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Köhler B, Brieger E, Brandstätter T, Hörterer E, Wilk U, Pöhmerer J, Jötten A, Paulitschke P, Broedersz CP, Zahler S, Rädler JO, Wagner E, Roidl A. Unraveling the metastasis-preventing effect of miR-200c in vitro and in vivo. Mol Oncol 2025; 19:1029-1053. [PMID: 39404181 PMCID: PMC11977663 DOI: 10.1002/1878-0261.13712] [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: 03/27/2024] [Revised: 05/28/2024] [Accepted: 07/05/2024] [Indexed: 04/09/2025] Open
Abstract
Advanced breast cancer, as well as ineffective treatments leading to surviving cancer cells, can result in the dissemination of these malignant cells from the primary tumor to distant organs. Recent research has shown that microRNA 200c (miR-200c) can hamper certain steps of the invasion-metastasis cascade. However, it is still unclear whether miR-200c expression alone is sufficient to prevent breast cancer cells from metastasis formation. Hence, we performed a xenograft mouse experiment with inducible miR-200c expression in MDA-MB 231 cells. The ex vivo analysis of metastatic sites in a multitude of organs, including lung, liver, brain, and spleen, revealed a dramatically reduced metastatic burden in mice with miR-200c-expressing tumors. A fundamental prerequisite for metastasis formation is the motility of cancer cells and, therefore, their migration. Consequently, we analyzed the effect of miR-200c on collective- and single-cell migration in vitro, utilizing MDA-MB 231 and MCF7 cell systems with genetically modified miR-200c expression. Analysis of collective-cell migration revealed confluence-dependent motility of cells with altered miR-200c expression. Additionally, scratch assays showed an enhanced predisposition of miR-200c-negative cells to leave cell clusters. The in-between stage of collective- and single-cell migration was validated using transwell assays, which showed reduced migration of miR-200c-positive cells. Finally, to measure migration at the single-cell level, a novel assay on dumbbell-shaped micropatterns was performed, which revealed that miR-200c critically determines confined cell motility. All of these results demonstrate that sole expression of miR-200c impedes metastasis formation in vivo and migration in vitro and highlights miR-200c as a metastasis suppressor in breast cancer.
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Affiliation(s)
- Bianca Köhler
- Pharmaceutical Biotechnology, Department of PharmacyLudwig‐Maximilians‐Universität MünchenGermany
| | - Emily Brieger
- Faculty of Physics and Center for NanoScienceLudwig‐Maximilians‐Universität MünchenGermany
| | - Tom Brandstätter
- Department of Physics and AstronomyVrije Universiteit AmsterdamThe Netherlands
- Arnold‐Sommerfeld‐Center for Theoretical PhysicsLudwig‐Maximilians‐Universität MünchenGermany
| | - Elisa Hörterer
- Pharmaceutical Biotechnology, Department of PharmacyLudwig‐Maximilians‐Universität MünchenGermany
| | - Ulrich Wilk
- Pharmaceutical Biotechnology, Department of PharmacyLudwig‐Maximilians‐Universität MünchenGermany
| | - Jana Pöhmerer
- Pharmaceutical Biotechnology, Department of PharmacyLudwig‐Maximilians‐Universität MünchenGermany
| | - Anna Jötten
- Faculty of Physics and Center for NanoScienceLudwig‐Maximilians‐Universität MünchenGermany
| | - Philipp Paulitschke
- Faculty of Physics and Center for NanoScienceLudwig‐Maximilians‐Universität MünchenGermany
- PHIO Scientific GmbHMunichGermany
| | - Chase P. Broedersz
- Department of Physics and AstronomyVrije Universiteit AmsterdamThe Netherlands
- Arnold‐Sommerfeld‐Center for Theoretical PhysicsLudwig‐Maximilians‐Universität MünchenGermany
| | - Stefan Zahler
- Pharmaceutical Biology, Department of PharmacyLudwig‐Maximilians‐Universität MünchenGermany
| | - Joachim O. Rädler
- Faculty of Physics and Center for NanoScienceLudwig‐Maximilians‐Universität MünchenGermany
| | - Ernst Wagner
- Pharmaceutical Biotechnology, Department of PharmacyLudwig‐Maximilians‐Universität MünchenGermany
| | - Andreas Roidl
- Pharmaceutical Biotechnology, Department of PharmacyLudwig‐Maximilians‐Universität MünchenGermany
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Doodmani SM, Safari MH, Akbari M, Farahani N, Alimohammadi M, Aref AR, Tajik F, Maghsoodlou A, Daneshi S, Tabari T, Taheriazam A, Entezari M, Nabavi N, Hashemi M. Metastasis and chemoresistance in breast cancer: Crucial function of ZEB1/2 proteins. Pathol Res Pract 2025; 267:155838. [PMID: 39954369 DOI: 10.1016/j.prp.2025.155838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 12/20/2024] [Accepted: 02/10/2025] [Indexed: 02/17/2025]
Abstract
Breast cancer remains one of the leading causes of mortality worldwide. While advancements in chemotherapy, immunotherapy, radiotherapy, and targeted therapies have significantly improved breast cancer treatment, many patients are diagnosed at advanced stages, where tumor cells exhibit aggressive behavior and therapy resistance. Understanding the mechanisms driving breast cancer progression is therefore critical. Metastasis is a major factor that drastically reduces patient prognosis and survival, accounting for most breast cancer-related deaths. ZEB proteins have emerged as key regulators of cancer metastasis. Beyond their role in metastasis, ZEB proteins also influence drug resistance. This review focuses on the role of ZEB1 and ZEB2 in regulating breast cancer metastasis. These proteins interact with components of the tumor microenvironment (TME) to drive cancer progression and metastasis. Additionally, ZEB proteins regulate angiogenesis through interactions with VEGF. Targeting ZEB proteins offers potential therapeutic benefits, particularly for aggressive breast cancer subtypes such as triple-negative breast cancer (TNBC), which often show poor therapeutic response. ZEB proteins also influence the sensitivity of breast cancer cells to chemotherapy, making them promising targets for enhancing treatment efficacy. Given their upregulation in breast cancer, ZEB proteins can serve as valuable diagnostic and prognostic markers.
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Affiliation(s)
- Seyed Mohammad Doodmani
- Department of Pathobiology, Faculty of Specialized Veterinary Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mohamad Hosein Safari
- Department of Internal Medicine, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Mohammadarian Akbari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences,Tehran, Iran
| | - Amir Reza Aref
- Department of Vitro Vision, DeepkinetiX, Inc, Boston, MA, USA
| | - Fatemeh Tajik
- Department of Surgery, University of California, Irvine Medical Center, Orange, CA, USA
| | - Amin Maghsoodlou
- Young Researchers and Elite Club, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Teimour Tabari
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Noushin Nabavi
- Independent Researcher, Victoria, British Columbia V8V 1P7, Canada
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Chen S, Karekad MMA, Liu T, Ding B, Wang R, Sun Q, Xu X, Shi Y. The combination of Shenhuang plaster and paclitaxel inhibits lung metastasis in breast cancer via modulation of the tumor microenvironment. Front Oncol 2025; 15:1531493. [PMID: 40094005 PMCID: PMC11906457 DOI: 10.3389/fonc.2025.1531493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 02/04/2025] [Indexed: 03/19/2025] Open
Abstract
Background Paclitaxel (PTX) is a chemotherapeutic agent that is frequently used for breast cancer treatment, but it has been associated with promoting distant metastases, including to the lungs, liver, and bones. Shenhuang plaster (SHP), a traditional Chinese medicine, has shown potential for modulating the tumor microenvironment (TME). This study investigates whether a combination of SHP and PTX can enhance the anti-tumor efficacy of PTX and mitigate its pro-metastatic effects in a 4T1 breast cancer mouse model. Methods Female Balb/c mice were injected with 4T1 breast cancer cells and then divided into four treatment groups: control, PTX, SHP, and PTX+SHP. The combination of SHP and PTX was evaluated using bioluminescence imaging (BLI), histological analysis, and hematoxylin and eosin (HE) staining to assess lung metastasis. Flow cytometry was employed to analyze immune cell populations, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and cytotoxic T cells (CD8+ and CD4+). Results SHP alone did not significantly inhibit lung metastasis but the combination of PTX and SHP led to a marked reduction in lung lesions, as confirmed by BLI and histological analysis. SHP improved the overall health of PTX-treated mice, reducing their body weight loss and mortality. Flow cytometry revealed that the combination therapy reduced the infiltration of M2 macrophages, MDSCs, and Tregs, while increasing the proportion of antitumor M1 macrophages, cytotoxic CD8+ T cells, and helper CD4+ T cells. Conclusions The combination of PTX and SHP has a synergistic effect, reducing lung metastasis and modulating immune cell populations within the TME. These results suggest that integrating traditional Chinese medicine with standard chemotherapy can enhance therapeutic efficacy and reduce adverse effects.
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Affiliation(s)
- Shiqi Chen
- The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | | | - Ting Liu
- The College of Nursing, Zhejiang Chinese Medical University, Hangzhou, China
| | - Bin Ding
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Rongyun Wang
- The College of Nursing, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiuhua Sun
- The College of Nursing, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiaohong Xu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
- Bozhou District Hospital of Traditional Chinese Medicine, Zunyi, China
| | - Yanan Shi
- The College of Nursing, Zhejiang Chinese Medical University, Hangzhou, China
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Basar E, Mead H, Shum B, Rauter I, Ay C, Skaletz-Rorowski A, Brockmeyer NH. Biological Barriers for Drug Delivery and Development of Innovative Therapeutic Approaches in HIV, Pancreatic Cancer, and Hemophilia A/B. Pharmaceutics 2024; 16:1207. [PMID: 39339243 PMCID: PMC11435036 DOI: 10.3390/pharmaceutics16091207] [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: 07/26/2024] [Revised: 09/06/2024] [Accepted: 09/07/2024] [Indexed: 09/30/2024] Open
Abstract
Biological barriers remain a major obstacle for the development of innovative therapeutics. Depending on a disease's pathophysiology, the involved tissues, cell populations, and cellular components, drugs often have to overcome several biological barriers to reach their target cells and become effective in a specific cellular compartment. Human biological barriers are incredibly diverse and include multiple layers of protection and obstruction. Importantly, biological barriers are not only found at the organ/tissue level, but also include cellular structures such as the outer plasma membrane, the endolysosomal machinery, and the nuclear envelope. Nowadays, clinicians have access to a broad arsenal of therapeutics ranging from chemically synthesized small molecules, biologicals including recombinant proteins (such as monoclonal antibodies and hormones), nucleic-acid-based therapeutics, and antibody-drug conjugates (ADCs), to modern viral-vector-mediated gene therapy. In the past decade, the therapeutic landscape has been changing rapidly, giving rise to a multitude of innovative therapy approaches. In 2018, the FDA approval of patisiran paved the way for small interfering RNAs (siRNAs) to become a novel class of nucleic-acid-based therapeutics, which-upon effective drug delivery to their target cells-allow to elegantly regulate the post-transcriptional gene expression. The recent approvals of valoctocogene roxaparvovec and etranacogene dezaparvovec for the treatment of hemophilia A and B, respectively, mark the breakthrough of viral-vector-based gene therapy as a new tool to cure disease. A multitude of highly innovative medicines and drug delivery methods including mRNA-based cancer vaccines and exosome-targeted therapy is on the verge of entering the market and changing the treatment landscape for a broad range of conditions. In this review, we provide insights into three different disease entities, which are clinically, scientifically, and socioeconomically impactful and have given rise to many technological advancements: acquired immunodeficiency syndrome (AIDS) as a predominant infectious disease, pancreatic carcinoma as one of the most lethal solid cancers, and hemophilia A/B as a hereditary genetic disorder. Our primary objective is to highlight the overarching principles of biological barriers that can be identified across different disease areas. Our second goal is to showcase which therapeutic approaches designed to cross disease-specific biological barriers have been promising in effectively treating disease. In this context, we will exemplify how the right selection of the drug category and delivery vehicle, mode of administration, and therapeutic target(s) can help overcome various biological barriers to prevent, treat, and cure disease.
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Affiliation(s)
- Emre Basar
- WIR—Walk In Ruhr, Center for Sexual Health & Medicine, Department of Dermatology, Venerology and Allergology, Ruhr-University Bochum, 44787 Bochum, Germany;
| | | | - Bennett Shum
- GenePath LLC, Sydney, NSW 2067, Australia
- EMBL Australia Node in Single Molecule Science, School of Medical Sciences, University of NSW, Sydney, NSW 2052, Australia
| | | | - Cihan Ay
- Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria
| | - Adriane Skaletz-Rorowski
- WIR—Walk In Ruhr, Center for Sexual Health & Medicine, Department of Dermatology, Venerology and Allergology, Ruhr-University Bochum, 44787 Bochum, Germany;
| | - Norbert H. Brockmeyer
- WIR—Walk In Ruhr, Center for Sexual Health & Medicine, Department of Dermatology, Venerology and Allergology, Ruhr-University Bochum, 44787 Bochum, Germany;
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Herndon ME, Ayers M, Gibson-Corley KN, Wendt MK, Wallrath LL, Henry MD, Stipp CS. The highly metastatic 4T1 breast carcinoma model possesses features of a hybrid epithelial/mesenchymal phenotype. Dis Model Mech 2024; 17:dmm050771. [PMID: 39104192 PMCID: PMC11391819 DOI: 10.1242/dmm.050771] [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: 02/27/2024] [Accepted: 07/29/2024] [Indexed: 08/07/2024] Open
Abstract
Epithelial-mesenchymal transitions (EMTs) are thought to promote metastasis via downregulation of E-cadherin (also known as Cdh1) and upregulation of mesenchymal markers such as N-cadherin (Cdh2) and vimentin (Vim). Contrary to this, E-cadherin is retained in many invasive carcinomas and promotes collective cell invasion. To investigate how E-cadherin regulates metastasis, we examined the highly metastatic, E-cadherin-positive murine 4T1 breast cancer model, together with the less metastatic, 4T1-related cell lines 4T07, 168FARN and 67NR. We found that 4T1 cells display a hybrid epithelial/mesenchymal phenotype with co-expression of epithelial and mesenchymal markers, whereas 4T07, 168FARN, and 67NR cells display progressively more mesenchymal phenotypes in vitro that relate inversely to their metastatic capacity in vivo. Using RNA interference and constitutive expression, we demonstrate that the expression level of E-cadherin does not determine 4T1 or 4T07 cell metastatic capacity in mice. Mechanistically, 4T1 cells possess highly dynamic, unstable cell-cell junctions and can undergo collective invasion without E-cadherin downregulation. However, 4T1 orthotopic tumors in vivo also contain subregions of EMT-like loss of E-cadherin. Thus, 4T1 cells function as a model for carcinomas with a hybrid epithelial/mesenchymal phenotype that promotes invasion and metastasis.
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Affiliation(s)
- Mary E. Herndon
- Department of Biology, University of Iowa, Iowa City, IA 52245, USA
| | - Mitchell Ayers
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
| | - Katherine N. Gibson-Corley
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
| | - Michael K. Wendt
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Lori L. Wallrath
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
- Department of Biochemistry and Molecular Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Michael D. Henry
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
- Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA
| | - Christopher S. Stipp
- Department of Biology, University of Iowa, Iowa City, IA 52245, USA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
- Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA
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Nagai T, Sato M, Nishita M. miR-200c-141 induces a hybrid E/M state and promotes collective cell migration in MDA-MB-231 cells. Biochem Biophys Res Commun 2024; 709:149829. [PMID: 38552553 DOI: 10.1016/j.bbrc.2024.149829] [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: 03/07/2024] [Accepted: 03/24/2024] [Indexed: 04/13/2024]
Abstract
The microRNA-200 (miR-200) family is a potent suppressor of epithelial-to-mesenchymal transition (EMT). While its role as a tumor suppressor has been well documented, recent studies suggested that it can promote cancer progression in several stages. In this study, we investigated whether the miR-200 family members play a role in the acquisition of a hybrid epithelial/mesenchymal (E/M) state, which is reported to be associated with cancer malignancy, in mesenchymal MDA-MB-231 cells. Our results demonstrated that the induction of miR-200c-141, a cluster of the miR-200 family member, can induce the expression of epithelial gene and cell-cell junction while mesenchymal markers are retained. Moreover, induction of miR-200c-141 promoted collective migration accompanied by the formation of F-actin cables anchored by adherens junction. These results suggest that the miR-200 family can induce a hybrid E/M state and endows with the ability of collective cell migration in mesenchymal cancer cells.
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Affiliation(s)
- Tomoaki Nagai
- Department of Biochemistry, Fukushima Medical University, School of Medicine, Fukushima, 960-1295, Japan.
| | - Misa Sato
- Department of Biochemistry, Fukushima Medical University, School of Medicine, Fukushima, 960-1295, Japan
| | - Michiru Nishita
- Department of Biochemistry, Fukushima Medical University, School of Medicine, Fukushima, 960-1295, Japan.
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Chen SY, Zhang FL, Zhang YL, Liao L, Deng L, Shao ZM, Liu GY, Li DQ. Spermatid perinuclear RNA-binding protein promotes UBR5-mediated proteolysis of Dicer to accelerate triple-negative breast cancer progression. Cancer Lett 2024; 586:216672. [PMID: 38280476 DOI: 10.1016/j.canlet.2024.216672] [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: 08/04/2023] [Revised: 12/17/2023] [Accepted: 01/20/2024] [Indexed: 01/29/2024]
Abstract
Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer with no targeted therapy. Spermatid perinuclear RNA binding protein (STRBP), a poorly characterized RNA-binding protein (RBP), has an essential role in normal spermatogenesis and sperm function, but whether and how its dysregulation contributing to cancer progression has not yet been explored. Here, we report that STRBP functions as a novel oncogene to drive TNBC progression. STRBP expression was upregulated in TNBC tissues and correlated with poor disease prognosis. Functionally, STRBP promoted TNBC cell proliferation, migration, and invasion in vitro, and enhanced xenograft tumor growth and lung colonization in mice. Mechanistically, STRBP interacted with Dicer, a core component of the microRNA biogenesis machinery, and promoted its proteasomal degradation through enhancing its interaction with E3 ubiquitin ligase UBR5. MicroRNA-sequencing analysis identified miR-200a-3p as a downstream effector of STRBP, which was regulated by Dicer and affected epithelial-mesenchymal transition. Importantly, the impaired malignant phenotypes of TNBC cells caused by STRBP depletion were largely rescued by knockdown of Dicer, and these effects were compromised by transfection of miR-200a-3p mimics. Collectively, these findings revealed a previously unrecognized oncogenic role of STRBP in TNBC progression and identified STRBP as a promising target against TNBC.
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Affiliation(s)
- Si-Yu Chen
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China
| | - Fang-Lin Zhang
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yin-Ling Zhang
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Li Liao
- Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Ling Deng
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Zhi-Min Shao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; Shanghai Key Laboratory of Breast Cancer, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Guang-Yu Liu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China.
| | - Da-Qiang Li
- Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; Shanghai Key Laboratory of Breast Cancer, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Shanghai Key Laboratory of Radiation Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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8
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Orbach SM, DeVaull CY, Bealer EJ, Ross BC, Jeruss JS, Shea LD. An engineered niche delineates metastatic potential of breast cancer. Bioeng Transl Med 2024; 9:e10606. [PMID: 38193115 PMCID: PMC10771563 DOI: 10.1002/btm2.10606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/29/2023] [Accepted: 09/20/2023] [Indexed: 01/10/2024] Open
Abstract
Metastatic breast cancer is often not diagnosed until secondary tumors have become macroscopically visible and millions of tumor cells have invaded distant tissues. Yet, metastasis is initiated by a cascade of events leading to formation of the pre-metastatic niche, which can precede tumor formation by a matter of years. We aimed to distinguish the potential for metastatic disease from nonmetastatic disease at early times in triple-negative breast cancer using sister cell lines 4T1 (metastatic), 4T07 (invasive, nonmetastatic), and 67NR (nonmetastatic). We used a porous, polycaprolactone scaffold, that serves as an engineered metastatic niche, to identify metastatic disease through the characteristics of the microenvironment. Analysis of the immune cell composition at the scaffold was able to distinguish noninvasive 67NR tumor-bearing mice from 4T07 and 4T1 tumor-bearing mice but could not delineate metastatic potential between the two invasive cell lines. Gene expression in the scaffolds correlated with the up-regulation of cancer hallmarks (e.g., angiogenesis, hypoxia) in the 4T1 mice relative to 4T07 mice. We developed a 9-gene signature (Dhx9, Dusp12, Fth1, Ifitm1, Ndufs1, Pja2, Slc1a3, Soga1, Spon2) that successfully distinguished 4T1 disease from 67NR or 4T07 disease throughout metastatic progression. Furthermore, this signature proved highly effective at distinguishing diseased lungs in publicly available datasets of mouse models of metastatic breast cancer and in human models of lung cancer. The early and accurate detection of metastatic disease that could lead to early treatment has the potential to improve patient outcomes and quality of life.
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Affiliation(s)
- Sophia M. Orbach
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMichiganUSA
| | | | - Elizabeth J. Bealer
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMichiganUSA
| | - Brian C. Ross
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMichiganUSA
| | - Jacqueline S. Jeruss
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMichiganUSA
- Department of PathologyUniversity of MichiganAnn ArborMichiganUSA
- Department of SurgeryUniversity of MichiganAnn ArborMichiganUSA
| | - Lonnie D. Shea
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMichiganUSA
- Department of Chemical EngineeringUniversity of MichiganAnn ArborMichiganUSA
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9
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Salman IT, Abulsoud AI, Abo-Elmatty DM, Fawzy A, Mesbah NM, Saleh SM. The long non-coding RNA ZFAS1 promotes colorectal cancer progression via miR200b/ZEB1 axis. Pathol Res Pract 2023; 247:154567. [PMID: 37245266 DOI: 10.1016/j.prp.2023.154567] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 05/21/2023] [Accepted: 05/23/2023] [Indexed: 05/30/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is a common tumor worldwide. CRC is influenced by several types of miRNAs and long non-coding RNAs. This study aims to evaluate the correlation of lncRNA ZFAS1/ miR200b/ ZEB1 protein with presence of CRC. METHODS Quantitative real-time polymerase chain reaction was used to measure serum expression of lncRNA ZFAS1 and microRNA-200b in 60 CRC patients and 28 control subjects. ZEB1 protein in serum was measured by ELISA. RESULTS Lnc ZFAS1 and ZEB1 were up-regulated in CRC patients in compare to control subjects while miR-200b was down-regulated. There was a linear correlation between ZAFS1 expression and miR-200b and ZEB1 in CRC. CONCLUSION ZFAS1 is a key player of CRC progression and could be a potential therapeutic target by sponging miR-200b. In-addition the association between ZFAS1, miR-200b and ZEB1 highlights their potential value as a novel diagnostic biomarker in human CRC.
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Affiliation(s)
- Islam T Salman
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed I Abulsoud
- Department of Biochemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11231, Egypt; Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt.
| | - Dina M Abo-Elmatty
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Amal Fawzy
- Department of Clinical and Chemical Pathology, National Cancer Institute, Cairo University, Cairo 11796, Egypt
| | - Noha M Mesbah
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Samy M Saleh
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
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ROSKOVA IVANA, VECERA MAREK, RADOVA LENKA, TRACHTOVA KAROLINA, SIEGL FRANTISEK, HERMANOVA MARKETA, HENDRYCH MICHAL, KREN LEOS, VYBIHAL VACLAV, VALEKOVA HANA, KASPAROVA PETRA, KOLOUSKOVA IVANA, KAZDA TOMAS, SLABY ONDREJ, JANCALEK RADIM, SANA JIRI, SMRCKA MARTIN. Small RNA Sequencing Identifies a Six-MicroRNA Signature Enabling Classification of Brain Metastases According to their Origin. Cancer Genomics Proteomics 2023; 20:18-29. [PMID: 36581345 PMCID: PMC9806667 DOI: 10.21873/cgp.20361] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 11/19/2022] [Accepted: 11/22/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND/AIM Brain metastases (BMs) are the most frequent intracranial tumors in adults and one of the greatest challenges for modern oncology. Most are derived from lung, breast, renal cell, and colorectal carcinomas and melanomas. Up to 14% of patients are diagnosed with BMs of unknown primary, which are commonly characterized by an early and aggressive metastatic spread. It is important to discover novel biomarkers for early identification of BM origin, allowing better management of patients with this disease. Our study focused on microRNAs (miRNAs), which are very stable in frozen native and FFPE tissues and have been shown to be sensitive and specific diagnostic biomarkers of cancer. We aimed to identify miRNAs with significantly different expression in the five most frequent groups of BMs and develop a diagnostic classifier capable of sensitive and specific classification of BMs. MATERIALS AND METHODS Total RNA enriched for miRNAs was isolated using the mirVana miRNA Isolation Kit from 71 fresh-frozen histopathologically confirmed BM tissues originating in 5 cancer types. Sequencing libraries were prepared using the QIAseq miRNA Library Kit and sequenced on the NextSeq 500 platform. MiRNA expression was further validated by RT-qPCR. RESULTS Differential analysis identified 373 miRNAs with significantly different expression between 5 BM groups (p<0.001). A classifier model was developed based on the expression of 6 miRNAs (hsa-miR-141-3p, hsa-miR-141-5p, hsa-miR-146a-5p, hsa-miR-194-5p, hsa-miR-200b-3p and hsa-miR-365b-5p) with the ability to correctly classify 91.5% of samples. Subsequent validation confirmed both significantly different expression of selected miRNAs in 5 BM groups as well as their diagnostic potential. CONCLUSION To date, our study is the first to analyze miRNA expression in various types of BMs using small RNA sequencing to develop a diagnostic classifier and, thus, to help stratify BMs of unknown primary. The presented results confirm the importance of studying the dysregulated expression of miRNAs in BMs and the diagnostic potential of the validated 6-miRNA signature.
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Affiliation(s)
- IVANA ROSKOVA
- Department of Neurosurgery, University Hospital Brno, Brno, Czech Republic,Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - MAREK VECERA
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - LENKA RADOVA
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - KAROLINA TRACHTOVA
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - FRANTISEK SIEGL
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - MARKETA HERMANOVA
- Faculty of Medicine, Masaryk University, Brno, Czech Republic,First Department of Pathology, St. Anne’s University Hospital, Brno, Czech Republic
| | - MICHAL HENDRYCH
- Faculty of Medicine, Masaryk University, Brno, Czech Republic,First Department of Pathology, St. Anne’s University Hospital, Brno, Czech Republic
| | - LEOS KREN
- Department of Pathology, University Hospital Brno, Brno, Czech Republic
| | - VACLAV VYBIHAL
- Department of Neurosurgery, University Hospital Brno, Brno, Czech Republic
| | - HANA VALEKOVA
- Faculty of Medicine, Masaryk University, Brno, Czech Republic,Department of Neurosurgery, St. Anne’s University Hospital, Brno, Czech Republic
| | - PETRA KASPAROVA
- The Fingerland Department of Pathology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | | | - TOMAS KAZDA
- Faculty of Medicine, Masaryk University, Brno, Czech Republic,Department of Radiation Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - ONDREJ SLABY
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic,Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - RADIM JANCALEK
- Faculty of Medicine, Masaryk University, Brno, Czech Republic,Department of Neurosurgery, St. Anne’s University Hospital, Brno, Czech Republic
| | - JIRI SANA
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic,Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - MARTIN SMRCKA
- Department of Neurosurgery, University Hospital Brno, Brno, Czech Republic,Faculty of Medicine, Masaryk University, Brno, Czech Republic
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11
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Elkholi IE, Lalonde A, Park M, Côté JF. Breast Cancer Metastatic Dormancy and Relapse: An Enigma of Microenvironment(s). Cancer Res 2022; 82:4497-4510. [PMID: 36214624 PMCID: PMC9755970 DOI: 10.1158/0008-5472.can-22-1902] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/01/2022] [Accepted: 10/04/2022] [Indexed: 01/24/2023]
Abstract
Multiple factors act in concert to define the fate of disseminated tumor cells (DTC) to enter dormancy or develop overt metastases. Here, we review these factors in the context of three stages of the metastatic cascade that impact DTCs. First, cells can be programmed within the primary tumor microenvironment to promote or inhibit dissemination, and the primary tumor can condition a premetastatic niche. Then, cancer cells from the primary tumor spread through hematogenous and lymphatic routes, and the primary tumor sends cues systematically to regulate the fate of DTCs. Finally, DTCs home to their metastatic site, where they are influenced by various organ-specific aspects of the new microenvironment. We discuss these factors in the context of breast cancer, where about one-third of patients develop metastatic relapse. Finally, we discuss how the standard-of-care options for breast cancer might affect the fate of DTCs.
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Affiliation(s)
- Islam E. Elkholi
- Montreal Clinical Research Institute (IRCM), Montreal, Québec, Canada.,Molecular Biology Programs, Université de Montréal, Montreal, Québec, Canada.,Corresponding Authors: Jean-François Côté, Montreal Clinical Research Institute (IRCM), 110 Avenue des Pins Ouest, Montréal H2W 1R7, Québec, Canada. Phone: 514-987-5647; E-mail: ; and Islam E. Elkholi, Montreal Clinical Research Institute (IRCM), 110 Avenue des Pins Ouest, Montréal (QC) Canada, H2W 1R7. Phone: 514-987-5656; E-mail:
| | - Andréane Lalonde
- Montreal Clinical Research Institute (IRCM), Montreal, Québec, Canada.,Molecular Biology Programs, Université de Montréal, Montreal, Québec, Canada
| | - Morag Park
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montréal, Québec, Canada
| | - Jean-François Côté
- Montreal Clinical Research Institute (IRCM), Montreal, Québec, Canada.,Molecular Biology Programs, Université de Montréal, Montreal, Québec, Canada.,Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Québec, Canada.,Department of Anatomy and Cell Biology, McGill University, Montréal, Québec, Canada.,Corresponding Authors: Jean-François Côté, Montreal Clinical Research Institute (IRCM), 110 Avenue des Pins Ouest, Montréal H2W 1R7, Québec, Canada. Phone: 514-987-5647; E-mail: ; and Islam E. Elkholi, Montreal Clinical Research Institute (IRCM), 110 Avenue des Pins Ouest, Montréal (QC) Canada, H2W 1R7. Phone: 514-987-5656; E-mail:
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12
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Cai G, Nguyen A, Bashirzadeh Y, Lin SS, Bi D, Liu AP. Compressive stress drives adhesion-dependent unjamming transitions in breast cancer cell migration. Front Cell Dev Biol 2022; 10:933042. [PMID: 36268514 PMCID: PMC9577106 DOI: 10.3389/fcell.2022.933042] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 09/12/2022] [Indexed: 11/13/2022] Open
Abstract
Cellular unjamming is the collective fluidization of cell motion and has been linked to many biological processes, including development, wound repair, and tumor growth. In tumor growth, the uncontrolled proliferation of cancer cells in a confined space generates mechanical compressive stress. However, because multiple cellular and molecular mechanisms may be operating simultaneously, the role of compressive stress in unjamming transitions during cancer progression remains unknown. Here, we investigate which mechanism dominates in a dense, mechanically stressed monolayer. We find that long-term mechanical compression triggers cell arrest in benign epithelial cells and enhances cancer cell migration in transitions correlated with cell shape, leading us to examine the contributions of cell–cell adhesion and substrate traction in unjamming transitions. We show that cadherin-mediated cell–cell adhesion regulates differential cellular responses to compressive stress and is an important driver of unjamming in stressed monolayers. Importantly, compressive stress does not induce the epithelial–mesenchymal transition in unjammed cells. Furthermore, traction force microscopy reveals the attenuation of traction stresses in compressed cells within the bulk monolayer regardless of cell type and motility. As traction within the bulk monolayer decreases with compressive pressure, cancer cells at the leading edge of the cell layer exhibit sustained traction under compression. Together, strengthened intercellular adhesion and attenuation of traction forces within the bulk cell sheet under compression lead to fluidization of the cell layer and may impact collective cell motion in tumor development and breast cancer progression.
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Affiliation(s)
- Grace Cai
- Applied Physics Program, University of Michigan, Ann Arbor, MI, United States
| | - Anh Nguyen
- Department of Physics, Northeastern University, Boston, MA, United States
| | - Yashar Bashirzadeh
- Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Shan-Shan Lin
- Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, United States
| | - Dapeng Bi
- Department of Physics, Northeastern University, Boston, MA, United States
| | - Allen P. Liu
- Applied Physics Program, University of Michigan, Ann Arbor, MI, United States
- Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, United States
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States
- Department of Biophysics, University of Michigan, Ann Arbor, MI, United States
- Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, United States
- *Correspondence: Allen P. Liu,
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13
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Li M, Li Q, Dong H, Zhao S, Ning J, Bai X, Yue X, Xie A. Pilose antler polypeptides enhance chemotherapy effects in triple-negative breast cancer by activating the adaptive immune system. Int J Biol Macromol 2022; 222:2628-2638. [DOI: 10.1016/j.ijbiomac.2022.10.045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/04/2022] [Accepted: 10/06/2022] [Indexed: 11/05/2022]
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14
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Marles H, Biddle A. Cancer stem cell plasticity and its implications in the development of new clinical approaches for oral squamous cell carcinoma. Biochem Pharmacol 2022; 204:115212. [PMID: 35985402 DOI: 10.1016/j.bcp.2022.115212] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/10/2022] [Accepted: 08/10/2022] [Indexed: 11/25/2022]
Abstract
Oral squamous cell carcinoma (SCC) represents a major worldwide disease burden, with high rates of recurrence and metastatic spread following existing treatment methods. Populations of treatment resistant cancer stem cells (CSCs) are well characterised in oral SCC. These populations of CSCs engage the cellular programme known as epithelial mesenchymal transition (EMT) to enhance metastatic spread and therapeutic resistance. EMT is characterised by specific morphological changes and the expression of certain cell surface markers that represent a transition from an epithelial phenotype to a mesenchymal phenotype. This process is regulated by several cellular pathways that interact both horizontally and hierarchically. The cellular changes in EMT occur along a spectrum, with sub-populations of cells displaying both epithelial and mesenchymal features. The unique features of these CSCs in terms of their EMT state, cell surface markers and metabolism may offer new druggable targets. In addition, these features could be used to identify more aggressive disease states and the opportunity to personalise therapy depending on the presence of certain CSC sub-populations.
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Affiliation(s)
- Henry Marles
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London, London E1 2AT, UK
| | - Adrian Biddle
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London, London E1 2AT, UK.
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15
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Plasma-Based microRNA Expression Analysis in Advanced Stage NSCLC Patients Treated with Nivolumab. Cancers (Basel) 2022; 14:cancers14194739. [PMID: 36230658 PMCID: PMC9564103 DOI: 10.3390/cancers14194739] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/18/2022] [Accepted: 09/25/2022] [Indexed: 11/21/2022] Open
Abstract
Simple Summary Nivolumab (anti-PD-1 inhibitor) is the first monoclonal antibody approved for the treatment of NSCLC, with research results showing that patients who had received previous lines of therapy had a better response to this treatment and better overall survival. Tissue-level analyses fail to capture the dynamic tumor-host relationship, in contrast to circulating biomarkers, which can reflect the systemic response of the tumor, allowing for repeated sampling and monitoring. In the context of liquid biopsy, microRNAs are studied as biomarkers of immunotherapy efficacy based on their role in regulating antitumor immunity. The present study suggests that miR-200c and miR-34a plasma expression levels have a prognostic role in patients with advanced NSCLC receiving Nivolumab. It further supports that the expression profile of circulating immunomodulatory microRNAs provides information on the survival of patients with advanced NSCLC receiving Nivolumab and could represent promising circulating biomarkers that may provide information about patients’ responses to immunotherapy. Abstract Since circulating microRNAs (miRNAs) are involved in the modulation of the immune response, they are tested as liquid biopsy-based biomarkers in patients with NSCLC treated with immunotherapy. We analyzed the expression levels and examined the clinical significance of immunoregulatory miRNAs involved in immune checkpoint regulation (miR-34a, miR-200b, miR-200c), T-cell activity (miR-155), and the function of myeloid-derived suppressive cells (MDSCs) (miR-223) or regulatory T lymphocytes (Tregs) (miR-146a), in patients with advanced NSCLC (N = 69) treated with anti-PD-1 (Nivolumab) immunotherapy as 2nd or 3rd line of treatment therapy. Plasma levels of circulating miRNAs were analyzed by RT-qPCR before the initiation of immunotherapy. Expression of miR-34a, miR-146a, mir-200c, and miR-223 was found to be associated with response to immunotherapy. High miR-200c expression emerged as an independent prognostic factor for inferior overall survival in all patients with NSCLC (OS, HR: 2.243, 95% CI: 1.208–4.163; p = 0.010) and in patients with non-Squamous (non-SqCC) subtype (N = 38) (HR: 2.809, 95% CI: 1.116–7.074; p = 0.028). Low miR-34a expression independently predicted for shorter OS (HR: 3.189, 95% CI: 1.193–8.527; p = 0.021) in the non-SqCC subgroup. Our findings suggest that alterations in circulating miR-200c and miR-34a expression levels are associated with the response and outcome in patients with advanced NSCLC treated with anti-PD1 immunotherapy.
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16
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Wu Y, Li X, Li Q, Cheng C, Zheng L. Adipose tissue-to-breast cancer crosstalk: Comprehensive insights. Biochim Biophys Acta Rev Cancer 2022; 1877:188800. [PMID: 36103907 DOI: 10.1016/j.bbcan.2022.188800] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/29/2022] [Accepted: 09/06/2022] [Indexed: 10/14/2022]
Abstract
The review focuses on mechanistic evidence for the link between obesity and breast cancer. According to the IARC study, there is sufficient evidence that obesity is closely related to a variety of cancers. Among them, breast cancer is particularly disturbed by adipose tissue due to the unique histological structure of the breast. The review introduces the relationship between obesity and breast cancer from two aspects, including factors that promote tumorigenesis or metastasis. We summarize alterations in adipokines and metabolic pathways that contribute to breast cancer development. Breast cancer metastasis is closely related to obesity-induced pro-inflammatory microenvironment, adipose stem cells, and miRNAs. Based on the mechanism by which obesity causes breast cancer, we list possible therapeutic directions, including reducing the risk of breast cancer and inhibiting the progression of breast cancer. We also discussed the risk of autologous breast remodeling and fat transplantation. Finally, the causes of the obesity paradox and the function of enhancing immunity are discussed. Evaluating the balance between obesity-induced inflammation and enhanced immunity warrants further study.
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Affiliation(s)
- Yuan Wu
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Xu Li
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, PR China
| | - Qiong Li
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Chienshan Cheng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China
| | - Lan Zheng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital, Shanghai 200025, China.
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17
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Circulating miR-200 Family and CTCs in Metastatic Breast Cancer before, during, and after a New Line of Systemic Treatment. Int J Mol Sci 2022; 23:ijms23179535. [PMID: 36076930 PMCID: PMC9455626 DOI: 10.3390/ijms23179535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 08/20/2022] [Accepted: 08/21/2022] [Indexed: 11/16/2022] Open
Abstract
The extracellular circulating microRNA (miR)-200 regulates epithelial-mesenchymal transition and, thus, plays an essential role in the metastatic cascade and has shown itself to be a promising prognostic and predictive biomarker in metastatic breast cancer (MBC). Expression levels of the plasma miR-200 family were analyzed in relationship to systemic treatment, circulating tumor cells (CTC) count, progression-free survival (PFS), and overall survival (OS). Expression of miR-200a, miR-200b, miR-200c, miR-141, and miR-429, and CTC status (CTC-positive ≥ 5 CTC/7.5 mL) was assessed in 47 patients at baseline (BL), after the first completed cycle of a new line of systemic therapy (1C), and upon the progression of disease (PD). MiR-200a, miR-200b, and miR-141 expression was reduced at 1C compared to BL. Upon PD, all miR-200s were upregulated compared to 1C. At all timepoints, the levels of miR-200s were elevated in CTC-positive versus CTC-negative patients. Further, heightened miR-200s expression and positive CTC status were associated with poorer OS at BL and 1C. In MBC patients, circulating miR-200 family members decreased after one cycle of a new line of systemic therapy, were elevated during PD, and were indicative of CTC status. Notably, increased levels of miR-200s and elevated CTC count correlated with poorer OS and PFS. As such, both are promising biomarkers for optimizing the clinical management of MBC.
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18
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Sundararajan V, Burk UC, Bajdak-Rusinek K. Revisiting the miR-200 Family: A Clan of Five Siblings with Essential Roles in Development and Disease. Biomolecules 2022; 12:781. [PMID: 35740906 PMCID: PMC9221129 DOI: 10.3390/biom12060781] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/29/2022] [Accepted: 06/01/2022] [Indexed: 12/07/2022] Open
Abstract
Over two decades of studies on small noncoding RNA molecules illustrate the significance of microRNAs (miRNAs/miRs) in controlling multiple physiological and pathological functions through post-transcriptional and spatiotemporal gene expression. Among the plethora of miRs that are essential during animal embryonic development, in this review, we elaborate the indispensable role of the miR-200 family (comprising miR-200a, -200b, 200c, -141, and -429) in governing the cellular functions associated with epithelial homeostasis, such as epithelial differentiation and neurogenesis. Additionally, in pathological contexts, miR-200 family members are primarily involved in tumor-suppressive roles, including the reversal of the cancer-associated epithelial-mesenchymal transition dedifferentiation process, and are dysregulated during organ fibrosis. Moreover, recent eminent studies have elucidated the crucial roles of miR-200s in the pathophysiology of multiple neurodegenerative diseases and tissue fibrosis. Lastly, we summarize the key studies that have recognized the potential use of miR-200 members as biomarkers for the diagnosis and prognosis of cancers, elaborating the application of these small biomolecules in aiding early cancer detection and intervention.
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Affiliation(s)
- Vignesh Sundararajan
- Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore 117599, Singapore;
| | - Ulrike C. Burk
- Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany;
| | - Karolina Bajdak-Rusinek
- Department of Medical Genetics, Faculty of Medical Sciences, Medical University of Silesia, 40-752 Katowice, Poland
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Circulating miR-200 family as predictive markers during systemic therapy of metastatic breast cancer. Arch Gynecol Obstet 2022; 306:875-885. [PMID: 35237856 PMCID: PMC9411224 DOI: 10.1007/s00404-022-06442-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 02/10/2022] [Indexed: 12/09/2022]
Abstract
Purpose Circulating miRNAs can provide valid prognostic and predictive information for breast cancer diagnosis and subsequent management. They may comprise quintessential biomarkers that can be obtained minimally invasively from liquid biopsy in metastatic breast cancer patients. Therefore, they would be clinically crucial for monitoring therapy response, with the goal of detecting early relapse. This study investigated miRNA expression in patients with early and/or late relapse, and the predictive value for assessing overall (OS) and progression-free survival (PFS). Methods Forty-seven patients with metastatic breast cancer from the University Women’s Hospital Heidelberg were enrolled in this study. Expression of miR-200a, miR-200b, miR-200c, miR-141, and miR-429 was analyzed by RT-qPCR before a new line of systemic therapy and after the first cycle of a respective therapy. Tumor response was assessed every 3 months using the RECIST criteria. Statistical analysis focused on the relation of miR-200s expression and early vs. late cancer relapse in relation to systemic treatment. The association of miRNAs with PFS and OS was investigated. Results Before starting a new line of systemic therapy, miR-429 (p = 0.024) expression was significantly higher in patients with early relapse (PFS ≤ 4 months) than in patients with late relapse (PFS > 4 months). After one cycle of systemic therapy, miR-200a (p = 0.039), miR-200b (p = 0.003), miR-141 (p = 0.017), and miR-429 (p = 0.010) expression was higher in early than in late progressive cancer. In addition, 4 out of 5 miR-200 family members (miR-200a, miR-200b, miR-141, and miR-429) predicted PFS (p = 0.048, p = 0.008, p = 0.026, and p = 0.016, respectively). Patients with heightened miRNA levels showed a significant reduction in OS and PFS. Conclusion Circulating miR-200s were differentially expressed among patients with late and/or early relapse. 4 of 5 members of the miR-200 family predicted significantly early relapse after systemic treatment. Our results encourage the use of circulating miR-200s as valuable prognostic biomarkers during metastatic breast cancer therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s00404-022-06442-2.
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Cavallari I, Ciccarese F, Sharova E, Urso L, Raimondi V, Silic-Benussi M, D’Agostino DM, Ciminale V. The miR-200 Family of microRNAs: Fine Tuners of Epithelial-Mesenchymal Transition and Circulating Cancer Biomarkers. Cancers (Basel) 2021; 13:5874. [PMID: 34884985 PMCID: PMC8656820 DOI: 10.3390/cancers13235874] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/13/2022] Open
Abstract
The miR-200 family of microRNAs (miRNAs) includes miR-200a, miR-200b, miR-200c, miR-141 and miR-429, five evolutionarily conserved miRNAs that are encoded in two clusters of hairpin precursors located on human chromosome 1 (miR-200b, miR-200a and miR-429) and chromosome 12 (miR-200c and miR-141). The mature -3p products of the precursors are abundantly expressed in epithelial cells, where they contribute to maintaining the epithelial phenotype by repressing expression of factors that favor the process of epithelial-to-mesenchymal transition (EMT), a key hallmark of oncogenic transformation. Extensive studies of the expression and interactions of these miRNAs with cell signaling pathways indicate that they can exert both tumor suppressor- and pro-metastatic functions, and may serve as biomarkers of epithelial cancers. This review provides a summary of the role of miR-200 family members in EMT, factors that regulate their expression, and important targets for miR-200-mediated repression that are involved in EMT. The second part of the review discusses the potential utility of circulating miR-200 family members as diagnostic/prognostic biomarkers for breast, colorectal, lung, ovarian, prostate and bladder cancers.
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Affiliation(s)
- Ilaria Cavallari
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Francesco Ciccarese
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Evgeniya Sharova
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Loredana Urso
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padova, Italy
| | - Vittoria Raimondi
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Micol Silic-Benussi
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
| | - Donna M. D’Agostino
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Biomedical Sciences, University of Padua, 35131 Padova, Italy
| | - Vincenzo Ciminale
- Veneto Institute of Oncology IOV–IRCCS, 35128 Padova, Italy; (I.C.); (F.C.); (E.S.); (L.U.); (V.R.); (M.S.-B.)
- Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padova, Italy
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Li M, Zheng K, Ma S, Hu P, Yuan B, Yue X, Li Q. Pilose antler polypeptides promote chemosensitization and T-cell infiltration of triple-negative breast cancer. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104664] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
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22
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Circulating miRNAs and tissue iron overload in transfusion-dependent β-thalassemia major: novel predictors and follow-up guide. Ann Hematol 2021; 100:2909-2917. [PMID: 34432101 DOI: 10.1007/s00277-021-04639-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 08/18/2021] [Indexed: 11/27/2022]
Abstract
Tissue iron overload is a life-threatening scenario in children with transfusion-dependent β-thalassemia major, miRNAs that are involved in iron hemostasis could serve as therapeutic targets for control of iron overload. We aimed to find out the association between three iron-related miRNAs "miR-let-7d, miR-122, and miR-200b" and excess iron in tissues, in transfusion-dependent β-thalassemia major patients. Circulating miRNA expressions are measured in peripheral blood (PB) samples using qPCR of transfusion-dependent (TDT) β-thalassemia patients (n = 140) and normalized to non-transfusion-dependent (NTDT) β-thalassemia (n = 45). Results revealed that plasma expression levels of miR-let-7d and miR-200b were significantly downregulated in TDT patients; however, miR-122 was upregulated. In terms of tissue iron load, aberrant expression of miRNAs was significantly associated with increased-iron accumulation in hepatic and cardiac tissues. We concluded that circulating miRNAs are strong candidates that associate iron hemostasis in transfusion-dependent β-thalassemia major patients. And by extension, targeting miR-let-7d, miR-122, and miR-200 might serve as novel sensitive, specific and non-invasive predictor biomarkers for cellular damage under condition of tissue iron excess.
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23
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Kvokačková B, Remšík J, Jolly MK, Souček K. Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial-Mesenchymal Plasticity. Cancers (Basel) 2021; 13:2188. [PMID: 34063254 PMCID: PMC8125677 DOI: 10.3390/cancers13092188] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 04/29/2021] [Indexed: 12/27/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial-mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal-epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer.
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Affiliation(s)
- Barbora Kvokačková
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic;
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic
| | - Ján Remšík
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India;
| | - Karel Souček
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic;
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic
- Department of Experimental Biology, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic
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24
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Schvarcz CA, Danics L, Krenács T, Viana P, Béres R, Vancsik T, Nagy Á, Gyenesei A, Kun J, Fonović M, Vidmar R, Benyó Z, Kaucsár T, Hamar P. Modulated Electro-Hyperthermia Induces a Prominent Local Stress Response and Growth Inhibition in Mouse Breast Cancer Isografts. Cancers (Basel) 2021; 13:1744. [PMID: 33917524 PMCID: PMC8038813 DOI: 10.3390/cancers13071744] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/20/2021] [Accepted: 03/24/2021] [Indexed: 02/07/2023] Open
Abstract
Modulated electro-hyperthermia (mEHT) is a selective cancer treatment used in human oncology complementing other therapies. During mEHT, a focused electromagnetic field (EMF) is generated within the tumor inducing cell death by thermal and nonthermal effects. Here we investigated molecular changes elicited by mEHT using multiplex methods in an aggressive, therapy-resistant triple negative breast cancer (TNBC) model. 4T1/4T07 isografts inoculated orthotopically into female BALB/c mice were treated with mEHT three to five times. mEHT induced the upregulation of the stress-related Hsp70 and cleaved caspase-3 proteins, resulting in effective inhibition of tumor growth and proliferation. Several acute stress response proteins, including protease inhibitors, coagulation and heat shock factors, and complement family members, were among the most upregulated treatment-related genes/proteins as revealed by next-generation sequencing (NGS), Nanostring and mass spectrometry (MS). pathway analysis demonstrated that several of these proteins belong to the response to stimulus pathway. Cell culture treatments confirmed that the source of these proteins was the tumor cells. The heat-shock factor inhibitor KRIBB11 reduced mEHT-induced complement factor 4 (C4) mRNA increase. In conclusion, mEHT monotherapy induced tumor growth inhibition and a complex stress response. Inhibition of this stress response is likely to enhance the effectiveness of mEHT and other cancer treatments.
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Affiliation(s)
- Csaba András Schvarcz
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (C.A.S.); (L.D.); (P.V.); (R.B.); (T.V.); (Z.B.); (T.K.)
| | - Lea Danics
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (C.A.S.); (L.D.); (P.V.); (R.B.); (T.V.); (Z.B.); (T.K.)
| | - Tibor Krenács
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary;
| | - Pedro Viana
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (C.A.S.); (L.D.); (P.V.); (R.B.); (T.V.); (Z.B.); (T.K.)
| | - Rita Béres
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (C.A.S.); (L.D.); (P.V.); (R.B.); (T.V.); (Z.B.); (T.K.)
| | - Tamás Vancsik
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (C.A.S.); (L.D.); (P.V.); (R.B.); (T.V.); (Z.B.); (T.K.)
| | - Ákos Nagy
- Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary;
| | - Attila Gyenesei
- Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, János Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary; (A.G.); (J.K.)
| | - József Kun
- Bioinformatics Research Group, Genomics and Bioinformatics Core Facility, János Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary; (A.G.); (J.K.)
- Department of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Centre, Molecular Pharmacology Research Group, Centre for Neuroscience, University of Pécs, H-7624 Pécs, Hungary
| | - Marko Fonović
- Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, 1000 Ljubljana, Slovenia; (M.F.); (R.V.)
| | - Robert Vidmar
- Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, 1000 Ljubljana, Slovenia; (M.F.); (R.V.)
| | - Zoltán Benyó
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (C.A.S.); (L.D.); (P.V.); (R.B.); (T.V.); (Z.B.); (T.K.)
| | - Tamás Kaucsár
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (C.A.S.); (L.D.); (P.V.); (R.B.); (T.V.); (Z.B.); (T.K.)
| | - Péter Hamar
- Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary; (C.A.S.); (L.D.); (P.V.); (R.B.); (T.V.); (Z.B.); (T.K.)
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25
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Peng F, Tang H, Du J, Chen J, Peng C. Isoliquiritigenin Suppresses EMT-Induced Metastasis in Triple-Negative Breast Cancer through miR-200c/C-JUN/
β
-Catenin. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2021; 49:505-523. [PMID: 33641651 DOI: 10.1142/s0192415x21500233] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Triple-negative breast cancer (TNBC) is the subtype of breast cancer with more aggressive growth and metastasis and without efficient therapies. Hence, it is worthwhile to search for potential effective drug candidates. According to our previous study, isoliquiritigenin (ISL) exerted a potent anticancer effect on breast cancer proliferation. Its effect on TNBC growth, metastasis and mechanism deserves further investigation. In this study, PCR array screened a significant increase of miR-200c in BT-549 and MDA-MB-231 cells after ISL treatment, and ISH exerted that miR-200c was expressed at a low level in breast cancer tissue of patients. We also found that ISL could up-regulate miR-200c, resulting in the inhibition of epithelial-mesenchymal transition. Meanwhile, ISL could inhibit metastasis and tumor growth in nude mice models through the increase of miR-200c. Further study displayed that ISL decreased c-Jun expression through the increase of miR-200c. Interestingly, we also detected that ISL might increase miR-200c expression through the demethylation of miR-200c promoter region. These findings indicated that ISL could be potentially developed as a novel drug candidate for TNBC in microRNA-based cancer therapies.
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Affiliation(s)
- Fu Peng
- School of Chinese Medicine, The University of Hong Kong, Hong Kong
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional, Chinese Medicine, Chengdu, P. R. China
- West China School of Pharmacy, Sichuan University, Chengdu, P. R. China
| | - Hailin Tang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong
- Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, P. R. China
| | - Junrong Du
- West China School of Pharmacy, Sichuan University, Chengdu, P. R. China
| | - Jianping Chen
- School of Chinese Medicine, The University of Hong Kong, Hong Kong
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional, Chinese Medicine, Chengdu, P. R. China
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26
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Nair MG, Somashekaraiah VM, Ramamurthy V, Prabhu JS, Sridhar TS. miRNAs: Critical mediators of breast cancer metastatic programming. Exp Cell Res 2021; 401:112518. [PMID: 33607102 DOI: 10.1016/j.yexcr.2021.112518] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/06/2021] [Accepted: 02/08/2021] [Indexed: 12/14/2022]
Abstract
MicroRNA mediated aberrant gene regulation has been implicated in several diseases including cancer. Recent research has highlighted the role of epigenetic modulation of the complex process of breast cancer metastasis by miRNAs. miRNAs play a crucial role in the process of metastatic evolution by facilitating alterations in the phenotype of tumor cells and the tumor microenvironment that promote this process. They act as critical determinants of the multi-step progression starting from carcinogenesis all the way to organotropism. In this review, we focus on the current understanding of the compelling role of miRNAs in breast cancer metastasis.
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Affiliation(s)
- Madhumathy G Nair
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
| | | | - Vishakha Ramamurthy
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India
| | - Jyothi S Prabhu
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India
| | - T S Sridhar
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India
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27
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Rezaei Z, Sadri F. MicroRNAs Involved in Inflammatory Breast Cancer: Oncogene and Tumor Suppressors with Possible Targets. DNA Cell Biol 2021; 40:499-512. [PMID: 33493414 DOI: 10.1089/dna.2020.6320] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Inflammatory breast cancer (IBC) as a rare and highly aggressive type of breast cancer displays phenotypic characteristics. To date, the IBC-associated molecular mechanisms are entirely unknown. In addition, there is an urgent need to identify the new biomarkers involved in the diagnosis and therapeutic purposes of IBC. MicroRNAs, a category of short noncoding RNAs, are capable of controlling the post-transcriptional expression of genes and thus can act as diagnostic predictive tools. In this review, we addressed the status of oncogenic and tumor suppressor miRNA-mediated IBC in current studies. Furthermore, based on their targets, their involvement in cancer progression, angiogenesis, metastasis, and apoptosis were determined.
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Affiliation(s)
- Zohreh Rezaei
- Department of Biology, University of Sistan and Baluchestan, Zahedan, Iran.,Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Farzad Sadri
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran.,Young Researchers and Elite Club, Yasooj Branch, Islamic Azad University, Yasooj, Iran
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28
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Tiny miRNAs Play a Big Role in the Treatment of Breast Cancer Metastasis. Cancers (Basel) 2021; 13:cancers13020337. [PMID: 33477629 PMCID: PMC7831489 DOI: 10.3390/cancers13020337] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/14/2021] [Accepted: 01/14/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary MicroRNAs (miRNAs) have emerged as important regulators of tumour progression and metastasis in breast cancer. Through a review of multiple studies, this paper has identified the key regulatory roles of oncogenic miRNAs in breast cancer metastasis including the potentiation of angiogenesis, epithelial-mesenchymal transition, the Warburg effect, and the tumour microenvironment. Several approaches have been studied for selective targeting of breast tumours by miRNAs, ranging from delivery systems such as extracellular vesicles and liposomes to the use of prodrugs and functionally modified vehicle-free miRNAs. While promising, these miRNA-based therapies face challenges including toxicity and immunogenicity, and greater research on their safety profiles must be performed before progressing to clinical trials. Abstract Distant organ metastases accounts for the majority of breast cancer deaths. Given the prevalence of breast cancer in women, it is imperative to understand the underlying mechanisms of its metastatic progression and identify potential targets for therapy. Since their discovery in 1993, microRNAs (miRNAs) have emerged as important regulators of tumour progression and metastasis in various cancers, playing either oncogenic or tumour suppressor roles. In the following review, we discuss the roles of miRNAs that potentiate four key areas of breast cancer metastasis—angiogenesis, epithelial-mesenchymal transition, the Warburg effect and the tumour microenvironment. We then evaluate the recent developments in miRNA-based therapies in breast cancer, which have shown substantial promise in controlling tumour progression and metastasis. Yet, certain challenges must be overcome before these strategies can be implemented in clinical trials.
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29
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Ravegnini G, Serrano C, Ricci R, Zhang Q, Terrenato I, Graziosi A, Valori G, Landolfi S, Hrelia P, Angelini S. miRNA landscape in primary tumors and matched metastases in gastrointestinal stromal tumors. Epigenomics 2021; 13:369-377. [PMID: 33432846 DOI: 10.2217/epi-2020-0303] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: Gastrointestinal stromal tumor management is extremely challenging, particularly the metastatic disease. The underlying mechanism in metastasis spread remains largely unknown. We aimed to characterize miRNAs involved in the metastatic process in gastrointestinal stromal tumor. Material & methods: Eight primary tumors and 18 synchronous metastases were analyzed through miRNA Taqman arrays or assays. Results: miRNAs profiles revealed similar expression in primary site and metastases. Pair-wise correlation coefficient between primary tumor and metastases was significant for each patient (p < 0.0001 for all profiled patients). Conclusion: Our study, the largest including primary tumors and metastases so far performed, highlighted perpetuation of miRNAs features in metastatic lesions and that the primary origin appears to be the main determinant of the metastases miRNA profile.
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Affiliation(s)
- Gloria Ravegnini
- Department of Pharmacy & Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Cèsar Serrano
- Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology, 08035 Barcelona, Spain.,Department of Medical Oncology, Vall d'Hebron University Hospital, 08035 Barcelona, Spain
| | - Riccardo Ricci
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, 00168 Rome, Italy
| | - Qianqian Zhang
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, 00168 Rome, Italy
| | - Irene Terrenato
- Biostatistics-Scientific Direction, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Agnese Graziosi
- Department of Pharmacy & Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Giorgia Valori
- Department of Pharmacy & Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Stefania Landolfi
- Department of Pathology, Vall d'Hebron University Hospital, 08035 Barcelona, Spain
| | - Patrizia Hrelia
- Department of Pharmacy & Biotechnology, University of Bologna, 40126 Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy & Biotechnology, University of Bologna, 40126 Bologna, Italy
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30
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Integrative p53, micro-RNA and Cathepsin Protease Co-Regulatory Expression Networks in Cancer. Cancers (Basel) 2020; 12:cancers12113454. [PMID: 33233599 PMCID: PMC7699684 DOI: 10.3390/cancers12113454] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/05/2020] [Accepted: 11/18/2020] [Indexed: 12/12/2022] Open
Abstract
Simple Summary This article describes an emerging area of significant interest in cancer and cell death and the relationships shared by these through the transcriptional regulation of cathepsin protease genes by micro-RNAs that are connected to p53 activation. While it has been demonstrated that the p53 protein can directly regulate some cathepsin genes and the expression of their upstream regulatory micro-RNAs, very little is known about what input the p53 isoform proteins may have in regulating this relationship. Herein, we draw attention to this important regulatory aspect in the context of describing mechanisms that are being established for the micro-RNA regulation of cathepsin protease genes and their collective use in diagnostic or prognostic assays. Abstract As the direct regulatory role of p53 and some of its isoform proteins are becoming established in modulating gene expression in cancer research, another aspect of this mode of gene regulation that has captured significant interest over the years is the mechanistic interplay between p53 and micro-RNA transcriptional regulation. The input of this into modulating gene expression for some of the cathepsin family members has been viewed as carrying noticeable importance based on their biological effects during normal cellular homeostasis and cancer progression. While this area is still in its infancy in relation to general cathepsin gene regulation, we review the current p53-regulated micro-RNAs that are generating significant interest through their regulation of cathepsin proteases, thereby strengthening the link between activated p53 forms and cathepsin gene regulation. Additionally, we extend our understanding of this developing relationship to how such micro-RNAs are being utilized as diagnostic or prognostic tools and highlight their future uses in conjunction with cathepsin gene expression as potential biomarkers within a clinical setting.
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31
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Expression pattern analysis and drug differential sensitivity of cancer-associated fibroblasts in triple-negative breast cancer. Transl Oncol 2020; 14:100891. [PMID: 33069102 PMCID: PMC7563008 DOI: 10.1016/j.tranon.2020.100891] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 08/29/2020] [Accepted: 09/21/2020] [Indexed: 12/18/2022] Open
Abstract
Triple-negative breast cancer (TNBC) has the characteristics of a complex molecular landscape, aggressive or high proliferation leading to poor prognosis, and behavioral heterogeneity. The purpose of the present study was to determine the spatiotemporal expression of α-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs) at histological level in 4T1 tumors and to predict the sensitivity to 138 drugs in patients with TNBC according to α-SMA expression. The quantitative results of fibrosis showed that the volume of 4T1 tumors correlated positively with the area of tumor fibrosis. Furthermore, we divided 4T1 tumors according to the degree of fibrosis and characterized the molecular characteristics of the four regions. Finally, the difference in the signaling pathways and sensitivity to 138 drugs was analyzed in patients with TNBC according to α-SMA expression combined with The Cancer Genome Atlas (TCGA) database. The myogenesis, TGF-β, and Notch signaling pathways were upregulated and the patients with TNBC were significantly differentially sensitive to 25 drugs. The results of in vivo experiments showed that the inhibitory effect of embelin on 4T1 tumors with high α-SMA expression was greater than that on 4TO7 tumors with low α-SMA expression. At the same time, embelin significantly decreased α-SMA and PDGFRA expression in 4T1 tumors compared with the control group. Our findings add to understanding of CAF distribution in the 4T1 tumor microenvironment and its possible role in treating cancer.
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32
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Bakir B, Chiarella AM, Pitarresi JR, Rustgi AK. EMT, MET, Plasticity, and Tumor Metastasis. Trends Cell Biol 2020; 30:764-776. [PMID: 32800658 PMCID: PMC7647095 DOI: 10.1016/j.tcb.2020.07.003] [Citation(s) in RCA: 636] [Impact Index Per Article: 127.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/02/2020] [Accepted: 07/10/2020] [Indexed: 01/06/2023]
Abstract
Cancer cell identity and plasticity are required in transition states, such as epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), in primary tumor initiation, progression, and metastasis. The functional roles of EMT, MET, and the partial state (referred to as pEMT) may vary based on the type of tumor, the state of dissemination, and the degree of metastatic colonization. Herein, we review EMT, MET, pEMT, and plasticity in the context of tumor metastasis.
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Affiliation(s)
- Basil Bakir
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Anna M Chiarella
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
| | - Jason R Pitarresi
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Anil K Rustgi
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
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33
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Abdalla F, Singh B, Bhat HK. MicroRNAs and gene regulation in breast cancer. J Biochem Mol Toxicol 2020; 34:e22567. [DOI: 10.1002/jbt.22567] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 06/01/2020] [Accepted: 06/18/2020] [Indexed: 12/15/2022]
Affiliation(s)
- Fatma Abdalla
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy University of Missouri‐Kansas City Kansas City Missouri
| | - Bhupendra Singh
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy University of Missouri‐Kansas City Kansas City Missouri
- Eurofins Lancaster Laboratories Lancaster PA 17605
| | - Hari K. Bhat
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy University of Missouri‐Kansas City Kansas City Missouri
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34
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Fahim SA, Abdullah MS, Espinoza-Sánchez NA, Hassan H, Ibrahim AM, Ahmed SH, Shakir G, Badawy MA, Zakhary NI, Greve B, El-Shinawi M, Götte M, Ibrahim SA. Inflammatory Breast Carcinoma: Elevated microRNA miR-181b-5p and Reduced miR-200b-3p, miR-200c-3p, and miR-203a-3p Expression as Potential Biomarkers with Diagnostic Value. Biomolecules 2020; 10:E1059. [PMID: 32708601 PMCID: PMC7407124 DOI: 10.3390/biom10071059] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/07/2020] [Accepted: 07/10/2020] [Indexed: 12/15/2022] Open
Abstract
Inflammatory breast cancer (IBC) is a rare yet aggressive breast cancer variant, associated with a poor prognosis. The major challenge for IBC is misdiagnosis due to the lack of molecular biomarkers. We profiled dysregulated expression of microRNAs (miRNAs) in primary samples of IBC and non-IBC tumors using human breast cancer miRNA PCR array. We discovered that 28 miRNAs were dysregulated (10 were upregulated, while 18 were underexpressed) in IBC vs. non-IBC tumors. We identified 128 hub genes, which are putative targets of the differentially expressed miRNAs and modulate important cancer biological processes. Furthermore, our qPCR analysis independently verified a significantly upregulated expression of miR-181b-5p, whereas a significant downregulation of miR-200b-3p, miR-200c-3p, and miR-203a-3p was detected in IBC tumors. Receiver operating characteristic (ROC) curves implied that the four miRNAs individually had a diagnostic accuracy in discriminating patients with IBC from non-IBC and that miR-203a-3p had the highest diagnostic value with an AUC of 0.821. Interestingly, a combination of miR-181b-5p, miR-200b-3p, and miR-200c-3p robustly improved the diagnostic accuracy, with an area under the curve (AUC) of 0.897. Intriguingly, qPCR revealed that the expression of zinc finger E box-binding homeobox 2 (ZEB2) mRNA, the putative target of miR-200b-3p, miR-200c-3p, and miR-203a-3p, was upregulated in IBC tumors. Overall, this study identified a set of miRNAs serving as potential biomarkers with diagnostic relevance for IBC.
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Affiliation(s)
- Sarah Atef Fahim
- Biochemistry Program, Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt;
| | - Mahmoud Salah Abdullah
- Biotechnology/Biomolecular Chemistry Program, Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt; (M.S.A.); (S.H.A.); (G.S.)
| | | | - Hebatallah Hassan
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt; (H.H.); (A.M.I.)
| | - Ayman M. Ibrahim
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt; (H.H.); (A.M.I.)
| | - Sarah Hamdy Ahmed
- Biotechnology/Biomolecular Chemistry Program, Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt; (M.S.A.); (S.H.A.); (G.S.)
| | - George Shakir
- Biotechnology/Biomolecular Chemistry Program, Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt; (M.S.A.); (S.H.A.); (G.S.)
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, 80539 Munich, Germany
| | - Mohamed A. Badawy
- Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt;
| | - Nadia I. Zakhary
- Cancer Biology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt;
| | - Burkhard Greve
- Department of Radiotherapy–Radiooncology, University Hospital Münster, 48149 Münster, Germany;
| | - Mohamed El-Shinawi
- Department of General Surgery, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt;
| | - Martin Götte
- Department of Gynecology and Obstetrics, Münster University Hospital, 48149 Münster, Germany;
| | - Sherif Abdelaziz Ibrahim
- Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Egypt; (H.H.); (A.M.I.)
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Lu JT, Tan CC, Wu XR, He R, Zhang X, Wang QS, Li XQ, Zhang R, Feng YM. FOXF2 deficiency accelerates the visceral metastasis of basal-like breast cancer by unrestrictedly increasing TGF-β and miR-182-5p. Cell Death Differ 2020; 27:2973-2987. [PMID: 32424142 DOI: 10.1038/s41418-020-0555-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 12/15/2022] Open
Abstract
The mesenchymal transcription factor forkhead box F2 (FOXF2) is a critical regulator of embryogenesis and tissue homeostasis. Our previous studies demonstrated that FOXF2 is ectopically expressed in basal-like breast cancer (BLBC) cells and that FOXF2 deficiency promotes the epithelial-mesenchymal transition and aggressiveness of BLBC cells. In this study, we found that FOXF2 controls transforming growth factor-beta (TGF-β)/SMAD signaling pathway activation through transrepression of TGF-β-coding genes in BLBC cells. FOXF2-deficient BLBC cells adopt a myofibroblast-/cancer-associated fibroblast (CAF)-like phenotype, and tend to metastasize to visceral organs by increasing autocrine TGF-β signaling and conferring aggressiveness to neighboring cells by increasing paracrine TGF-β signaling. In turn, TGF-β silences FOXF2 expression through upregulating miR-182-5p, a posttranscriptional regulator of FOXF2 and inducer of metastasis. In addition to mediating a reciprocal repression loop between FOXF2 and TGF-β through direct transrepression by SMAD3, miR-182-5p forms a reciprocal repression loop with FOXF2 that directly transrepresses MIR182 expression. Therefore, FOXF2 deficiency accelerates the visceral metastasis of BLBC through unrestricted increases in autocrine and paracrine TGF-β signaling, and miR-182-5p expression. Our findings provide novel mechanisms underlying the roles of TGF-β, miR-182-5p, and FOXF2 in accelerating BLBC dissemination and metastasis, and may facilitate the development of therapeutic strategies for aggressive BLBC.
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Affiliation(s)
- Jun-Tao Lu
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
| | - Cong-Cong Tan
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
| | - Xiao-Ran Wu
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
| | - Rui He
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
| | - Xiao Zhang
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
| | - Qing-Shan Wang
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
| | - Xiao-Qing Li
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
| | - Rui Zhang
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China.,Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China
| | - Yu-Mei Feng
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China. .,Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin, 300060, China.
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36
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Kong D, Hughes CJ, Ford HL. Cellular Plasticity in Breast Cancer Progression and Therapy. Front Mol Biosci 2020; 7:72. [PMID: 32391382 PMCID: PMC7194153 DOI: 10.3389/fmolb.2020.00072] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/31/2020] [Indexed: 12/24/2022] Open
Abstract
With the exception of non-melanoma skin cancer, breast cancer is the most frequently diagnosed malignant disease among women, with the majority of mortality being attributable to metastatic disease. Thus, even with improved early screening and more targeted treatments which may enable better detection and control of early disease progression, metastatic disease remains a significant problem. While targeted therapies exist for breast cancer patients with particular subtypes of the disease (Her2+ and ER/PR+), even in these subtypes the therapies are often not efficacious once the patient's tumor metastasizes. Increases in stemness or epithelial-to-mesenchymal transition (EMT) in primary breast cancer cells lead to enhanced plasticity, enabling tumor progression, therapeutic resistance, and distant metastatic spread. Numerous signaling pathways, including MAPK, PI3K, STAT3, Wnt, Hedgehog, and Notch, amongst others, play a critical role in maintaining cell plasticity in breast cancer. Understanding the cellular and molecular mechanisms that regulate breast cancer cell plasticity is essential for understanding the biology of breast cancer progression and for developing novel and more effective therapeutic strategies for targeting metastatic disease. In this review we summarize relevant literature on mechanisms associated with breast cancer plasticity, tumor progression, and drug resistance.
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Affiliation(s)
- Deguang Kong
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Connor J. Hughes
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Heide L. Ford
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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microRNAs in the Antitumor Immune Response and in Bone Metastasis of Breast Cancer: From Biological Mechanisms to Therapeutics. Int J Mol Sci 2020; 21:ijms21082805. [PMID: 32316552 PMCID: PMC7216039 DOI: 10.3390/ijms21082805] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/03/2020] [Accepted: 04/15/2020] [Indexed: 12/11/2022] Open
Abstract
Breast cancer is the most common type of cancer in women, and the occurrence of metastasis drastically worsens the prognosis and reduces overall survival. Understanding the biological mechanisms that regulate the transformation of malignant cells, the consequent metastatic transformation, and the immune surveillance in the tumor progression would contribute to the development of more effective and targeted treatments. In this context, microRNAs (miRNAs) have proven to be key regulators of the tumor-immune cells crosstalk for the hijack of the immunosurveillance to promote tumor cells immune escape and cancer progression, as well as modulators of the metastasis formation process, ranging from the preparation of the metastatic site to the transformation into the migrating phenotype of tumor cells. In particular, their deregulated expression has been linked to the aberrant expression of oncogenes and tumor suppressor genes to promote tumorigenesis. This review aims at summarizing the role and functions of miRNAs involved in antitumor immune response and in the metastasis formation process in breast cancer. Additionally, miRNAs are promising targets for gene therapy as their modulation has the potential to support or inhibit specific mechanisms to negatively affect tumorigenesis. With this perspective, the most recent strategies developed for miRNA-based therapeutics are illustrated.
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Prabhu KS, Raza A, Karedath T, Raza SS, Fathima H, Ahmed EI, Kuttikrishnan S, Therachiyil L, Kulinski M, Dermime S, Junejo K, Steinhoff M, Uddin S. Non-Coding RNAs as Regulators and Markers for Targeting of Breast Cancer and Cancer Stem Cells. Cancers (Basel) 2020; 12:351. [PMID: 32033146 PMCID: PMC7072613 DOI: 10.3390/cancers12020351] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 01/27/2020] [Accepted: 02/02/2020] [Indexed: 02/07/2023] Open
Abstract
Breast cancer is regarded as a heterogeneous and complicated disease that remains the prime focus in the domain of public health concern. Next-generation sequencing technologies provided a new perspective dimension to non-coding RNAs, which were initially considered to be transcriptional noise or a product generated from erroneous transcription. Even though understanding of biological and molecular functions of noncoding RNA remains enigmatic, researchers have established the pivotal role of these RNAs in governing a plethora of biological phenomena that includes cancer-associated cellular processes such as proliferation, invasion, migration, apoptosis, and stemness. In addition to this, the transmission of microRNAs and long non-coding RNAs was identified as a source of communication to breast cancer cells either locally or systemically. The present review provides in-depth information with an aim at discovering the fundamental potential of non-coding RNAs, by providing knowledge of biogenesis and functional roles of micro RNA and long non-coding RNAs in breast cancer and breast cancer stem cells, as either oncogenic drivers or tumor suppressors. Furthermore, non-coding RNAs and their potential role as diagnostic and therapeutic moieties have also been summarized.
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Affiliation(s)
- Kirti S. Prabhu
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (H.F.); (E.I.A.); (S.K.); (L.T.); (M.K.); (M.S.); (S.U.)
| | - Afsheen Raza
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha 3050, Qatar; (A.R.); (S.D.)
| | | | - Syed Shadab Raza
- Department of Stem Cell Biology and Regenerative Medicine, Era University, Lucknow 226003, India;
| | - Hamna Fathima
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (H.F.); (E.I.A.); (S.K.); (L.T.); (M.K.); (M.S.); (S.U.)
| | - Eiman I. Ahmed
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (H.F.); (E.I.A.); (S.K.); (L.T.); (M.K.); (M.S.); (S.U.)
| | - Shilpa Kuttikrishnan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (H.F.); (E.I.A.); (S.K.); (L.T.); (M.K.); (M.S.); (S.U.)
- Qatar College of Pharmacy, Qatar University, Doha 3050, Qatar
| | - Lubna Therachiyil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (H.F.); (E.I.A.); (S.K.); (L.T.); (M.K.); (M.S.); (S.U.)
- Qatar College of Pharmacy, Qatar University, Doha 3050, Qatar
| | - Michal Kulinski
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (H.F.); (E.I.A.); (S.K.); (L.T.); (M.K.); (M.S.); (S.U.)
| | - Said Dermime
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha 3050, Qatar; (A.R.); (S.D.)
| | - Kulsoom Junejo
- General Surgery Department, Hamad General Hospital, Hamad Medical Corporation, Doha 3050, Qatar;
| | - Martin Steinhoff
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (H.F.); (E.I.A.); (S.K.); (L.T.); (M.K.); (M.S.); (S.U.)
- Department of Dermatology Venereology, Hamad Medical Corporation, Doha 3050, Qatar
- Department of Dermatology, Weill Cornell Medicine, Qatar Foundation, Education City, Doha 24144, Qatar
- Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; (H.F.); (E.I.A.); (S.K.); (L.T.); (M.K.); (M.S.); (S.U.)
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Williams ED, Gao D, Redfern A, Thompson EW. Controversies around epithelial-mesenchymal plasticity in cancer metastasis. Nat Rev Cancer 2019; 19:716-732. [PMID: 31666716 PMCID: PMC7055151 DOI: 10.1038/s41568-019-0213-x] [Citation(s) in RCA: 287] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/18/2019] [Indexed: 02/07/2023]
Abstract
Experimental evidence accumulated over decades has implicated epithelial-mesenchymal plasticity (EMP), which collectively encompasses epithelial-mesenchymal transition and the reverse process of mesenchymal-epithelial transition, in tumour metastasis, cancer stem cell generation and maintenance, and therapeutic resistance. However, the dynamic nature of EMP processes, the apparent need to reverse mesenchymal changes for the development of macrometastases and the likelihood that only minor cancer cell subpopulations exhibit EMP at any one time have made such evidence difficult to accrue in the clinical setting. In this Perspectives article, we outline the existing preclinical and clinical evidence for EMP and reflect on recent controversies, including the failure of initial lineage-tracing experiments to confirm a major role for EMP in dissemination, and discuss accumulating data suggesting that epithelial features and/or a hybrid epithelial-mesenchymal phenotype are important in metastasis. We also highlight strategies to address the complexities of therapeutically targeting the EMP process that give consideration to its spatially and temporally divergent roles in metastasis, with the view that this will yield a potent and broad class of therapeutic agents.
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Affiliation(s)
- Elizabeth D Williams
- Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Queensland, Australia
- Translational Research Institute (TRI), Brisbane, Queensland, Australia
- Australian Prostate Cancer Research Centre - Queensland (APCRC-Q) and Queensland Bladder Cancer Initiative (QBCI), Brisbane, Queensland, Australia
| | - Dingcheng Gao
- Department of Cardiothoracic Surgery, Department of Cell and Developmental Biology and Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | - Andrew Redfern
- Department of Medicine, School of Medicine, University of Western Australia, Fiona Stanley Hospital Campus, Perth, Western Australia, Australia
| | - Erik W Thompson
- Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Queensland, Australia.
- Translational Research Institute (TRI), Brisbane, Queensland, Australia.
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Rezaeian AH, Khanbabaei H, Calin GA. Therapeutic Potential of the miRNA-ATM Axis in the Management of Tumor Radioresistance. Cancer Res 2019; 80:139-150. [PMID: 31767626 DOI: 10.1158/0008-5472.can-19-1807] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 10/09/2019] [Accepted: 11/14/2019] [Indexed: 11/16/2022]
Abstract
The ataxia-telangiectasia mutated (ATM) protein kinase is widely known for its function as a chief mobilizer of the DNA damage response (DDR) upon DNA double-strand breaks. ATM orchestrates the DDR by modulating the expression of various miRNAs through several mechanisms. On the other hand, a set of miRNAs contribute to tight regulation of ATM by directly targeting the 3'-untranslated region of ATM mRNA. This review addresses the therapeutic application and molecular mechanisms that underlie the intricate interactions between miRNAs and ATM. It also describes therapeutic delivery of miRNAs in different environments such as hypoxic tumor microenvironments.
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Affiliation(s)
- Abdol-Hossein Rezaeian
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Hashem Khanbabaei
- Department of Medical Physics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - George A Calin
- Departments of Experimental Therapeutics and Leukemia and the Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Kaban K, Salva E, Akbuga J. Modulation of the dual-faced effects of miR-141 with chitosan/miR-141 nanoplexes in breast cancer cells. J Gene Med 2019; 21:e3116. [PMID: 31389101 DOI: 10.1002/jgm.3116] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 07/24/2019] [Accepted: 07/24/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND miR-141, known as a tumor suppressive microRNA, is downregulated in breast cancer. However, recent contrasting studies report that it also acts as oncogene when it is upregulated. The present study aimed to investigate whether miR-141 is a tumor suppressor or oncogenic when it reaches normal levels in chitosan/miR-141 nanoplexes. METHODS Chitosan nanoplexes were prepared using simple complexation method. Nanoplexes were characterized by a gel retardation assay and zeta potential and particle size measurements. To determine the expression level of miR-141, a quantitative real-time polymerase chain reaction was performed. The effects of miR-141 mimics were investigated with respect to angiogenesis by vascular endothelial growth factor (VEGF), epithelial-mesenchymal transition (EMT) by E-cadherin, metastasis by Igfbp-4 and Tinagl1 enzyme-linked immunosorbent assays, invasion by an invasion chamber, and apoptosis by Annexin V. RESULTS The miR-141 expression levels of MDA-MB-231 and MDA-MB-435 cells by administration of chitosan/mimic miR-141 nanoplexes reached endogenous miR-141 levels of a non-tumorigenic epithelial breast cell line, MCF-10A. According to our results, metastasis, VEGF, EMT and invasion in breast cancer cells were diminished, whereas apoptosis increased by 1.5- and 2.4-fold in breast cancer cell lines as a result of the miR-141 mimics. CONCLUSIONS In conclusion, we have demonstrated that administration of miR-141 mimics at the determined doses to breast cancer cells revealed a tumor suppressor effect, and not the oncogenic face. The delivery of miR-141 by chitosan nanoplexes presents a promising approach for the suppression of breast cancer.
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Affiliation(s)
- Kubra Kaban
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, Istanbul, Turkey
| | - Emine Salva
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Inonu University, Malatya, Turkey
| | - Julide Akbuga
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Marmara University, Istanbul, Turkey
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Carter JV, O'Brien SJ, Burton JF, Oxford BG, Stephen V, Hallion J, Bishop C, Galbraith NJ, Eichenberger MR, Sarojini H, Hattab E, Galandiuk S. The microRNA-200 family acts as an oncogene in colorectal cancer by inhibiting the tumor suppressor RASSF2. Oncol Lett 2019; 18:3994-4007. [PMID: 31565080 PMCID: PMC6759516 DOI: 10.3892/ol.2019.10753] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 04/03/2019] [Indexed: 12/17/2022] Open
Abstract
This study aimed to determine whether manipulation of the microRNA-200 (miR-200) family could influence colon adenocarcinoma cell behavior. The miR-200 family has a significant role in tumor suppression and functions as an oncogene. In vitro studies on gain and loss of function with small interfering RNA demonstrated that the miR-200 family could regulate RASSF2 expression. Knockdown of the miR-200 family in the HT-29 colon cancer cell line increased KRAS expression but decreased signaling in the MAPK/ERK signaling pathway through reduced ERK phosphorylation. Increased expression of the miR-200 family in the CCD-841 colon epithelium cell line increased KRAS expression and led to increased signaling in the MAPK/ERK signaling pathway but increased ERK phosphorylation. Functionally, knockdown of the miR-200 family led to decreased cell proliferation in the HT-29 cells; therefore, increased miR-200 family expression could increase cell proliferation in the CCD-841 cell line. The present study included a large paired miR array dataset (n=632), in which the miR-200 family was significantly found to be increased in colon cancer when compared with normal adjacent colon epithelium. In a miR-seq dataset (n=199), the study found that miR-200 family expression was increased in localized colon cancer compared with metastatic disease. Decreased expression was associated with poorer overall survival. The miR-200 family directly targeted RASSF2 and was inversely correlated with RASSF2 expression (n=199, all P<0.001). Despite the well-defined role of the miR-200 family in tumor suppression, the present findings demonstrated a novel function of the miR-200 family in tumor proliferation.
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Affiliation(s)
- Jane V Carter
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA.,Department of Surgery, North Cumbria University Hospitals NHS Trust, Carlisle, Cumbria CA2 7HY, UK
| | - Stephen J O'Brien
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - James F Burton
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Brent G Oxford
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA.,School of Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Vince Stephen
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA.,School of Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Jake Hallion
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Campbell Bishop
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Norman J Galbraith
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA.,Department of Surgery, University Hospital Wishaw, Wishaw, North Lanarkshire ML2 0DP, UK
| | - Maurice R Eichenberger
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Harshini Sarojini
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Eyas Hattab
- Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Susan Galandiuk
- Price Institute of Surgical Research, University of Louisville School of Medicine, Louisville, KY 40202, USA
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Diaz-Riascos ZV, Ginesta MM, Fabregat J, Serrano T, Busquets J, Buscail L, Cordelier P, Capellá G. Expression and Role of MicroRNAs from the miR-200 Family in the Tumor Formation and Metastatic Propensity of Pancreatic Cancer. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 17:491-503. [PMID: 31336236 PMCID: PMC6656921 DOI: 10.1016/j.omtn.2019.06.015] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/13/2019] [Accepted: 06/14/2019] [Indexed: 12/21/2022]
Abstract
MicroRNAs from the miR-200 family are commonly associated with the inhibition of the metastatic potential of cancer cells, following inhibition of ZEB transcription factors expression and epithelial-to-mesenchymal transition. However, previous studies performed in pancreatic adenocarcinoma revealed a more complex picture challenging this canonical model. To gain better insights into the role of miR-200 family members in this disease, we analyzed the expression of miR-200a, miR-200b, miR-200c, miR-141, miR-429, and miR-205, and ZEB1, ZEB2, and CDH1 in pancreatic tumors and matching normal adjacent parenchyma and patient-derived xenografts. We found that miR-200a, miR-429, and miR-205 are frequently overexpressed in pancreatic tumors, whereas CDH1 is downregulated, and ZEB1 and ZEB2 levels remain unchanged. Furthermore, we measured a positive correlation between miR-200 family members and CDH1 expression, and a negative correlation between ZEB1 and miR-200c, miR-141, and miR-205 expression, respectively. Interestingly, we identified significant changes in expression of epithelial-to-mesenchymal transition regulators and miR-200 members in patient-derived xenografts. Lastly, functional studies revealed that miR-141 and miR-429 inhibit the tumorigenic potential of pancreatic cancer cells. Taken together, this comprehensive analysis strongly suggests that miRNAs from the miR-200 family, and in particular miR-429, may act as a tumor suppressor gene in pancreatic cancer.
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Affiliation(s)
- Zamira Vanessa Diaz-Riascos
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Mireia M Ginesta
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; CIBERONC, Centro de Investigación Biomédica en Red en Cáncer, Madrid, Spain
| | - Joan Fabregat
- Department of Surgery, Hepatobiliopancreatic Unit, IDIBELL-Hospital Universitari Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Teresa Serrano
- Department of Pathology, IDIBELL-Hospital Universitari Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Juli Busquets
- Department of Surgery, Hepatobiliopancreatic Unit, IDIBELL-Hospital Universitari Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Louis Buscail
- Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, INSERM U1037, Cancer Research Centre of Toulouse (CRCT), Toulouse, France; Department of Gastroenterology, CHU Toulouse-Rangueil, Toulouse, France
| | - Pierre Cordelier
- Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, INSERM U1037, Cancer Research Centre of Toulouse (CRCT), Toulouse, France.
| | - Gabriel Capellá
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; CIBERONC, Centro de Investigación Biomédica en Red en Cáncer, Madrid, Spain.
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Gao Z, Zhou H, Wang Y, Chen J, Ou Y. Regulatory effects of lncRNA ATB targeting miR-200c on proliferation and apoptosis of colorectal cancer cells. J Cell Biochem 2019; 121:332-343. [PMID: 31222825 DOI: 10.1002/jcb.29180] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/22/2019] [Accepted: 05/23/2019] [Indexed: 01/17/2023]
Abstract
This investigation was intended to elucidate whether long noncoding RNA (lncRNA)-activated by transforming growth factor-β (ATB) interacting with miR-200c could mediate colorectal cancer (CRC) progression, offering potential strategies for diagnosing and treating CRC. Here totally 315 patients with CRC were recruited, and their CRC tissues and adjacent normal tissues were gathered. Concurrently, four colon cancer cell lines (ie, SW620, Lovo, HCT116, and SW480) and the human colon mucosal epithelial cell line (NCM460) were also purchased. Moreover, si-ATB, si-NC, miR-200c mimic, miR-200c inhibitor, and miR-NC were prepared for transfection into the CRC cells, and their effects on CRC cell lines were evaluated based on the conduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, and flow cytometry assay. Eventually, the Luciferase reporter gene assay was carried out to judge if there existed a targeted relationship between ATB and miR-200c. The results of Cox regression analyses suggested that overexpressed lncRNA ATB, underexpressed miR-200c, poor tumor differentiation, lymph-vascular invasion, and perineural invasion were symbolic of shortened survival of the patients with CRC (all P < .05). Besides, transfection of pcDNA3.1-ATB and miR-200c inhibitor could boost the viability and proliferation of Lovo and SW620 cell lines (all P < .05). Meanwhile, the expressions of p53 and p21 were also reduced under treatments of pcDNA3.1-ATB and miR-200c inhibitor (P < .05). In addition, CDK2 seemed to reverse the contribution of miR-200c to intensifying viability and proliferation of Lovo and SW420 cell lines (P < .05). Furthermore, ATB might downregulate miR-200c expression by targeting it (P < .05), and CDK2 was subjected to dual regulation of both ATB and miR-200c (P < .05). In conclusion, the lncRNA ATB/miR-200c/CDK2 signaling was responsible for intensified proliferation and prohibited apoptosis of CRC cells, which might provide effective approaches for diagnosing and treating CRC.
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Affiliation(s)
- Zhenyuan Gao
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Hairong Zhou
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Yaping Wang
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Juan Chen
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Yimei Ou
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
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Smigiel JM, Taylor SE, Bryson BL, Tamagno I, Polak K, Jackson MW. Cellular plasticity and metastasis in breast cancer: a pre- and post-malignant problem. JOURNAL OF CANCER METASTASIS AND TREATMENT 2019; 5:47. [PMID: 32355893 PMCID: PMC7192216 DOI: 10.20517/2394-4722.2019.26] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
As a field we have made tremendous strides in treating breast cancer, with a decline in the past 30 years of overall breast cancer mortality. However, this progress is met with little affect once the disease spreads beyond the primary site. With a 5-year survival rate of 22%, 10-year of 13%, for those patients with metastatic breast cancer (mBC), our ability to effectively treat wide spread disease is minimal. A major contributing factor to this ineffectiveness is the complex make-up, or heterogeneity, of the primary site. Within a primary tumor, secreted factors, malignant and pre-malignant epithelial cells, immune cells, stromal fibroblasts and many others all reside alongside each other creating a dynamic environment contributing to metastasis. Furthermore, heterogeneity contributes to our lack of understanding regarding the cells' remarkable ability to undergo epithelial/non-cancer stem cell (CSC) to mesenchymal/CSC (E-M/CSC) plasticity. The enhanced invasion & motility, tumor-initiating potential, and acquired therapeutic resistance which accompanies E-M/CSC plasticity implicates a significant role in metastasis. While most work trying to understand E-M/CSC plasticity has been done on malignant cells, recent evidence is emerging concerning the ability for pre-malignant cells to undergo E-M/CSC plasticity and contribute to the metastatic process. Here we will discuss the importance of E-M/CSC plasticity within malignant and pre-malignant populations of the tumor. Moreover, we will discuss how one may potentially target these populations, ultimately disrupting the metastatic cascade and increasing patient survival for those with mBC.
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Affiliation(s)
- Jacob M. Smigiel
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Sarah E. Taylor
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Benjamin L. Bryson
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Ilaria Tamagno
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Kelsey Polak
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Mark W. Jackson
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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Huang L, Liu X. microRNA-370 Promotes Cell Growth by Targeting WNK2 in Breast Cancer. DNA Cell Biol 2019; 38:501-509. [PMID: 31009242 DOI: 10.1089/dna.2018.4602] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Li Huang
- Central Hospital of Zibo, Zhangdian District, Zibo, Shandong, China
| | - Xiangyu Liu
- Central Hospital of Zibo, Zhangdian District, Zibo, Shandong, China
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Abstract
MicroRNAs (miRNAs) are small non-coding RNAs regulating post-transcriptional gene expression. They play important roles in many biological processes under physiological or pathological conditions, including development, metabolism, tumorigenesis, metastasis, and immune response. Over the past 15 years, significant insights have been gained into the roles of miRNAs in cancer. Depending on the cancer type, miRNAs can act as oncogenes, tumor suppressors, or metastasis regulators. In this review, we focus on the role of miRNAs as components of molecular networks regulating metastasis. These miRNAs, termed metastamiRs, promote or inhibit metastasis through various mechanisms, including regulation of migration, invasion, colonization, cancer stem cell properties, epithelial-mesenchymal transition, and microenvironment. Some of these metastamiRs represent attractive therapeutic targets for cancer treatment.
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Affiliation(s)
- Jongchan Kim
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Fan Yao
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Zhenna Xiao
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.,UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yutong Sun
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - Li Ma
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. .,UTHealth Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
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Kontomanolis EN, Fasoulakis Z, Papamanolis V, Koliantzaki S, Dimopoulos G, Kambas NJ. The Impact of microRNAs in Breast Cancer Angiogenesis and Progression. Microrna 2019; 8:101-109. [PMID: 30332982 DOI: 10.2174/2211536607666181017122921] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 03/22/2018] [Accepted: 10/11/2018] [Indexed: 06/08/2023]
Abstract
OBJECTIVE The study aims to review the recent data considering the expression profile and the role of microRNAs in breast tumorigenesis, and their impact on -the vital for breast cancer progression- angiogenesis. METHODS PubMed was searched for studies focused on data that associate microRNA with breast cancer, using the terms ''breast", "mammary gland", "neoplasia'', "angiogenesis" and ''microRNA'' between 1997-2018. RESULTS Aberrant expression of several circulating and tissue miRNAs is observed in human breast neoplasms with the deregulation of several miRNAs having a major participation in breast cancer progression. Angiogenesis seems to be directly affected by either overexpression or down regulation of many miRNAs, defining the overall prognostic rates. Many miRNAs differentially expressed in breast cancer that reveal a key role in suppression - progression and metastasis of breast cancer along with the contribution of the EGF, TNF-a and EGF cytokines. Conclusion Angiogenesis has proven to be vital for tumor development and metastasis while microRNAs are proposed to have multiple biological roles, including participation in immunosuppressive, immunomodulatory and recent studies reveal their implication in angiogenesis and its possible use as prognostic factors in cancer Even though larger studies are needed in order to reach safe conclusions, important steps are made that reveal the connection of serum microRNA expression to the angiogenic course of breast cancer, while miRNAs could be potential prognostic factors for the different breast cancer types.
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Affiliation(s)
- Emmanuel N. Kontomanolis
- Department of Obstetrics & Gynecology, Democritus University in Alexandroupolis, Dragana, Greece
| | - Zacharias Fasoulakis
- Department of Obstetrics & Gynecology, Democritus University in Alexandroupolis, Dragana, Greece
| | | | - Sofia Koliantzaki
- Department of Obstetrics & Gynecology, General Hospital of Korinthos, Corinth, Greece
| | - Georgios Dimopoulos
- Department of Obstetrics & Gynecology, General Hospital of Korinthos, Corinth, Greece
| | - Nikolaos J. Kambas
- Department of Obstetrics & Gynecology, General Hospital of Korinthos, Corinth, Greece
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Dong H, Weng C, Bai R, Sheng J, Gao X, Li L, Xu Z. The regulatory network of miR-141 in the inhibition of angiogenesis. Angiogenesis 2018; 22:251-262. [DOI: 10.1007/s10456-018-9654-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 11/12/2018] [Indexed: 12/15/2022]
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Chow K, McCoy P, Stuchbery R, Corcoran NM, Hovens CM. Developments in oligometastatic hormone-sensitive prostate cancer. World J Urol 2018; 37:2549-2555. [PMID: 30382379 DOI: 10.1007/s00345-018-2542-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 10/21/2018] [Indexed: 02/06/2023] Open
Abstract
PURPOSE To review the current understanding and recent developments regarding the concept of oligometastases in hormone-sensitive prostate cancer. METHODS A comprehensive literature search of electronic databases, including PubMed and Embase was conducted for the search term 'oligometastases' in combinations with 'prostate cancer', 'hormone sensitive', 'genetics', and 'molecular'. All articles relating to these search terms have been taken into account. RESULTS Prostate cancer remains a major cause of morbidity and mortality worldwide. The majority of these cancer-related deaths result from metastases. Currently, there is a dichotomy in prostate cancer management where it is only deemed curable if it is localized, while any signs of metastasis relegate patients to systemic therapies to delay their inevitable death. A growing body of evidence supports the notion that aggressive treatments during the stable 'oligometastatic' state can have significant clinical benefits and potentially 'reset' prostate cancer to an earlier time point in cancer progression. This concept of oligometastases has been adopted in other cancer settings such as colorectal and non-small-cell lung cancers. CONCLUSION Multiple clinical and molecular biological studies have been influential in the support of a stable state in metastatic cancer progression coined 'oligometastases'. As our understanding of oligometastases in hormone-sensitive prostate cancer develops, we will be able to molecularly define the oligometastatic state and develop clinically available diagnostic tests. In doing so, prostate cancer patients will experience significant clinical benefits and the burden of prostate cancer worldwide will likely be reduced.
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Affiliation(s)
- Ken Chow
- Department of Surgery, The University of Melbourne, 5th Floor Clinical Sciences Building, Royal Melbourne Hospital, Grattan Street, Parkville, VIC, Australia.,Department of Urology, Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Patrick McCoy
- Department of Surgery, The University of Melbourne, 5th Floor Clinical Sciences Building, Royal Melbourne Hospital, Grattan Street, Parkville, VIC, Australia
| | - Ryan Stuchbery
- Australian Prostate Cancer Research Centre Epworth, Richmond, VIC, Australia
| | - Niall M Corcoran
- Department of Surgery, The University of Melbourne, 5th Floor Clinical Sciences Building, Royal Melbourne Hospital, Grattan Street, Parkville, VIC, Australia.,Department of Urology, Royal Melbourne Hospital, Parkville, VIC, Australia.,Australian Prostate Cancer Research Centre Epworth, Richmond, VIC, Australia
| | - Christopher M Hovens
- Department of Surgery, The University of Melbourne, 5th Floor Clinical Sciences Building, Royal Melbourne Hospital, Grattan Street, Parkville, VIC, Australia. .,Australian Prostate Cancer Research Centre Epworth, Richmond, VIC, Australia.
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