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Sobral DV, Salgado MRT, Martins MR, Vasconcelos CDS, Anunciação CEC, de Andrade VP, Torres LC. Prognostic role of SOX2 and STAT3 expression on circulating T lymphocytes and CD44+/CD24 neg cells in the locally advanced and metastatic breast cancer. J Surg Oncol 2024. [PMID: 38825982 DOI: 10.1002/jso.27716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 05/22/2024] [Accepted: 05/25/2024] [Indexed: 06/04/2024]
Abstract
BACKGROUND Breast cancer (BC) is associated with a continuous increase in incidence, with high mortality rates in several countries. CD44, STAT3, and SOX2 are related to regulating of somatic cell division, tumorigenesis, and metastasis in BC. METHODS A cross-sectional study was carried out at the Hospital de Cancer de Pernambuco (HCP) between 2017 and 2018. Fifty-one women with locally advanced (LA) and 14 with metastatic BC were included in the study. RESULTS High CD44+/CD24neg and CD44+/CD24neg/SOX2+ levels in Luminal B (LB), HER2+, and triple-negative breast cancer (TNBC) compared with controls (p < 0.05). Low CD44+/CD24negSTAT3+ levels in LB, HER2+, and TNBC compared with controls (p < 0.05). High T lymphocytes, and low STAT3 + T, and SOX2 + T levels in BC patients (p < 0.05). High SOX2 + T levels in patients with axillary lymph node-negative (N0) compared with the axillary lymph node-positives (N1 and N2 groups; p < 0.05). High SOX2 + T levels in N1 compared to N2 (p < 0.05). High T lymphocytes and low SOX2 + T levels in the LA tumor compared to metastatic disease (p = 0.0007 and p = 0.02, respectively). High CD44 + /CD24negSTAT3+, and T lymphocyte levels in TNBC patients with LA tumor compared to metastatic (p < 0.05). Low STAT3 + T levels in TBNC patients with LA tumor compared to metastatic (p = 0.0266). CONCLUSION SOX2 and STAT3 expression on circulating T lymphocytes and CD44 + /CD24neg cells in peripheral blood have prognostic roles in breast cancer. SOX2 and STAT3 expression are potential predictive biomarkers of disease progression in breast cancer regardless of tumor subtype.
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Affiliation(s)
- Denise V Sobral
- Translational Research Laboratory, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Brazil
- Sociedade Pernambucana de Combate ao Cancer, Hospital de Câncer de Pernambuco (HCP), Recife, Brazil
- International Research Center, A.C. Camargo Cancer, CenterSão Paulo, Brazil
| | - Marcelo R T Salgado
- Translational Research Laboratory, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Brazil
- Sociedade Pernambucana de Combate ao Cancer, Hospital de Câncer de Pernambuco (HCP), Recife, Brazil
- International Research Center, A.C. Camargo Cancer, CenterSão Paulo, Brazil
| | - Mario R Martins
- Translational Research Laboratory, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Brazil
- Sociedade Pernambucana de Combate ao Cancer, Hospital de Câncer de Pernambuco (HCP), Recife, Brazil
- International Research Center, A.C. Camargo Cancer, CenterSão Paulo, Brazil
| | - Carolina de S Vasconcelos
- Translational Research Laboratory, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Brazil
- Sociedade Pernambucana de Combate ao Cancer, Hospital de Câncer de Pernambuco (HCP), Recife, Brazil
| | - Carlos E C Anunciação
- Translational Research Laboratory, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Brazil
- Sociedade Pernambucana de Combate ao Cancer, Hospital de Câncer de Pernambuco (HCP), Recife, Brazil
- International Research Center, A.C. Camargo Cancer, CenterSão Paulo, Brazil
| | | | - Leuridan C Torres
- Translational Research Laboratory, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife, Brazil
- Sociedade Pernambucana de Combate ao Cancer, Hospital de Câncer de Pernambuco (HCP), Recife, Brazil
- Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
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2
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Geng DY, Chen QS, Chen WX, Zhou LS, Han XS, Xie QH, Guo GH, Chen XF, Chen JS, Zhong XP. Molecular targets and mechanisms of different aberrant alternative splicing in metastatic liver cancer. World J Clin Oncol 2024; 15:531-539. [PMID: 38689626 PMCID: PMC11056863 DOI: 10.5306/wjco.v15.i4.531] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 01/29/2024] [Accepted: 03/07/2024] [Indexed: 04/22/2024] Open
Abstract
Metastasis remains a major challenge in the successful management of malignant diseases. The liver is a major site of metastatic disease and a leading cause of death from gastrointestinal malignancies such as colon, stomach, and pancreatic cancers, as well as melanoma, breast cancer, and sarcoma. As an important factor that influences the development of metastatic liver cancer, alternative splicing drives the diversity of RNA transcripts and protein subtypes, which may provide potential to broaden the target space. In particular, the dysfunction of splicing factors and abnormal expression of splicing variants are associated with the occurrence, progression, aggressiveness, and drug resistance of cancers caused by the selective splicing of specific genes. This review is the first to provide a detailed summary of the normal splicing process and alterations that occur during metastatic liver cancer. It will cover the role of alternative splicing in the mechanisms of metastatic liver cancer by examining splicing factor changes, abnormal splicing, and the contribution of hypoxia to these changes during metastasis.
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Affiliation(s)
- De-Yi Geng
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Qing-Shan Chen
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Wan-Xian Chen
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Lin-Sa Zhou
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Xiao-Sha Han
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Qi-Hu Xie
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Geng-Hong Guo
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Xue-Fen Chen
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Jia-Sheng Chen
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
| | - Xiao-Ping Zhong
- Department of Plastic and Burns Surgery, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515000, Guangdong Province, China
- Plastic Surgery Research Institute, Ear Deformities Treatment Center and Cleft Lip and Palate Treatment Center of Shantou University Medical College, Shantou 515000, Guangdong Province, China
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3
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Everest‐Dass A, Nersisyan S, Maar H, Novosad V, Schröder‐Schwarz J, Freytag V, Stuke JL, Beine MC, Schiecke A, Haider M, Kriegs M, Elakad O, Bohnenberger H, Conradi L, Raygorodskaya M, Krause L, von Itzstein M, Tonevitsky A, Schumacher U, Maltseva D, Wicklein D, Lange T. Spontaneous metastasis xenograft models link CD44 isoform 4 to angiogenesis, hypoxia, EMT and mitochondria-related pathways in colorectal cancer. Mol Oncol 2024; 18:62-90. [PMID: 37849446 PMCID: PMC10766209 DOI: 10.1002/1878-0261.13535] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 08/10/2023] [Accepted: 10/12/2023] [Indexed: 10/19/2023] Open
Abstract
Hematogenous metastasis limits the survival of colorectal cancer (CRC) patients. Here, we illuminated the roles of CD44 isoforms in this process. Isoforms 3 and 4 were predominantly expressed in CRC patients. CD44 isoform 4 indicated poor outcome and correlated with epithelial-mesenchymal transition (EMT) and decreased oxidative phosphorylation (OxPhos) in patients; opposite associations were found for isoform 3. Pan-CD44 knockdown (kd) independently impaired primary tumor formation and abrogated distant metastasis in CRC xenografts. The xenograft tumors mainly expressed the clinically relevant CD44 isoforms 3 and 4. Both isoforms were enhanced in the paranecrotic, hypoxic tumor regions but were generally absent in lung metastases. Upon CD44 kd, tumor angiogenesis was increased in the paranecrotic areas, accompanied by reduced hypoxia-inducible factor-1α and CEACAM5 but increased E-cadherin expression. Mitochondrial genes and proteins were induced upon pan-CD44 kd, as were OxPhos genes. Hypoxia increased VEGF release from tumor spheres, particularly upon CD44 kd. Genes affected upon CD44 kd in xenografts specifically overlapped concordantly with genes correlating with CD44 isoform 4 (but not isoform 3) in patients, validating the clinical relevance of the used model and highlighting the metastasis-promoting role of CD44 isoform 4.
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Affiliation(s)
- Arun Everest‐Dass
- Institute for GlycomicsGriffith University, Gold Coast CampusAustralia
| | - Stepan Nersisyan
- Faculty of Biology and BiotechnologyHSE UniversityMoscowRussia
- Institute of Molecular BiologyThe National Academy of Sciences of the Republic of ArmeniaYerevanArmenia
- Armenian Bioinformatics Institute (ABI)YerevanArmenia
- Present address:
Computational Medicine CenterThomas Jefferson UniversityPhiladelphiaPAUSA
| | - Hanna Maar
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Victor Novosad
- Faculty of Biology and BiotechnologyHSE UniversityMoscowRussia
- Shemyakin‐Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of SciencesMoscowRussia
| | | | - Vera Freytag
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Johanna L. Stuke
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Mia C. Beine
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Alina Schiecke
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Marie‐Therese Haider
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Malte Kriegs
- Department of Radiobiology and Radiation OncologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Omar Elakad
- Institute of PathologyUniversity Medical Center GöttingenGermany
| | | | - Lena‐Christin Conradi
- Clinic for General, Visceral and Pediatric SurgeryUniversity Medical Center GöttingenGermany
| | | | - Linda Krause
- Institute of Medical Biometry and EpidemiologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Mark von Itzstein
- Institute for GlycomicsGriffith University, Gold Coast CampusAustralia
| | - Alexander Tonevitsky
- Faculty of Biology and BiotechnologyHSE UniversityMoscowRussia
- Shemyakin‐Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of SciencesMoscowRussia
- Art Photonics GmbHBerlinGermany
| | - Udo Schumacher
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
- Medical School BerlinGermany
| | - Diana Maltseva
- Faculty of Biology and BiotechnologyHSE UniversityMoscowRussia
| | - Daniel Wicklein
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
- Department of Anatomy and Cell BiologyUniversity of MarburgGermany
| | - Tobias Lange
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
- Institute of Anatomy IJena University HospitalGermany
- Comprehensive Cancer Center Central Germany (CCCG)Jena and LeipzigGermany
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4
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Nolan E, Kang Y, Malanchi I. Mechanisms of Organ-Specific Metastasis of Breast Cancer. Cold Spring Harb Perspect Med 2023; 13:a041326. [PMID: 36987584 PMCID: PMC10626265 DOI: 10.1101/cshperspect.a041326] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
Cancer metastasis, or the development of secondary tumors in distant tissues, accounts for the vast majority of fatalities in patients with breast cancer. Breast cancer cells show a striking proclivity to metastasize to distinct organs, specifically the lung, liver, bone, and brain, where they face unique environmental pressures and a wide variety of tissue-resident cells that together create a strong barrier for tumor survival and growth. As a consequence, successful metastatic colonization is critically dependent on reciprocal cross talk between cancer cells and host cells within the target organ, a relationship that shapes the formation of a tumor-supportive microenvironment. Here, we discuss the mechanisms governing organ-specific metastasis in breast cancer, focusing on the intricate interactions between metastatic cells and specific niche cells within a secondary organ, and the remarkable adaptations of both compartments that cooperatively support cancer growth. More broadly, we aim to provide a framework for the microenvironmental prerequisites within each distinct metastatic site for successful breast cancer metastatic seeding and outgrowth.
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Affiliation(s)
- Emma Nolan
- Tumour Host Interaction laboratory, The Francis Crick Institute, NW1 1AT London, United Kingdom
- Auckland Cancer Society Research Centre, University of Auckland, Auckland 1023, New Zealand
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, New Jersey 08544, USA
| | - Ilaria Malanchi
- Tumour Host Interaction laboratory, The Francis Crick Institute, NW1 1AT London, United Kingdom
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5
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Ahmad SMS, Nazar H, Rahman MM, Rusyniak RS, Ouhtit A. ITGB1BP1, a Novel Transcriptional Target of CD44-Downstream Signaling Promoting Cancer Cell Invasion. BREAST CANCER (DOVE MEDICAL PRESS) 2023; 15:373-380. [PMID: 37252376 PMCID: PMC10225144 DOI: 10.2147/bctt.s404565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 04/25/2023] [Indexed: 05/31/2023]
Abstract
Breast cancer (BC) is the most common malignancy worldwide and has a poor prognosis, because it begins in the breast and disseminates to lymph nodes and distant organs. While invading, BC cells acquire aggressive characteristics from the tumor microenvironment through several mechanisms. Thus, understanding the mechanisms underlying the process of BC cell invasion can pave the way towards the development of targeted therapeutics focused on metastasis. We have previously reported that the activation of CD44 receptor with its major ligand hyaluronan (HA) promotes BC metastasis to the liver in vivo. Next, a gene expression profiling microarray analysis was conducted to identify and validate CD44-downstream transcriptional targets mediating its pro-metastatic function from RNA samples collected from Tet CD44-induced versus control MCF7-B5 cells. We have already validated a number of novel CD44-target genes and published their underlying signaling pathways in promoting BC cell invasion. From the same microarray analysis, Integrin subunit beta 1 binding protein 1 (ITGB1BP1) was also identified as a potential CD44-target gene that was upregulated (2-fold) upon HA activation of CD44. This report will review the lines of evidence collected from the literature to support our hypothesis, and further discuss the possible mechanisms linking HA activation of CD44 to its novel potential transcriptional target ITGB1BP1.
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Affiliation(s)
- Salma M S Ahmad
- Biological Sciences Program, Department of Biological and Environmental Sciences, College of Arts and Science, Qatar University, Doha, Qatar
| | - Hanan Nazar
- Biological Sciences Program, Department of Biological and Environmental Sciences, College of Arts and Science, Qatar University, Doha, Qatar
| | - Md Mizanur Rahman
- Biological Sciences Program, Department of Biological and Environmental Sciences, College of Arts and Science, Qatar University, Doha, Qatar
| | - Radoslaw Stefan Rusyniak
- Biological Sciences Program, Department of Biological and Environmental Sciences, College of Arts and Science, Qatar University, Doha, Qatar
| | - Allal Ouhtit
- Biological Sciences Program, Department of Biological and Environmental Sciences, College of Arts and Science, Qatar University, Doha, Qatar
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6
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Mansoori-Kermani A, Khalighi S, Akbarzadeh I, Niavol FR, Motasadizadeh H, Mahdieh A, Jahed V, Abdinezhad M, Rahbariasr N, Hosseini M, Ahmadkhani N, Panahi B, Fatahi Y, Mozafari M, Kumar AP, Mostafavi E. Engineered hyaluronic acid-decorated niosomal nanoparticles for controlled and targeted delivery of epirubicin to treat breast cancer. Mater Today Bio 2022; 16:100349. [PMID: 35875198 PMCID: PMC9304880 DOI: 10.1016/j.mtbio.2022.100349] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/17/2022] [Accepted: 07/01/2022] [Indexed: 12/24/2022] Open
Abstract
Targeted drug delivery systems using nanocarriers offer a versatile platform for breast cancer treatment; however, a robust, CD44-targeted niosomal formulation has not been developed and deeply studied (both in vitro and in vivo) yet. Here, an optimized system of epirubicin (Epi)-loaded niosomal nanoparticles (Nio) coated with hyaluronic acid (HA) has been engineered for targeting breast cancer cells. The nanoformulation was first optimized (based on size, polydispersity index, and entrapment efficiency); then, we characterized the morphology, stability, and release behavior of the nanoparticles. Epirubicin release from the HA-coated system (Epi-Nio-HA) showed a 21% (acidic buffer) and 20% (neutral buffer) reduction in comparison with the non-coated group (Epi-Nio). The cytotoxicity and apoptosis results of 4T1 and SkBr3 cells showed an approximately 2-fold increase in the Epi-Nio-HA system over Epi-Nio and free epirubicin, which confirms the superiority of the engineered nanocarriers. Moreover, real-time PCR data demonstrated the down-regulation of the MMP-2, MMP-9, cyclin D, and cyclin E genes expression while caspase-3 and caspase-9 gene expression were up-regulated. Confocal microscopy and flow cytometry studies uncovered the cellular uptake mechanism of the Epi-Nio-HA system, which was CD44-mediated. Furthermore, in vivo studies indicated Epi-Nio-HA decreased mice breast tumor volume by 28% (compared to epirubicin) without side effects on the liver and kidney. Conclusively, our results indicated that the HA-functionalized niosomes provide a promising nanoplatform for efficient and targeted delivery of epirubicin to potentially treat breast cancer.
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Affiliation(s)
| | - Sadaf Khalighi
- Department of Chemical and Petrochemical Engineering, Sharif University of Technology, Tehran, Iran
| | - Iman Akbarzadeh
- Department of Chemical and Petrochemical Engineering, Sharif University of Technology, Tehran, Iran
| | - Fazeleh Ranjbar Niavol
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hamidreza Motasadizadeh
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Athar Mahdieh
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Jahed
- Rudolfs Cimdins Riga Biomaterials Innovations and Development Centre of RTU, Institute of General Chemical Engineering, Faculty of Materials Science and Applied Chemistry, Riga Technical University, Pulka St. 3/3, Riga, LV, 1007, Latvia
| | - Masoud Abdinezhad
- School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran
| | - Nikoo Rahbariasr
- Polymer Research Laboratory, Department of Chemistry, Sharif University of Technology, Tehran, Iran
| | - Mahshid Hosseini
- Department of Chemical and Petrochemical Engineering, Sharif University of Technology, Tehran, Iran
| | - Nima Ahmadkhani
- Department of Chemical and Petrochemical Engineering, Sharif University of Technology, Tehran, Iran
| | - Behnam Panahi
- Department of Chemical and Petrochemical Engineering, Sharif University of Technology, Tehran, Iran
| | - Yousef Fatahi
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Mozafari
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
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7
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Ahmad SMS, Al-Mansoob M, Ouhtit A. SIRT1, a novel transcriptional downstream target of CD44, linking its deacetylase activity to tumor cell invasion/metastasis. Front Oncol 2022; 12:1038121. [PMID: 36505828 PMCID: PMC9727296 DOI: 10.3389/fonc.2022.1038121] [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: 09/06/2022] [Accepted: 10/11/2022] [Indexed: 11/24/2022] Open
Abstract
Our tetracycline-off-inducible CD44 expression system previously established in mouse model, revealed that activation of CD44 with its major ligand hyaluronan (HA) promoted breast cancer (BC) metastasis to the liver. To identify the mechanisms that underpin CD44-promoted BC cell invasion, microarray gene expression profiling using RNA samples from (Tet)-Off-regulated expression system of CD44s in MCF7 cells, revealed a set of upregulated genes including, nuclear sirtuin-1 (SIRT1 also known as NAD-dependent deacetylase), an enzyme that requires NAD+ as a cofactor to deacetylate several histones and transcription factors. It stimulates various oncogenic pathways promoting tumorigenesis. This data suggests that SIRT1 is a potential novel transcriptional target of CD44-downstream signaling that promote BC cell invasion/metastasis. This review will discuss the evidence supporting this hypothesis as well as the mechanisms linking SIRT1 to cell proliferation and invasion.
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Liu C, Mohan SC, Wei J, Seki E, Liu M, Basho R, Giuliano AE, Zhao Y, Cui X. Breast cancer liver metastasis: Pathogenesis and clinical implications. Front Oncol 2022; 12:1043771. [PMID: 36387238 PMCID: PMC9641291 DOI: 10.3389/fonc.2022.1043771] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 10/04/2022] [Indexed: 09/30/2023] Open
Abstract
Breast cancer is the most common malignant disease in female patients worldwide and can spread to almost every place in the human body, most frequently metastasizing to lymph nodes, bones, lungs, liver and brain. The liver is a common metastatic location for solid cancers as a whole, and it is also the third most common metastatic site for breast cancer. Breast cancer liver metastasis (BCLM) is a complex process. Although the hepatic microenvironment and liver sinusoidal structure are crucial factors for the initial arrest of breast cancer and progression within the liver, the biological basis of BCLM remains to be elucidated. Importantly, further understanding of the interaction between breast cancer cells and hepatic microenvironment in the liver metastasis of breast cancer will suggest ways for the development of effective therapy and prevention strategies for BCLM. In this review, we provide an overview of the recent advances in the understanding of the molecular mechanisms of the hepatic microenvironment in BCLM formation and discuss current systemic therapies for treating patients with BCLM as well as potential therapeutic development based on the liver microenvironment-associated signaling proteins governing BCLM.
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Affiliation(s)
- Cuiwei Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Srivarshini C. Mohan
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Jielin Wei
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ekihiro Seki
- Department of Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Manran Liu
- Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Reva Basho
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- The Lawrence J. Ellison Institute for Transformative Medicine, Los Angeles, CA, United States
| | - Armando E. Giuliano
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Yanxia Zhao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaojiang Cui
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
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Vadhan A, Hou MF, Vijayaraghavan P, Wu YC, Hu SCS, Wang YM, Cheng TL, Wang YY, Yuan SSF. CD44 Promotes Breast Cancer Metastasis through AKT-Mediated Downregulation of Nuclear FOXA2. Biomedicines 2022; 10:2488. [PMID: 36289750 PMCID: PMC9599046 DOI: 10.3390/biomedicines10102488] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/29/2022] [Accepted: 09/29/2022] [Indexed: 12/09/2022] Open
Abstract
The primary cause of breast cancer mortality is the metastatic invasion of cancerous stem cells (CSC). Cluster of differentiation 44 (CD44) is a well-known CSC marker in various cancers, as well as a key role player in metastasis and relapse of breast cancer. CD44 is a cell-membrane embedded protein, and it interacts with different proteins to regulate cancer cell behavior. Transcription factor forkhead box protein A2 (FOXA2) acts as an important regulator in multiple cancers, including breast cancer. However, the biological significance of CD44-FOXA2 association in breast cancer metastasis remains unclear. Herein, we observed that CD44 expression was higher in metastatic lymph nodes compared to primary tumors using a flow cytometric analysis. CD44 overexpression in breast cancer cell lines significantly promoted cell migration and invasion abilities, whereas the opposite effects occurred upon the knockdown of CD44. The stem cell array analysis revealed that FOXA2 expression was upregulated in CD44 knockdown cells. However, the knockdown of FOXA2 in CD44 knockdown cells reversed the effects on cell migration and invasion. Furthermore, we found that CD44 mediated FOXA2 localization in breast cancer cells through the AKT pathway. Moreover, the immunofluorescence assay demonstrated that AKT inhibitor wortmannin and AKT activator SC79 treatment in breast cancer cells impacted FOXA2 localization. Collectively, this study highlights that CD44 promotes breast cancer metastasis by downregulating nuclear FOXA2.
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Affiliation(s)
- Anupama Vadhan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Ming-Feng Hou
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Priya Vijayaraghavan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yi-Chia Wu
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Stephen Chu-Sung Hu
- Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Yun-Ming Wang
- Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, 75 Bo-Ai Street, Hsinchu 300, Taiwan
- Department of Biomedical Science and Environmental Biology, Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Tian-Lu Cheng
- Department of Biomedical and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yen-Yun Wang
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
| | - Shyng-Shiou F. Yuan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, 75 Bo-Ai Street, Hsinchu 300, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
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10
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Liu H, Li X, Li H, Feng L, Sun G, Sun G, Wu L, Hu Y, Liu L, Wang H. Potential molecular mechanisms and clinical progress in liver metastasis of breast cancer. Biomed Pharmacother 2022; 149:112824. [PMID: 35306430 DOI: 10.1016/j.biopha.2022.112824] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/11/2022] [Accepted: 03/11/2022] [Indexed: 11/18/2022] Open
Abstract
Breast cancer is the most common malignant tumor in women and the leading cause of cancer death in women. About 30% of breast cancer patients have metastasis every year, which greatly increases the mortality rate of breast cancer. The main target organs for metastasis are bone, brain, liver and lung. The breast cancer liver metastasis (BCLM) mechanism is not fully clarified. This is a complex process involving multiple factors, which is not only related to the microenvironment of the primary tumor and liver, but also regulated by a variety of signaling pathways. Clarifying these mechanisms is of great help to guide clinical treatment. With the in-depth study of BCLM, a variety of new treatment schemes such as targeted therapy and endocrine therapy provide new ideas for the cure of BCLM. In this review, we will summarize the molecular mechanism and treatment of BCLM.
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Affiliation(s)
- Hanyuan Liu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiao Li
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haiyang Li
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lei Feng
- School of Public Health, Fudan University, Shanghai, China
| | - Guangshun Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Guoqiang Sun
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Liangliang Wu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yun Hu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China.
| | - Li Liu
- Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Hanjin Wang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
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11
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Qiu S, Iimori M, Edahiro K, Fujimoto Y, Matsuoka K, Oki E, Maehara Y, Mori M, Kitao H. A CD44 variant is essential for Slug-dependent vimentin gene expression to acquire TGF-β1-induced tumor cell motility. Cancer Sci 2022; 113:2654-2667. [PMID: 35363934 PMCID: PMC9357650 DOI: 10.1111/cas.15353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 03/02/2022] [Accepted: 03/07/2022] [Indexed: 11/28/2022] Open
Abstract
CD44 is a widely expressed polymorphic adhesion molecule that has pleiotropic functions in development and tumor progression. Its mRNA undergoes alternative splicing to generate multiple variant (CD44v) isoforms, although the function of each CD44v isoform is not fully elucidated. Here, we show that CD44v plays an important role in the induction of vimentin expression upon transforming growth factor‐β1 (TGF‐β1)‐induced epithelial–mesenchymal transition (EMT). Among multiple CD44v isoforms expressed in NUGC3 gastric cancer cells, CD44v8‐10 and CD44v3,8‐10 are involved in the acquisition of migratory and invasive properties associated with TGF‐β1‐induced EMT, and only CD44v3,8‐10 induces the transcription of vimentin mediated by the EMT transcription factor Slug. In primary tumor specimens obtained from patients with gastric cancer, CD44‐containing variant exon 9 (CD44v9) expression and EMT features [E‐cadherin(−)vimentin(+)] were significantly correlated, and EMT features in the cells expressing CD44v9 were associated with tumor invasion depth, lymph node metastasis, and pStage, which indicate invasive and metastatic properties, and poor prognosis. These results indicate that certain CD44v isoforms promote tumor cell motility and metastasis in gastric cancer in association with EMT features, and CD44v3,8‐10 may contribute to these clinical characteristics.
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Affiliation(s)
- Shichao Qiu
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Makoto Iimori
- Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Keitaro Edahiro
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshiaki Fujimoto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiko Maehara
- Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Graduate School of Medicine, Tokai University School of Medicine, Kanagawa, Japan
| | - Hiroyuki Kitao
- Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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12
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Rezakhani L, Rahmati S, Ghasemi S, Alizadeh M, Alizadeh A. A comparative study of the effects of crab derived exosomes and doxorubicin in 2 & 3-dimensional in vivo models of breast cancer. Chem Phys Lipids 2022; 243:105179. [PMID: 35150707 DOI: 10.1016/j.chemphyslip.2022.105179] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 02/03/2022] [Accepted: 02/06/2022] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Using tissue engineering and modifying the tumor microenvironment, three-dimensional (3D) in vitro and in vivo cancer modeling can be performed with appropriate similarity to native. Exosomes derived from different sources have recently been used in cancer studies due to their anticancer effects. In this study, the effect of crab derived exosomes in 2 & 3-dimensional (2& 3D) in vivo models of breast cancer (BC) were investigated and compared with the doxorubicin (DOX). METHODS 2D and 3D models of BC were induced using the chitosan/β-glycerol phosphate hydrogel (Ch/β-GP) and 1 × 106 4T1 cells in the female mice aged 6-8 weeks. 1 mg/ml exosome and 5 mg/kg DOX were injected by intratumoral (IT), intravenous (IV), and intraperitoneal (IP) methods into mice on day 9, 13, and 17 with and without hydrogel as a drug delivery system. After 21 days, the mice were sacrificed, and the tissues (lung, liver, and tumor) were removed. The weight and size of the tumor were measured. Real-time PCR assessed changes of VEGF, Bcl2, and P53 genes expression levels. Nitric oxide (NO) secretion from the cancer 3D model was evaluated by Griess assay. RESULTS AND CONCLUSION Based on the results, the size and weight of tumors in treated groups with exosomes and DOX were reduced significantly (P ≤ 0.001, P ≤ 0.002, P ≤ 0.02) in 2D and 3D models. Changes in VEGF, Bcl2 and P53 gene expression levels were less in the 3D model than in the 2D model. Drug delivery with hydrogel increased tumor inhibition compared to drug injection without hydrogel. Decreased NO secretion was observed in all treatment groups compared to the control group (untreated). Crab exosomes showed anti cancer effects on 2&3D models of BC. 3D model of BC showed greater drug resistance than the 2D model after treating with crab derived exosomes and DOX. 3D model of BC mimics native tumor better than 2D and can be used in cancer studies and for drug screening with greater confidence than 2D model. Also, the use of slow release drug delivery system reduced drug resistance in both models.
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Affiliation(s)
- Leila Rezakhani
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran; Department of tissue engineering, school of medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shima Rahmati
- Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Sorayya Ghasemi
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Morteza Alizadeh
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Akram Alizadeh
- Nervous system stem cells research center, Semnan university of medical sciences, Semnan, Iran; Department of Tissue Engineering and Applied Cell Sciences, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
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13
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SOD2, a Potential Transcriptional Target Underpinning CD44-Promoted Breast Cancer Progression. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27030811. [PMID: 35164076 PMCID: PMC8839817 DOI: 10.3390/molecules27030811] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 11/17/2022]
Abstract
CD44, a cell-adhesion molecule has a dual role in tumor growth and progression; it acts as a tumor suppressor as well as a tumor promoter. In our previous work, we developed a tetracycline-off regulated expression of CD44's gene in the breast cancer (BC) cell line MCF-7 (B5 clone). Using cDNA oligo gene expression microarray, we identified SOD2 (superoxide dismutase 2) as a potential CD44-downstream transcriptional target involved in BC metastasis. SOD2 gene belongs to the family of iron/manganese superoxide dismutase family and encodes a mitochondrial protein. SOD2 plays a role in cell proliferation and cell invasion via activation of different signaling pathways regulating angiogenic abilities of breast tumor cells. This review will focus on the findings supporting the underlying mechanisms associated with the oncogenic potential of SOD2 in the onset and progression of cancer, especially in BC and the potential clinical relevance of its various inhibitors.
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14
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Hsiao Y, Chi J, Li C, Chen L, Chen Y, Liang H, Lo Y, Hong J, Chuu C, Hung L, Du J, Chang W, Wang J. Disruption of the pentraxin 3/CD44 interaction as an efficient therapy for triple-negative breast cancers. Clin Transl Med 2022; 12:e724. [PMID: 35090088 PMCID: PMC8797470 DOI: 10.1002/ctm2.724] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 12/29/2022] Open
Abstract
Due to the heterogeneity and high frequency of genome mutations in cancer cells, targeting vital protumour factors found in stromal cells in the tumour microenvironment may represent an ideal strategy in cancer therapy. However, the regulation and mechanisms of potential targetable therapeutic candidates need to be investigated. An in vivo study demonstrated that loss of pentraxin 3 (PTX3) in stromal cells significantly decreased the metastasis and growth of cancer cells. Clinically, our results indicate that stromal PTX3 expression correlates with adverse prognostic features and is associated with worse survival outcomes in triple-negative breast cancer (TNBC). We also found that transforming growth factor beta 1 (TGF-β1) induces PTX3 expression by activating the transcription factor CCAAT/enhancer binding protein delta (CEBPD) in stromal fibroblasts. Following PTX3 stimulation, CD44, a PTX3 receptor, activates the downstream ERK1/2, AKT and NF-κB pathways to specifically contribute to the metastasis/invasion and stemness of TNBC MDA-MB-231 cells. Two types of PTX3 inhibitors were developed to disrupt the PTX3/CD44 interaction and they showed a significant effect on attenuating growth and restricting the metastasis/invasion of MDA-MB-231 cells, suggesting that targeting the PTX3/CD44 interaction could be a new strategy for future TNBC therapies.
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Affiliation(s)
- Yu‐Wei Hsiao
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and BiotechnologyNational Cheng Kung UniversityTainanTaiwan R. O. C.
| | - Jhih‐Ying Chi
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and BiotechnologyNational Cheng Kung UniversityTainanTaiwan R. O. C.
| | - Chien‐Feng Li
- Department of PathologyChi‐Mei Medical CenterTainanTaiwan R. O. C.
| | - Lei‐Yi Chen
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and BiotechnologyNational Cheng Kung UniversityTainanTaiwan R. O. C.
| | - Yi‐Ting Chen
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and BiotechnologyNational Cheng Kung UniversityTainanTaiwan R. O. C.
| | - Hsin‐Yin Liang
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and BiotechnologyNational Cheng Kung UniversityTainanTaiwan R. O. C.
| | - Yu‐Chih Lo
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and BiotechnologyNational Cheng Kung UniversityTainanTaiwan R. O. C.
| | - Jhen‐Yi Hong
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and BiotechnologyNational Cheng Kung UniversityTainanTaiwan R. O. C.
| | - Chin‐Pin Chuu
- Institute of Cellular and System MedicineNational Health Research InstitutesMiaoli CountyTaiwan R. O. C.
| | - Liang‐Yi Hung
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and BiotechnologyNational Cheng Kung UniversityTainanTaiwan R. O. C.
| | - Jyun‐Yi Du
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and BiotechnologyNational Cheng Kung UniversityTainanTaiwan R. O. C.
| | - Wen‐Chang Chang
- Graduate Institute of Medical Sciences, College of MedicineTaipei Medical UniversityTaipeiTaiwan R. O. C.
| | - Ju‐Ming Wang
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and BiotechnologyNational Cheng Kung UniversityTainanTaiwan R. O. C.
- Graduate Institute of Medical Sciences, College of MedicineTaipei Medical UniversityTaipeiTaiwan R. O. C.
- International Research Center for Wound Repair and RegenerationNational Cheng Kung UniversityTainanTaiwan R. O. C.
- Department of Physiology, College of MedicineNational Cheng Kung UniversityTainanTaiwan R. O. C.
- Graduate Institute of Medicine, College of MedicineKaohsiung Medical UniversityKaohsiungTaiwan R. O. C.
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15
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Lyu J, Cheng C. Regulation of Alternative Splicing during Epithelial-Mesenchymal Transition. Cells Tissues Organs 2022; 211:238-251. [PMID: 34348273 PMCID: PMC8741878 DOI: 10.1159/000518249] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/28/2021] [Indexed: 01/03/2023] Open
Abstract
Alternative splicing is an essential mechanism of gene regulation, giving rise to remarkable protein diversity in higher eukaryotes. Epithelial-mesenchymal transition (EMT) is a developmental process that plays an essential role in metazoan embryogenesis. Recent studies have revealed that alternative splicing serves as a fundamental layer of regulation that governs cells to undergo EMT. In this review, we summarize recent findings on the functional impact of alternative splicing in EMT and EMT-associated activities. We then discuss the regulatory mechanisms that control alternative splicing changes during EMT.
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Affiliation(s)
- Jingyi Lyu
- Lester and Sue Smith Breast Center, Department of Molecular
& Human Genetics, Department of Molecular & Cellular Biology, Baylor College
of Medicine, Houston, TX 77030, USA,Integrative Molecular and Biomedical Sciences Graduate
Program, Baylor College of Medicine, Houston, TX 77030, USA
| | - Chonghui Cheng
- Lester and Sue Smith Breast Center, Department of Molecular
& Human Genetics, Department of Molecular & Cellular Biology, Baylor College
of Medicine, Houston, TX 77030, USA,Integrative Molecular and Biomedical Sciences Graduate
Program, Baylor College of Medicine, Houston, TX 77030, USA.,To whom correspondence should be addressed:
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16
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Neupane AS, Kubes P. Imaging reveals novel innate immune responses in lung, liver, and beyond. Immunol Rev 2021; 306:244-257. [PMID: 34816440 DOI: 10.1111/imr.13040] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 11/03/2021] [Indexed: 12/14/2022]
Abstract
Highly dynamic immune responses are generated toward pathogens or injuries, in vivo. Multiple immune cell types participate in various facets of the response which leads to a concerted effort in the removal and clearance of pathogens or injured tissue and a return to homeostasis. Intravital microscopy (IVM) has been extensively utilized to unravel the dynamics of immune responses, visualizing immune cell behavior in intact living tissues, within a living organism. For instance, the phenomenon of leukocyte recruitment cascade. Importantly, IVM has led to a deep appreciation that immune cell behavior and responses in individual organs are distinct, but also can influence one another. In this review, we discuss how IVM as a tool has been used to study the innate immune responses in various tissues during homeostasis, injury, and infection.
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Affiliation(s)
- Arpan Sharma Neupane
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, AB, Canada.,Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.,Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, California, USA
| | - Paul Kubes
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, AB, Canada.,Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
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17
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Ebrahimie E, Rahimirad S, Tahsili M, Mohammadi-Dehcheshmeh M. Alternative RNA splicing in stem cells and cancer stem cells: Importance of transcript-based expression analysis. World J Stem Cells 2021; 13:1394-1416. [PMID: 34786151 PMCID: PMC8567453 DOI: 10.4252/wjsc.v13.i10.1394] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/21/2021] [Accepted: 09/14/2021] [Indexed: 02/06/2023] Open
Abstract
Alternative ribonucleic acid (RNA) splicing can lead to the assembly of different protein isoforms with distinctive functions. The outcome of alternative splicing (AS) can result in a complete loss of function or the acquisition of new functions. There is a gap in knowledge of abnormal RNA splice variants promoting cancer stem cells (CSCs), and their prospective contribution in cancer progression. AS directly regulates the self-renewal features of stem cells (SCs) and stem-like cancer cells. Notably, octamer-binding transcription factor 4A spliced variant of octamer-binding transcription factor 4 contributes to maintaining stemness properties in both SCs and CSCs. The epithelial to mesenchymal transition pathway regulates the AS events in CSCs to maintain stemness. The alternative spliced variants of CSCs markers, including cluster of differentiation 44, aldehyde dehydrogenase, and doublecortin-like kinase, α6β1 integrin, have pivotal roles in increasing self-renewal properties and maintaining the pluripotency of CSCs. Various splicing analysis tools are considered in this study. LeafCutter software can be considered as the best tool for differential splicing analysis and identification of the type of splicing events. Additionally, LeafCutter can be used for efficient mapping splicing quantitative trait loci. Altogether, the accumulating evidence re-enforces the fact that gene and protein expression need to be investigated in parallel with alternative splice variants.
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Affiliation(s)
- Esmaeil Ebrahimie
- School of Animal and Veterinary Sciences, The University of Adelaide, Adelaide 5005, South Australia, Australia
- La Trobe Genomics Research Platform, School of Life Sciences, College of Science, Health and Engineering, La Trobe University, Melbourne 3086, Australia
- School of Biosciences, The University of Melbourne, Melbourne 3010, Australia,
| | - Samira Rahimirad
- Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran 1497716316, Iran
- Division of Urology, Department of Surgery, McGill University and the Research Institute of the McGill University Health Centre, Montreal H4A 3J1, Quebec, Canada
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18
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Oshiba RT, Touson E, Elsherbini YM, Abdraboh ME. Melatonin: A regulator of the interplay between FoxO1, miR96, and miR215 signaling to diminish the growth, survival, and metastasis of murine adenocarcinoma. Biofactors 2021; 47:740-753. [PMID: 34058789 DOI: 10.1002/biof.1758] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 05/12/2021] [Indexed: 01/20/2023]
Abstract
Melatonin (Mel.), also known as the magic hormone, is a nocturnally secreted hormone orchestrates the clearance of free radicals that have been built up and cumulated during day. This study aims to detect the impact of pineal gland removal on the incidence of tumor development and to assess the signaling pathways via which exogenous melatonin counteract cancer growth. This goal has been achieved by novel approach for pineal destruction using dental micromotor which validated by melatonin downregulation in blood plasma. Mice were injected sub-cutenously with Ehrlich cells to develop solid tumor as a murine model of breast cancer. The increase at tumor markers carcino embryonic antigen, TNFα, and nuclear factor kappa-light-chain-enhancer of activated B cells was over countered by exogenous melatonin supplementation (20 mg/kg) daily for 1 month. The anticancer effects of melatonin were significantly mediated by scavenging H2 O2 and NO and diminishing of lipid peroxidation marker malondialdehyde. The real-time polymerase chain Rx analyses indicated a significant effect of Melatonin in upregulating the expression of miR215, fork head box protein O1 (foxO1), and downregulation of miR96. Flowcytometric analyses indicated a significant effect of melatonin on induction of cell cycle arrest at G1 phase which was further confirmed by Ki67 downregulation. Immunohistochemical analyses indicated the role of melatonin in upregulating P53-dependent apoptosis and downregulating CD44 signaling for survivin, matrix metallo-protein kinase 2, and vascular endothelial growth factor to inhibit cell survival and metastasis. In conclusion, this study sheds the light on M./P53/miR215/CD44 with an emphasis on M./miR96//foxO1 signaling cascades, as a novel pathway of melatonin signaling in adenocarcinoma to diminish cancer cell growth, survival and metastasis.
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Affiliation(s)
- Rehab T Oshiba
- Department of Zoology, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Ehab Touson
- Department of Zoology, Faculty of Science, Tanta University, Tanta, Egypt
| | - Yasser M Elsherbini
- School of Allied Health, Faculty of Health, Education, Medicine and Social care, Anglia Ruskin University, Chelmsford, UK
| | - Mohamed E Abdraboh
- Department of Zoology, Faculty of Science, Mansoura University, Mansoura, Egypt
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19
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Abdel-Hamid NM, Fathy M, Koike C, Yoshida T, Okabe M, Zho K, Abouzied M, Nikaido T. Identification of Chemo and Radio-Resistant Sub-Population of Stem Cells in Human Cervical Cancer HeLa Cells. Cancer Invest 2021; 39:661-674. [PMID: 34076552 DOI: 10.1080/07357907.2021.1931875] [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: 12/16/2022]
Abstract
BACKGROUND Cervical cancer ranks the second female malignancy after breast cancer. Cancer stem cells (CSCs) are hard to be eradicated, so can recur. We aim to isolate and characterize CSCs from HeLa cells. METHODS These cells express clusters of differentiation (CDs), 44 and 24, to be sorted by fluorescence-activated cell sorting (FACS). RESULTS CD44+CD24+ cells showed potential to form spheres, tumorigenicity, stemness genes and higher resistance to cisplatin, X-ray. CONCLUSION CD44+CD24+ HeLa cells hold characteristics of CSCs, in vitro, in vivo studies, suggesting that targeting may lead to screening of new anti-cancer therapies.
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Affiliation(s)
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Egypt.,Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Chika Koike
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Toshiko Yoshida
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Motonori Okabe
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Kaixuan Zho
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Mekky Abouzied
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Egypt
| | - Toshio Nikaido
- Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
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20
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Al-Mansoob M, Gupta I, Stefan Rusyniak R, Ouhtit A. KYNU, a novel potential target that underpins CD44-promoted breast tumour cell invasion. J Cell Mol Med 2021; 25:2309-2314. [PMID: 33486887 PMCID: PMC7933956 DOI: 10.1111/jcmm.16296] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 12/29/2020] [Indexed: 12/14/2022] Open
Abstract
Using a validated tetracycline‐off‐inducible CD44 expression system in mouse model, we have previously demonstrated that the hyaluronan (HA) receptor CD44 promotes breast cancer (BC) metastasis to the liver. To unravel the mechanisms that underpin CD44‐promoted BC cell invasion, RNA samples were isolated from two cell models: (a) a tetracycline (Tet)‐Off‐regulated expression system of the CD44s in MCF‐7 cells and; (b) as a complementary approach, the highly metastatic BC cells, MDA‐MB‐231, were cultured in the presence and absence of 50 µg/mL of HA. Kynureninase (KYNU), identified by Microarray analysis, was up‐regulated by 3‐fold upon induction and activation of CD44 by HA; this finding suggests that KYNU is a potential novel transcriptional target of CD44‐downtstream signalling. KYNU is a pyridoxal phosphate (PLP) dependent enzyme involved in the biosynthesis of NAD cofactors from tryptophan that has been associated with the onset and development of BC. This review will attempt to identify and discuss the findings supporting this hypothesis and the mechanisms linking KYNU cell invasion via CD44.
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Affiliation(s)
- Maryam Al-Mansoob
- Department of Biological & Environmental Sciences, College of Arts and Science, Qatar University, Doha, Qatar
| | - Ishita Gupta
- College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Radoslaw Stefan Rusyniak
- Department of Biological & Environmental Sciences, College of Arts and Science, Qatar University, Doha, Qatar
| | - Allal Ouhtit
- Department of Biological & Environmental Sciences, College of Arts and Science, Qatar University, Doha, Qatar
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The 3D genomic landscape of differential response to EGFR/HER2 inhibition in endocrine-resistant breast cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2020; 1863:194631. [PMID: 32956836 DOI: 10.1016/j.bbagrm.2020.194631] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/10/2020] [Accepted: 09/14/2020] [Indexed: 11/23/2022]
Abstract
BACKGROUND Recent studies suggested that crosstalk between ERα and EGFR/HER2 pathways plays a critical role in mediating endocrine therapy resistance. Several inhibitors targeting EGFR/HER2 signaling, including FDA-approved lapatinib and gefitinib as well as a novel dual tyrosine kinase inhibitor (TKI) sapitinib, showed greater therapeutic efficacies. However, how 3D chromatin landscape responds to the inhibition of EGFR/HER2 pathway remains to be elucidated. METHODS In this study, we conducted in situ Hi-C and RNA-seq in two ERα+ breast cancer cell systems, 1) parental MCF7 cells and its associated tamoxifen-resistant MCF7TR cells; and 2) parental T47D cells and its associated tamoxifen-resistant T47DTR cells, before and after the treatment of sapitinib. RESULTS We identified differential responses in topologically associated domains (TADs), looping genes and expressed genes. Interestingly, we found that many differential TADs and looping genes are reversible after sapitinib treatment, indicating that EGFR/HER2 signaling may play a role in reshaping and rewiring the high order genome organization. We further examined and recapitulated the reversible looping genes in 3D spheroids of breast cancer cells, demonstrating that 3D cell culture spheroid of breast cancer cells could be a potential preclinical breast cancer model for studying 3D chromatin regulation. CONCLUSIONS Our study has provided significant insights into our understanding of 3D genomic landscape changes in response to EGFR/HER2 Inhibition in endocrine-resistant breast cancer cells. Our data provides a rich resource for further evaluating chromatin structural responses to EGFR/HER2 targeted therapies in endocrine-resistant breast cancer cells. Our analyses suggest that these alterations of chromatin structures and transcriptional programs may provide new avenues for intervention or designing of patient selection for targeted endocrine treatment.
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Kato H, Naiki-Ito A, Yamada T, Suzuki S, Yamashita Y, Inaguma S, Kondo N, Wanifuchi-Endo Y, Toyama T, Takahashi S. The standard form of CD44 as a marker for invasion of encapsulated papillary carcinoma of the breast. Pathol Int 2020; 70:835-843. [PMID: 32783311 DOI: 10.1111/pin.13001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 07/14/2020] [Accepted: 07/22/2020] [Indexed: 01/03/2023]
Abstract
Encapsulated papillary carcinoma (EPC), a rare variant of papillary carcinoma of the breast, is regarded as a transition form between carcinoma in situ and invasive carcinoma. Here, we tried to identify differences in immunohistochemical phenotype between 10 EPCs with invasive properties (EPC with invasion) and 17 non-invasive EPCs (EPC). We immunohistochemically assessed the expression of hormone receptors, matrix metalloproteinase (MMP) 2 and MMP9, vascular endothelial growth factor (VEGF), CD31, and D2-40, markers of tumor-associated macrophages (CD163, CD206), Ki-67 and stem cell markers (CD44 and CD24). The frequency of MMP9-positive cases and the number of tumor-associated macrophages infiltrating into the fibrous capsule were significantly higher in EPC with invasion than in EPC. The expression of the standard form of CD44 (CD44s) was significantly stronger in EPC with invasion than in EPC (P = 0.0036) and was correlated with MMP2 expression and M2-like macrophage infiltration. A multivariate logistic model analysis showed that CD44s expression in tumor cell and infiltration of CD163 positive macrophage in EPC capsule showed an independent odds ratio for invasion of EPC. Thus, CD44s may be a potential marker predicting invasive potential of EPC and could play an important role in progression to the invasive phase of EPC.
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Affiliation(s)
- Hiroyuki Kato
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Aya Naiki-Ito
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takehiro Yamada
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shugo Suzuki
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yoriko Yamashita
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shingo Inaguma
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,Department of Pathology, Nagoya City East Medical Center, Nagoya, Japan
| | - Naoto Kondo
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yumi Wanifuchi-Endo
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Tatsuya Toyama
- Department of Breast Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Chen X, Shi X, Liu Y, He Y, Du Y, Zhang G, Yang C, Gao F. Remodelling of the bone marrow microenvironment by stromal hyaluronan modulates the malignancy of breast cancer cells. Cell Commun Signal 2020; 18:89. [PMID: 32517712 PMCID: PMC7285718 DOI: 10.1186/s12964-020-00592-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 05/07/2020] [Indexed: 12/24/2022] Open
Abstract
Background Hyaluronan (HA) is an abundant component of the bone marrow (BM) extracellular matrix. Here, we investigated the abnormal deposition of HA in the BM microenvironment and its remodelling in mediating the malignancy of breast cancer cells (BCCs). Methods BCCs were transplanted into nude mice by intracardiac injection. The BCCs were cocultured with BM-derived stromal HS5 cells. Then, the abnormal metabolism of HA and its correlation with the malignant growth and the intracellular signalling pathways of the BCCs were investigated. After knockdown/out of the HA receptor CD44 in cancer cells by shRNA and CRISPR/Cas9, the mechanism was investigated in vivo through intratibial inoculation and in vitro by coculture with HS5 cells. Results The malignancy of cancer cells was highly related to the degree of accumulation of HA in the BM. Further, stromal cell-derived HA, especially the mixed complex, significantly promoted the growth of BCCs and osteolysis by binding to the CD44 receptor. Additionally, the investigation of the underlying mechanism revealed that the PI3K, Cyclin D1, and CDK4 pathways were involved in the effect of bone stromal cell-derived HA on the BCC activities. Conclusion These data suggested that HA in abnormal BM stroma might be a therapeutic candidate for bone metastasis of breast cancer.
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