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Mosoane B, McCabe M, Jackson BS, Dlamini Z. CD44 Variant Expression in Follicular Cell-Derived Thyroid Cancers: Implications for Overcoming Multidrug Resistance. Molecules 2025; 30:1899. [PMID: 40363706 PMCID: PMC12073131 DOI: 10.3390/molecules30091899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2025] [Revised: 03/22/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
Thyroid cancer (TC) is a significant global health issue that exhibits notable heterogeneity in incidence and outcomes. In low-resource settings such as Africa, delayed diagnosis and limited healthcare access exacerbate mortality rates. Among follicular cell-derived thyroid cancers-including papillary (PTC), follicular (FTC), anaplastic (ATC), and poorly differentiated (PDTC) subtypes-the role of CD44 variants has emerged as a critical factor influencing tumor progression and multidrug resistance (MDR). CD44, a transmembrane glycoprotein, and its splice variants (CD44v) mediate cell adhesion, migration, and survival, contributing to cancer stem cell (CSC) maintenance and therapy resistance. Differential expression patterns of CD44 isoforms across TC subtypes have shown diagnostic, prognostic, and therapeutic implications. Specifically, CD44v6 expression in PTC has been correlated with metastasis and aggressive tumor behavior, while in FTC, its expression aids in distinguishing malignant from benign lesions. Furthermore, CD44 contributes to MDR through enhanced drug efflux via ABC transporters, apoptosis evasion, and CSC maintenance via the Wnt/β-catenin and PI3K/Akt pathways. Targeted therapies against CD44 such as monoclonal antibodies, hyaluronic acid-based nanocarriers, and gene-editing technologies hold promise in overcoming MDR. However, despite the mounting evidence supporting CD44-targeted strategies in various cancers, research on this therapeutic potential in TC remains limited. This review synthesizes existing knowledge on CD44 variant expression in follicular cell-derived thyroid cancers and highlights potential therapeutic strategies to mitigate MDR, particularly in high-burden regions, thereby improving patient outcomes and survival.
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Affiliation(s)
- Benny Mosoane
- Department of Anatomical Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa;
| | - Michelle McCabe
- Department of Anatomical Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa;
| | - Brandon S. Jackson
- Breast and Endocrine Unit, Department of General Surgery, University of Pretoria, Kalafong Provincial Tertiary Hospital, Pretoria 0001, South Africa;
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), DSI/NRF SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Pretoria 0001, South Africa
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Naderi S, Khodagholi F, Janahmadi M, Motamedi F, Torabi A, Batool Z, Heydarabadi MF, Pourbadie HG. Ferroptosis and cognitive impairment: Unraveling the link and potential therapeutic targets. Neuropharmacology 2025; 263:110210. [PMID: 39521042 DOI: 10.1016/j.neuropharm.2024.110210] [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: 08/24/2024] [Revised: 10/24/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, share key characteristics, notably cognitive impairment and significant cell death in specific brain regions. Cognition, a complex mental process allowing individuals to perceive time and place, is disrupted in these conditions. This consistent disruption suggests the possibility of a shared underlying mechanism across all neurodegenerative diseases. One potential common factor is the activation of pathways leading to cell death. Despite significant progress in understanding cell death pathways, no definitive treatments have emerged. This has shifted focus towards less-explored mechanisms like ferroptosis, which holds potential due to its involvement in oxidative stress and iron metabolism. Unlike apoptosis or necrosis, ferroptosis offers a novel therapeutic avenue due to its distinct biochemical and genetic underpinnings, making it a promising target in neurodegenerative disease treatment. Ferroptosis is distinguished from other cellular death mechanisms, by distinctive characteristics such as an imbalance of iron hemostasis, peroxidation of lipids in the plasma membrane, and dysregulated glutathione metabolism. In this review, we discuss the potential role of ferroptosis in cognitive impairment. We then summarize the evidence linking ferroptosis biomarkers to cognitive impairment brought on by neurodegeneration while highlighting recent advancements in our understanding of the molecular and genetic mechanisms behind the condition. Finally, we discuss the prospective therapeutic implications of targeting ferroptosis for the treatment of cognitive abnormalities associated with neurodegeneration, including natural and synthetic substances that suppress ferroptosis via a variety of mechanisms. Promising therapeutic candidates, including antioxidants and iron chelators, are being explored to inhibit ferroptosis and mitigate cognitive decline.
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Affiliation(s)
- Soudabeh Naderi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fariba Khodagholi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahyar Janahmadi
- Neuroscience Research Center, Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fereshteh Motamedi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolfazl Torabi
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zehra Batool
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | | | - Hamid Gholami Pourbadie
- Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran.
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Fan G, Liu J, Liu M, Huang Y. Piceatannol-3'-O-β-D-glucopyranoside inhibits neuroexcitotoxicity and ferroptosis through NMDAR/NRF2/BACH1/ACSL4 pathway in acute ischemic stroke. Free Radic Biol Med 2025; 227:667-679. [PMID: 39675532 DOI: 10.1016/j.freeradbiomed.2024.12.029] [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: 08/20/2024] [Revised: 12/08/2024] [Accepted: 12/09/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND Neuronal protection is a well-established method of acute ischemic stroke (AIS) treatment. The pharmacodynamic effect of Piceatannol-3'-O-β-D-glucopyranoside (Chinese name: Hartigan, QZZG) on AIS has been reported, but the molecular mechanism of this effect remains unknown. PURPOSE The purpose of this study is to elucidate the pharmacodynamic effects and mechanisms of QZZG in the treatment of AIS. METHODS A combined network pharmacology and metabolomics approach was used to predict the key targets and pathways of QZZG in the treatment of AIS and to elucidate the mechanism of QZZG through experimental validation. RESULTS In this study, QZZG improved histopathologic features and reduced infarct volume and neurologic deficit scores. Integrated network pharmacology and metabolomics revealed that QZZG may protect neurons by regulating glutamate and its receptors, and that glutamate is closely related to NMDAR1, NRF2, and Caspase-3. Pathway analysis results suggested that NMDAR-mediated Ca2+ inward flow is one of the critical pathways. In terms of neuroexcitotoxicity QZZG inhibited glutamate content, reduced Ca2+ inward flow, protected mitochondrial function, and reduced ROS, as well as being able to effectively inhibit the expression of NMDAR1, Caspase-3, Bax, and promote the expression of Bcl-2, NMDAR2A. In terms of ferroptosis QZZG promoted NRF2, HO-1, GPX4 and nuclear-NRF2, inhibited the expression of BACH1 and ACSL4, and suppressed Fe2+ accumulation and lipid peroxidation. Silencing of BACH1 resulted in elevated expression of NRF2 and decreased expression of ACSL4, which inhibited the sensitivity of neurons to ferroptosis. QZZG was able to further increase NRF2 expression under conditions of silencing BACH1. QZZG induced NRF2 and inhibited BACH1, ACSL4 was inhibited by ML385, and inhibition of NRF2 induced the expression of BACH1 and ACSL4, QZZG protects neurons in an NRF2-dependent manner. CONCLUSION In summary, QZZG inhibited neuroexcitotoxicity and ferroptosis by regulating the NMDAR/NRF2/BACH1/ACSL4 pathway. The study provided a relatively novel perspective on the mechanism of traditional Chinese medicine (TCM) treatment of the disease.
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Affiliation(s)
- Genhao Fan
- The Second Affiliated Hospital of Tianjin University of Chinese Medicine, 69 Zengchan Road, Hebei District, Tianjin 300250, China; Department of Cardiovascular Disease, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Jia Liu
- The Second Affiliated Hospital of Tianjin University of Chinese Medicine, 69 Zengchan Road, Hebei District, Tianjin 300250, China
| | - Menglin Liu
- Department of Encephalopathy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
| | - Yuhong Huang
- The Second Affiliated Hospital of Tianjin University of Chinese Medicine, 69 Zengchan Road, Hebei District, Tianjin 300250, China.
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Liao C, Huang Z, Liu J, Deng M, Wang L, Chen Y, Li J, Zhao J, Luo X, Zhu J, Wu Q, Fu W, Sun B, Zheng J. Role of extracellular vesicles in castration-resistant prostate cancer. Crit Rev Oncol Hematol 2024; 197:104348. [PMID: 38588967 DOI: 10.1016/j.critrevonc.2024.104348] [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: 03/13/2024] [Revised: 04/03/2024] [Accepted: 04/04/2024] [Indexed: 04/10/2024] Open
Abstract
Prostate cancer (PCa) is a common health threat to men worldwide, and castration-resistant PCa (CRPC) is the leading cause of PCa-related deaths. Extracellular vesicles (EVs) are lipid bilayer compartments secreted by living cells that are important mediators of intercellular communication. EVs regulate the biological processes of recipient cells by transmitting heterogeneous cargoes, contributing to CRPC occurrence, progression, and drug resistance. These EVs originate not only from malignant cells, but also from various cell types within the tumor microenvironment. EVs are widely dispersed throughout diverse biological fluids and are attractive biomarkers derived from noninvasive liquid biopsy techniques. EV quantities and cargoes have been tested as potential biomarkers for CRPC diagnosis, progression, drug resistance, and prognosis; however, technical barriers to their clinical application continue to exist. Furthermore, exogenous EVs may provide tools for new therapies for CRPC. This review summarizes the current evidence on the role of EVs in CRPC.
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Affiliation(s)
- Chaoyu Liao
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Zeyu Huang
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Jingui Liu
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Min Deng
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Leyi Wang
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Yutong Chen
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Jia Li
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Jiang Zhao
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Xing Luo
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Jingzhen Zhu
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Qingjian Wu
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Weihua Fu
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Bishao Sun
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China.
| | - Ji Zheng
- Department of Urology, Urologic Surgery Center, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China.
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Boman BM, Viswanathan V, Facey COB, Fields JZ, Stave JW. The v8-10 variant isoform of CD44 is selectively expressed in the normal human colonic stem cell niche and frequently is overexpressed in colon carcinomas during tumor development. Cancer Biol Ther 2023; 24:2195363. [PMID: 37005380 PMCID: PMC10072056 DOI: 10.1080/15384047.2023.2195363] [Citation(s) in RCA: 8] [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: 11/10/2021] [Revised: 02/02/2023] [Accepted: 03/20/2023] [Indexed: 04/04/2023] Open
Abstract
CD44 protein and its variant isoforms are expressed in cancer stem cells (CSCs), and various CD44 isoforms can have different functional roles in cells. Our goal was to investigate how different CD44 isoforms contribute to the emergence of stem cell (SC) overpopulation that drives colorectal cancer (CRC) development. Specific CD44 variant isoforms are selectively expressed in normal colonic SCs and become overexpressed in CRCs during tumor development. We created a unique panel of anti-CD44 rabbit genomic antibodies to 16 specific epitopes that span the entire length of the CD44 molecule. Our panel was used to comprehensively investigate the expression of different CD44 isoforms in matched pairs (n = 10) of malignant colonic tissue and adjacent normal mucosa, using two (IHC & IF) immunostaining approaches. We found that: i) CD44v8-10 is selectively expressed in the normal human colonic SC niche; ii) CD44v8-10 is co-expressed with the SC markers ALDH1 and LGR5 in normal and malignant colon tissues; iii) colon carcinoma tissues frequently (80%) stain for CD44v8-10 while staining for CD44v6 was less frequent (40%). Given that CD44v8-10 expression is restricted to cells in the normal human colonic SC niche and CD44v8-10 expression progressively increases during CRC development, CD44v8-10 expression likely contributes to the SC overpopulation that drives the development and growth of colon cancers. Since the CD44 variant v8-10 epitope is located on CD44's extracellular region, it offers great promise for targeted anti-CSC treatment approaches.
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Affiliation(s)
- Bruce M. Boman
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE, USA
- Department of Biologic Sciences, University of Delaware, Newark, DE, USA
- Jefferson Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Vignesh Viswanathan
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE, USA
- Department of Biologic Sciences, University of Delaware, Newark, DE, USA
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
| | - Caroline O. B. Facey
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE, USA
| | - Jeremy Z. Fields
- Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE, USA
- Department of Cancer Research and Innovation, CA*TX Inc, Princeton, NJ, USA
| | - James W. Stave
- Department of Cancer Research and Innovation, Strategic Diagnostics Inc, Newark, DE, USA
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6
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Maltseva D, Tonevitsky A. RNA-binding proteins regulating the CD44 alternative splicing. Front Mol Biosci 2023; 10:1326148. [PMID: 38106992 PMCID: PMC10722200 DOI: 10.3389/fmolb.2023.1326148] [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: 10/22/2023] [Accepted: 11/15/2023] [Indexed: 12/19/2023] Open
Abstract
Alternative splicing is often deregulated in cancer, and cancer-specific isoform switches are part of the oncogenic transformation of cells. Accumulating evidence indicates that isoforms of the multifunctional cell-surface glycoprotein CD44 play different roles in cancer cells as compared to normal cells. In particular, the shift of CD44 isoforms is required for epithelial to mesenchymal transition (EMT) and is crucial for the maintenance of pluripotency in normal human cells and the acquisition of cancer stem cells phenotype for malignant cells. The growing and seemingly promising use of splicing inhibitors for treating cancer and other pathologies gives hope for the prospect of using such an approach to regulate CD44 alternative splicing. This review integrates current knowledge about regulating CD44 alternative splicing by RNA-binding proteins.
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Affiliation(s)
- Diana Maltseva
- Faculty of Biology and Biotechnology, HSE University, Moscow, Russia
| | - Alexander Tonevitsky
- Faculty of Biology and Biotechnology, HSE University, Moscow, Russia
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
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Suzuki H, Goto N, Tanaka T, Ouchida T, Kaneko MK, Kato Y. Development of a Novel Anti-CD44 Variant 8 Monoclonal Antibody C 44Mab-94 against Gastric Carcinomas. Antibodies (Basel) 2023; 12:45. [PMID: 37489367 PMCID: PMC10366929 DOI: 10.3390/antib12030045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/28/2023] [Accepted: 07/03/2023] [Indexed: 07/26/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. GC with peritoneal metastasis exhibits a poor prognosis due to the lack of effective therapy. A comprehensive analysis of malignant ascites identified the genomic alterations and significant amplifications of cancer driver genes, including CD44. CD44 and its splicing variants are overexpressed in tumors, and play crucial roles in the acquisition of invasiveness, stemness, and resistance to treatments. Therefore, the development of CD44-targeted monoclonal antibodies (mAbs) is important for GC diagnosis and therapy. In this study, we immunized mice with CD44v3-10-overexpressed PANC-1 cells and established several dozens of clones that produce anti-CD44v3-10 mAbs. One of the clones (C44Mab-94; IgG1, kappa) recognized the variant-8-encoded region and peptide, indicating that C44Mab-94 is a specific mAb for CD44v8. Furthermore, C44Mab-94 could recognize CHO/CD44v3-10 cells, oral squamous cell carcinoma cell line (HSC-3), or GC cell lines (MKN45 and NUGC-4) in flow cytometric analyses. C44Mab-94 could detect the exogenous CD44v3-10 and endogenous CD44v8 in western blotting and stained the formalin-fixed paraffin-embedded gastric cancer cells. These results indicate that C44Mab-94 is useful for detecting CD44v8 in a variety of experimental methods and is expected to become usefully applied to GC diagnosis and therapy.
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Affiliation(s)
- Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Nohara Goto
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Tomohiro Tanaka
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Tsunenori Ouchida
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Mika K Kaneko
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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Ishikawa K, Suzuki H, Kaneko MK, Kato Y. Establishment of a Novel Anti-CD44 Variant 10 Monoclonal Antibody C 44Mab-18 for Immunohistochemical Analysis against Oral Squamous Cell Carcinomas. Curr Issues Mol Biol 2023; 45:5248-5262. [PMID: 37504249 PMCID: PMC10378409 DOI: 10.3390/cimb45070333] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/14/2023] [Accepted: 06/19/2023] [Indexed: 07/29/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck cancer, and has been revealed as the second-highest expression of CD44 in cancers. CD44 has been investigated as a cancer stem cell marker of HNSCC and plays a critical role in tumor malignant progression. Especially, splicing variant isoforms of CD44 (CD44v) are overexpressed in cancers and considered a promising target for cancer diagnosis and therapy. We developed monoclonal antibodies (mAbs) against CD44 by immunizing mice with CD44v3-10-overexpressed PANC-1 cells. Among the established clones, C44Mab-18 (IgM, kappa) reacted with CHO/CD44v3-10, but not with CHO/CD44s and parental CHO-K1 using flow cytometry. The epitope mapping using peptides that cover variant exon-encoded regions revealed that C44Mab-18 recognized the border sequence between variant 10 and the constant exon 16-encoded sequence. These results suggest that C44Mab-18 recognizes variant 10-containing CD44v, but not CD44s. Furthermore, C44Mab-18 could recognize the human oral squamous cell carcinoma (OSCC) cell line, HSC-3, in flow cytometry. The apparent dissociation constant (KD) of C44Mab-18 for CHO/CD44v3-10 and HSC-3 was 1.6 × 10-7 M and 1.7 × 10-7 M, respectively. Furthermore, C44Mab-18 detected CD44v3-10 but not CHO/CD44s in Western blotting, and endogenous CD44v10 in immunohistochemistry using OSCC tissues. These results indicate that C44Mab-18 is useful for detecting CD44v10 in flow cytometry and immunohistochemistry.
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Affiliation(s)
- Kenichiro Ishikawa
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Mika K Kaneko
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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Tawara M, Suzuki H, Goto N, Tanaka T, Kaneko MK, Kato Y. A Novel Anti-CD44 Variant 9 Monoclonal Antibody C 44Mab-1 Was Developed for Immunohistochemical Analyses against Colorectal Cancers. Curr Issues Mol Biol 2023; 45:3658-3673. [PMID: 37185762 PMCID: PMC10137259 DOI: 10.3390/cimb45040238] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
Cluster of differentiation 44 (CD44) is a type I transmembrane glycoprotein and has been shown to be a cell surface marker of cancer stem-like cells in various cancers. In particular, the splicing variants of CD44 (CD44v) are overexpressed in cancers and play critical roles in cancer stemness, invasiveness, and resistance to chemotherapy and radiotherapy. Therefore, the understanding of the function of each CD44v is indispensable for CD44-targeting therapy. CD44v9 contains the variant 9-encoded region, and its expression predicts poor prognosis in patients with various cancers. CD44v9 plays critical roles in the malignant progression of tumors. Therefore, CD44v9 is a promising target for cancer diagnosis and therapy. Here, we developed sensitive and specific monoclonal antibodies (mAbs) against CD44 by immunizing mice with CD44v3-10-overexpressed Chinese hamster ovary-K1 (CHO/CD44v3-10) cells. We first determined their critical epitopes using enzyme-linked immunosorbent assay and characterized their applications as flow cytometry, western blotting, and immunohistochemistry. One of the established clones, C44Mab-1 (IgG1, kappa), reacted with a peptide of the variant 9-encoded region, indicating that C44Mab-1 recognizes CD44v9. C44Mab-1 could recognize CHO/CD44v3-10 cells or colorectal cancer cell lines (COLO201 and COLO205) in flow cytometric analysis. The apparent dissociation constant (KD) of C44Mab-1 for CHO/CD44v3-10, COLO201, and COLO205 was 2.5 × 10-8 M, 3.3 × 10-8 M, and 6.5 × 10-8 M, respectively. Furthermore, C44Mab-1 was able to detect the CD44v3-10 in western blotting and the endogenous CD44v9 in immunohistochemistry using colorectal cancer tissues. These results indicated that C44Mab-1 is useful for detecting CD44v9 not only in flow cytometry or western blotting but also in immunohistochemistry against colorectal cancers.
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Affiliation(s)
- Mayuki Tawara
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (M.T.); (N.G.); (T.T.); (M.K.K.)
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (M.T.); (N.G.); (T.T.); (M.K.K.)
| | - Nohara Goto
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (M.T.); (N.G.); (T.T.); (M.K.K.)
| | - Tomohiro Tanaka
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (M.T.); (N.G.); (T.T.); (M.K.K.)
| | - Mika K. Kaneko
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (M.T.); (N.G.); (T.T.); (M.K.K.)
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (M.T.); (N.G.); (T.T.); (M.K.K.)
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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10
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Fan G, Liu M, Liu J, Huang Y. The initiator of neuroexcitotoxicity and ferroptosis in ischemic stroke: Glutamate accumulation. Front Mol Neurosci 2023; 16:1113081. [PMID: 37033381 PMCID: PMC10076579 DOI: 10.3389/fnmol.2023.1113081] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 03/06/2023] [Indexed: 04/11/2023] Open
Abstract
Glutamate plays an important role in excitotoxicity and ferroptosis. Excitotoxicity occurs through over-stimulation of glutamate receptors, specifically NMDAR, while in the non-receptor-mediated pathway, high glutamate concentrations reduce cystine uptake by inhibiting the System Xc-, leading to intracellular glutathione depletion and resulting in ROS accumulation, which contributes to increased lipid peroxidation, mitochondrial damage, and ultimately ferroptosis. Oxidative stress appears to crosstalk between excitotoxicity and ferroptosis, and it is essential to maintain glutamate homeostasis and inhibit oxidative stress responses in vivo. As researchers work to develop natural compounds to further investigate the complex mechanisms and regulatory functions of ferroptosis and excitotoxicity, new avenues will be available for the effective treatment of ischaemic stroke. Therefore, this paper provides a review of the molecular mechanisms and treatment of glutamate-mediated excitotoxicity and ferroptosis.
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Affiliation(s)
- Genhao Fan
- Graduate School, Tianjin University of Chinese Medicine, Tianjin, China
| | - Menglin Liu
- Graduate School, Tianjin University of Chinese Medicine, Tianjin, China
| | - Jia Liu
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Tianjin University of Chinese Medicine, Tianjin, China
| | - Yuhong Huang
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Tianjin University of Chinese Medicine, Tianjin, China
- *Correspondence: Yuhong Huang,
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11
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Zhang Q, Li W. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy. World J Stem Cells 2022; 14:267-286. [PMID: 35662861 PMCID: PMC9136564 DOI: 10.4252/wjsc.v14.i4.267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/19/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
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Affiliation(s)
- Qi Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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12
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Matsuoka Y, Yoshida R, Kawahara K, Sakata J, Arita H, Nkashima H, Takahashi N, Hirayama M, Nagata M, Hirosue A, Kuwahara Y, Fukumoto M, Toya R, Murakami R, Nakayama H. The antioxidative stress regulator Nrf2 potentiates radioresistance of oral squamous cell carcinoma accompanied with metabolic modulation. J Transl Med 2022; 102:896-907. [PMID: 35414650 PMCID: PMC9309095 DOI: 10.1038/s41374-022-00776-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 01/27/2022] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of critical antioxidant proteins, was recently demonstrated to play a key role in cancer progression. Resistance to radiotherapy is a major obstacle in treating oral squamous cell carcinoma (OSCC). However, little is known about the association between Nrf2 and radioresistance in OSCC. Two OSCC cell lines (SAS and HSC-2) and their clinically relevant radioresistant (CRR) clones (SAS-R, HSC-2-R) were used. The effects of Nrf2 downregulation on radiosensitivity and the involvement of glycolysis in Nrf2-mediated radioresistance were evaluated. Immunohistochemistry of phosphorylated Nrf2 (p-Nrf2) was performed in 110 patients with OSCC who underwent preoperative chemoradiotherapy and surgery. Nrf2 was stably upregulated in CRR cells in vitro and in a mouse xenograft model. Moreover, elevated Nrf2 expression was associated with radioresistance. The enhancement of Nrf2-dependent glycolysis and glutathione synthesis was involved in the development of radioresistance. Additionally, p-Nrf2 expression was closely related to the pathological response to chemoradiotherapy, and its expression was predictive of prognosis in patients with advanced OSCC. Our results suggest that Nrf2 plays an important role in the radioresistance of OSCC accompanied by metabolic reprogramming. Targeting Nrf2 antioxidant pathway may represent a promising treatment strategy for highly malignant OSCC.
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Affiliation(s)
- Yuichiro Matsuoka
- grid.274841.c0000 0001 0660 6749Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556 Japan
| | - Ryoji Yoshida
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.
| | - Kenta Kawahara
- grid.274841.c0000 0001 0660 6749Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556 Japan
| | - Junki Sakata
- grid.274841.c0000 0001 0660 6749Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556 Japan
| | - Hidetaka Arita
- grid.274841.c0000 0001 0660 6749Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556 Japan
| | - Hikaru Nkashima
- grid.274841.c0000 0001 0660 6749Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556 Japan
| | - Nozomu Takahashi
- grid.274841.c0000 0001 0660 6749Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556 Japan
| | - Masatoshi Hirayama
- grid.274841.c0000 0001 0660 6749Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556 Japan
| | - Masashi Nagata
- grid.274841.c0000 0001 0660 6749Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556 Japan
| | - Akiyuki Hirosue
- grid.274841.c0000 0001 0660 6749Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556 Japan
| | - Yoshikazu Kuwahara
- grid.412755.00000 0001 2166 7427Division of Radiation Biology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Miyagi, 981-8558 Japan
| | - Manabu Fukumoto
- grid.410793.80000 0001 0663 3325Department of Molecular Pathology, Tokyo Medical University, Tokyo, 160-8402 Japan
| | - Ryo Toya
- grid.274841.c0000 0001 0660 6749Department of Radiation Oncology, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556 Japan
| | - Ryuji Murakami
- grid.274841.c0000 0001 0660 6749Department of Medical Radiation Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, 862-0976 Japan
| | - Hideki Nakayama
- Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556, Japan.
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13
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Hassn Mesrati M, Syafruddin SE, Mohtar MA, Syahir A. CD44: A Multifunctional Mediator of Cancer Progression. Biomolecules 2021; 11:1850. [PMID: 34944493 PMCID: PMC8699317 DOI: 10.3390/biom11121850] [Citation(s) in RCA: 218] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/23/2021] [Accepted: 11/02/2021] [Indexed: 12/15/2022] Open
Abstract
CD44, a non-kinase cell surface transmembrane glycoprotein, has been widely implicated as a cancer stem cell (CSC) marker in several cancers. Cells overexpressing CD44 possess several CSC traits, such as self-renewal and epithelial-mesenchymal transition (EMT) capability, as well as a resistance to chemo- and radiotherapy. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The interaction of such isoforms with ligands, particularly hyaluronic acid (HA), osteopontin (OPN) and matrix metalloproteinases (MMPs), drive numerous cancer-associated signalling. However, there are contradictory results regarding whether high or low CD44 expression is associated with worsening clinicopathological features, such as a higher tumour histological grade, advanced tumour stage and poorer survival rates. Nonetheless, high CD44 expression significantly contributes to enhanced tumourigenic mechanisms, such as cell proliferation, metastasis, invasion, migration and stemness; hence, CD44 is an important clinical target. This review summarises current research regarding the different CD44 isoform structures and their roles and functions in supporting tumourigenesis and discusses CD44 expression regulation, CD44-signalling pathways and interactions involved in cancer development. The clinical significance and prognostic value of CD44 and the potential of CD44 as a therapeutic target in cancer are also addressed.
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Affiliation(s)
- Malak Hassn Mesrati
- Nanobiotechnology Research Group, Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia;
| | - Saiful Effendi Syafruddin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.E.S.); (M.A.M.)
| | - M. Aiman Mohtar
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.E.S.); (M.A.M.)
| | - Amir Syahir
- Nanobiotechnology Research Group, Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia;
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia
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14
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Inoue J, Kishikawa M, Tsuda H, Nakajima Y, Asakage T, Inazawa J. Identification of PDHX as a metabolic target for esophageal squamous cell carcinoma. Cancer Sci 2021; 112:2792-2802. [PMID: 33964039 PMCID: PMC8253269 DOI: 10.1111/cas.14938] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 12/13/2022] Open
Abstract
The metabolism in tumors is reprogrammed to meet its energetic and substrate demands. However, this metabolic reprogramming creates metabolic vulnerabilities, providing new opportunities for cancer therapy. Metabolic vulnerability as a therapeutic target in esophageal squamous cell carcinoma (ESCC) has not been adequately clarified. Here, we identified pyruvate dehydrogenase (PDH) component X (PDHX) as a metabolically essential gene for the cell growth of ESCC. PDHX expression was required for the maintenance of PDH activity and the production of ATP, and its knockdown inhibited the proliferation of cancer stem cells (CSCs) and in vivo tumor growth. PDHX was concurrently upregulated with the CD44 gene, a marker of CSCs, by co-amplification at 11p13 in ESCC tumors and these genes coordinately functioned in cancer stemness. Furthermore, CPI-613, a PDH inhibitor, inhibited the proliferation of CSCs in vitro and the growth of ESCC xenograft tumors in vivo. Thus, our study provides new insights related to the development of novel therapeutic strategies for ESCC by targeting the PDH complex-associated metabolic vulnerability.
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Affiliation(s)
- Jun Inoue
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Masahiro Kishikawa
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.,Department of Head and Neck Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hitoshi Tsuda
- Department of Basic Pathology, National Defense Medical College, Saitama, Japan
| | - Yasuaki Nakajima
- Department of Surgical Gastroenterology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takahiro Asakage
- Department of Head and Neck Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Johji Inazawa
- Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.,Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan
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15
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Zhang H, Si J, Yue J, Ma S. The mechanisms and reversal strategies of tumor radioresistance in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol 2021; 147:1275-1286. [PMID: 33687564 DOI: 10.1007/s00432-020-03493-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 12/02/2020] [Indexed: 01/16/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of most lethal malignancies with high aggressive potential in the world. Radiotherapy is used as one curative treatment modality for ESCC patients. Due to radioresistance, the 5-year survival rates of patients after radiotherapy is less than 20%. Tumor radioresistance is very complex and heterogeneous. Cancer-associated fibroblasts (CAFs), as one major component of tumor microenvironment (TME), play critical roles in regulating tumor radioresponse through multiple mechanisms and are increasingly considered as important anti-cancer targets. Cancer stemness, which renders cancer cells to be extremely resistant to conventional therapies, is involved in ESCC radioresistance due to the activation of Wnt/β-catenin, Notch, Hedgehog and Hippo (HH) pathways, or the induction of epithelial-mesenchymal transition (EMT), hypoxia and autophagy. Non-protein-coding RNAs (ncRNAs), which account for more than 90% of the genome, are involved in esophageal cancer initiation and progression through regulating the activation or inactivation of downstream signaling pathways and the expressions of target genes. Herein, we mainly reviewed the role of CAFs, cancer stemness, non-coding RNAs as well as others in the development of radioresistance and clarify the involved mechanisms. Furthermore, we summarized the potential strategies which were reported to reverse radioresistance in ESCC. Together, this review gives a systematic coverage of radioresistance mechanisms and reversal strategies and contributes to better understanding of tumor radioresistance for the exploitation of novel intervention strategies in ESCC.
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Affiliation(s)
- Hongfang Zhang
- Hangzhou Cancer Institution, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Jingxing Si
- Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, 310014, China
| | - Jing Yue
- Hangzhou Cancer Institution, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
| | - Shenglin Ma
- Hangzhou Cancer Institution, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China.
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
- Zhejiang University Cancer Center, Hangzhou, 310058, China.
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16
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Kagami T, Yamade M, Suzuki T, Uotani T, Tani S, Hamaya Y, Iwaizumi M, Osawa S, Sugimoto K, Miyajima H, Baba S, Sugimura H, Murai J, Pommier Y, Furuta T. The first evidence for SLFN11 expression as an independent prognostic factor for patients with esophageal cancer after chemoradiotherapy. BMC Cancer 2020; 20:1123. [PMID: 33218331 PMCID: PMC7678160 DOI: 10.1186/s12885-020-07574-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 10/26/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Schlafen 11 (SLFN11) was recently identified as a dominant determinant of sensitivity to DNA-targeting agents including platinum-based drugs. SLFN11 also reportedly enhances cellular radiosensitivity. In this study, we examined the prognostic value of SLFN11 expression in esophageal squamous cell carcinoma (ESCC) patients treated with definitive chemoradiotherapy (dCRT), including the platinum derivative nedaplatin. METHODS Seventy-three patients with ESCC who received dCRT were examined. SLFN11 expression was analyzed in pre-dCRT biopsies using immunohistochemistry and evaluated using a histo-score (H-score). Correlation between the H-score and overall survival was analyzed. An H-score ≥ 51 was provisionally defined as indicating high SLFN11 expression. Viability assays were performed using previously established isogenic human cell lines differentially expressing SLFN11 to test the usefulness of SLFN11 as marker of response to the dCRT regimen. RESULTS High SLFN11 expression was independently associated with better prognosis in ESCC patients (hazard ratio = 0.295, 95% CI = 0.143-0.605, p = 0.001 for multivariate analysis). Kaplan-Meier survival curves showed that the prognostic value of high SLFN11 expression was most evident in patients at clinical stages II and III (p = 0.004). In in vitro study, SLFN11-proficient cells were highly sensitive to platinum derivatives compared to SLFN11-deficient cells. CONCLUSION SLFN11 expression is an independent prognostic factor for ESCC patients treated with dCRT and a potential biomarker for treatment selection of ESCC. Examination of SLFN11 may be particularly useful for clinical Stage II-III patients who wish to choose dCRT (instead of surgery) to preserve esophageal function.
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Affiliation(s)
- Takuma Kagami
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
| | - Mihoko Yamade
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Takahiro Suzuki
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Takahiro Uotani
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Shinya Tani
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Moriya Iwaizumi
- Department of Clinical Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Hiroaki Miyajima
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan
| | - Satoshi Baba
- Department of Diagnostic Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Haruhiko Sugimura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Junko Murai
- Institute of Advanced Biosciences, Keio University, Turuoka, Yamagata, Japan
| | - Yves Pommier
- Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan
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17
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Interplay between Podoplanin, CD44s and CD44v in Squamous Carcinoma Cells. Cells 2020; 9:cells9102200. [PMID: 33003440 PMCID: PMC7601683 DOI: 10.3390/cells9102200] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 09/26/2020] [Accepted: 09/26/2020] [Indexed: 01/05/2023] Open
Abstract
Podoplanin and CD44 are transmembrane glycoproteins involved in inflammation and cancer. In this paper, we report that podoplanin is coordinately expressed with the CD44 standard (CD44s) and variant (CD44v) isoforms in vivo—in hyperplastic skin after a pro-inflammatory stimulus with 12-O-tetradecanoylphorbol-13-acetate (TPA)—and in vitro—in cell lines representative of different stages of mouse-skin chemical carcinogenesis, as well as in human squamous carcinoma cell (SCC) lines. Moreover, we identify CD44v10 in the mouse-skin carcinogenesis model as the only CD44 variant isoform expressed in highly aggressive spindle carcinoma cell lines together with CD44s and podoplanin. We also characterized CD44v3-10, CD44v6-10 and CD44v8-10 as the major variant isoforms co-expressed with CD44s and podoplanin in human SCC cell lines. Immunofluorescence confocal microscopy experiments show that these CD44v isoforms colocalize with podoplanin at plasma membrane protrusions and cell–cell contacts of SCC cells, as previously reported for CD44s. Furthermore, CD44v isoforms colocalize with podoplanin in chemically induced mouse-skin SCCs in vivo. Co-immunoprecipitation experiments indicate that podoplanin physically binds to CD44v3-10, CD44v6-10 and CD44v8-10 isoforms, as well as to CD44s. Podoplanin–CD44 interaction is mediated by the transmembrane and cytosolic regions and is negatively modulated by glycosylation of the extracellular domain. These results point to a functional interplay of podoplanin with both CD44v and CD44s isoforms in SCCs and give insight into the regulation of the podoplanin–CD44 association.
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18
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Kato T, Mizutani K, Kawakami K, Fujita Y, Ehara H, Ito M. CD44v8-10 mRNA contained in serum exosomes as a diagnostic marker for docetaxel resistance in prostate cancer patients. Heliyon 2020; 6:e04138. [PMID: 32642575 PMCID: PMC7334415 DOI: 10.1016/j.heliyon.2020.e04138] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 04/28/2020] [Accepted: 06/01/2020] [Indexed: 01/10/2023] Open
Abstract
Background Docetaxel is first-line chemotherapy for castration-resistant prostate cancer (CRPC), but most patients acquire docetaxel resistance. CD44 has been shown to be involved in drug resistance of cancers including prostate cancer. We hypothesized that CD44 in serum exosomes could be a diagnostic marker for docetaxel resistance in CRPC patients. In this study, we examined CD44 protein and mRNA expression in cell lysates and exosomes isolated from prostate cancer cells, evaluated the effect of CD44v8-10 knockdown on docetaxel sensitivity and measured CD44 mRNA copy numbers contained in serum exosomes in prostate cancer patients. Materials and methods Docetaxel-sensitive PC-3 prostate cancer cells and docetaxel-resistant PC-3R cells established previously from parental PC-3 cells were used. CD44v8-10 knockdown was performed by siRNA transfection. Blood was collected from 50 docetaxel-naïve and 10 docetaxel-resistant patients and 15 control males. CD44 protein expression was evaluated by Western blotting. CD44 mRNA expression was measured by RT-digital PCR. Results The levels of CD44v8-10 protein and mRNA in cell lysates and exosomes were higher in PC-3R cells than in PC-3 cells. CD44v8-10 knockdown significantly increased docetaxel sensitivity of PC-3R cells. The CD44v8-10 mRNA copy numbers in serum exosomes were higher in docetaxel-resistant patients than in docetaxel-naïve patients and control males (median 46, 12 and 17 copies/mL serum, respectively, P = 0.032). In contrast, the serum exosomal mRNA copy numbers of CD44 standard isoform (CD44s) were not different among 3 groups (median 25, 14 and 13 copies/mL serum, respectively, P = 0.150). Conclusions CD44v8-10 may be involved in docetaxel resistance in prostate cancer and serum exosomal CD44v8-10 mRNA could be a diagnostic marker for docetaxel-resistant CRPC.
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Affiliation(s)
- Taku Kato
- Department of Urology, Gifu University Graduate School of Medicine, Gifu 501-1193, Japan.,Department of Urology, Asahi University Hospital, Gifu 500-8523, Japan
| | - Kosuke Mizutani
- Department of Urology, Gifu University Graduate School of Medicine, Gifu 501-1193, Japan
| | - Kyojiro Kawakami
- Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
| | - Yasunori Fujita
- Research Team for Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
| | - Hidetoshi Ehara
- Department of Urology, Asahi University Hospital, Gifu 500-8523, Japan
| | - Masafumi Ito
- Research Team for Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
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19
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Zhang X, Yuan A, Zhao X, Li Z, Cui G. Tumoral Expression of CD166 in Human Esophageal Squamous Cell Carcinoma: Implications for Cancer Progression and Prognosis. Cancer Biother Radiopharm 2020; 35:214-222. [PMID: 32196367 DOI: 10.1089/cbr.2019.3089] [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] [Indexed: 02/06/2023] Open
Abstract
Accumulating data showed that cancer stem cells (CSCs) identified by cell surface markers contribute to the initiation, progression, and prognosis of human cancers. In this study, the expression of CSC candidates CD166, CD44, and Lgr5 in 65 cases of esophageal squamous cell carcinoma (ESCC) and 16 cases of control esophageal tissues were examined with immunohistochemistry (IHC). The correlation between tumoral expression levels of these CSC candidates and clinicopathological variables was analyzed. IHC results showed that the expression of CD166 in esophageal control tissues was completely negative, but it was in 87.69% (57/65) ESCC tissues. The expression of CD44 and Lgr5 did not differ between esophageal control tissues and ESCC tissues (p > 0.05). In addition, there were not correlations found among the expression levels of CD166, CD44, and Lgr5 in ESCC tissues. Clinicopathological analysis revealed that the tumoral expression level of CD166 correlated with lymph node involvement and TNM staging in patients with ESCC, and lower tumoral expression of CD44 was found in patients with advanced TNM staging. Kaplan-Meier survival curves suggested that expression level of CD166 appeared to have a negative impact on overall survival rate after surgery in patients with ESCC. Such impact was not found in other two CSC candidates. The authors therefore conclude that CD166 is a potential prognostic biomarker and correlates with advanced progression features in patients with ESCC.
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Affiliation(s)
- Xiaoshan Zhang
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China.,The Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Aping Yuan
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China.,Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway
| | - Xueru Zhao
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Zhenfeng Li
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Guanglin Cui
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China.,Faculty of Health Science, Nord University, Campus Levanger, Levanger, Norway
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20
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Moreira IB, Pinto F, Gomes C, Campos D, Reis CA. Impact of Truncated O-glycans in Gastric-Cancer-Associated CD44v9 Detection. Cells 2020; 9:cells9020264. [PMID: 31973075 PMCID: PMC7072479 DOI: 10.3390/cells9020264] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/16/2020] [Accepted: 01/17/2020] [Indexed: 02/06/2023] Open
Abstract
CD44 variant isoforms are often upregulated in cancer and associated with increased aggressive tumor phenotypes. The CD44v9 is one of the major protein splice variant isoforms expressed in human gastrointestinal cancer cells. Immunodetection of CD44 isoforms like CD44v9 in tumor tissue is almost exclusively performed by using specific monoclonal antibodies. However, the structural variability conferred by both the alternative splicing and CD44 protein glycosylation is disregarded. In the present work, we have evaluated the role of O-glycosylation using glycoengineered gastric cancer models in the detection of CD44v9 by monoclonal antibodies. We demonstrated, using different technical approaches, that the presence of immature O-glycan structures, such as Tn and STn, enhance CD44v9 protein detection. These findings can have significant implications in clinical applications mainly at the detection and targeting of this cancer-related CD44v9 isoform and highlight the utmost importance of considering glycan structures in cancer biomarker detection and in therapy targeting.
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Affiliation(s)
- Inês B. Moreira
- I3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (I.B.M.); (F.P.); (C.G.)
- IPATIMUP–Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
| | - Filipe Pinto
- I3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (I.B.M.); (F.P.); (C.G.)
- IPATIMUP–Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
| | - Catarina Gomes
- I3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (I.B.M.); (F.P.); (C.G.)
- IPATIMUP–Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
| | - Diana Campos
- I3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (I.B.M.); (F.P.); (C.G.)
- IPATIMUP–Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
- Correspondence: (D.C.); (C.A.R.)
| | - Celso A. Reis
- I3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (I.B.M.); (F.P.); (C.G.)
- IPATIMUP–Institute of Molecular Pathology and Immunology, University of Porto, 4200-135 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, University of Porto, 4050-313 Porto, Portugal
- Correspondence: (D.C.); (C.A.R.)
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