad2/3 signaling pathway. As a member of the cadherin family, PCDHGA9 functions in both cell-cell adhesion and nuclear signaling. However, its role in tumorigenicity or metastasis has not been reported. In the present study, we found that PCDHGA9 was decreased in GC tissues compared with corresponding normal mucosae and its expression was correlated with the GC TNM stage, the UICC stage, differentiation, relapse, and metastasis (p < 0.01). Multivariate Cox analysis revealed that PCDHGA9 was an independent prognostic indicator for overall survival (OS) and disease-free survival (DFS) (p < 0.01). The effects of PCDHGA9 on GC tumor growth and metastasis were examined both in vivo and in vitro. PCDHGA9 knockdown promoted GC cell proliferation, migration, and invasion, whereas PCDHGA9 overexpression inhibited GC tumor growth and metastasis but induced apoptosis, autophagy, and G1 cell cycle arrest. Furthermore, PCDHGA9 suppressed epithelial-mesenchymal transition (EMT) induced by TGF-β, decreased the phosphorylation of Smad2/3, and inhibited the nuclear translocation of pSmad2/3. Our results suggest that PCDHGA9 might interact with β-catenin to prevent β-catenin from dissociating in the cytoplasm and translocating to the nucleus. Moreover, PCDHGA9 overexpression restrained cell proliferation and reduced the nuclear β-catenin, an indicator of Wnt/β-catenin pathway activation, suggesting that PCDHGA9 negatively regulates Wnt signaling. Together, these data indicate that PCDHGA9 acts as a tumor suppressor with anti-proliferative activity and anti-invasive ability, and the reduction of PCDHGA9 could serve as an independent prognostic biomarker in GC.
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Affiliation(s)
- Junyong Weng
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 200080, Shanghai, China
| | - Jingbo Xiao
- Shanghai Key Laboratory of Pancreatic Diseases & Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, 200080, Shanghai, China
| | - Yushuai Mi
- Department of General Surgery, The Second Hospital of Shandong University, Jinan, 250033, Shandong, China
| | - Xu Fang
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 200080, Shanghai, China
| | - Yahuang Sun
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 200080, Shanghai, China
| | - Shanbao Li
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 200080, Shanghai, China
| | - Zhiwei Qin
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 200080, Shanghai, China
| | - Xu Li
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 200080, Shanghai, China
| | - Tingting Liu
- Department of Pathology, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 200080, Shanghai, China
| | - Senlin Zhao
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 200080, Shanghai, China
| | - Lisheng Zhou
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 200080, Shanghai, China.
| | - Yugang Wen
- Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, 200080, Shanghai, China.
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40
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Abstract
NUMB, and its close homologue NUMBL, behave as tumor suppressor genes by regulating the Notch pathway. The downregulation of these genes in tumors is common, allowing aberrant Notch pathway activation and tumor progression. However, some known differences between NUMB and NUMBL have raised unanswered questions regarding the redundancy and/or combined regulation of the Notch pathway by these genes during the tumorigenic process. We have found that NUMB and NUMBL exhibit mutual exclusivity in human tumors, suggesting that the associated tumor suppressor role is regulated by only one of the two proteins in a specific cell, avoiding duplicate signaling and simplifying the regulatory network. We have also found differences in gene expression due to NUMB or NUMBL downregulation. These differences in gene regulation extend to pathways, such as WNT or Hedgehog. In addition to these differences, the downregulation of either gene triggers a cancer stem cell-like related phenotype. These results show the importance of both genes as an intersection with different effects over cancer stem cell signaling pathways.
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41
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Lin JW, Wang H. Progress in research of cancer stem cells. Shijie Huaren Xiaohua Zazhi 2017; 25:2776-2781. [DOI: 10.11569/wcjd.v25.i31.2776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells are a class of malignant cancer cells characterized by self-renewal, high tumorigenicity, differentiation potential, and drug resistance. They not only retain the characteristics of normal stem cells, but also possess their unique features. The study of cancer stem cells can help us develop new strategies for targeted therapy of cancer. In this paper, we will discuss the definition of cancer stem cells, their surface markers, detection methods, and separation methods.
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Affiliation(s)
- Ji-Wang Lin
- Department of Hepatobiliary Surgery, Liuyang People's Hospital, Liuyang Hospital Affiliated to Changsha Medical University, Liuyang 410300, Hunan Province, China
| | - Hong Wang
- Department of Hepatobiliary Surgery, Liuyang People's Hospital, Liuyang Hospital Affiliated to Changsha Medical University, Liuyang 410300, Hunan Province, China
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Liu TJ, Guo JL, Xu X. CXC chemokine‑7 inhibits growth and migration of oral tongue squamous cell carcinoma cells, mediated by the epithelial‑mesenchymal transition signaling pathway. Mol Med Rep 2017; 16:6896-6903. [PMID: 28901471 DOI: 10.3892/mmr.2017.7441] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 05/11/2017] [Indexed: 11/05/2022] Open
Abstract
Oral tongue squamous cell carcinoma (OTSCC) is the most common oral malignancy with different histopathological symptoms and etiology of tumorigenesis. Migration and invasion is the most important characteristics of OTSCC, and limits tumor therapy in clinics. The epithelial‑to‑mesenchymal transition (EMT) signaling pathway is an important process in the progress of tumor cell migration and invasion. Previous studies have indicated that C‑X‑C chemokine receptor‑7 (CXCR‑7) promotes the progression and metastasis of tumor cells, presenting a potential target molecule for cancer therapy. The present study investigated the inhibitory effects of C‑X‑C chemokine‑7 (CXC‑7) on human OTSCC cells both in vitro and in vivo. The results demonstrated that the Tca8113 human OTSCC cell line expressed higher levels of CXC‑7 mRNA compared with the hNOE human normal oral epithelial cell line. MTT assays indicated that CXC‑7 suppressed Tca8113 cell growth, and the cytotoxicity of CXC‑7 was indicated as the cell survival of the negative control group was significantly decreased compared with the blank control and hNOE cells. Migration and invasion assays revealed that CXC‑7 inhibited Tca8113 cell local expansion and distant metastasis. In addition, the results demonstrated that the extracellular signal‑regulated kinase (ERK)/protein kinase B (AKT) signaling pathway was inhibited after CXC‑7 treatment in Tca8113 cells. N‑cadherin, E‑Cadherin, Snail and Slug expression levels in the ERK/AKT signaling pathway were inhibited in Tca8113 cells after treatment with CXC‑7. It was demonstrated that important extracellular matrix proteins involved in cell migration, including Slug, collagen type I and Vimentin, were significantly downregulated by CXC‑7 treatment. In conclusion, CXC‑7 inhibited growth and migration in OTSCC cells, mediated by the EMT signaling pathway. This suggests that CXC‑7 serves an inhibitory role in OTSCC migration, implicating CXCR‑7 as a promising biomarker for chemokine receptor‑based drug development.
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Affiliation(s)
- Tong-Jun Liu
- Department of Implantology, Shandong Provincial Key Laboratory of Oral Biomedicine, School of Stomatology, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jian-Lian Guo
- Department of Ophthalmology, The Eighth People's Hospital of Jinan, Jinan, Shandong 250014, P.R. China
| | - Xin Xu
- Department of Implantology, Shandong Provincial Key Laboratory of Oral Biomedicine, School of Stomatology, Shandong University, Jinan, Shandong 250012, P.R. China
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Prognostic implication of NOTCH1 in early stage oral squamous cell cancer with occult metastases. Clin Oral Investig 2017; 22:1131-1138. [PMID: 28866747 DOI: 10.1007/s00784-017-2197-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 08/24/2017] [Indexed: 01/19/2023]
Abstract
OBJECTIVE The objective of this study was to explore the prognostic value of cancer stem cell markers, namely CD133, NANOG, and NOTCH1, in early stage oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS One hundred forty-four patients with early stage (cT1T2N0) OSCC were identified from a pre-existing database of patients with oral cancer. We examined the impact of the immunohistochemical expression of CD133, NANOG, and NOTCH1 in OSCC. Overall survival (OS) curves were calculated using the Kaplan-Meier method. Predictors of outcome were identified using multivariate analysis. RESULTS We found that CD133, NANOG, and NOTCH1 were significantly associated with lymph node metastasis, and NOTCH1 was also significantly associated with depth of invasion and locoregional recurrence. CONCLUSIONS NOTCH1 was identified as an independent prognostic factor for OS. CLINICAL RELEVANCE NOTCH1 might prove to be a useful indicator for high-risk patients with occult metastases from early stage OSCC.
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Zhang J, Chen S, Gu J, Zhu Y, Zhan Q, Cheng D, Chen H, Deng X, Shen B, Peng C. Retracted:
MicroRNA‐300 promotes apoptosis and inhibits proliferation, migration, invasion and epithelial‐mesenchymal transition via the Wnt/β‐catenin signaling pathway by targeting CUL4B in pancreatic cancer cells. J Cell Biochem 2017; 119:1027-1040. [DOI: 10.1002/jcb.26270] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 07/06/2017] [Indexed: 12/30/2022]
Affiliation(s)
- Jia‐Qiang Zhang
- Department of General Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
- Research Institute of Digestive Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
| | - Shi Chen
- Department of General Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
- Department of Hepatobiliary Surgery, Fujian Provincial HospitalFujian Medical UniversityFuzhouP.R. China
| | - Jiang‐Ning Gu
- Department of General Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
- Research Institute of Digestive Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
| | - Yi Zhu
- Department of General Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
- Department of General Surgerythe Second Hospital of Zhejiang UniversityHangzhouP.R. China
| | - Qian Zhan
- Department of General Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
- Research Institute of Digestive Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
| | - Dong‐Feng Cheng
- Department of General Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
- Research Institute of Digestive Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
| | - Hao Chen
- Department of General Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
- Research Institute of Digestive Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
| | - Xia‐Xing Deng
- Department of General Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
- Research Institute of Digestive Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
| | - Bai‐Yong Shen
- Department of General Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
- Research Institute of Digestive Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
| | - Cheng‐Hong Peng
- Department of General Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
- Research Institute of Digestive Surgery, Ruijin HospitalShanghai Jiaotong University School of MedicineShanghaiP.R. China
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Garcia-Heredia JM, Lucena-Cacace A, Verdugo-Sivianes EM, Pérez M, Carnero A. The Cargo Protein MAP17 (PDZK1IP1) Regulates the Cancer Stem Cell Pool Activating the Notch Pathway by Abducting NUMB. Clin Cancer Res 2017; 23:3871-3883. [PMID: 28153862 DOI: 10.1158/1078-0432.ccr-16-2358] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 12/23/2016] [Accepted: 01/12/2017] [Indexed: 11/16/2022]
Abstract
Purpose: Cancer stem cells (CSC) are self-renewing tumor cells, with the ability to generate diverse differentiated tumor cell subpopulations. They differ from normal stem cells in the deregulation of the mechanisms that normally control stem cell physiology. CSCs are the origin of metastasis and highly resistant to therapy. Therefore, the understanding of the CSC origin and deregulated pathways is important for tumor control.Experimental Design: We have included experiments in vitro, in cell lines and tumors of different origins. We have used patient-derived xenografts (PDX) and public transcriptomic databases of human tumors.Results: MAP17 (PDZKIP1), a small cargo protein overexpressed in tumors, interacts with NUMB through the PDZ-binding domain activating the Notch pathway, leading to an increase in stem cell factors and cancer-initiating-like cells. Identical behavior was mimicked by inhibiting NUMB. Conversely, MAP17 downregulation in a tumor cell line constitutively expressing this gene led to Notch pathway inactivation and a marked reduction of stemness. In PDX models, MAP17 levels directly correlated with tumorsphere formation capability. Finally, in human colon, breast, or lung there is a strong correlation of MAP17 expression with a signature of Notch and stem cell genes.Conclusions: MAP17 overexpression activates Notch pathway by sequestering NUMB. High levels of MAP17 correlated with tumorsphere formation and Notch and Stem gene transcription. Its direct modification causes direct alteration of tumorsphere number and Notch and Stem pathway transcription. This defines a new mechanism of Notch pathway activation and Stem cell pool increase that may be active in a large percentage of tumors. Clin Cancer Res; 23(14); 3871-83. ©2017 AACR.
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Affiliation(s)
- Jose Manuel Garcia-Heredia
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain
- Department of Vegetal Biochemistry and Molecular Biology, University of Seville, Seville, Spain
- CIBER de Cancer, Seville, Spain
| | - Antonio Lucena-Cacace
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain
- CIBER de Cancer, Seville, Spain
| | - Eva M Verdugo-Sivianes
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain
- CIBER de Cancer, Seville, Spain
| | - Marco Pérez
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain
- CIBER de Cancer, Seville, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocio/Universidad de Sevilla/Consejo Superior de Investigaciones Cientificas, Seville, Spain.
- CIBER de Cancer, Seville, Spain
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Gao R, Chen R, Cao Y, Wang Y, Song K, Zhang Y, Yang J. Emodin suppresses TGF-β1-induced epithelial-mesenchymal transition in alveolar epithelial cells through Notch signaling pathway. Toxicol Appl Pharmacol 2017; 318:1-7. [DOI: 10.1016/j.taap.2016.12.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 11/17/2016] [Accepted: 12/13/2016] [Indexed: 12/17/2022]
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Gao K, Ji Z, She K, Yang Q, Shao L. Long non-coding RNA ZFAS1 is an unfavourable prognostic factor and promotes glioma cell progression by activation of the Notch signaling pathway. Biomed Pharmacother 2017; 87:555-560. [PMID: 28081466 DOI: 10.1016/j.biopha.2017.01.014] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 01/01/2017] [Accepted: 01/02/2017] [Indexed: 11/15/2022] Open
Abstract
Survival of patients with glioma remains poor, which is largely attributed to active carcinogenesis. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) play key roles in tumor initiation and progression. However, the function of lncRNA ZFAS1 in glioma is still unclear. In the current study, we found that ZFAS1 was upregulated in glioma tissues and cell lines. High ZFAS1 expression in glioma tissues was significantly correlated with advanced tumor stage and poor overall survival. Furthermore, in vitro assays demonstrated that ZFAS1 inhibition significantly suppressed glioma cell proliferation, migration and invasion. Importantly, we further confirmed that epithelial-mesenchymal transition (EMT) and the Notch signaling pathway was inactivated in the glioma cells after ZFAS1 knockdown. Thus, our findings indicated that ZFAS1 could exhibit a tumor oncogenic role in glioma progression by regulating EMT and Notch signaling pathway. LncRNA ZFAS1 might serve as a therapeutic target for the treatment of glioma patients.
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Affiliation(s)
- Kai Gao
- Department of Neurosurgery, Affiliated Hospital of Hebei University of Engineering, Handan, 056002, China
| | - Zhiwu Ji
- Department of Neurosurgery, Affiliated Hospital of Hebei University of Engineering, Handan, 056002, China
| | - Kun She
- Department of Neurosurgery, Affiliated Hospital of Hebei University of Engineering, Handan, 056002, China
| | - Qingyan Yang
- Department of Neurosurgery, Affiliated Hospital of Hebei University of Engineering, Handan, 056002, China
| | - Lianbin Shao
- Department of Neurosurgery, Affiliated Hospital of Hebei University of Engineering, Handan, 056002, China.
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Lu L, Wang J, Wu Y, Wan P, Yang G. Rap1A promotes ovarian cancer metastasis via activation of ERK/p38 and notch signaling. Cancer Med 2016; 5:3544-3554. [PMID: 27925454 PMCID: PMC5224839 DOI: 10.1002/cam4.946] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 09/15/2016] [Accepted: 09/28/2016] [Indexed: 01/04/2023] Open
Abstract
As one of the Ras-associated proteins, Rap1A has been linked to cancer initiation and development. However, the precise function of Rap1A in ovarian cancer is still not understood. Here, we show that Rap1A promotes ovarian cancer tumorigenesis and metastasis via stimulating cell proliferation, migration and invasion both in vivo and in vitro. Mechanistic study showed that Rap1A activates extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and Notch pathways, leading to the enhanced expression of several epithelial-mesenchymal transition (EMT) markers such as slug, zeb1, vimentin, fibronectin, and MMP9. However, the pretreatment of Rap1A-overexpressing cells with the Notch inhibitor DAPT or ERK inhibitor (U0126) inhibited the up-regulated expression of those molecules. These findings provide the first evidence linking Rap1A with ovarian cancer development through the ERK/p38 and Notch signaling pathways, indicating that Rap1A may be used as a novel diagnostic marker or a therapeutic target for ovarian cancer.
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Affiliation(s)
- Lili Lu
- Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China.,Department of Biology, College of Life and Environmental Sciences, Shanghai Normal University, 100 Guilin Road, Shanghai, 200234, China
| | - Jingshu Wang
- Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China
| | - Yougen Wu
- Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China
| | - Ping Wan
- Department of Biology, College of Life and Environmental Sciences, Shanghai Normal University, 100 Guilin Road, Shanghai, 200234, China
| | - Gong Yang
- Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical School, Fudan University, Shanghai, 200032, China.,Central Laboratory, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China.,Department of Gynecological Oncology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, 200240, China
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Rosa R, D'Amato V, De Placido S, Bianco R. Approaches for targeting cancer stem cells drug resistance. Expert Opin Drug Discov 2016; 11:1201-1212. [PMID: 27700193 DOI: 10.1080/17460441.2016.1243525] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Several reports have suggested that a population of undifferentiated cells known as cancer stem cells (CSCs), is responsible for cancer formation and maintenance. In the last decade, the presence of CSCs in solid cancers have been reported. Areas covered: This review summarizes the main approaches for targeting CSCs drug resistance. It is indeed known that CSCs may contribute to resistance to conventional chemotherapy, radiotherapy and targeted agents. Among the mechanisms by which CSCs escape anticancer therapies, removal of therapeutic agents by drug efflux pumps, enhanced DNA damage repair, activation of mitogenic/anti-apoptotic pathways; the main features of CSCs, stemness and EMT, are involved, as well as the capability to evade immune response. Expert opinion: Different approaches are suitable to target CSCs mediated drug resistance. Some of them are currently under clinical evaluation in different cancer types. A better understanding of CSC biology, as well as more accurate study design, may maximize the therapeutic effects of these agents. In this respect, it is important to establish: (i) which molecules should be targeted; (ii) what drug combinations may be suitable; (iii) which patient settings will CSC targeting offer the highest clinical benefit; and (iv) how to integrate therapeutic approaches targeting CSCs with standard cancer therapy.
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Affiliation(s)
- Roberta Rosa
- a Dipartimento di Medicina Clinica e Chirurgia , Università di Napoli Federico II , Napoli , Italy
| | - Valentina D'Amato
- a Dipartimento di Medicina Clinica e Chirurgia , Università di Napoli Federico II , Napoli , Italy
| | - Sabino De Placido
- a Dipartimento di Medicina Clinica e Chirurgia , Università di Napoli Federico II , Napoli , Italy
| | - Roberto Bianco
- a Dipartimento di Medicina Clinica e Chirurgia , Università di Napoli Federico II , Napoli , Italy
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DMXL2 drives epithelial to mesenchymal transition in hormonal therapy resistant breast cancer through Notch hyper-activation. Oncotarget 2016; 6:22467-79. [PMID: 26093085 PMCID: PMC4673176 DOI: 10.18632/oncotarget.4164] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 05/22/2015] [Indexed: 12/21/2022] Open
Abstract
The acquisition of endocrine therapy resistance in estrogen receptor α (ERα) breast cancer patients represents a major clinical problem. Notch signalling has been extensively linked to breast cancer especially in patients who fail to respond to endocrine therapy. Following activation, Notch intracellular domain is released and enters the nucleus where activates transcription of target genes. The numerous steps that cascade after activation of the receptor complicate using Notch as biomarker. Hence, this warrants the development of reliable indicators of Notch activity. DMXL2 is a novel regulator of Notch signalling not yet investigated in breast cancer. Here, we demonstrate that DMXL2 is overexpressed in a subset of endocrine therapy resistant breast cancer cell lines where it promotes epithelial to mesenchymal transition through hyper-activation of Notch signalling via V-ATPase dependent acidification. Following DMXL2 depletion or treatment with Bafilomycin A1, both EMT targets and Notch signalling pathway significantly decrease. We show for the first time that DMXL2 protein levels are significantly increased in ERα positive breast cancer patients that progress after endocrine therapy. Finally, we demonstrate that DMXL2 is a transmembrane protein with a potential extra-cellular domain. These findings identify DMXL2 as a novel, functional biomarker for ERα positive breast cancer.
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