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Wu Z, Tang Y, Liu Y, Chen Z, Feng Y, Hu H, Liu H, Chen G, Lu Y, Hu Y, Xu R. Co-delivery of fucoxanthin and Twist siRNA using hydroxyethyl starch-cholesterol self-assembled polymer nanoparticles for triple-negative breast cancer synergistic therapy. J Adv Res 2025; 70:463-479. [PMID: 38636588 PMCID: PMC11976571 DOI: 10.1016/j.jare.2024.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 03/22/2024] [Accepted: 04/15/2024] [Indexed: 04/20/2024] Open
Abstract
INTRODUCTION Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer with an extremely dismal prognosis and few treatment options. As a desmoplastic tumor, TNBC tumor cells are girdled by stroma composed of cancer-associated fibroblasts (CAFs) and their secreted stromal components. The rapidly proliferating tumor cells, together with the tumor stroma, exert additional solid tissue pressure on tumor vasculature and surrounding tissues, severely obstructing therapeutic agent from deep intratumoral penetration, and resulting in tumor metastasis and treatment resistance. OBJECTIVES Fucoxanthin (FX), a xanthophyll carotenoid abundant in marine algae, has attracted widespread attention as a promising alternative candidate for tumor prevention and treatment. Twist is a pivotal regulator of epithelial to mesenchymal transition, and its depletion has proven to sensitize antitumor drugs, inhibit metastasis, reduce CAFs activation and the following interstitial deposition, and increase tumor perfusion. The nanodrug delivery system co-encapsulating FX and nucleic acid drug Twist siRNA (siTwist) was expected to form a potent anti-TNBC therapeutic cyclical feedback loop. METHODS AND RESULTS Herein, our studies constituted a novel self-assembled polymer nanomedicine (siTwist/FX@HES-CH) based on the amino-modified hydroxyethyl starch (HES-NH2) grafted with hydrophobic segment cholesterol (CH). The MTT assay, flow cytometry apoptosis analysis, transwell assay, western blot, and 3D multicellular tumor spheroids growth inhibition assay all showed that siTwist/FX@HES-CH could kill tumor cells and inhibit their metastasis in a synergistic manner. The in vivo anti-TNBC efficacy was demonstrated that siTwist/FX@HES-CH remodeled tumor microenvironment, facilitated interstitial barrier crossing, killed tumor cells synergistically, drastically reduced TNBC orthotopic tumor burden and inhibited lung metastasis. CONCLUSION Systematic studies revealed that this dual-functional nanomedicine that targets both tumor cells and tumor microenvironment significantly alleviates TNBC orthotopic tumor burden and inhibits lung metastasis, establishing a new paradigm for TNBC therapy.
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Affiliation(s)
- Zeliang Wu
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yuxiang Tang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan 430022, China
| | - Yuanhui Liu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Zhaozhao Chen
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yuao Feng
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hang Hu
- School of Pharmacy, Changzhou University, Changzhou 213164, China
| | - Hui Liu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China
| | - Gang Chen
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Youming Lu
- Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Innovation Center for Brain Medical Sciences of the Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan 430022, China.
| | - Rong Xu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China; Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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Jacob S, Ahluwalia C, Chintamani C. Expression of EMT Markers Snail, Slug, and Twist and their Association with Known Prognostic Indicators of Breast Cancer. Indian J Surg Oncol 2024; 15:706-712. [PMID: 39555342 PMCID: PMC11564478 DOI: 10.1007/s13193-024-01975-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 05/22/2024] [Indexed: 11/19/2024] Open
Abstract
Breast cancer is trending its way as the most common cancer globally. Surgery remains the mainstream treatment modality. The gene expression signatures predict the prognosis in cancer patients. However, they are a limitation in resource-poor settings. India is predicted to see a rise in breast cancer patients in the years to come. New therapeutic target and prognostic indicators feasible to use are the need of the hour. Our study aims to evaluate the immunohistochemical expression of epithelial mesenchymal transition (EMT) markers, Snail + Slug and Twist, in breast cancer and their association with known prognostic indicators. The study was conducted on 60 patients of breast cancer who were primarily treated by surgery. IHC expression of Snail + Slug and Twist was evaluated and scored. They were categorized into high and low expression based on the median obtained on statistical analysis. Increased expression of EMT markers showed statistically significant association with the higher grade of the tumor and triple-negative and luminal B molecular subtype. Immunohistochemical expression of EMT markers Snail + Slug and Twist proves to be a reliable, efficient, and feasible in predicting the prognosis of breast cancer, and they should be targeted for novel therapeutic intervention.
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Affiliation(s)
- Sherrin Jacob
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| | - Charanjeet Ahluwalia
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
| | - Chintamani Chintamani
- Department of Surgery, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India
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3
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Goyal A, Murkute SL, Bhowmik S, Prasad CP, Mohapatra P. Belling the "cat": Wnt/β-catenin signaling and its significance in future cancer therapies. Biochim Biophys Acta Rev Cancer 2024; 1879:189195. [PMID: 39413855 DOI: 10.1016/j.bbcan.2024.189195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 09/15/2024] [Accepted: 10/07/2024] [Indexed: 10/18/2024]
Abstract
The WNT/β-catenin is among one of the most extensively studied cellular signaling pathways involved in the initiation and progression of several deadly cancers. It is now understood that the WNT/β-catenin signaling, during tumor progression operates in a very complex fashion beyond the earlier assumed simple WNT 'On' or 'Off' mode as it recruits numerous WNT ligands, receptors, transcriptional factors and also cross-talks with other signaling molecules including the noncanonical WNT regulators. WNT/β-catenin signaling molecules are often mutated in different cancers which makes them very challenging to inhibit and sometimes ranks them among the undruggable targets. Furthermore, due to the evolutionary conservation of this pathway, inhibiting WNT/β-catenin has caused significant toxicity in normal cells. These challenges are reflected in clinical trial data, where the use of WNT/β-catenin inhibitors as standalone treatments remains limited. In this review, we have highlighted the crucial functional associations of diverse WNT/β-catenin signaling regulators with cancer progression and the phenotypic switching of tumor cells. Next, we have shed light on the roles of WNT/β-catenin signaling in drug resistance, clonal evolution, tumor heterogeneity, and immune evasion. The present review also focuses on various classes of routine and novel WNT/β-catenin therapeutic regimes while addressing the challenges associated with targeting the regulators of this complex pathway. In the light of multiple case studies on WNT/β-catenin inhibitors, we also highlighted the challenges and opportunities for future clinical trial strategies involving these treatments. Additionally, we have proposed strategies for future WNT/β-catenin-based drug discovery trials, emphasizing the potential of combination therapies and AI/ML-driven prediction approaches. Overall, here we showcased the opportunities, possibilities, and potentialities of WNT/β-catenin signaling modulatory therapeutic regimes as promising precision cancer medicines for the future.
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Affiliation(s)
- Akansha Goyal
- Department of Biotechnology, NIPER Guwahati, Sila Katamur, Changsari, 781101 Kamrup, Assam, India
| | - Satyajit Laxman Murkute
- Department of Biotechnology, NIPER Guwahati, Sila Katamur, Changsari, 781101 Kamrup, Assam, India
| | - Sujoy Bhowmik
- Department of Biotechnology, NIPER Guwahati, Sila Katamur, Changsari, 781101 Kamrup, Assam, India
| | - Chandra Prakash Prasad
- Department of Medical Oncology Lab, DR BRA-IRCH, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
| | - Purusottam Mohapatra
- Department of Biotechnology, NIPER Guwahati, Sila Katamur, Changsari, 781101 Kamrup, Assam, India.
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Xue JD, Xiang WF, Cai MQ, Lv XY. Biological functions and therapeutic potential of SRY related high mobility group box 5 in human cancer. Front Oncol 2024; 14:1332148. [PMID: 38835366 PMCID: PMC11148273 DOI: 10.3389/fonc.2024.1332148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 04/26/2024] [Indexed: 06/06/2024] Open
Abstract
Cancer is a heavy human burden worldwide, with high morbidity and mortality. Identification of novel cancer diagnostic and prognostic biomarkers is important for developing cancer treatment strategies and reducing mortality. Transcription factors, including SRY associated high mobility group box (SOX) proteins, are thought to be involved in the regulation of specific biological processes. There is growing evidence that SOX transcription factors play an important role in cancer progression, including tumorigenesis, changes in the tumor microenvironment, and metastasis. SOX5 is a member of SOX Group D of Sox family. SOX5 is expressed in various tissues of human body and participates in various physiological and pathological processes and various cellular processes. However, the abnormal expression of SOX5 is associated with cancer of various systems, and the abnormal expression of SOX5 acts as a tumor promoter to promote cancer cell viability, proliferation, invasion, migration and EMT through multiple mechanisms. In addition, the expression pattern of SOX5 is closely related to cancer type, stage and adverse clinical outcome. Therefore, SOX5 is considered as a potential biomarker for cancer diagnosis and prognosis. In this review, the expression of SOX5 in various human cancers, the mechanism of action and potential clinical significance of SOX5 in tumor, and the therapeutic significance of Sox5 targeting in cancer were reviewed. In order to provide a new theoretical basis for cancer clinical molecular diagnosis, molecular targeted therapy and scientific research.
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Affiliation(s)
- Juan-di Xue
- The School of Basic Medicine Sciences of Lanzhou University, Lanzhou, China
| | - Wan-Fang Xiang
- School/Hospital of Stomatology of Lanzhou University, Lanzhou, China
| | - Ming-Qin Cai
- School/Hospital of Stomatology of Lanzhou University, Lanzhou, China
| | - Xiao-Yun Lv
- The School of Basic Medicine Sciences of Lanzhou University, Lanzhou, China
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Martínez-Campa C, Álvarez-García V, Alonso-González C, González A, Cos S. Melatonin and Its Role in the Epithelial-to-Mesenchymal Transition (EMT) in Cancer. Cancers (Basel) 2024; 16:956. [PMID: 38473317 DOI: 10.3390/cancers16050956] [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: 01/12/2024] [Revised: 02/13/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
The epithelial-to-mesenchymal transition (EMT) is a cell-biological program that occurs during the progression of several physiological processes and that can also take place during pathological situations such as carcinogenesis. The EMT program consists of the sequential activation of a number of intracellular signaling pathways aimed at driving epithelial cells toward the acquisition of a series of intermediate phenotypic states arrayed along the epithelial-mesenchymal axis. These phenotypic features include changes in the motility, conformation, polarity and functionality of cancer cells, ultimately leading cells to stemness, increased invasiveness, chemo- and radioresistance and the formation of cancer metastasis. Amongst the different existing types of the EMT, type 3 is directly involved in carcinogenesis. A type 3 EMT occurs in neoplastic cells that have previously acquired genetic and epigenetic alterations, specifically affecting genes involved in promoting clonal outgrowth and invasion. Markers such as E-cadherin; N-cadherin; vimentin; and transcription factors (TFs) like Twist, Snail and ZEB are considered key molecules in the transition. The EMT process is also regulated by microRNA expression. Many miRNAs have been reported to repress EMT-TFs. Thus, Snail 1 is repressed by miR-29, miR-30a and miR-34a; miR-200b downregulates Slug; and ZEB1 and ZEB2 are repressed by miR-200 and miR-205, respectively. Occasionally, some microRNA target genes act downstream of the EMT master TFs; thus, Twist1 upregulates the levels of miR-10b. Melatonin is an endogenously produced hormone released mainly by the pineal gland. It is widely accepted that melatonin exerts oncostatic actions in a large variety of tumors, inhibiting the initiation, progression and invasion phases of tumorigenesis. The molecular mechanisms underlying these inhibitory actions are complex and involve a great number of processes. In this review, we will focus our attention on the ability of melatonin to regulate some key EMT-related markers, transcription factors and micro-RNAs, summarizing the multiple ways by which this hormone can regulate the EMT. Since melatonin has no known toxic side effects and is also known to help overcome drug resistance, it is a good candidate to be considered as an adjuvant drug to conventional cancer therapies.
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Affiliation(s)
- Carlos Martínez-Campa
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Virginia Álvarez-García
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Carolina Alonso-González
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Alicia González
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Samuel Cos
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
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De Rosa C, De Rosa V, Tuccillo C, Tirino V, Amato L, Papaccio F, Ciardiello D, Napolitano S, Martini G, Ciardiello F, Morgillo F, Iommelli F, Della Corte CM. ITGB1 and DDR activation as novel mediators in acquired resistance to osimertinib and MEK inhibitors in EGFR-mutant NSCLC. Sci Rep 2024; 14:500. [PMID: 38177190 PMCID: PMC10766645 DOI: 10.1038/s41598-023-50568-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 12/21/2023] [Indexed: 01/06/2024] Open
Abstract
Osimertinib is a third-generation tyrosine kinase inhibitor clinically approved for first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC) patients. Although an impressive drug response is initially observed, in most of tumors, resistance occurs after different time and an alternative therapeutic strategy to induce regression disease is currently lacking. The hyperactivation of MEK/MAPKs, is one the most common event identified in osimertinib-resistant (OR) NSCLC cells. However, in response to selective drug pressure, the occurrence of multiple mechanisms of resistance may contribute to treatment failure. In particular, the epithelial-to-mesenchymal transition (EMT) and the impaired DNA damage repair (DDR) pathways are recognized as additional cause of resistance in NSCLC thus promoting tumor progression. Here we showed that concurrent upregulation of ITGB1 and DDR family proteins may be associated with an increase of EMT pathways and linked to both osimertinib and MEK inhibitor resistance to cell death. Furthermore, this study demonstrated the existence of an interplay between ITGB1 and DDR and highlighted, for the first time, that combined treatment of MEK inhibitor with DDRi may be relevant to downregulate ITGB1 levels and increase cell death in OR NSCLC cells.
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Affiliation(s)
- Caterina De Rosa
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Viviana De Rosa
- Institute of Biostructures and Bioimaging, National Research Council, Naples, Italy
| | - Concetta Tuccillo
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Virginia Tirino
- Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luisa Amato
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Federica Papaccio
- Department of Medicine, Surgery and Dentistry, Scuola Medica Salernitana", University of Salerno, Baronissi, Italy
| | - Davide Ciardiello
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan, Italy
| | - Stefania Napolitano
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Giulia Martini
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Fortunato Ciardiello
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Floriana Morgillo
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Francesca Iommelli
- Institute of Biostructures and Bioimaging, National Research Council, Naples, Italy
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Mirjat D, Kashif M, Roberts CM. Shake It Up Baby Now: The Changing Focus on TWIST1 and Epithelial to Mesenchymal Transition in Cancer and Other Diseases. Int J Mol Sci 2023; 24:17539. [PMID: 38139368 PMCID: PMC10743446 DOI: 10.3390/ijms242417539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/11/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023] Open
Abstract
TWIST1 is a transcription factor that is necessary for healthy neural crest migration, mesoderm development, and gastrulation. It functions as a key regulator of epithelial-to-mesenchymal transition (EMT), a process by which cells lose their polarity and gain the ability to migrate. EMT is often reactivated in cancers, where it is strongly associated with tumor cell invasion and metastasis. Early work on TWIST1 in adult tissues focused on its transcriptional targets and how EMT gave rise to metastatic cells. In recent years, the roles of TWIST1 and other EMT factors in cancer have expanded greatly as our understanding of tumor progression has advanced. TWIST1 and related factors are frequently tied to cancer cell stemness and changes in therapeutic responses and thus are now being viewed as attractive therapeutic targets. In this review, we highlight non-metastatic roles for TWIST1 and related EMT factors in cancer and other disorders, discuss recent findings in the areas of therapeutic resistance and stemness in cancer, and comment on the potential to target EMT for therapy. Further research into EMT will inform novel treatment combinations and strategies for advanced cancers and other diseases.
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Affiliation(s)
- Dureali Mirjat
- Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308, USA
| | - Muhammad Kashif
- Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308, USA
| | - Cai M. Roberts
- Department of Pharmacology, Midwestern University, Downers Grove, IL 60515, USA
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Zheng S, Guerrero-Haughton E, Foijer F. Chromosomal Instability-Driven Cancer Progression: Interplay with the Tumour Microenvironment and Therapeutic Strategies. Cells 2023; 12:2712. [PMID: 38067140 PMCID: PMC10706135 DOI: 10.3390/cells12232712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/20/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
Chromosomal instability (CIN) is a prevalent characteristic of solid tumours and haematological malignancies. CIN results in an increased frequency of chromosome mis-segregation events, thus yielding numerical and structural copy number alterations, a state also known as aneuploidy. CIN is associated with increased chances of tumour recurrence, metastasis, and acquisition of resistance to therapeutic interventions, and this is a dismal prognosis. In this review, we delve into the interplay between CIN and cancer, with a focus on its impact on the tumour microenvironment-a driving force behind metastasis. We discuss the potential therapeutic avenues that have resulted from these insights and underscore their crucial role in shaping innovative strategies for cancer treatment.
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Affiliation(s)
- Siqi Zheng
- European Research Institute for the Biology of Ageing (ERIBA), University Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands
| | - Erika Guerrero-Haughton
- European Research Institute for the Biology of Ageing (ERIBA), University Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands
- Department of Research in Sexual and Reproductive Health, Gorgas Memorial Institute for Health Studies, Panama City 0816-02593, Panama
- Sistema Nacional de Investigación, SENACYT, Panama City 0816-02593, Panama
| | - Floris Foijer
- European Research Institute for the Biology of Ageing (ERIBA), University Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands
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Cordani N, Mologni L, Piazza R, Tettamanti P, Cogliati V, Mauri M, Villa M, Malighetti F, Di Bella C, Jaconi M, Cerrito MG, Cavaletti G, Lavitrano M, Cazzaniga ME. TWIST1 Upregulation Is a Potential Target for Reversing Resistance to the CDK4/6 Inhibitor in Metastatic Luminal Breast Cancer Cells. Int J Mol Sci 2023; 24:16294. [PMID: 38003483 PMCID: PMC10671583 DOI: 10.3390/ijms242216294] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 11/08/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly improved progression-free survival in hormone-receptor-positive (HR+), human-epidermal-growth-factor-receptor-type-2-negative (HER2-) metastatic luminal breast cancer (mLBC). Several studies have shown that in patients with endocrine-sensitive or endocrine-resistant LBC, the addition of CDK4/6 inhibitors to endocrine therapy significantly prolongs progression-free survival. However, the percentage of patients who are unresponsive or refractory to these therapies is as high as 40%, and no reliable and reproducible biomarkers have been validated to select a priori responders or refractory patients. The selection of mutant clones in the target oncoprotein is the main cause of resistance. Other mechanisms such as oncogene amplification/overexpression or mutations in other pathways have been described in several models. In this study, we focused on palbociclib, a selective CDK4/6 inhibitor. We generated a human MCF-7 luminal breast cancer cell line that was able to survive and proliferate at different concentrations of palbociclib and also showed cross-resistance to abemaciclib. The resistant cell line was characterized via RNA sequencing and was found to strongly activate the epithelial-to-mesenchymal transition. Among the top deregulated genes, we found a dramatic downregulation of the CDK4 inhibitor CDKN2B and an upregulation of the TWIST1 transcription factor. TWIST1 was further validated as a target for the reversal of palbociclib resistance. This study provides new relevant information about the mechanisms of resistance to CDK4/6 inhibitors and suggests potential new markers for patients' follow-up care during treatment.
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Affiliation(s)
- Nicoletta Cordani
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy; (L.M.); (R.P.); (P.T.); (M.M.); (M.V.); (F.M.); (M.G.C.); (G.C.); (M.L.); (M.E.C.)
| | - Luca Mologni
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy; (L.M.); (R.P.); (P.T.); (M.M.); (M.V.); (F.M.); (M.G.C.); (G.C.); (M.L.); (M.E.C.)
| | - Rocco Piazza
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy; (L.M.); (R.P.); (P.T.); (M.M.); (M.V.); (F.M.); (M.G.C.); (G.C.); (M.L.); (M.E.C.)
| | - Pietro Tettamanti
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy; (L.M.); (R.P.); (P.T.); (M.M.); (M.V.); (F.M.); (M.G.C.); (G.C.); (M.L.); (M.E.C.)
| | - Viola Cogliati
- Phase 1 Research Centre, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy (C.D.B.); (M.J.)
| | - Mario Mauri
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy; (L.M.); (R.P.); (P.T.); (M.M.); (M.V.); (F.M.); (M.G.C.); (G.C.); (M.L.); (M.E.C.)
| | - Matteo Villa
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy; (L.M.); (R.P.); (P.T.); (M.M.); (M.V.); (F.M.); (M.G.C.); (G.C.); (M.L.); (M.E.C.)
| | - Federica Malighetti
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy; (L.M.); (R.P.); (P.T.); (M.M.); (M.V.); (F.M.); (M.G.C.); (G.C.); (M.L.); (M.E.C.)
| | - Camillo Di Bella
- Phase 1 Research Centre, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy (C.D.B.); (M.J.)
| | - Marta Jaconi
- Phase 1 Research Centre, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy (C.D.B.); (M.J.)
| | - Maria Grazia Cerrito
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy; (L.M.); (R.P.); (P.T.); (M.M.); (M.V.); (F.M.); (M.G.C.); (G.C.); (M.L.); (M.E.C.)
| | - Guido Cavaletti
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy; (L.M.); (R.P.); (P.T.); (M.M.); (M.V.); (F.M.); (M.G.C.); (G.C.); (M.L.); (M.E.C.)
| | - Marialuisa Lavitrano
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy; (L.M.); (R.P.); (P.T.); (M.M.); (M.V.); (F.M.); (M.G.C.); (G.C.); (M.L.); (M.E.C.)
| | - Marina Elena Cazzaniga
- School of Medicine and Surgery, Milano-Bicocca University, 20900 Monza, Italy; (L.M.); (R.P.); (P.T.); (M.M.); (M.V.); (F.M.); (M.G.C.); (G.C.); (M.L.); (M.E.C.)
- Phase 1 Research Centre, Fondazione IRCCS San Gerardo dei Tintori, 20900 Monza, Italy (C.D.B.); (M.J.)
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O'Connell I, Dongre A. Immune Checkpoint Blockade Therapy for Breast Cancer: Lessons from Epithelial-Mesenchymal Transition. Mol Diagn Ther 2023; 27:433-444. [PMID: 37193859 PMCID: PMC10299941 DOI: 10.1007/s40291-023-00652-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/10/2023] [Indexed: 05/18/2023]
Abstract
Immune checkpoint blockade therapies have generated efficacious responses in certain tumor types; however, the responses of breast carcinomas have been largely limited. Moreover, the identity of various parameters that can predict responses to immunotherapies, and at the same time, serve as putative biomarkers that can be therapeutically targeted to enhance the effectiveness of immunotherapies for breast cancers, remains to be comprehensively delineated. Activation of epithelial-mesenchymal plasticity in cancer cells, including those of the breast, increases their tumor-initiating potential and promotes their aggressiveness and resistance to multiple treatment regimens. Moreover, the residence of cancer cells in alternating epithelial or mesenchymal plastic phenotypic states can also influence their immuno-modulatory properties and susceptibilities to immune checkpoint blockade therapies. In this current opinion, we discuss the lessons that can be learnt from epithelial-mesenchymal transition to potentiate the efficacy of immunotherapy for breast cancers. We also discuss strategies to sensitize more-mesenchymal cancer cells to anti-tumor immunity and immune checkpoint blockade therapies, with the hope that these can serve as new translational avenues for the treatment of human breast tumors.
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Affiliation(s)
- Isabel O'Connell
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, T7-012A VRT, 930 Campus Road, Ithaca, NY, 14853, USA
| | - Anushka Dongre
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, T7-012A VRT, 930 Campus Road, Ithaca, NY, 14853, USA.
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11
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Vesuna F, Penet MF, Mori N, Bhujwalla ZM, Raman V. Twist alters the breast tumor microenvironment via choline kinase to facilitate an aggressive phenotype. Mol Cell Biochem 2023; 478:939-948. [PMID: 36136285 PMCID: PMC11299248 DOI: 10.1007/s11010-022-04555-5] [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: 03/20/2022] [Accepted: 08/30/2022] [Indexed: 11/26/2022]
Abstract
Twist (TWIST1) is a gene required for cell fate specification in embryos and its expression in mammary epithelium can initiate tumorigenesis through the epithelial-mesenchymal transition. To identify downstream target genes of Twist in breast cancer, we performed microarray analysis on the transgenic breast cancer cell line, MCF-7/Twist. One of the targets identified was choline kinase whose upregulation resulted in increased cellular phosphocholine and total choline containing compounds-a characteristic observed in highly aggressive metastatic cancers. To study the interactions between Twist, choline kinase, and their effect on the microenvironment, we used 1H magnetic resonance spectroscopy and found significantly higher phosphocholine and total choline, as well as increased phosphocholine/glycerophosphocholine ratio in MCF-7/Twist cells. We also observed significant increases in extracellular glucose, lactate, and [H +] ion concentrations in the MCF-7/Twist cells. Magnetic resonance imaging of MCF-7/Twist orthotopic breast tumors showed a significant increase in vascular volume and permeability surface area product compared to control tumors. In addition, by reverse transcription-quantitative polymerase chain reaction, we discovered that Twist upregulated choline kinase expression in estrogen receptor negative breast cancer cell lines through FOXA1 downregulation. Moreover, using The Cancer Genome Atlas database, we observed a significant inverse relationship between FOXA1 and choline kinase expression and propose that it could act as a modulator of the Twist/choline kinase axis. The data presented indicate that Twist is a driver of choline kinase expression in breast cancer cells via FOXA1 resulting in the generation of an aggressive breast cancer phenotype.
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Affiliation(s)
- Farhad Vesuna
- Division of Cancer Imaging Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Marie-France Penet
- Division of Cancer Imaging Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Noriko Mori
- Division of Cancer Imaging Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Zaver M Bhujwalla
- Division of Cancer Imaging Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Venu Raman
- Division of Cancer Imaging Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
- Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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12
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Lin YP, Hseu YC, Thiyagarajan V, Vadivalagan C, Pandey S, Lin KY, Hsu YT, Liao JW, Lee CC, Yang HL. The in vitro and in vivo anticancer activities of Antrodia salmonea through inhibition of metastasis and induction of ROS-mediated apoptotic and autophagic cell death in human glioblastoma cells. Biomed Pharmacother 2023; 158:114178. [PMID: 36916401 DOI: 10.1016/j.biopha.2022.114178] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Antrodia salmonea (AS) exhibits anticancer activities against various cancers. OBJECTIVE This study investigated the anticancer activities of AS on human glioblastoma (GBM8401 and U87MG) cells both in vitro and in vivo and explained the underlying molecular mechanism. METHODS MTT, colony formation, migration/invasion assay, immunoblotting, immunofluorescence, TUNEL, Annexin V/PI staining, AO staining, GFP-LC3 transfection, TEM, qPCR, siLC3, DCFH2-DA assay, and xenografted-nude mice were used to assess the potential of AS therapy. RESULTS AS treatment retarded growth and suppressed colony formation in glioblastoma cells. AS attenuates EMT by suppressing invasion and migration, increasing E-cadherin expression, decreasing Twist, Snail, and N-cadherin expression, and inhibiting Wnt/β-catenin pathways in GBM8401 and U87MG cells. Furthermore, AS induced apoptosis by activating caspase-3, cleaving PARP, and dysregulating Bax and Bcl-2 in both cell lines. TUNEL assay and Annexin V/PI staining indicated AS-mediated late apoptosis. Interestingly, AS induced autophagic cell death by LC3-II accumulation, AVO formation, autophagosome GFP-LC3 puncta, p62/SQSTM1 expression, and ATG4B inhibition in GBM8401 and U87MG cells. TEM data revealed that AS favored autophagosome and autolysosome formation. The autophagy inhibitors 3-MA/CQ and LC3 knockdown suppressed AS-induced apoptosis in glioblastoma cells, indicating that the inhibition of autophagy decreased AS-induced apoptosis. Notably, the antioxidant N-acetylcysteine (NAC) inhibited AS-mediated ROS production and AS-induced apoptotic and autophagic cell death. Furthermore, AS induced ROS-mediated inhibition of the PI3K/AKT/mTOR signaling pathway. AS reduced the tumor burden in GBM8401-xenografted nude mice and significantly modulated tumor xenografts by inducing anti-EMT, apoptosis, and autophagy. AS could be a potential antitumor agent in human glioblastoma treatment.
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Affiliation(s)
- Yi-Pin Lin
- Institute of Nutrition, College of Health Care, China Medical University, Taichung 40402, Taiwan, ROC
| | - You-Cheng Hseu
- Department of Cosmeceutics, College of Pharmacy, China Medical University, Taichung 40402, Taiwan, ROC; Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan, ROC; Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan, ROC; Research Center of Chinese Herbal Medicine, China Medical University, Taichung 40402, Taiwan, ROC.
| | - Varadharajan Thiyagarajan
- Department of Cosmeceutics, College of Pharmacy, China Medical University, Taichung 40402, Taiwan, ROC
| | - Chithravel Vadivalagan
- Department of Cosmeceutics, College of Pharmacy, China Medical University, Taichung 40402, Taiwan, ROC
| | - Sudhir Pandey
- Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand
| | - Kai-Yuan Lin
- Department of Medical Research, Chi-Mei Medical Center, Tainan 710, Taiwan, ROC; Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan, ROC
| | - Yuan-Tai Hsu
- Institute of Nutrition, College of Health Care, China Medical University, Taichung 40402, Taiwan, ROC
| | - Jiunn-Wang Liao
- Graduate Institute of Veterinary Pathology, National Chung-Hsing University, Taichung 402, Taiwan, ROC
| | - Chuan-Chen Lee
- Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan, ROC
| | - Hsin-Ling Yang
- Institute of Nutrition, College of Health Care, China Medical University, Taichung 40402, Taiwan, ROC.
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13
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Yimingjiang M, Aini A, Tuergan T, Zhang W. Differential Gene Expression Profiling in Alveolar Echinococcosis Identifies Potential Biomarkers Associated With Angiogenesis. Open Forum Infect Dis 2023; 10:ofad031. [PMID: 36817746 PMCID: PMC9927572 DOI: 10.1093/ofid/ofad031] [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: 09/05/2022] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
Background Alveolar echinococcosis (AE) is a worldwide zoonosis caused by Echinococcus multilocularis. Alveolar echinococcosis is a severe chronic parasitic disease that exhibits a tumor-like growth, with the potential for invasion and distant metastasis; however, the molecular mechanism underlying this condition remains unclear. Methods Transcriptome analyses were performed to detect differentially expressed genes (DEGs) in samples from patients with AE with invasion and distant metastasis. The results were further verified by immunohistochemistry. Results A total of 1796 DEGs were identified, including 1742 upregulated and 54 downregulated DEGs. A subsequent functional analysis showed that the significant DEGs were involved in the angiogenesis process. Immunohistochemical analysis confirmed the reliability of the transcriptomic data. Conclusions These results suggest that angiogenesis is a possible mechanism underlying the tumor-like biological behavior observed during E multilocularis infection. Genes related to this process may play important roles in AE invasion and distant metastasis.
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Affiliation(s)
- Maiweilidan Yimingjiang
- Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Abudusalamu Aini
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Talaiti Tuergan
- Department of Hepatic Hydatid and Hepatobiliary Surgery, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Wei Zhang
- Correspondence: Dr. Wei Zhang, Department of Pathology, The First Affiliated Hospital of Xinjiang Medical University, 137 Liyushan Southern Road, Urumqi, Xinjiang 830054, China ( )
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Castellanos G, Valbuena DS, Pérez E, Villegas VE, Rondón-Lagos M. Chromosomal Instability as Enabling Feature and Central Hallmark of Breast Cancer. BREAST CANCER (DOVE MEDICAL PRESS) 2023; 15:189-211. [PMID: 36923397 PMCID: PMC10010144 DOI: 10.2147/bctt.s383759] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 10/11/2022] [Indexed: 03/11/2023]
Abstract
Chromosomal instability (CIN) has become a topic of great interest in recent years, not only for its implications in cancer diagnosis and prognosis but also for its role as an enabling feature and central hallmark of cancer. CIN describes cell-to-cell variation in the number or structure of chromosomes in a tumor population. Although extensive research in recent decades has identified some associations between CIN with response to therapy, specific associations with other hallmarks of cancer have not been fully evidenced. Such associations place CIN as an enabling feature of the other hallmarks of cancer and highlight the importance of deepening its knowledge to improve the outcome in cancer. In addition, studies conducted to date have shown paradoxical findings about the implications of CIN for therapeutic response, with some studies showing associations between high CIN and better therapeutic response, and others showing the opposite: associations between high CIN and therapeutic resistance. This evidences the complex relationships between CIN with the prognosis and response to treatment in cancer. Considering the above, this review focuses on recent studies on the role of CIN in cancer, the cellular mechanisms leading to CIN, its relationship with other hallmarks of cancer, and the emerging therapeutic approaches that are being developed to target such instability, with a primary focus on breast cancer. Further understanding of the complexity of CIN and its association with other hallmarks of cancer could provide a better understanding of the cellular and molecular mechanisms involved in prognosis and response to treatment in cancer and potentially lead to new drug targets.
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Affiliation(s)
- Giovanny Castellanos
- Maestría en Ciencias Biológicas, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia.,School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia
| | - Duván Sebastián Valbuena
- School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia
| | - Erika Pérez
- School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia
| | - Victoria E Villegas
- Centro de Investigaciones en Microbiología y Biotecnología-UR (CIMBIUR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá, Colombia
| | - Milena Rondón-Lagos
- School of Biological Sciences, Universidad Pedagógica y Tecnológica de Colombia, Tunja, Colombia
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15
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Zhou Z, Jin L, Shen J, Shi W, Xu Y, Ye L, Liu J, Pan J. COM33 suppresses carboplatin-induced epithelial-mesenchymal transition via inhibition of Twist1 in ovarian cancer. Acta Biochim Biophys Sin (Shanghai) 2022; 55:34-42. [PMID: 36647720 PMCID: PMC10157527 DOI: 10.3724/abbs.2022195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 05/08/2022] [Indexed: 12/23/2022] Open
Abstract
Despite favorable responses to platinum-based chemotherapy in ovarian cancer (OC), chemoresistance is still a major cause of treatment failure. Hence, we develop a novel synthetic agent, COM33, to relieve the chemoresistance caused by carboplatin. The anti-cancerous effects of the combination of COM33 and carboplatin on OC are evaluated by cell viability, wound healing, and transwell invasion assays. A mechanistic investigation is carried out by using RNA-Seq analysis and then verified by western blot analysis and immunofluorescence microscopy. The safety and efficacy in vivo are evaluated using SKOV3 tumor-bearing nude mice. Results show that the co-administration of COM33 enhances the inhibitory effects of carboplatin on cancer cell viability, migration, and invasion in vitro and tumor growth in vivo. Furthermore, COM33 suppresses the carboplatin-induced epithelial-mesenchymal transition (EMT) by inhibiting the ERK signaling pathway. Additionally, we show that Twist1, the effector of the ERK signaling pathway, participates in carboplatin-induced EMT and is also inhibited by COM33. Our data show that the combination of carboplatin with COM33 is beneficial for chemotherapy against OC, which may be a potential novel anti-tumor strategy.
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Affiliation(s)
- Zhiyang Zhou
- Obstetrics & Gynecology HospitalInstitute of Reproduction and DevelopmentFudan UniversityShanghai200011China
| | - Li Jin
- Obstetrics & Gynecology HospitalInstitute of Reproduction and DevelopmentFudan UniversityShanghai200011China
| | - Jian Shen
- College of Life ScienceZhejiang Chinese Medical UniversityHangzhou310053China
| | - Weihui Shi
- Obstetrics & Gynecology HospitalInstitute of Reproduction and DevelopmentFudan UniversityShanghai200011China
| | - Yue Xu
- Obstetrics & Gynecology HospitalInstitute of Reproduction and DevelopmentFudan UniversityShanghai200011China
| | - Longyun Ye
- Department of Pancreatic SurgeryFudan University Shanghai Cancer CenterShanghai200032China
- Department of OncologyShanghai Medical CollegeFudan UniversityShanghai200032China
| | - Junxi Liu
- Chinese Academy of Science Key Laboratory of Chemistry of Northwestern Plant Resources and Key Laboratory for Natural Medicine of Gansu ProvinceLanzhou Institute of Chemical PhysicsChinese Academy of SciencesLanzhou730000China
| | - Jiexue Pan
- Obstetrics & Gynecology HospitalInstitute of Reproduction and DevelopmentFudan UniversityShanghai200011China
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Sepporta MV, Praz V, Balmas Bourloud K, Joseph JM, Jauquier N, Riggi N, Nardou-Auderset K, Petit A, Scoazec JY, Sartelet H, Renella R, Mühlethaler-Mottet A. TWIST1 expression is associated with high-risk neuroblastoma and promotes primary and metastatic tumor growth. Commun Biol 2022; 5:42. [PMID: 35022561 PMCID: PMC8755726 DOI: 10.1038/s42003-021-02958-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 12/09/2021] [Indexed: 11/09/2022] Open
Abstract
The embryonic transcription factors TWIST1/2 are frequently overexpressed in cancer, acting as multifunctional oncogenes. Here we investigate their role in neuroblastoma (NB), a heterogeneous childhood malignancy ranging from spontaneous regression to dismal outcomes despite multimodal therapy. We first reveal the association of TWIST1 expression with poor survival and metastasis in primary NB, while TWIST2 correlates with good prognosis. Secondly, suppression of TWIST1 by CRISPR/Cas9 results in a reduction of tumor growth and metastasis colonization in immunocompromised mice. Moreover, TWIST1 knockout tumors display a less aggressive cellular morphology and a reduced disruption of the extracellular matrix (ECM) reticulin network. Additionally, we identify a TWIST1-mediated transcriptional program associated with dismal outcome in NB and involved in the control of pathways mainly linked to the signaling, migration, adhesion, the organization of the ECM, and the tumor cells versus tumor stroma crosstalk. Taken together, our findings confirm TWIST1 as promising therapeutic target in NB.
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Affiliation(s)
- Maria-Vittoria Sepporta
- Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Viviane Praz
- Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Experimental Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Katia Balmas Bourloud
- Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Jean-Marc Joseph
- Pediatric Surgery, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Nicolas Jauquier
- Pediatric Surgery, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Nicolò Riggi
- Experimental Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Katya Nardou-Auderset
- Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Ophthalmic Hospital Jules-Gonin - Fondation Asile Des Aveugles, Lausanne, Switzerland
| | - Audrey Petit
- Department of Pathology, Medical University of Grenoble, Grenoble, France
- Pediatric Hematology Oncology Department, CHU de la Timone, Marseille, France
| | - Jean-Yves Scoazec
- Department of Biology and Medical Pathology, Gustave Roussy Cancer Campus, Villejuif, France
| | - Hervé Sartelet
- Department of Pathology, Medical University of Grenoble, Grenoble, France
- Department of Biopathology, CHRU de Nancy, University of Lorraine, Nancy, France
| | - Raffaele Renella
- Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Annick Mühlethaler-Mottet
- Pediatric Hematology-Oncology Research Laboratory, Woman-Mother-Child Department, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
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17
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Lu JW, Lin LI, Sun Y, Liu D, Gong Z. Effect of Lipopolysaccharides on Liver Tumor Metastasis of twist1a/krasV12 Double Transgenic Zebrafish. Biomedicines 2022; 10:biomedicines10010095. [PMID: 35052775 PMCID: PMC8773574 DOI: 10.3390/biomedicines10010095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/23/2021] [Accepted: 12/30/2021] [Indexed: 12/24/2022] Open
Abstract
The poor prognosis of patients diagnosed with hepatocellular carcinoma (HCC) is directly associated with the multi-step process of tumor metastasis. TWIST1, a basic helix-loop-helix (bHLH) transcription factor, is the most important epithelial-mesenchymal transition (EMT) gene involved in embryonic development, tumor progression, and metastasis. However, the role that TWIST1 gene plays in the process of liver tumor metastasis in vivo is still not well understood. Zebrafish can serve as a powerful model for cancer research. Thus, in this study, we crossed twist1a+ and kras+ transgenic zebrafish, which, respectively, express hepatocyte-specific mCherry and enhanced green fluorescent protein (EGFP); they also drive overexpression of their respective transcription factors. This was found to exacerbate the development of metastatic HCC. Fluorescence of mCherry and EGFP-labeled hepatocytes revealed that approximately 37.5% to 45.5% of the twist1a+/kras+ double transgenic zebrafish exhibited spontaneous tumor metastasis from the liver to the abdomen and tail areas, respectively. We also investigated the inflammatory effects of lipopolysaccharides (LPS) on the hepatocyte-specific co-expression of twist1a+ and kras+ in double transgenic zebrafish. Following LPS exposure, co-expression of twist1a+ and kras+ was found to increase tumor metastasis by 57.8%, likely due to crosstalk with the EMT pathway. Our results confirm that twist1a and kras are important mediators in the development of metastatic HCC. Taken together, our in-vivo model demonstrated that co-expression of twist1a+/kras+ in conjunction with exposure to LPS enhanced metastatic HCC offers a useful platform for the study of tumor initiation and metastasis in liver cancer.
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Affiliation(s)
- Jeng-Wei Lu
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore;
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 10048, Taiwan;
- Correspondence: (J.-W.L.); (Z.G.); Tel.: +65-6516-2860 (Z.G.)
| | - Liang-In Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 10048, Taiwan;
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 10048, Taiwan
| | - Yuxi Sun
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore;
- Brain Research Center, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China;
| | - Dong Liu
- Brain Research Center, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China;
| | - Zhiyuan Gong
- Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore;
- Correspondence: (J.-W.L.); (Z.G.); Tel.: +65-6516-2860 (Z.G.)
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18
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Twist1 Influences the Expression of Leading Members of the IL-17 Signaling Pathway in HER2-Positive Breast Cancer Cells. Int J Mol Sci 2021; 22:ijms222212144. [PMID: 34830027 PMCID: PMC8620489 DOI: 10.3390/ijms222212144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 10/28/2021] [Accepted: 11/04/2021] [Indexed: 12/16/2022] Open
Abstract
Breast cancer (BC) is a heterogeneous disease composed of multiple subtypes with different molecular characteristics and clinical outcomes. The metastatic process in BC depends on the transcription factors (TFs) related to epithelial-mesenchymal transition (EMT), including the master regulator Twist1. However, its role beyond EMT in BC subtypes remains unclear. Our study aimed to investigate the role of Twist1, beyond EMT, in the molecular subtypes of BC. In patients, we observed the overexpression of TWIST1 in the HER2+ group. The silencing of TWIST1 in HER2+ BC cells resulted in the upregulation of 138 genes and the downregulation of 174 genes compared to control cells in a microarray assay. In silico analysis revealed correlations between Twist1 and important biological processes such as the Th17-mediated immune response, suggesting that Twist1 could be relevant for IL-17 signaling in HER2+ BC. IL-17 signaling was then examined, and it was shown that TWIST1 knockdown caused the downregulation of leading members of IL-17 signaling pathway. Taken together, our findings suggest that Twist1 plays a role on IL-17 signaling in HER2+ BC.
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Greco L, Rubbino F, Morelli A, Gaiani F, Grizzi F, de’Angelis GL, Malesci A, Laghi L. Epithelial to Mesenchymal Transition: A Challenging Playground for Translational Research. Current Models and Focus on TWIST1 Relevance and Gastrointestinal Cancers. Int J Mol Sci 2021; 22:11469. [PMID: 34768901 PMCID: PMC8584071 DOI: 10.3390/ijms222111469] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 12/15/2022] Open
Abstract
Resembling the development of cancer by multistep carcinogenesis, the evolution towards metastasis involves several passages, from local invasion and intravasation, encompassing surviving anoikis into the circulation, landing at distant sites and therein establishing colonization, possibly followed by the outgrowth of macroscopic lesions. Within this cascade, epithelial to mesenchymal transition (EMT) works as a pleiotropic program enabling cancer cells to overcome local, systemic, and distant barriers against diffusion by replacing traits and functions of the epithelial signature with mesenchymal-like ones. Along the transition, a full-blown mesenchymal phenotype may not be accomplished. Rather, the plasticity of the program and its dependency on heterotopic signals implies a pendulum with oscillations towards its reversal, that is mesenchymal to epithelial transition. Cells in intermixed E⇔M states can also display stemness, enabling their replication together with the epithelial reversion next to successful distant colonization. If we aim to include the EMT among the hallmarks of cancer that could modify clinical practice, the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers needs to be filled. We review the knowledge on EMT, derived from models and mechanistic studies as well as from translational studies, with an emphasis on gastrointestinal cancers (GI).
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Affiliation(s)
- Luana Greco
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
| | - Federica Rubbino
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
| | - Alessandra Morelli
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
| | - Federica Gaiani
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Fabio Grizzi
- Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy;
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy;
| | - Gian Luigi de’Angelis
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
- Gastroenterology and Endoscopy Unit, University-Hospital of Parma, Via Gramsci 14, 43126 Parma, Italy
| | - Alberto Malesci
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Italy;
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy
| | - Luigi Laghi
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; (L.G.); (F.R.); (A.M.)
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.G.); (G.L.d.)
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Effect of Dickkopf-1 (Dkk-1) and SP600125, a JNK Inhibitor, on Wnt Signaling in Canine Prostate Cancer Growth and Bone Metastases. Vet Sci 2021; 8:vetsci8080153. [PMID: 34437475 PMCID: PMC8402794 DOI: 10.3390/vetsci8080153] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/16/2021] [Accepted: 07/28/2021] [Indexed: 11/17/2022] Open
Abstract
Human Dickkopf-1 (Dkk-1) upregulates a noncanonical Wnt/JNK pathway, resulting in osteoclast stimulation, cell proliferation, and epithelial-to-mesenchymal transition (EMT) of cancer cells. Ace-1-Dkk-1, a canine prostate cancer (PCa) cell line overexpressing Dkk-1, was used to investigate Wnt signaling pathways in PCa tumor growth. SP600125, a JNK inhibitor, was used to examine whether it would decrease tumor growth and bone tumor phenotype in canine PCa cells in vitro and in vivo. Ace-1-VectorYFP-Luc and Ace-1-Dkk-1YFP-Luc cells were transplanted subcutaneously, while Ace-1-Dkk-1YFP-Luc was transplanted intratibially into nude mice. The effects of Dkk-1 and SP600125 on cell proliferation, in vivo tumor growth, and bone tumor phenotype were investigated. The mRNA expression levels of Wnt/JNK-related genes were measured using RT-qPCR. Dkk-1 significantly increased the mRNA expression of Wnt/JNK-signaling-related genes. SP600125 significantly upregulated the mRNA expression of osteoblast differentiation genes and downregulated osteoclastic-bone-lysis-related genes in vitro. SP600125 significantly decreased tumor volume and induced spindle-shaped tumor cells in vivo. Mice bearing intratibial tumors had increased radiographic density of the intramedullary new bone, large foci of osteolysis, and increased cortical lysis with abundant periosteal new bone formation. Finally, SP600125 has the potential to serve as an alternative adjuvant therapy in some early-stage PCa patients, especially those with high Dkk-1 expression.
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Liang H, Dong J, Cheng Z, Li Q, Feng D, Ling B. B-cell receptor-associated protein 31 promotes migration and invasion in ovarian cancer cells. Exp Ther Med 2021; 22:858. [PMID: 34178131 DOI: 10.3892/etm.2021.10290] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 05/10/2021] [Indexed: 12/15/2022] Open
Abstract
B cell receptor associated protein 31 (BAP31) is a member of the B cell receptor that functions as a transporter for numerous types of newly formed proteins from the endoplasmic reticulum to the Golgi apparatus. Previous studies found that that BAP31 serves an important role in the pathogenesis of malignancy but its specific effect on ovarian cancer is not clear. The present study aimed to investigate whether BAP31 affects ovarian cancer and its underlying mechanism. In the present study, ovarian cancer tissue, human ovarian normal epithelial cell line IOSE80 and five ovarian cancer cell lines (A2780, Hey-T30, COC1, SKOV3 and OVCAR3) underwent reverse transcription-quantitative PCR, western blotting, Cell Counting Kit-8, Transwell and co-immunoprecipitation (Co-IP) assay and transcriptome sequencing. Previous studies showed that compared with healthy tissues, the expression level of BAP31 protein was found to be significantly higher in various types of cancer tissues, implying that BAP31 may serve an important role in the pathogenesis of cancer. The present study found that BAP31 expression was upregulated in five ovarian cancer cell lines and ovarian cancer tissue, such that BAP31 knockdown [performed using two short hairpin (sh)RNA plasmids] decreased proliferation, invasion and migration. In addition, BAP31 knockdown was found to downregulate the expression of N-cadherin and upregulate the expression of E-cadherin on transcriptional level by controlling the nuclear aggregation of TWIST1, a transcriptional regulator of N-cadherin and E-cadherin. There was no interaction between BAP31 and E-cadherin or N-cadherin using Co-IP detection, while BAP31, E-cadherin and N-cadherin interacted with TWIST1 protein. E-cadherin and N-cadherin expression levels recovered when TWIST1 was overexpressed in the shBCAP31 cells. These results suggest that BAP31 can regulate the migration and invasion of ovarian cancer cells through the epithelial-mesenchymal transition pathway at the transcriptional level, which may be beneficial for the identification of potentially novel targets for ovarian cancer therapy.
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Affiliation(s)
- Haiyan Liang
- Department of Gynecology and Obstetrics, China-Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Jiqiao Dong
- GeneX Health Life Co., Ltd., Beijing 100195, P.R. China
| | - Ziyan Cheng
- The Experimental High School Attached To Beijing Normal University, Beijing 100032, P.R. China
| | - Qian Li
- Department of Gynecology and Obstetrics, China-Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Dingqing Feng
- Department of Gynecology and Obstetrics, China-Japan Friendship Hospital, Beijing 100029, P.R. China
| | - Bin Ling
- Department of Gynecology and Obstetrics, China-Japan Friendship Hospital, Beijing 100029, P.R. China
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Børretzen A, Gravdal K, Haukaas SA, Mannelqvist M, Beisland C, Akslen LA, Halvorsen OJ. The epithelial-mesenchymal transition regulators Twist, Slug, and Snail are associated with aggressive tumour features and poor outcome in prostate cancer patients. J Pathol Clin Res 2021; 7:253-270. [PMID: 33605548 PMCID: PMC8073012 DOI: 10.1002/cjp2.202] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 12/22/2020] [Accepted: 01/08/2021] [Indexed: 12/17/2022]
Abstract
The prognostic importance of transcription factors promoting epithelial-mesenchymal transition (EMT) and angiogenesis has not been well explored in prostate cancer patients with long follow-up, nor the interplay between these factors. The objective of this study was to assess the individual protein expression and co-expression of Twist, Slug (Snai2), Snail (Snai1), and hypoxia-inducible factor-1 alpha (Hif-1α) in prostate cancer in relation to EMT, angiogenesis, hypoxia, tumour features, disease recurrence, and patient survival. Immunohistochemical staining was performed on tissue microarray sections from 338 radical prostatectomies with long follow-up. In addition, 41 cases of prostatic hyperplasia, 33 non-skeletal metastases, 13 skeletal metastases, and 33 castration-resistant prostate carcinomas were included. Our findings were validated in external gene expression data sets. Twist was overexpressed in primary prostate cancer and markedly reduced in distant metastases (p < 0.0005). Strong expression of Twist and Slug was associated with Hif-1α in localised prostate cancer (p ≤ 0.001), and strong Twist was associated with Hif-1α in castration-resistant carcinomas (p = 0.044). Twist, Slug, and increased Snail at the tumour stromal border were associated with vascular factors (p ≤ 0.045). Each of the three EMT-regulating transcription factors were associated with aggressive tumour features and shorter time to recurrence and cancer-specific death. Notably, the co-expression of factors demonstrated an enhanced influence on outcome. In the subgroup of E-cadherinlow carcinomas, strong Slug was associated with shorter time to all end points and was an independent predictor of time to multiple end points, including cancer-specific death (hazard ratio 3.0, p = 0.041). To conclude, we demonstrate an important relation between EMT, hypoxia, and angiogenesis and a strong link between the investigated EMT regulators and aggressive tumour features and poor patient outcome in prostate cancer. Despite the retrospective nature of this long-term study, our findings could have a significant impact on the future treatment of prostate cancer, where tailored therapies might be directed simultaneously against epithelial-mesenchymal phenotypes, angiogenesis, and tumour hypoxia.
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Affiliation(s)
- Astrid Børretzen
- Centre for Cancer Biomarkers CCBIO, Gade Laboratory for Pathology, Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of PathologyHaukeland University HospitalBergenNorway
| | - Karsten Gravdal
- Department of PathologyHaukeland University HospitalBergenNorway
| | - Svein A Haukaas
- Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of UrologyHaukeland University HospitalBergenNorway
| | - Monica Mannelqvist
- Centre for Cancer Biomarkers CCBIO, Gade Laboratory for Pathology, Department of Clinical MedicineUniversity of BergenBergenNorway
| | - Christian Beisland
- Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of UrologyHaukeland University HospitalBergenNorway
| | - Lars A Akslen
- Centre for Cancer Biomarkers CCBIO, Gade Laboratory for Pathology, Department of Clinical MedicineUniversity of BergenBergenNorway
- Department of PathologyHaukeland University HospitalBergenNorway
| | - Ole J Halvorsen
- Centre for Cancer Biomarkers CCBIO, Gade Laboratory for Pathology, Department of Clinical MedicineUniversity of BergenBergenNorway
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Hu K, Zheng QK, Ma RJ, Ma C, Sun ZG, Zhang N. Krüppel-Like Factor 6 Splice Variant 1: An Oncogenic Transcription Factor Involved in the Progression of Multiple Malignant Tumors. Front Cell Dev Biol 2021; 9:661731. [PMID: 33816511 PMCID: PMC8017371 DOI: 10.3389/fcell.2021.661731] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 02/23/2021] [Indexed: 01/03/2023] Open
Abstract
Krüppel-like factor 6 (KLF6) is one of the most studied members of the specificity protein/Krüppel-like factor (SP/KLF) transcription factor family. It has a typical zinc finger structure and plays a pivotal role in regulating the biological processes of cells. Recently, it has been considered to play a role in combatting cancer. Krüppel-like factor 6 splice variant 1 (KLF6-SV1), being one of the alternative KLF6 splicing isoforms, participates in tumor occurrence and development and has the potential to become a new target for molecular targeted therapy, although its action mechanism remains to be determined. The purpose of this article is to provide a comprehensive and systematic review of the important role of KLF6-SV1 in human malignant tumors to provide novel insights for oncotherapy.
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Affiliation(s)
- Kang Hu
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Qing-Kang Zheng
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Rui-Jie Ma
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chao Ma
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Zhi-Gang Sun
- Department of Thoracic Surgery, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Nan Zhang
- Department of Oncology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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24
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Flores-Huerta N, Silva-Cázares MB, Arriaga-Pizano LA, Prieto-Chávez JL, López-Camarillo C. LncRNAs and microRNAs as Essential Regulators of Stemness in Breast Cancer Stem Cells. Biomolecules 2021; 11:380. [PMID: 33802575 PMCID: PMC7998729 DOI: 10.3390/biom11030380] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/13/2021] [Accepted: 02/22/2021] [Indexed: 12/24/2022] Open
Abstract
Breast cancer is an aggressive disease with a high incidence in women worldwide. Two decades ago, a controversial hypothesis was proposed that cancer arises from a subpopulation of "tumor initiating cells" or "cancer stem cells-like" (CSC). Today, CSC are defined as small subset of somatic cancer cells within a tumor with self-renewal properties driven by the aberrant expression of genes involved in the maintenance of a stemness-like phenotype. The understanding of the underlying cellular and molecular mechanisms involved in the maintenance of CSC subpopulation are fundamental in the development and persistence of breast cancer. Nowadays, the hypothesis suggests that genetic and epigenetic alterations give rise to breast cancer stem cells (bCSC), which are responsible for self-renewal, tumor growth, chemoresistance, poor prognosis and low survival in patients. However, the prominence of bCSC, as well as the molecular mechanisms that regulates and promotes the malignant phenotypes, are still poorly understood. The role of non-coding RNAs (ncRNAs), such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) acting as oncogenes or tumor suppressor genes has been recently highlighted by a plethora of studies in breast cancer. These ncRNAs positively or negatively impact on different signaling pathways that govern the cancer hallmarks associated with bCSC, making them attractive targets for therapy. In this review, we present a current summary of the studies on the pivotal roles of lncRNAs and microRNAs in the regulation of genes associated to stemness of bCSC.
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Affiliation(s)
- Nadia Flores-Huerta
- Laboratorio de Oncogenómica y Proteómica del Cáncer, Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, 03100 CDMX, Mexico;
| | - Macrina B. Silva-Cázares
- Doctorado Institucional en Ingeniería y Ciencias de los Materiales, Universidad Autónoma de San Luis Potosí, 78210 San Luis Potosí, Mexico;
| | - Lourdes A. Arriaga-Pizano
- Unidad de Investigación Médica en Inmunoquímica, Hospital de Especialidades del Centro Médico Siglo XXI, Instituto Mexicano del Seguro Social, 06720 CDMX, Mexico;
| | - Jessica L. Prieto-Chávez
- Laboratorio de Citometría de Flujo, Centro de Instrumentos, Coordinación de Investigación en Salud, Hospital de Especialidades del Centro Médico Siglo XXI, Instituto Mexicano del Seguro Social, 06720 CDMX, Mexico;
| | - César López-Camarillo
- Laboratorio de Oncogenómica y Proteómica del Cáncer, Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, 03100 CDMX, Mexico;
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25
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Twist activates miR-22 to suppress estrogen receptor alpha in breast cancer. Mol Cell Biochem 2021; 476:2295-2306. [PMID: 33582945 DOI: 10.1007/s11010-021-04065-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 01/11/2021] [Indexed: 12/16/2022]
Abstract
TWIST1 (Twist) is a basic helix-loop-helix transcription factor that is overexpressed in many cancers and promotes tumor cell invasion, metastasis, and recurrence. In this study, we demonstrate that Twist upregulates expression of microRNA 22 (miR-22) which, in turn, downregulates estrogen receptor alpha (ER) expression in breast cancer. Initial analysis of miR-22 and Twist expression in a panel of breast cancer cell lines showed a direct correlation between Twist and miR-22 levels with miR-22 being highly expressed in ER negative cell lines. Overexpressing Twist caused increased miR-22 levels while downregulating it led to decreased miR-22 expression. To characterize the upstream promoter region of miR-22, we utilized rapid amplification of cDNA ends and identified the transcription start site and the putative promoter region of miR-22. Mechanistically, we determined that Twist, in combination with HDAC1 and DNMT3B, transcriptionally upregulates miR-22 expression by binding to E-boxes in the proximal miR-22 promoter. We also established that miR-22 causes an increase in growth in 3D but not 2D cultures. Importantly, we observed a direct correlation between increased breast cancer grade and Twist and miR-22 expression. We also identified two potential miR-22 binding sites in the 3'-UTR region of ER and confirmed by promoter assays that miR-22 regulates ER expression by binding to both target sites. These results reveal a novel pathway of ER suppression by Twist through miR-22 activation that could potentially promote the ER negative phenotype in breast cancers.
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26
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Ghafouri-Fard S, Abak A, Bahroudi Z, Shoorei H, Abbas Raza SH, Taheri M. The interplay between non-coding RNAs and Twist1 signaling contribute to human disorders. Biomed Pharmacother 2021; 135:111220. [PMID: 33433357 DOI: 10.1016/j.biopha.2021.111220] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 12/23/2020] [Accepted: 12/31/2020] [Indexed: 12/14/2022] Open
Abstract
Twist-related protein 1 (Twist1) is a basic helix-loop-helix (bHLH) transcription factor (TF) being coded by the TWIST1 gene. This TF has a fundamental effect on the normal development and in the pathogenesis of various diseases especially cancer. Twist1 has interactions with some long non-coding RNAs and miRNAs. The interactions between this TF and various miRNAs such as miR-16, miR-26b-5p, miR-1271, miR-539, miR-214, miR-200b/c, miR-335, miR-10b, and miR-381 are implicated in the carcinogenic processes. TP73-AS1, LINC01638, ATB, NONHSAT101069, CASC15, H19, PVT1, LINC00339, LINC01385, TANAR, SNHG5, DANCR, CHRF, and TUG1 are among long non-coding RNAs which interact with Twist1 and participate in the carcinogenesis. This review aims at depicting the interaction between these non-coding transcripts and Twist1 and the consequence of these interactions in human neoplasms.
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Affiliation(s)
- Soudeh Ghafouri-Fard
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atefe Abak
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Bahroudi
- Department of Anatomical Sciences, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamed Shoorei
- Department of Anatomical Sciences, Faculty of Medicine, Biranjd University of Medical Sciences, Birjand, Iran
| | - Sayed Haidar Abbas Raza
- College of Animal Science and Technology, Northwest A&F University, Yangling, Xianyang, China
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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27
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Tang H, Zheng J, Bai X, Yue KL, Liang JH, Li DY, Wang LP, Wang JL, Guo Q. Forkhead Box Q1 Is Critical to Angiogenesis and Macrophage Recruitment of Colorectal Cancer. Front Oncol 2020; 10:564298. [PMID: 33330033 PMCID: PMC7734287 DOI: 10.3389/fonc.2020.564298] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 10/23/2020] [Indexed: 12/14/2022] Open
Abstract
Angiogenesis and the tumor microenvironment (TME) play important roles in tumorigenesis. Forkhead box Q1 (FOXQ1) is a well-established oncogene in multiple tumors, including colorectal cancer (CRC); however, whether FOXQ1 contributes to angiogenesis and TME modification in CRC remains largely uncharacterized. Here, we demonstrate an essential role of FOXQ1-induced angiogenesis and macrophage recruitment in CRC that is related to its ability to promote the migration of endothelial cells and macrophages through activation of the EGF/PDGF pathway and the Twist1/CCL2 axis. We also provide evidence showing that the clinical significance between FOXQ1, Twist1, CCL2, and macrophage infiltration is associated with reduced 8-year survival in CRC patients. Our findings suggest FOXQ1 plays critical roles in the malignancy and progression of CRC, Therefore, FOXQ1 may serve as a therapeutic target for inhibiting angiogenesis and reducing macrophage recruitment in CRC.
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Affiliation(s)
- Hui Tang
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Ji Zheng
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
- Genetic Testing Center, Qingdao Women and Children’s Hospital, Qingdao, China
| | - Xuan Bai
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Ke-Lin Yue
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Jian-Hua Liang
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Dan-Yang Li
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Lin-Ping Wang
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Jin-Li Wang
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Qiang Guo
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, The First People’s Hospital of Yunnan Province, Kunming, China
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
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Ertosun MG, PehlİvanoĞlu S, DİlmaÇ S, TanriÖver G, ÖzeŞ ON. AKT-mediated phosphorylation of TWIST1 is essential for breast cancer cell metastasis. ACTA ACUST UNITED AC 2020; 44:158-165. [PMID: 32922123 PMCID: PMC7478131 DOI: 10.3906/biy-1912-74] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Previously, it was shown that human TWIST1 (basic helix-loop-helix (b-HLH) is phosphorylated by Akt kinase at S42, T121, and S123. To show in vivo effect of these phosphorylations, we created mouse TWIST1 expression vector and converted the codons of S42, T125, and S127 to unphosphorylatable alanine and phosphorylation mimicking Glutamic acid. We hypothesized that alanine mutants would inhibit the metastatic ability of 4T1 cells while glutamic acid mutants would convert nonmetastatic 67NR cells into metastatic phenotype. To confirm this hypothesis, we created metastatic 4T1 and nonmetastatic 67NR cells expressing alanine mutants and glutamic acid mutants mouse TWIST1, respectively. Then, we injected 1 × 106 67NR and 1 × 105 4T1 cells overexpressing mutants of TWIST1 into the breast tissue of BALB/c mice. At the end of the 4th week, we sacrificed the animals, determined the numbers of tumors at lungs and liver. Although 67NR cells overexpressing wild-type TWIST1 did not show any metastasis, cells overexpressing S42E and T125E mutants showed 15–30 macroscopic metastasis to liver and lungs. Parallel to this, 4T1 cells expressing S42A and T125A mutants of TWIST1 showed no macroscopic metastasis. Our results indicate that phosphorylation of S42 and T125 by AKT is essential for TWIST1-mediated tumor growth and metastasis.
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Affiliation(s)
- Mustafa Gökhan Ertosun
- Department Plastic, Reconstructive and Aesthetic Surgery, Faculty of Medicine, Akdeniz University, Antalya Turkey
| | - Suray PehlİvanoĞlu
- Department of Molecular Biology, Faculty of Science, Necmettin Erbakan University, Konya Turkey
| | - Sayra DİlmaÇ
- Department of Histology and Embryology, Faculty of Medicine, Akdeniz University, Antalya Turkey
| | - Gamze TanriÖver
- Department of Histology and Embryology, Faculty of Medicine, Akdeniz University, Antalya Turkey
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Holmes G, Gonzalez-Reiche AS, Lu N, Zhou X, Rivera J, Kriti D, Sebra R, Williams AA, Donovan MJ, Potter SS, Pinto D, Zhang B, van Bakel H, Jabs EW. Integrated Transcriptome and Network Analysis Reveals Spatiotemporal Dynamics of Calvarial Suturogenesis. Cell Rep 2020; 32:107871. [PMID: 32640236 PMCID: PMC7379176 DOI: 10.1016/j.celrep.2020.107871] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 05/14/2020] [Accepted: 06/15/2020] [Indexed: 11/28/2022] Open
Abstract
Craniofacial abnormalities often involve sutures, the growth centers of the skull. To characterize the organization and processes governing their development, we profile the murine frontal suture, a model for sutural growth and fusion, at the tissue- and single-cell level on embryonic days (E)16.5 and E18.5. For the wild-type suture, bulk RNA sequencing (RNA-seq) analysis identifies mesenchyme-, osteogenic front-, and stage-enriched genes and biological processes, as well as alternative splicing events modifying the extracellular matrix. Single-cell RNA-seq analysis distinguishes multiple subpopulations, of which five define a mesenchyme-osteoblast differentiation trajectory and show variation along the anteroposterior axis. Similar analyses of in vivo mouse models of impaired frontal suturogenesis in Saethre-Chotzen and Apert syndromes, Twist1+/- and Fgfr2+/S252W, demonstrate distinct transcriptional changes involving angiogenesis and ribogenesis, respectively. Co-expression network analysis reveals gene expression modules from which we validate key driver genes regulating osteoblast differentiation. Our study provides a global approach to gain insights into suturogenesis.
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Affiliation(s)
- Greg Holmes
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Ana S Gonzalez-Reiche
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Na Lu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Xianxiao Zhou
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Joshua Rivera
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Divya Kriti
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Robert Sebra
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Anthony A Williams
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Michael J Donovan
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - S Steven Potter
- Division of Developmental Biology, Cincinnati Children's Medical Center, Cincinnati, OH 45229, USA
| | - Dalila Pinto
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, and Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Harm van Bakel
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Ethylin Wang Jabs
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Cell, Developmental and Regenerative Biology and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Blocking C-Raf alleviated high-dose small-volume radiation-induced epithelial mesenchymal transition in mice lung. Sci Rep 2020; 10:11158. [PMID: 32636458 PMCID: PMC7341876 DOI: 10.1038/s41598-020-68175-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 06/12/2020] [Indexed: 11/08/2022] Open
Abstract
The goal of this study was to develop a potential druggable target for lung injury after SABR through the small animal model. Utilising the model, a radiation dose of 70 Gy or 90 Gy was focally (small volume) delivered to the left lung of mice. The highly expressed phosphorylation form of C-Raf was discovered through a protein array experiment, with the protein being extracted from the area of radiated mouse lung tissue, and was confirmed by IHC and western blot. C-Raf activation, along with morphological change and EMT (Epithelial to Mesenchymal Transition) marker expression, was observed after radiation to the mouse type II alveolar cell line MLE-12. C-Raf inhibitor GW5074 was able to reverse the EMT in cells effectively, and was found to be dependent on Twist1 expression. In the animal experiment, pretreatment of GW5074 alleviated EMT and lung injury after 70 Gy radiation was focally delivered to the lung of mice. Conclusively, these results demonstrate that C-Raf inhibitor GW5074 inhibits high-dose small-volume radiation-induced EMT via the C-Raf/Twist1 signalling pathway in mice. Therefore, pharmacological C-Raf inhibitors may be used effectively as inhibitors of SABR-induced lung fibrosis.
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Khot M, Sreekumar D, Jahagirdar S, Kulkarni A, Hari K, Faseela EE, Sabarinathan R, Jolly MK, Sengupta K. Twist1 induces chromosomal instability (CIN) in colorectal cancer cells. Hum Mol Genet 2020; 29:1673-1688. [PMID: 32337580 PMCID: PMC7322571 DOI: 10.1093/hmg/ddaa076] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 04/22/2020] [Accepted: 04/22/2020] [Indexed: 12/22/2022] Open
Abstract
Twist1 is a basic helix-loop-helix transcription factor, essential during early development in mammals. While Twist1 induces epithelial-to-mesenchymal transition (EMT), here we show that Twist1 overexpression enhances nuclear and mitotic aberrations. This is accompanied by an increase in whole chromosomal copy number gains and losses, underscoring the role of Twist1 in inducing chromosomal instability (CIN) in colorectal cancer cells. Array comparative genomic hybridization (array CGH) analysis further shows sub-chromosomal deletions, consistent with an increased frequency of DNA double strand breaks (DSBs). Remarkably, Twist1 overexpression downmodulates key cell cycle checkpoint factors-Bub1, BubR1, Mad1 and Mad2-that regulate CIN. Mathematical simulations using the RACIPE tool show a negative correlation of Twist1 with E-cadherin and BubR1. Data analyses of gene expression profiles of patient samples from The Cancer Genome Atlas (TCGA) reveal a positive correlation between Twist1 and mesenchymal genes across cancers, whereas the correlation of TWIST1 with CIN and DSB genes is cancer subtype-specific. Taken together, these studies highlight the mechanistic involvement of Twist1 in the deregulation of factors that maintain genome stability during EMT in colorectal cancer cells. Twist1 overexpression enhances genome instability in the context of EMT that further contributes to cellular heterogeneity. In addition, these studies imply that Twist1 downmodulates nuclear lamins that further alter spatiotemporal organization of the cancer genome and epigenome. Notwithstanding their genetic background, colorectal cancer cells nevertheless maintain their overall ploidy, while the downstream effects of Twist1 enhance CIN and DNA damage enriching for sub-populations of aggressive cancer cells.
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Affiliation(s)
- Maithilee Khot
- B-216, Chromosome Biology Lab (CBL), Indian Institute of Science Education and Research (IISER), Dr Homi Bhabha Road, Pashan, Pune 411008, India
| | - Dyuthi Sreekumar
- B-216, Chromosome Biology Lab (CBL), Indian Institute of Science Education and Research (IISER), Dr Homi Bhabha Road, Pashan, Pune 411008, India
| | - Sanika Jahagirdar
- B-216, Chromosome Biology Lab (CBL), Indian Institute of Science Education and Research (IISER), Dr Homi Bhabha Road, Pashan, Pune 411008, India
| | - Apoorva Kulkarni
- B-216, Chromosome Biology Lab (CBL), Indian Institute of Science Education and Research (IISER), Dr Homi Bhabha Road, Pashan, Pune 411008, India
| | - Kishore Hari
- Center for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru 560012, India
| | | | - Radhakrishnan Sabarinathan
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru 560065, India
| | - Mohit Kumar Jolly
- Center for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru 560012, India
| | - Kundan Sengupta
- B-216, Chromosome Biology Lab (CBL), Indian Institute of Science Education and Research (IISER), Dr Homi Bhabha Road, Pashan, Pune 411008, India
- To whom correspondence should be addressed at: B-216, Chromosome Biology Lab (CBL), Indian Institute of Science Education and Research (IISER), Dr Homi Bhabha Road, Pashan, Pune 411008, India. Tel: +91 20 25908071; Fax: +91-20-20251566;
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Intrinsic and Extrinsic Factors Governing the Transcriptional Regulation of ESR1. Discov Oncol 2020; 11:129-147. [PMID: 32592004 DOI: 10.1007/s12672-020-00388-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Accepted: 06/02/2020] [Indexed: 02/06/2023] Open
Abstract
Transcriptional regulation of ESR1, the gene that encodes for estrogen receptor α (ER), is critical for regulating the downstream effects of the estrogen signaling pathway in breast cancer such as cell growth. ESR1 is a large and complex gene that is regulated by multiple regulatory elements, which has complicated our understanding of how ESR1 expression is controlled in the context of breast cancer. Early studies characterized the genomic structure of ESR1 with subsequent studies focused on identifying intrinsic (chromatin environment, transcription factors, signaling pathways) and extrinsic (tumor microenvironment, secreted factors) mechanisms that impact ESR1 gene expression. Currently, the introduction of genomic sequencing platforms and additional genome-wide technologies has provided additional insight on how chromatin structures may coordinate with these intrinsic and extrinsic mechanisms to regulate ESR1 expression. Understanding these interactions will allow us to have a clearer understanding of how ESR1 expression is regulated and eventually provide clues on how to influence its regulation with potential treatments. In this review, we highlight key studies concerning the genomic structure of ESR1, mechanisms that affect the dynamics of ESR1 expression, and considerations towards affecting ESR1 expression and hormone responsiveness in breast cancer.
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Li QH, Liu ZZ, Ge YΝ, Liu X, Xie XD, Zheng ZD, Ma YH, Liu B. Small breast epithelial mucin promotes the invasion and metastasis of breast cancer cells via promoting epithelial‑to‑mesenchymal transition. Oncol Rep 2020; 44:509-518. [PMID: 32627029 PMCID: PMC7336452 DOI: 10.3892/or.2020.7640] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 04/23/2020] [Indexed: 01/13/2023] Open
Abstract
The aim of the present study was to observe the influence of the small breast epithelial mucin (MUCL1) (also known as SBEM) gene on migration and invasion ability of breast cancer cells and to explore the potentially involved mechanism. SBEM‑interference plasmid and SBEM‑overexpressing plasmid were constructed. SBEM‑knockdown or SBEM‑overexpressing MCF‑7 and MDA‑MB‑231 breast cancer cells were established by lentivirus‑mediated stable transfection method. The scratch wound‑healing assay and Transwell chamber experiment were used to detect the influence of the SBEM gene on the migration and invasion abilities of MCF‑7 and MDA‑MB‑231 cells. Real‑time PCR (polymerase chain reaction) and western blotting were used to detect the expression of epithelial‑to‑mesenchymal transition (EMT)‑related markers and regulators. The cell morphology was observed after transfection. The SBEM‑knockdown or SBEM‑overexpressing MCF‑7 and MDA‑MB‑231 cells were established successfully. The migration and invasion abilities were decreased after SBEM was downregulated, and were increased after SBEM was overexpressed both in MCF‑7 and MDA‑MB‑231 cell lines. The mRNA and protein expressions of N‑cadherin, Twist and vimentin were elevated following SBEM overexpression, while the expression of E‑cadherin and claudin‑1 were found to be decreased following SBEM overexpression. In conclusion, SBEM has the potential to promote migration and invasion ability of breast cancer cells via promoting epithelial‑to‑mesenchymal transition.
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Affiliation(s)
- Qiu-Hua Li
- Oncology Department, The Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110034, P.R. China
| | - Zhao-Zhe Liu
- Oncology Department, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, P.R. China
| | - Ya-Νan Ge
- Oncology Department, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, P.R. China
| | - Xing Liu
- Oncology Department, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, P.R. China
| | - Xiao-Dong Xie
- Oncology Department, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, P.R. China
| | - Zhen-Dong Zheng
- Oncology Department, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, P.R. China
| | - Yue-Hai Ma
- Oncology Department, The Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning 110034, P.R. China
| | - Bin Liu
- Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning 110042, P.R. China
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Li C, Chen Y, Zhang Q, Guo C, Chen F, Xi S, Zeng J, Ke C, Sharma HS, Chen Z. Expression of Twist associated to microcirculation patterns of human glioma correlated with progression and survival of the patient. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 151:201-217. [PMID: 32448608 DOI: 10.1016/bs.irn.2020.03.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Twist is a transcription factor involved in the process of epithelial to mesenchymal transition (EMT) of carcinoma cells, and the promotion of invasion of gliomas through the mesenchymal adjusting process. However, its clinical significance in human glioma has not yet to be understood. To delineate the clinical-pathological significance and prognostic value of Twist, the expression of Twist was evaluated by Immunohistochemistry for 187 glioma samples. We found that Twist demonstrated frequent nuclear expression in the glioma samples and its expression levels were associated with tumor grade (P<0.001). Furthermore, high Twist expression was correlated with a poor outcome in patients with glioma (P=0.001), particularly with high grade glioma (P=0.026). Interestingly, Twist expression showed positive correlation with microvascular density (MVD) (r=0.145, P=0.048) as well as vasculogenic mimicry (VM) (r=0.273, P<0.001) in the tumors. These results suggest that Twist could be a predictor for poor prognosis in glioma patients. Additionally, Twist expression was associated with two major microcirculation patterns: endothelial-dependent vessels and VM in glioma, indicating that Twist could be a potential molecular target for anti-glioma therapy.
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Affiliation(s)
- Cong Li
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yinsheng Chen
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Qingping Zhang
- Department of Neurosurgery, Shenzhen Nanshan People's Hospital (Shenzhen University Sixth Affiliated Hospital), Shenzhen, China
| | - Chengcheng Guo
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Furong Chen
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Shaoyan Xi
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jing Zeng
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chao Ke
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, University Hospital, Uppsala University, S-75185 Uppsala, Sweden.
| | - Zhongping Chen
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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Mammoto A, Hendee K, Muyleart M, Mammoto T. Endothelial Twist1-PDGFB signaling mediates hypoxia-induced proliferation and migration of αSMA-positive cells. Sci Rep 2020; 10:7563. [PMID: 32371931 PMCID: PMC7200682 DOI: 10.1038/s41598-020-64298-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 04/10/2020] [Indexed: 02/01/2023] Open
Abstract
Remodeling of distal pulmonary arterioles (PAs) associated with marked accumulation of pulmonary artery smooth muscle cells (PASMCs) represents one of the major pathologic features of pulmonary hypertension (PH). We have reported that the transcription factor Twist1 mediates hypoxia-induced PH. However, the mechanism by which endothelial Twist1 stimulates SMC accumulation to distal PAs in PH remains unclear. Here, we have demonstrated that Twist1 overexpression increases the expression of platelet-derived growth factor (PDGFB) in human pulmonary arterial endothelial (HPAE) cells. Hypoxia upregulates the levels of Twist1 and PDGFB in HPAE cells. When we implant hydrogel supplemented with endothelial cells (ECs) on the mouse lung, these ECs form vascular lumen structures and hypoxia upregulates PDGFB expression and stimulates accumulation of αSMA–positive cells in the gel, while knockdown of endothelial Twist1 suppresses the effects. The levels of Twist1 and PDGFB are higher in PAE cells isolated from idiopathic pulmonary arterial hypertension (IPAH) patients compared to those from healthy controls. IPAH patient-derived PAE cells stimulate accumulation of αSMA–positive cells in the implanted gel, while Twist1 knockdown in PAE cells inhibits the effects. Endothelial Twist1-PDGFB signaling plays a key role in αSMA–positive cell proliferation and migration in PH.
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Affiliation(s)
- Akiko Mammoto
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, 53226, United States. .,Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, United States.
| | - Kathryn Hendee
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, 53226, United States
| | - Megan Muyleart
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, 53226, United States
| | - Tadanori Mammoto
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, 53226, United States.
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36
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Bialkowska K, Sossey-Alaoui K, Pluskota E, Izem L, Qin J, Plow EF. Site-specific phosphorylation regulates the functions of kindlin-3 in a variety of cells. Life Sci Alliance 2020; 3:3/3/e201900594. [PMID: 32024667 PMCID: PMC7010036 DOI: 10.26508/lsa.201900594] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 01/22/2020] [Accepted: 01/23/2020] [Indexed: 12/12/2022] Open
Abstract
Studies of isolated cells, mice, and humans have demonstrated the vital role of the FERM domain protein kindlin-3 in integrin activation in certain hematopoietic and non-hematopoietic cells, consequent to binding to integrin β-subunits. To explore regulatory mechanisms, we developed a monoclonal antibody that selectively recognizes the phosphorylated form of Ser484 (pS484) in kindlin-3. Activation of platelets, HEL megakaryocytic-like cells and BT549 breast cancer cells led to enhanced expression of pS484 as assessed by immunofluorescence or Western blotting. In platelets, pS484 rose rapidly and transiently upon stimulation. When a mutant form of kindlin-3, T482S484/AA kindlin-3, was transduced into mouse megakaryocytes, it failed to support activation of integrin αIIbβ3, whereas wild-type kindlin-3 did. In MDA-MB231 breast cancer cells, expression of T482S484/AA kindlin-3 suppressed cell spreading, migration, invasion, and VEGF production. Wild-type kindlin-3 expressing cells markedly increased tumor growth in vivo, whereas T482S484/AA kindlin-3 significantly blunted tumor progression. Thus, our data establish that a unique phosphorylation event in kindlin-3 regulates its cellular functions.
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Affiliation(s)
- Katarzyna Bialkowska
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA
| | - Khalid Sossey-Alaoui
- Department of Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Elzbieta Pluskota
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA
| | - Lahoucine Izem
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA
| | - Jun Qin
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA
| | - Edward F Plow
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA
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Cheong CM, Mrozik KM, Hewett DR, Bell E, Panagopoulos V, Noll JE, Licht JD, Gronthos S, Zannettino ACW, Vandyke K. Twist-1 is upregulated by NSD2 and contributes to tumour dissemination and an epithelial-mesenchymal transition-like gene expression signature in t(4;14)-positive multiple myeloma. Cancer Lett 2020; 475:99-108. [PMID: 32014459 DOI: 10.1016/j.canlet.2020.01.040] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 01/28/2020] [Accepted: 01/29/2020] [Indexed: 12/11/2022]
Abstract
Approximately 15% of patients with multiple myeloma (MM) harbour the t(4;14) chromosomal translocation, leading to the overexpression of the histone methyltransferase NSD2. Patients with this translocation display increased tumour dissemination, accelerated disease progression and rapid relapse. Using publicly available gene expression profile data from NSD2high (n = 135) and NSD2low (n = 878) MM patients, we identified 39 epithelial-mesenchymal transition (EMT)-associated genes which are overexpressed in NSD2high MM plasma cells. In addition, our analyses identified Twist-1 as a key transcription factor upregulated in NSD2high MM patients and t(4;14)-positive cell lines. Overexpression and knockdown studies confirmed that Twist-1 is involved in driving the expression of EMT-associated genes in the human MM cell line KMS11 and promoted the migration of myeloma cell lines in vitro. Notably, Twist-1 overexpression in the mouse MM cell line 5TGM1 significantly increased tumour dissemination in an intratibial tumour model. These findings demonstrate that Twist-1, downstream of NSD2, contributes to the induction of an EMT-like signature in t(4;14)-positive MM and enhances the dissemination of MM plasma cells in vivo, which may, in part, explain the aggressive disease features associated with t(4;14)-positive MM.
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Affiliation(s)
- Chee Man Cheong
- Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia
| | - Krzysztof M Mrozik
- Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia
| | - Duncan R Hewett
- Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia
| | - Elyse Bell
- Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia
| | - Vasilios Panagopoulos
- Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia
| | - Jacqueline E Noll
- Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia
| | - Jonathan D Licht
- Departments of Medicine, Biochemistry and Molecular Biology and University of Florida Health Cancer Center, The University of Florida, Gainesville, FL, USA
| | - Stan Gronthos
- Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia; Mesenchymal Stem Cell Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia
| | - Andrew C W Zannettino
- Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia
| | - Kate Vandyke
- Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, Australia.
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Ruan Y, Dong W, Kang L, Lei X, Zhang R, Wang F, Zhu X. The Changes of Twist1 Pathway in Pulmonary Microvascular Permeability in a Newborn Rat Model of Hyperoxia-Induced Acute Lung Injury. Front Pediatr 2020; 8:190. [PMID: 32391293 PMCID: PMC7190807 DOI: 10.3389/fped.2020.00190] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 03/31/2020] [Indexed: 01/12/2023] Open
Abstract
Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm infants, which is characterized by alveolar and vascular dysplasia and increased vascular permeability. Hyperoxia is a critical factor in the pathogenesis of BPD, hyperoxia-induced acute lung injury (HALI) model has similar pathological manifestations as human BPD, therefore, may provide insight into the pathogenesis of human BPD. Studies have shown that Twist1 regulates pulmonary vascular permeability of LPS-induced lung injury through the Ang-Tie2 pathway. However, the effect of Twist1 pathway on vascular permeability in HALI has not been reported. Methods: We randomly exposed newborn rats to the room air or hyperoxia for 14 days. Lung histopathology, immunofluorescence, vascular permeability, mRNA and protein expression was assessed on day 1,7,14. Results: Our results verified that hyperoxia caused alveolar and vascular developmental disorders and increased pulmonary vascular permeability, which was consistent with previous findings. In hyperoxia-exposed rat lungs, the expressions of Twist1, Ang1, Tie1, Tie2, and pTie2 were significantly reduced, whereas the expression of Ang2 was significantly increased. Next, we observed a significant down-regulation of the Akt/Foxo1 pathway. Conclusion: In HALI, the pulmonary microvascular permeability was increased, accompanied by changes in Twist1-Tie2 pathway which combined to Angs, and downregulation of Tie1 and Akt/Foxo1 pathway.
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Affiliation(s)
- Ying Ruan
- Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wenbin Dong
- Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lan Kang
- Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiaoping Lei
- Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Rong Zhang
- Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Fan Wang
- Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiaodan Zhu
- Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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Wang H, Li JM, Wei W, Yang R, Chen D, Ma XD, Jiang GM, Wang BL. Regulation of ATP-binding cassette subfamily B member 1 by Snail contributes to chemoresistance in colorectal cancer. Cancer Sci 2019; 111:84-97. [PMID: 31774615 PMCID: PMC6942434 DOI: 10.1111/cas.14253] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 10/15/2019] [Accepted: 10/31/2019] [Indexed: 12/18/2022] Open
Abstract
Although accumulating evidence has indicated the intimate association between epithelial‐mesenchymal transition (EMT) and acquired resistance to chemotherapy for colorectal cancer (CRC), the underlying mechanisms remain elusive. Herein, we reported that Snail, a crucial EMT controller, was upregulated in CRC tissues. Colorectal cancer cells overexpressing Snail were found to be more resistant to 5‐fluorouracil (5‐Fu). Mechanistic studies reveal that Snail could increase the expression of ATP‐binding cassette subfamily B member 1 (ABCB1) rather than the other 23 chemoresistance‐related genes. Additionally, knockdown of ABCB1 significantly attenuated Snail‐induced 5‐Fu resistance in CRC cells. Oxaliplatin increased Snail and ABCB1 expression in CRC cells. Snail and ABCB1 were upregulated in 5‐Fu‐resistant HCT‐8 (HCT‐8/5‐Fu) cells and inhibition of Snail decreased ABCB1 in HCT‐8/5‐Fu cells. These results confirm the vital role played by ABCB1 in Snail‐induced chemoresistance. Further investigation into the relevant molecular mechanism revealed Snail‐mediated ABCB1 upregulation was independent of β‐catenin, STAT3, PXR, CAR and Foxo3a, which are commonly involved in modulating ABCB1 transcription. Instead, Snail upregulated ABCB1 transcription by directly binding to its promoter. Clinical analysis confirms that increased Snail expression correlated significantly with tumor size (P = .018), lymph node metastasis (P = .033), distant metastasis (P = .025), clinical stage grade (P = .024), and poor prognosis (P = .045) of CRC patients. Moreover, coexpression of Snail and ABCB1 was observed in CRC patients. Our study revealed that direct regulation of ABCB1 by Snail was critical for conferring chemoresistance in CRC cells. These findings unraveled the mechanisms underlying the association between EMT and chemoresistance, and provided potential targets for CRC clinical treatment.
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Affiliation(s)
- Hao Wang
- Division of Life Sciences and Medicine, Department of Clinical Laboratory, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Ji-Min Li
- Division of Life Sciences and Medicine, Department of Clinical Laboratory, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Wei Wei
- Division of Life Sciences and Medicine, Department of Clinical Laboratory, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Rui Yang
- Division of Life Sciences and Medicine, Department of Clinical Laboratory, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Dong Chen
- School of Bengbu Medical College, Bengbu, China
| | - Xiao-Dong Ma
- Department of Medicinal Chemistry, School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.,Department of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei, China
| | - Guan-Min Jiang
- Department of Clinical Laboratory, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China
| | - Bao-Long Wang
- Division of Life Sciences and Medicine, Department of Clinical Laboratory, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
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40
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Ma L, Zhang Z, Dong K, Ma Y. TWIST1 Alleviates Hypoxia-induced Damage of Trophoblast Cells by inhibiting mitochondrial apoptosis pathway. Exp Cell Res 2019; 385:111687. [DOI: 10.1016/j.yexcr.2019.111687] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 10/21/2019] [Accepted: 10/23/2019] [Indexed: 11/28/2022]
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Georgess D, Padmanaban V, Sirka OK, Coutinho K, Choi A, Frid G, Neumann NM, Inoue T, Ewald AJ. Twist1-Induced Epithelial Dissemination Requires Prkd1 Signaling. Cancer Res 2019; 80:204-218. [PMID: 31676574 DOI: 10.1158/0008-5472.can-18-3241] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 08/02/2019] [Accepted: 10/28/2019] [Indexed: 12/19/2022]
Abstract
Dissemination is an essential early step in metastasis but its molecular basis remains incompletely understood. To define the essential targetable effectors of this process, we developed a 3D mammary epithelial culture model, in which dissemination is induced by overexpression of the transcription factor Twist1. Transcriptomic analysis and ChIP-PCR together demonstrated that protein kinase D1 (Prkd1) is a direct transcriptional target of Twist1 and is not expressed in the normal mammary epithelium. Pharmacologic and genetic inhibition of Prkd1 in the Twist1-induced dissemination model demonstrated that Prkd1 was required for cells to initiate extracellular matrix (ECM)-directed protrusions, release from the epithelium, and migrate through the ECM. Antibody-based protein profiling revealed that Prkd1 induced broad phosphorylation changes, including an inactivating phosphorylation of β-catenin and two microtubule depolymerizing phosphorylations of Tau, potentially explaining the release of cell-cell contacts and persistent activation of Prkd1. In patients with breast cancer, TWIST1 and PRKD1 expression correlated with metastatic recurrence, particularly in basal breast cancer. Prkd1 knockdown was sufficient to block dissemination of both murine and human mammary tumor organoids. Finally, Prkd1 knockdown in vivo blocked primary tumor invasion and distant metastasis in a mouse model of basal breast cancer. Collectively, these data identify Prkd1 as a novel and targetable signaling node downstream of Twist1 that is required for epithelial invasion and dissemination. SIGNIFICANCE: Twist1 is a known regulator of metastatic cell behaviors but not directly targetable. This study provides a molecular explanation for how Twist1-induced dissemination works and demonstrates that it can be targeted. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/2/204/F1.large.jpg.
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Affiliation(s)
- Dan Georgess
- Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland. .,Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, Beirut, Lebanon
| | - Veena Padmanaban
- Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Orit Katarina Sirka
- Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kester Coutinho
- Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Alex Choi
- Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Gabriela Frid
- Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Neil M Neumann
- Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Takanari Inoue
- Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Andrew J Ewald
- Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland. .,Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Cancer Invasion and Metastasis Program, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205
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The TWIST1-centered competing endogenous RNA network promotes proliferation, invasion, and migration of lung adenocarcinoma. Oncogenesis 2019; 8:62. [PMID: 31645542 PMCID: PMC6811597 DOI: 10.1038/s41389-019-0167-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 09/11/2019] [Accepted: 09/13/2019] [Indexed: 12/24/2022] Open
Abstract
The proposed competing endogenous RNA (ceRNA) mechanism suggested that diverse RNA species, including protein-coding messenger RNAs and non-coding RNAs such as long non-coding RNAs, pseudogenes and circular RNAs could communicate with each other by competing for binding to shared microRNAs. The ceRNA network (ceRNET) is involved in tumor progression and has become a hot research topic in recent years. To date, more attention has been paid to the role of non-coding RNAs in ceRNA crosstalk. However, coding transcripts are more abundant and powerful than non-coding RNAs and make up the majority of miRNA targets. In this study, we constructed a mRNA-mRNA related ceRNET of lung adenocarcinoma (LUAD) and identified the highlighted TWIST1-centered ceRNET, which recruits SLC12A5 and ZFHX4 as its ceRNAs. We found that TWIST1/SLC12A5/ZFHX4 are all upregulated in LUAD and are associated with poorer prognosis. SLC12A5 and ZFHX4 facilitated proliferation, migration, and invasion in vivo and in vitro, and their effects were reversed by miR-194–3p and miR-514a-3p, respectively. We further verified that SLC12A5 and ZFHX4 affected the function of TWIST1 by acting as ceRNAs. In summary, we constructed a mRNA-mRNA related ceRNET for LUAD and highlighted the well-known oncogene TWIST1. Then we verified that SLC12A5 and ZFHX4 exert their oncogenic function by regulating TWIST1 expression through a ceRNA mechanism.
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Zhang YQ, Chen WL, Zhang F, Wei XL, Zeng D, Liang YK, Wu JD, Zhang LY, Guo CP, Zeng HC, Hao SS, Li RH, Huang WH, Zhang GJ. Over-expression of both VEGF-C and Twist predicts poor prognosis in human breast cancer. Clin Transl Oncol 2019; 21:1250-1259. [PMID: 30788837 DOI: 10.1007/s12094-019-02051-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 01/24/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Angiogenesis is an indispensable step in the growth and invasiveness of breast cancers involving a series of exquisite molecular steps. Pro-angiogenic factors, including vascular endothelial growth factor (VEGF), have been recognized as pivotal therapeutic targets in the treatment of breast cancer. More recently, a highly conserved transcription factor Twist has been reported to be involved in tumor angiogenesis and metastasis. METHODS The expression of VEGF-C and Twist was immunohistochemically determined in tissue samples of primary tumors from 408 patients undergoing curative surgical resection for breast cancer. The correlations of VEGF-C and Twist expressions with clinicopathologic parameters as well as survival outcomes were evaluated. RESULTS Of the 408 patients evaluated, approximately 70% had high expression of VEGF-C which was significantly associated with advanced tumor stages (P = 0.019). Similarly, VEGF-C expression was associated with the proliferation index Ki67, N3 lymph node metastasis, and D2-40-positive lymphatic vessel invasion (LVI) in a univariate analysis. Furthermore, patients with high expressions of VEGF-C and Twist (V + T+) had significantly increased lymph node metastasis, higher clinical stage, and worse disease-free survival, DFS (P = 0.001) and overall survival, OS (P = 0.011). CONCLUSIONS Our results suggested that co-expression of VEGF-C and Twist was associated with larger tumor size, higher numbers of lymph node involvement, D2-40-positive LVI, higher risk of distant metastasis, and worse DFS or OS in breast cancer patients.
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Affiliation(s)
- Y-Q Zhang
- The Breast Center, Cancer Hospital of Shantou University Medical College, 7 Rao ping Road, Shantou, China
- Chang Jiang Scholar's Laboratory of Shantou University Medical College, 22 Xin ling Road, Shantou, China
| | - W-L Chen
- Department of Head Neck and Breast Surgery, Yue Bei People's Hospital, 133 Huimin South Road, Shao Guan, China
| | - F Zhang
- Guangdong Provincial Key Laboratory for Breast Cancer Diagnosis and Treatment, Cancer Hospital of Shantou University Medical College, 7 Rao ping Road, Shantou, China
| | - X-L Wei
- Department of Pathology, Cancer Hospital of Shantou University Medical College, 7 Rao ping Road, Shantou, China
| | - D Zeng
- Chang Jiang Scholar's Laboratory of Shantou University Medical College, 22 Xin ling Road, Shantou, China
| | - Y-K Liang
- Chang Jiang Scholar's Laboratory of Shantou University Medical College, 22 Xin ling Road, Shantou, China
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
| | - J-D Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, 7 Rao ping Road, Shantou, China
| | - L-Y Zhang
- Department of Pathology, Cancer Hospital of Shantou University Medical College, 7 Rao ping Road, Shantou, China
| | - C-P Guo
- The Breast Center, Cancer Hospital of Shantou University Medical College, 7 Rao ping Road, Shantou, China
| | - H-C Zeng
- The Breast Center, Cancer Hospital of Shantou University Medical College, 7 Rao ping Road, Shantou, China
| | - S-S Hao
- Chang Jiang Scholar's Laboratory of Shantou University Medical College, 22 Xin ling Road, Shantou, China
| | - R-H Li
- Chang Jiang Scholar's Laboratory of Shantou University Medical College, 22 Xin ling Road, Shantou, China
| | - W-H Huang
- The Breast Center, Cancer Hospital of Shantou University Medical College, 7 Rao ping Road, Shantou, China.
- The Cancer Center and Breast-Thyroid-Surgery, Xiang' an Hospital of Xiamen University, Xiamen, China.
| | - G-J Zhang
- Chang Jiang Scholar's Laboratory of Shantou University Medical College, 22 Xin ling Road, Shantou, China.
- The Cancer Center and Breast-Thyroid-Surgery, Xiang' an Hospital of Xiamen University, Xiamen, China.
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Menéndez-Menéndez J, Hermida-Prado F, Granda-Díaz R, González A, García-Pedrero JM, Del-Río-Ibisate N, González-González A, Cos S, Alonso-González C, Martínez-Campa C. Deciphering the Molecular Basis of Melatonin Protective Effects on Breast Cells Treated with Doxorubicin: TWIST1 a Transcription Factor Involved in EMT and Metastasis, a Novel Target of Melatonin. Cancers (Basel) 2019; 11:1011. [PMID: 31331001 PMCID: PMC6679136 DOI: 10.3390/cancers11071011] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 07/13/2019] [Accepted: 07/16/2019] [Indexed: 02/07/2023] Open
Abstract
Melatonin mitigates cancer initiation, progression and metastasis through inhibition of both the synthesis of estrogens and the transcriptional activity of the estradiol-ER (Estrogen receptor) complex in the estrogen-dependent breast cancer cell line MCF-7. Moreover, melatonin improves the sensitivity of MCF-7 to chemotherapeutic agents and protects against their side effects. It has been described that melatonin potentiates the anti-proliferative effects of doxorubicin; however, the molecular changes involving gene expression and the activation/inhibition of intracellular signaling pathways remain largely unknown. Here we found that melatonin enhanced the anti-proliferative effect of doxorubicin in MCF-7 but not in MDA-MB-231 cells. Strikingly, doxorubicin treatment induced cell migration and invasion, and melatonin effectively counteracted these effects in MCF-7 but not in estrogen-independent MDA-MB-231 cells. Importantly, we describe for the first time the ability of melatonin to downregulate TWIST1 (Twist-related protein 1) in estrogen-dependent but not in estrogen-independent breast cancer cells. Combined with doxorubicin, melatonin inhibited the activation of p70S6K and modulated the expression of breast cancer, angiogenesis and clock genes. Moreover, melatonin regulates the levels of TWIST1-related microRNAs, such as miR-10a, miR-10b and miR-34a. Since TWIST1 plays a pivotal role in the epithelial to mesenchymal transition, acquisition of metastatic phenotype and angiogenesis, our results suggest that inhibition of TWIST1 by melatonin might be a crucial mechanism of overcoming resistance and improving the oncostatic potential of doxorubicin in estrogen-dependent breast cancer cells.
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Affiliation(s)
- Javier Menéndez-Menéndez
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Francisco Hermida-Prado
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain
| | - Rocío Granda-Díaz
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain
| | - Alicia González
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Juana María García-Pedrero
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain
| | - Nagore Del-Río-Ibisate
- Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain
- Instituto Universitario de Oncología del Principado de Asturias, University of Oviedo, 33011 Oviedo, Spain
| | - Alicia González-González
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Samuel Cos
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Carolina Alonso-González
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain.
| | - Carlos Martínez-Campa
- Department of Physiology and Pharmacology, School of Medicine, University of Cantabria and Instituto de Investigación Valdecilla (IDIVAL), 39011 Santander, Spain.
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Rivera-Soto R, Damania B. Modulation of Angiogenic Processes by the Human Gammaherpesviruses, Epstein-Barr Virus and Kaposi's Sarcoma-Associated Herpesvirus. Front Microbiol 2019; 10:1544. [PMID: 31354653 PMCID: PMC6640166 DOI: 10.3389/fmicb.2019.01544] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 06/20/2019] [Indexed: 12/25/2022] Open
Abstract
Angiogenesis is the biological process by which new blood vessels are formed from pre-existing vessels. It is considered one of the classic hallmarks of cancer, as pathological angiogenesis provides oxygen and essential nutrients to growing tumors. Two of the seven known human oncoviruses, Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), belong to the Gammaherpesvirinae subfamily. Both viruses are associated with several malignancies including lymphomas, nasopharyngeal carcinomas, and Kaposi’s sarcoma. The viral genomes code for a plethora of viral factors, including proteins and non-coding RNAs, some of which have been shown to deregulate angiogenic pathways and promote tumor growth. In this review, we discuss the ability of both viruses to modulate the pro-angiogenic process.
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Affiliation(s)
- Ricardo Rivera-Soto
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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46
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Hung JJ, Kao YS, Huang CH, Hsu WH. Overexpression of Aiolos promotes epithelial-mesenchymal transition and cancer stem cell-like properties in lung cancer cells. Sci Rep 2019; 9:2991. [PMID: 30816208 PMCID: PMC6395617 DOI: 10.1038/s41598-019-39545-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 01/23/2019] [Indexed: 12/13/2022] Open
Abstract
Aiolos/Ikaros family zinc finger 3 (IKZF3), a member of the Ikaros family of lymphocyte maturation-driving transcription factors, is highly expressed in hematopoietic malignancies. However, its role in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-like properties in lung cancer remains unknown. Human lung cancer cell lines H1299 with overexpressing Aiolos (H1299-Aiolos) and A549 with overexpressing Aiolos (A549-Aiolos) were generated by stable transfection. Cell migration and invasion assays were done to demonstrate their invasion and migration ability. Sphere formation assay was used to determine their tumor-initiating capability. Aiolos overexpression induced EMT and increased migration/invasiveness in H1299 and A549 cells. Aiolos overexpression also increased metastatic ability in vivo. Aiolos overexpression upregulated the expression of Twist and matrix metalloproteinase 16 (MMP16). By using knockdown of Twist or an inhibitor of phosphatidylinositol (PI) 3-kinase, EMT, migration/invasiveness ability, and MMP16 expression were reversed in H1299-Aiolos and A549-Aiolos cells. Overexpression of Aiolos upregulated the CSC-like properties in lung cancer cells, and were also reversed by an inhibitor of PI 3-kinase. For lung cancer cells, Aiolos overexpression promotes EMT and CSC-like properties through upregulating the PI 3-kinase/Akt pathway. The information is helpful for developing therapeutic strategies targeting Aiolos expression for lung cancer treatment.
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Affiliation(s)
- Jung-Jyh Hung
- Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan.
| | - Ying-Shiun Kao
- Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chi-Hung Huang
- Taiwan Advance Biopharm (TABP), Inc., Xizhi District, New Taipei City, Taiwan
| | - Wen-Hu Hsu
- Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan
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α-Parvin promotes breast cancer progression and metastasis through interaction with G3BP2 and regulation of TWIST1 signaling. Oncogene 2019; 38:4856-4874. [PMID: 30804457 DOI: 10.1038/s41388-019-0762-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 02/09/2019] [Accepted: 02/11/2019] [Indexed: 12/19/2022]
Abstract
Identification of molecular alterations driving breast cancer progression is critical for the development of effective therapy. In this study, we show that the level of α-parvin is elevated in triple-negative breast cancer cells. The depletion of α-parvin from triple-negative breast cancer cells effectively inhibits breast cancer cell growth, migration, and invasion in vitro, and tumor progression and metastasis in vivo. At the molecular level, we identify Ras-GTPase-activing protein SH3-domain-binding protein 2 (G3BP2) as an α-parvin-binding protein. Knockdown of α-parvin promotes G3BP2 interaction with TWIST1, increases ubiquitination and proteasome-dependent degradation of TWIST1, and consequently reduces the cellular level of TWIST1 and its downstream signaling. Importantly, the depletion of G3BP2 reverses the reduction in the level and signaling of TWIST1 and the suppression of breast cancer progression induced by the loss of α-parvin. Furthermore, the re-expression of an α-parvin mutant in which the G3BP2-binding site is ablated, unlike that of wild-type α-parvin, in α-parvin-deficient breast cancer cells, is unable to restore the level and signaling of TWIST1 and promote breast cancer progression. Finally, we show that protein level of α-parvin is highly positively correlated with that of TWIST1 in human triple-negative breast cancer patients. Our studies reveal a novel signaling pathway consisting of α-parvin, G3BP2, and TWIST1 that regulates breast cancer progression and metastasis, and suggest that the activation of this signaling pathway is a key factor for driving the progression and poor clinical outcome of human ER-negative breast cancer.
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48
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Savci-Heijink CD, Halfwerk H, Hooijer GKJ, Koster J, Horlings HM, Meijer SL, van de Vijver MJ. Epithelial-to-mesenchymal transition status of primary breast carcinomas and its correlation with metastatic behavior. Breast Cancer Res Treat 2019; 174:649-659. [PMID: 30610490 PMCID: PMC6438946 DOI: 10.1007/s10549-018-05089-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 12/06/2018] [Indexed: 01/01/2023]
Abstract
Background Epithelial-to-mesenchymal transition (EMT) has been implicated as an important step in the development of distant metastases. We therefore wished to study EMT status of primary breast carcinomas from patients who during follow-up developed distant metastases. Methods mRNA expression profiles of primary breast carcinoma samples (n = 151) from patients who developed metastatic disease were analyzed and EMT status was designated using a previously described EMT-core signature. EMT status of the primary tumor was correlated to clinicopathological characteristics, molecular subtypes, metastasis pattern, chemotherapy response and survival outcomes. In addition, using immunohistochemistry, the expression levels of several proteins implicated in EMT were studied (CDH1, CDH2, NAT1, SNAI2, TWIST1, VIM, and ZEB1) compared with the designated EMT status and survival. Results Utilizing the 130-gene-EMT-core signature, 66.2% of the primary tumors in the current study was assessed as EMT-activated. In contrast to our expectations, analyses revealed that 84.6% of Luminal A tumors, 65.1% of Luminal B tumors, and 55.6% of HER2-like had an activated EMT status, compared to only 25% of the basal-type tumors (p < 0.001). EMT status was not correlated to the pattern of metastatic disease, metastasis-specific survival, and overall survival. Similarly, there was not a significant association between EMT status of the primary tumor and chemotherapy response in the metastatic setting. Immunostaining for NAT1 and TWIST1 correlated with the EMT status (p 0.003 and p 0.047, respectively). Multivariate analyses showed that NAT1 and TWIST1 staining was significantly associated with EMT status regardless of the estrogen receptor status of the tumors (p values: 0.020 and 0.027, respectively). Conclusions The EMT status of breast cancers, as defined by the presence of a core EMT gene expression signature is associated with non-basal-type tumors, but not with the pattern of distant metastasis. Of several potential immunohistochemical EMT markers, only NAT1 and TWIST1 expression levels were associated with the gene expression-based EMT status. Electronic supplementary material The online version of this article (10.1007/s10549-018-05089-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- C D Savci-Heijink
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
| | - H Halfwerk
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - G K J Hooijer
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - J Koster
- Department of Oncogenomics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - H M Horlings
- Department of Pathology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands
| | - S L Meijer
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
| | - M J van de Vijver
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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Li Y, Gong Y, Ning X, Peng D, Liu L, He S, Gong K, Zhang C, Li X, Zhou L. Downregulation of CLDN7 due to promoter hypermethylation is associated with human clear cell renal cell carcinoma progression and poor prognosis. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:276. [PMID: 30428910 PMCID: PMC6234584 DOI: 10.1186/s13046-018-0924-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 10/02/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Metastasis is the primary cause of death in renal cell carcinoma (RCC). Loss of cell-to-cell adhesion, including tight junctions (TJs) is the initial step in the process of metastasis. Claudin-7 (CLDN7) is a major component of TJs. However, the clinical significance and its regulation of kidney tumorigenesis remain poorly understood. METHODS A total of 120 fresh clear cell RCC (ccRCC) specimens and 144 primary RCC and adjacent nonmalignant renal paraffin specimens were obtained from Department of Urology, Peking University First Hospital. Expression of CLDN7 in ccRCC tissues and cell lines were determined using bioinformatic data mining, quantitative real-time PCR (qRT-PCR), Western blotting and immunostaining. The clinical significance of CLDN7 expression and promoter DNA methylation status was analyzed in ccRCC patients from Peking University First Hospital and The Cancer Genome Atlas. Additionally, the methylation specific-PCR, bisulfite genomic sequencing and demethylation analysis of CLDN7 were performed. Biological functions of CLDN7 were investigated by examining cell proliferation using MTS assays and EdU incorporation assays, cell migration by in vitro wound healing assays and transwell migration assays, cell invasion by transwell invasion assays, and cell apoptosis by flow cytometry. Mouse model experiments were performed to confirm the effects of CLDN7 on tumor growth and metastasis in vivo. The molecular mechanism of CLDN7 function was investigated using gene-set enrichment analysis (GSEA) and high-throughput cDNA sequencing (RNA-Seq) and confirmed by qRT-PCR, Western blot and immunostaining in vitro and in vivo. RESULTS Our findings revealed that CLDN7 is frequently downregulated via hypermethylation of its promoter in ccRCC. CLDN7 can help predict aggressive tumor status and poor prognosis in ccRCC patients. Interestingly, hypermethylation of the CLDN7 promoter was related to advanced ccRCC status and poor prognosis. Moreover, overexpression of CLDN7 induced cell apoptosis, suppressed proliferation, migration and invasion abilities of ccRCC cells both in vitro and in vivo. Additionally, GSEA and RNA-Seq results showed that CLDN7 had negative effects in cancer-associated signaling pathways and (epithelial-mesenchymal transition) EMT-related pathways. These results were validated by qRT-PCR, Western blot and immunostaining. CONCLUSIONS We have demonstrated a previously undescribed role of CLDN7 as a ccRCC suppressor and suggest that loss of CLDN7 potentiates EMT and tumor progression. CLDN7 may serve as a functional tumor suppressor in tumor progression and a potential biomarker and target in patients with ccRCC.
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Affiliation(s)
- Yifan Li
- Department of Urology, Peking University First Hospital, Beijing, 100034, China.,Institute of Urology, Peking University, Beijing, 100034, China.,National Urological Cancer Center, Beijing, 100034, China
| | - Yanqing Gong
- Department of Urology, Peking University First Hospital, Beijing, 100034, China.,Institute of Urology, Peking University, Beijing, 100034, China.,National Urological Cancer Center, Beijing, 100034, China
| | - Xianghui Ning
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Henan, 450052, China
| | - Ding Peng
- Department of Urology, Peking University First Hospital, Beijing, 100034, China.,Institute of Urology, Peking University, Beijing, 100034, China.,National Urological Cancer Center, Beijing, 100034, China
| | - Libo Liu
- Department of Urology, Peking University First Hospital, Beijing, 100034, China.,Institute of Urology, Peking University, Beijing, 100034, China.,National Urological Cancer Center, Beijing, 100034, China
| | - Shiming He
- Department of Urology, Peking University First Hospital, Beijing, 100034, China.,Institute of Urology, Peking University, Beijing, 100034, China.,National Urological Cancer Center, Beijing, 100034, China
| | - Kan Gong
- Department of Urology, Peking University First Hospital, Beijing, 100034, China.,Institute of Urology, Peking University, Beijing, 100034, China.,National Urological Cancer Center, Beijing, 100034, China
| | - Cuijian Zhang
- Department of Urology, Peking University First Hospital, Beijing, 100034, China. .,Institute of Urology, Peking University, Beijing, 100034, China. .,National Urological Cancer Center, Beijing, 100034, China.
| | - Xuesong Li
- Department of Urology, Peking University First Hospital, Beijing, 100034, China. .,Institute of Urology, Peking University, Beijing, 100034, China. .,National Urological Cancer Center, Beijing, 100034, China.
| | - Liqun Zhou
- Department of Urology, Peking University First Hospital, Beijing, 100034, China. .,Institute of Urology, Peking University, Beijing, 100034, China. .,National Urological Cancer Center, Beijing, 100034, China.
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Olea-Flores M, Juárez-Cruz JC, Mendoza-Catalán MA, Padilla-Benavides T, Navarro-Tito N. Signaling Pathways Induced by Leptin during Epithelial⁻Mesenchymal Transition in Breast Cancer. Int J Mol Sci 2018; 19:E3493. [PMID: 30404206 PMCID: PMC6275018 DOI: 10.3390/ijms19113493] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 10/27/2018] [Accepted: 11/01/2018] [Indexed: 12/12/2022] Open
Abstract
Leptin is an adipokine that is overexpressed in obese and overweight people. Interestingly, women with breast cancer present high levels of leptin and of its receptor ObR. Leptin plays an important role in breast cancer progression due to the biological processes it participates in, such as epithelial⁻mesenchymal transition (EMT). EMT consists of a series of orchestrated events in which cell⁻cell and cell⁻extracellular matrix interactions are altered and lead to the release of epithelial cells from the surrounding tissue. The cytoskeleton is also re-arranged, allowing the three-dimensional movement of epithelial cells into the extracellular matrix. This transition provides cells with the ability to migrate and invade adjacent or distal tissues, which is a classic feature of invasive or metastatic carcinoma cells. In recent years, the number of cases of breast cancer has increased, making this disease a public health problem worldwide and the leading cause of death due to cancer in women. In this review, we focus on recent advances that establish: (1) leptin as a risk factor for the development of breast cancer, and (2) leptin as an inducer of EMT, an event that promotes tumor progression.
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Affiliation(s)
- Monserrat Olea-Flores
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas s/n, Chilpancingo, GRO 39090, México.
| | - Juan Carlos Juárez-Cruz
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas s/n, Chilpancingo, GRO 39090, México.
| | - Miguel A Mendoza-Catalán
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas s/n, Chilpancingo, GRO 39090, México.
| | - Teresita Padilla-Benavides
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
| | - Napoleón Navarro-Tito
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Av. Lázaro Cárdenas s/n, Chilpancingo, GRO 39090, México.
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