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Arabi K, Nazemi Salman B, Rahimzadeh-Bajgiran F, Moghbeli M, Moghadas S, Saburi E. miRNAs in oral cancer; diagnostic and prognostic roles. Gene 2025; 951:149382. [PMID: 40049425 DOI: 10.1016/j.gene.2025.149382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 02/26/2025] [Accepted: 02/28/2025] [Indexed: 03/15/2025]
Abstract
Oral cancer (OC) has become increasingly prevalent in recent years, making it one of the most often occurring types of cancer in patients. The clinical identification of OC is usually a time-consuming procedure, and the outlook for individuals with OC is generally unfavorable, as no particular biomarkers have been established to far. The main risk factors linked to OC are high levels of tobacco and alcohol intake, together with a reduced occurrence of viral infections, such as human papillomavirus. Furthermore, there is evidence suggesting that genetic characteristics that can be passed down from parents to offspring play a role in increasing the likelihood of getting ovarian cancer. MicroRNAs (miRNAs) are brief RNA molecules that do not code for proteins and have the ability to either repress or promote the growth of tumors during cancer development. They have been discovered to control multiple signaling pathways within cells, and their abnormal regulation has been demonstrated to be crucial in initiating and furthering the development of cancer. Additionally, they have the ability to either facilitate or impede the entire multi-stage process of cancer metastasis, including epithelial-mesenchymal transition (EMT), migration, and invasion, by selectively targeting essential genes involved in these pathways. Several microRNAs have the ability to regulate gene expression through various ways. In addition, like other types of cancer, OC has shown alterations in the expression of miRNAs, and certain miRNAs may have the ability to be used for diagnosis and treatment. The investigation of these miRNA could perhaps result in advancements in the specified instances of OC.
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Affiliation(s)
- Kimia Arabi
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
| | - Bahareh Nazemi Salman
- Department of Pediatric Dentistry, School of Dentistry, Zanjan University of Medical Sciences, Zanjan 4513956184, Iran.
| | | | - Meysam Moghbeli
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Sepehr Moghadas
- Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
| | - Ehsan Saburi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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2
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Hu X, Li Y, Wang X, Xue X. Role of M2 macrophage-derived exosomes in cancer drug resistance via noncoding RNAs. Discov Oncol 2025; 16:741. [PMID: 40355722 PMCID: PMC12069209 DOI: 10.1007/s12672-025-02195-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 03/20/2025] [Indexed: 05/14/2025] Open
Abstract
This review summarizes recent findings on the role of M2 tumor-associated macrophages (TAMs) and their exosome-derived non-coding RNAs (ncRNAs) in cancer cell resistance to therapeutics. M2 TAMs promote angiogenesis, suppress immune responses, and facilitate metastasis, thereby creating a tumor-supporting microenvironment. A range of antitumor drugs, including 5-FU, cisplatin, and gemcitabine, are mediated by M2 exosomes, each with distinct mechanisms of action. M2 exosomes transfer drug resistance capabilities via extracellular vesicles, especially exosomes containing miRNAs, lncRNAs, and circRNAs. These exosome mediate the development of tumor drug resistance by regulating signaling pathways such as PI3K/AKT, MAPK/ERK, Wnt/β-catenin M2 exosomes can regulate cellular responses by delivering bioactive molecules, including proteins, lipids, and ncRNA, which can also modulate cellular reactions to ionizing radiation, ultraviolet light, and chemotherapeutic agents. Targeting M2 TAMs and their exosome-mediated ncRNAs may offer new strategies to overcome drug resistance in cancer.
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Affiliation(s)
- Xiaopeng Hu
- Medical Research Center, People's Hospital of Longhua, Shenzhen, 518000, China
| | - Yanhua Li
- Department of Pathology, Shenzhen Longhua Maternity and Child Healthcare Hospital, Shenzhen, 518000, China
| | - Xisheng Wang
- Medical Research Center, People's Hospital of Longhua, Shenzhen, 518000, China
| | - Xingkui Xue
- Medical Research Center, People's Hospital of Longhua, Shenzhen, 518000, China.
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3
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Li Y, Sun Y, Yu K, Li Z, Miao H, Xiao W. Keratin: A potential driver of tumor metastasis. Int J Biol Macromol 2025; 307:141752. [PMID: 40049479 DOI: 10.1016/j.ijbiomac.2025.141752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 02/26/2025] [Accepted: 03/03/2025] [Indexed: 03/19/2025]
Abstract
Keratins, as essential components of intermediate filaments in epithelial cells, play a crucial role in maintaining cell structure and function. In various malignant epithelial tumors, abnormal keratin expression is frequently observed and serves not only as a diagnostic marker but also closely correlates with tumor progression. Extensive research has demonstrated that keratins are pivotal in multiple stages of tumor metastasis, including responding to mechanical forces, evading the immune system, reprogramming metabolism, promoting angiogenesis, and resisting apoptosis. Here we emphasize that keratins significantly enhance the migratory and invasive capabilities of tumor cells, making them critical drivers of tumor metastasis. These findings highlight the importance of targeting keratins as a strategic approach to combat tumor metastasis, thereby advancing our understanding of their role in cancer progression and offering new therapeutic opportunities.
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Affiliation(s)
- Yuening Li
- Army Medical University, Chongqing, China
| | - Yiming Sun
- Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Kun Yu
- Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Zhixi Li
- Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China.
| | - Hongming Miao
- Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University, Chongqing 400038, China; Jinfeng Laboratory, Chongqing, China.
| | - Weidong Xiao
- Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China.
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Xu D, Liu B, Wang L. MiR-365-3p inhibits lung cancer proliferation and migration via CPT1A-mediated fatty acid oxidation. Sci Rep 2025; 15:7076. [PMID: 40016582 PMCID: PMC11868381 DOI: 10.1038/s41598-025-91665-x] [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: 09/15/2024] [Accepted: 02/21/2025] [Indexed: 03/01/2025] Open
Abstract
The relationship between abnormal lipid acid metabolism and the progression of lung cancer is increasingly evident. Carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme in fatty acid oxidation, has been implicated in the advancement of various cancers. However, the role of CPT1A in lung cancer and the regulatory mechanisms of microRNAs on CPT1A-mediated fatty acid oxidation remain largely unknown. In our study, we demonstrate that miR-365-3p inhibits CPT1A expression by targeting its 3'-untranslated region in lung cancer cells. The inhibition of CPT1A by miR-365-3p leads to increased lipid droplet accumulation, diminished ATP production, and a decrease in fatty acid oxidation levels. Furthermore, the disruption of fatty acid oxidation attenuates the ability of the miR-365-3p/CPT1A axis to modulate lung cancer cell proliferation and migration both in vitro and in vivo. Clinical data reveal that CPT1A expression is significantly upregulated while miR-365-3p is markedly downregulated. Additionally, there exists a negative correlation between miR-365-3p and CPT1A expression, and both are predictive of clinical outcome in lung cancer patients. Collectively, our findings shed light on the function and mechanistic pathway of the miR-365-3p/CPT1A axis in lung cancer, which might provide a potential therapeutic target for lung cancer.
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Affiliation(s)
- Dan Xu
- Beihua University Affiliated Hospital, Jilin, 132013, China
| | - Bohong Liu
- Department of Chest Medicine, Changchun Tumor Hospital, Changchun, 130012, China
| | - Lingling Wang
- Beihua University Affiliated Hospital, Jilin, 132013, China.
- Department of Neurology, Beihua University Affiliated Hospital, No. 12 Jiefang Middle Road, Jilin city, 132013, Jilin Province, China.
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Dehghannasiri R, Kokot M, Starr AL, Maziarz J, Gordon T, Tan SY, Wang PL, Voskoboynik A, Musser JM, Deorowicz S, Salzman J. sc-SPLASH provides ultra-efficient reference-free discovery in barcoded single-cell sequencing. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.24.630263. [PMID: 39763839 PMCID: PMC11703226 DOI: 10.1101/2024.12.24.630263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Typical high-throughput single-cell RNA-sequencing (scRNA-seq) analyses are primarily conducted by (pseudo)alignment, through the lens of annotated gene models, and aimed at detecting differential gene expression. This misses diversity generated by other mechanisms that diversify the transcriptome such as splicing and V(D)J recombination, and is blind to sequences missing from imperfect reference genomes. Here, we present sc-SPLASH, a highly efficient pipeline that extends our SPLASH framework for statistics-first, reference-free discovery to barcoded scRNA-seq (10x Chromium) and spatial transcriptomics (10x Visium); we also provide its optimized module for preprocessing and k-mer counting in barcoded data, BKC, as a standalone tool. sc-SPLASH rediscovers known biology including V(D)J recombination and cell-type-specific alternative splicing in human and trans-splicing in tunicate (Ciona) and when applied to spatial datasets, detects sequence variation including tumor-specific somatic mutation. In sponge (Spongilla) and tunicate (Ciona), we uncover secreted repeat proteins expressed in immune-type cells and regulated during development; the sponge genes were absent from the reference assembly. sc-SPLASH provides a powerful alternative tool for exploring transcriptomes that is applicable to the breadth of life's diversity.
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Affiliation(s)
| | - Marek Kokot
- Department of Algorithmics and Software, v, Gliwice, Poland
| | | | - Jamie Maziarz
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, 06511, USA
| | - Tal Gordon
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, 94305 USA
| | - Serena Y. Tan
- Department of Pathology, Stanford University Medical Center, Stanford, 94305, USA
| | - Peter L. Wang
- Department of Biomedical Data Science, Stanford University, Stanford, 94305, USA
- Department of Biochemistry, Stanford University, Stanford, 94305, USA
| | - Ayelet Voskoboynik
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, 94305 USA
- Department of Biology, Hopkins Marine Station, Stanford University, Pacific Grove, 93950, USA
| | - Jacob M. Musser
- Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, 06511, USA
- Wu Tsai Institute, Yale University, New Haven, 06510, USA
| | | | - Julia Salzman
- Department of Biomedical Data Science, Stanford University, Stanford, 94305, USA
- Department of Biochemistry, Stanford University, Stanford, 94305, USA
- Department of Statistics (by courtesy), Stanford University, Stanford, 94305, USA
- Department of Biology (by Courtesy), Stanford University, Stanford, 94305, CA, USA
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Gallo S, Folco CB, Crepaldi T. The MET Oncogene Network of Interacting Cell Surface Proteins. Int J Mol Sci 2024; 25:13692. [PMID: 39769452 PMCID: PMC11728269 DOI: 10.3390/ijms252413692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/11/2024] [Accepted: 12/13/2024] [Indexed: 01/16/2025] Open
Abstract
The MET oncogene, encoding the hepatocyte growth factor (HGF) receptor, plays a key role in tumorigenesis, invasion, and resistance to therapy, yet its full biological functions and activation mechanisms remain incompletely understood. A feature of MET is its extensive interaction network, encompassing the following: (i) receptor tyrosine kinases (RTKs); (ii) co-receptors (e.g., CDCP1, Neuropilin1); (iii) adhesion molecules (e.g., integrins, tetraspanins); (iv) proteases (e.g., ADAM10); and (v) other receptors (e.g., CD44, plexins, GPCRs, and NMDAR). These interactions dynamically modulate MET's activation, signaling, intracellular trafficking, and degradation, enhancing its functional versatility and oncogenic potential. This review offers current knowledge on MET's partnerships, focusing on their functional impact on signaling output, therapeutic resistance, and cellular behavior. Finally, we evaluate emerging combination therapies targeting MET and its interactors, highlighting their potential to overcome resistance and improve clinical outcomes. By exploring the complex interplay within the MET network of interacting cell surface proteins, this review provides insights into advancing anti-cancer strategies and understanding the broader implications of RTK crosstalk in oncology.
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Affiliation(s)
- Simona Gallo
- Department of Oncology, University of Turin, Regione Gonzole 10, 10143 Orbassano, Italy; (S.G.); (C.B.F.)
- Candiolo Cancer Institute, FPO-IRCCS, SP142, Km 3.95, 10060 Candiolo, Italy
| | - Consolata Beatrice Folco
- Department of Oncology, University of Turin, Regione Gonzole 10, 10143 Orbassano, Italy; (S.G.); (C.B.F.)
- Candiolo Cancer Institute, FPO-IRCCS, SP142, Km 3.95, 10060 Candiolo, Italy
| | - Tiziana Crepaldi
- Department of Oncology, University of Turin, Regione Gonzole 10, 10143 Orbassano, Italy; (S.G.); (C.B.F.)
- Candiolo Cancer Institute, FPO-IRCCS, SP142, Km 3.95, 10060 Candiolo, Italy
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Piccinno E, Scalavino V, Labarile N, Armentano R, Giannelli G, Serino G. miR-195-5p Inhibits Colon Cancer Progression via KRT23 Regulation. Pharmaceutics 2024; 16:1554. [PMID: 39771533 PMCID: PMC11680050 DOI: 10.3390/pharmaceutics16121554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/15/2024] [Accepted: 12/02/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/OBJECTIVES KRT23 was recently discovered as an epithelial-specific intermediate filament protein in the type I keratin family. Many studies have underlined keratin's involvement in several biological processes as well as in the pathogenesis of different diseases. Specifically, KRT23 was reported to affect the structural integrity of epithelial cells and to trigger cellular signaling leading to the onset of cancer. The aim of this study is to characterize a novel mechanism based on miR-195-5p/KRT23 in colorectal cancer. METHODS KRT23 mRNA and protein expression were characterized in FFPE sections from patients with CRC. The effects of miR-195-5p on KRT23 expression at the mRNA and protein levels were assessed by transient transfection experiments with mimic and inhibitor molecules. Cell attachment/detachment, migration, invasion, clone formation, and apoptosis were evaluated in human CRC cell lines after miR-195-5p mimic transfection. RESULTS We identified KRT23 as a putative target of miR-195-5p, a microRNA that we previously demonstrated to be reduced in CRC. We have proved the KRT23 expression deregulation in the tumoral section compared to adjacent normal mucosa in patients with CRC, according to the data derived from the public repository. We proved that the gain of miR-195-5p decreased the KRT23 expression. Conversely, we demonstrated that the inhibition of miR-195-5p led to an increase in KRT23 expression levels. We have demonstrated the in vitro effectiveness of miR-195-5p on CRC progression and that the in vivo intraperitoneal delivery of miR-195-5p mimic lowered colonic KRT23 mRNA and protein expression. CONCLUSIONS These findings highlight a new regulatory mechanism by miR-195-5p in CRC affecting the keratin intermediate filaments and underline the miR-195-5p potential clinical properties.
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Affiliation(s)
| | | | | | | | | | - Grazia Serino
- National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013 Castellana Grotte, BA, Italy; (E.P.); (V.S.); (N.L.); (R.A.); (G.G.)
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Hashemi M, Khoushab S, Aghmiuni MH, Anaraki SN, Alimohammadi M, Taheriazam A, Farahani N, Entezari M. Non-coding RNAs in oral cancer: Emerging biomarkers and therapeutic frontier. Heliyon 2024; 10:e40096. [PMID: 39583806 PMCID: PMC11582460 DOI: 10.1016/j.heliyon.2024.e40096] [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: 06/09/2024] [Revised: 10/13/2024] [Accepted: 11/01/2024] [Indexed: 11/26/2024] Open
Abstract
Around the world, oral cancer (OC) is a major public health problem, resulting in a significant number of deaths each year. Early detection and treatment are crucial for improving patient outcomes. Recent progress in DNA sequencing and transcriptome profiling has revealed extensive non-coding RNAs (ncRNAs) transcription, underscoring their regulatory importance. NcRNAs influence genomic transcription and translation and molecular signaling pathways, making them valuable for various clinical applications. Combining spatial transcriptomics (ST) and spatial metabolomics (SM) with single-cell RNA sequencing provides deeper insights into tumor microenvironments, enhancing diagnostic and therapeutic precision for OC. Additionally, the exploration of salivary biomarkers offers a non-invasive diagnostic avenue. This article explores the potential of ncRNAs as diagnostic and therapeutic tools for OC.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saloomeh Khoushab
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mina Hobabi Aghmiuni
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saeid Nemati Anaraki
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Operative, Faculty of Dentistry, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University,Tehran, Iran
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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Chan XY, Chang KP, Yang CY, Liu CR, Hung CM, Huang CC, Liu HP, Wu CC. Upregulation of ENAH by a PI3K/AKT/β-catenin cascade promotes oral cancer cell migration and growth via an ITGB5/Src axis. Cell Mol Biol Lett 2024; 29:136. [PMID: 39511483 PMCID: PMC11545229 DOI: 10.1186/s11658-024-00651-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 10/11/2024] [Indexed: 11/15/2024] Open
Abstract
BACKGROUND Oral cancer accounts for 2% of cancer-related deaths globally, with over 90% of cases being oral cavity squamous cell carcinomas (OSCCs). Approximately 50% of patients with OSCC succumb to the disease within 5 years, primarily due to the advanced stage at which it is typically diagnosed. This underscores an urgent need to identify proteins related to OSCC progression to develop effective diagnostic and therapeutic strategies. METHODS To identify OSCC progression-related proteins, we conducted integrated proteome and transcriptome analyses on cancer tissues from patients and patient-derived xenograft (PDX) model mice. We investigated the role of protein-enabled homolog (ENAH), identified as an OSCC progression-associated protein, through proliferation, transwell migration, and invasion assays in OSCC cells. The mechanisms underlying ENAH-mediated functions were elucidated using gene knockdown and ectopic expression techniques in OSCC cells. RESULTS ENAH was identified as a candidate associated with OSCC progression based on integrated analyses, which showed increased ENAH levels in primary OSCC tissues compared with adjacent noncancerous counterparts, and sustained overexpression in the cancer tissues of PDX models. We confirmed that level of ENAH is increased in OSCC tissues and that its elevated expression correlates with poorer survival rates in patients with OSCC. Furthermore, the upregulation of ENAH in OSCC cells results from the activation of the GSK3β/β-catenin axis by the EGFR/PI3K/AKT cascade. ENAH expression enhances cell proliferation and mobility by upregulating integrin β5 in oral cancer cells. CONCLUSIONS The upregulation of ENAH through a PI3K/AKT/β-catenin signaling cascade enhances oral cancer cell migration and growth via the ITGB5/Src axis. These findings offer a new interpretation of the ENAH function in the OSCC progression and provide crucial information for developing new OSCC treatment strategies.
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Affiliation(s)
- Xiu-Ya Chan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Kai-Ping Chang
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Department of Otolaryngology-Head and Neck Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chia-Yu Yang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Department of Otolaryngology-Head and Neck Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chiao-Rou Liu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chu-Mi Hung
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chun-Chueh Huang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Hao-Ping Liu
- Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Chih-Ching Wu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
- Department of Otolaryngology-Head and Neck Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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Wang Y, Qin J, Sharma A, Dakal TC, Wang J, Pan T, Bhushan R, Chen P, Setiawan MF, Schmidt-Wolf IGH, Li F. Exploring the promise of regulator of G Protein Signaling 20: insights into potential mechanisms and prospects across solid cancers and hematological malignancies. Cancer Cell Int 2024; 24:305. [PMID: 39227952 PMCID: PMC11373255 DOI: 10.1186/s12935-024-03487-y] [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: 04/19/2024] [Accepted: 08/18/2024] [Indexed: 09/05/2024] Open
Abstract
RGS (Regulator of G protein signaling) proteins have long captured the fascination of researchers due to their intricate involvement across a wide array of signaling pathways within cellular systems. Their diverse and nuanced functions have positioned them as continual subjects of scientific inquiry, especially given the implications of certain family members in various cancer types. Of particular note in this context is RGS20, whose clinical relevance and molecular significance in hepatocellular carcinoma we have recently investigated. These investigations have prompted questions into the prevalence of pathogenic mutations within the RGS20 gene and the intricate network of interacting proteins that could contribute to the complex landscape of cancer biology. In our study, we aim to unravel the mutations within the RGS20 gene and the multifaceted interplay between RGS20 and other proteins within the context of cancer. Expanding on this line of inquiry, our research is dedicated to uncovering the intricate mechanisms of RGS20 in various cancers. In particular, we have redirected our attention to examining the role of RGS20 within hematological malignancies, with a specific focus on multiple myeloma and follicular lymphoma. These hematological cancers hold significant promise for further investigation, as understanding the involvement of RGS20 in their pathogenesis could unveil novel therapeutic strategies and treatment avenues. Furthermore, our exploration has extended to encompass the latest discoveries concerning the potential involvement of RGS20 in diseases affecting the central nervous system, thereby broadening the scope of its implications beyond oncology to encompass neurobiology and related fields.
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Affiliation(s)
- Yulu Wang
- Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Jiading Qin
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Amit Sharma
- Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital of Bonn, Bonn, Germany
- Department of Neurosurgery, University Hospital of Bonn, Bonn, Germany
| | - Tikam Chand Dakal
- Department of Biotechnology, Mohanlal Sukhadia University, Udaipur, Rajasthan, India
| | - Jieyu Wang
- Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Tiantian Pan
- Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Ravi Bhushan
- Department of Zoology, M.S. College, Motihari, Bihar, India
| | - Peng Chen
- Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital of Bonn, Bonn, Germany
| | - Maria F Setiawan
- Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital of Bonn, Bonn, Germany
| | - Ingo G H Schmidt-Wolf
- Department of Integrated Oncology, Center for Integrated Oncology (CIO), University Hospital of Bonn, Bonn, Germany
| | - Fei Li
- Jiangxi Provincial Key Laboratory of Hematological Diseases, Department of Hematology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
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Chen W, Yang H, Huang L, Fang C, Yao L, Liu F, Jin T. ROS-mediated ITGB5 promotes tongue squamous cell carcinoma metastasis through epithelial mesenchymal transition and cell adhesion signal pathway. J Cancer Res Clin Oncol 2024; 150:398. [PMID: 39180583 PMCID: PMC11344732 DOI: 10.1007/s00432-024-05922-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 08/12/2024] [Indexed: 08/26/2024]
Abstract
PURPOSE Integrin β5 (ITGB5) is an integrin β subunit member widely expressed in the human bodies, especially in cancer cells and tissues, which is a key factor in promoting tumor metastasis. In this study we investigated the differential expression of ITGB5 in tongue squamous cell carcinoma (TSCC), especially in those with lymph node metastasis, and revealed the possible mechanism. METHODS The expression of ITGB5 in TSCC was analyzed by database and verified by immunohistochemistry through 135 TSCC patients' tissue sections from Sun Yat-sen Memorial Hospital and Guangzhou First People's Hospital. The relationship between ITGB5 and lymph node metastasis or prognosis was analyzed retrospectively. The effects of ITGB5 on TSCC cells were examined through knocking down or overexpression and its possible regulator and signal pathway were explored. RESULTS The expression of ITGB5 in TSCC was higher than that in adjacent tissue, and the expression in patients with lymph node metastasis was higher than that in patients without lymph node metastasis. The high expression of ITGB5 predicted a worse prognosis. Knock down of ITGB5 suppressed invasion and migration of TSCC cells, while overexpression of ITGB5 contributed to invasion and migration. Reactive oxygen species (ROS) regulated epithelial mesenchymal transition (EMT), and we further verified that ROS enhanced the expression of ITGB5 to promote the metastasis of TSCC. Mechanistically, ITGB5 functions through cell adhesion signal pathway. CONCLUSION The increased expression of ITGB5 in tongue squamous cell carcinoma with lymph node metastasis may be a potential target for evaluating lymph node metastasis and worse prognosis of tongue squamous cell carcinoma. Scavenge of ROS or knock down of ITGB5 may be the strategies to overcome metastasis of TSCC.
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Affiliation(s)
- Weixiong Chen
- Department of Stomatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, PR China.
- Department of Stomatology, Longgang District Central Hospital, Chinese University of Hong Kong, Shenzhen, 518116, PR China.
| | - Haojie Yang
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China
| | - Lei Huang
- Department of Stomatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, PR China
| | - Caihong Fang
- Department of Stomatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, PR China
| | - Limin Yao
- Department of Stomatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, PR China
| | - Faxin Liu
- Department of Stomatology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, PR China
| | - Tingting Jin
- Department of Oral and Maxillofacial Surgery, Stomatological Hospital, Southern Medical University, Guangzhou, 510115, PR China.
- Department of Stomatology, Longgang District Central Hospital, Chinese University of Hong Kong, Shenzhen, 518116, PR China.
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12
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Romashin DD, Tolstova TV, Varshaver AM, Kozhin PM, Rusanov AL, Luzgina NG. Keratins 6, 16, and 17 in Health and Disease: A Summary of Recent Findings. Curr Issues Mol Biol 2024; 46:8627-8641. [PMID: 39194725 DOI: 10.3390/cimb46080508] [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: 06/05/2024] [Revised: 07/17/2024] [Accepted: 07/23/2024] [Indexed: 08/29/2024] Open
Abstract
Keratins 6, 16, and 17 occupy unique positions within the keratin family. These proteins are not commonly found in the healthy, intact epidermis, but their expression increases in response to damage, inflammation, and hereditary skin conditions, as well as cancerous cell transformations and tumor growth. As a result, there is an active investigation into the potential use of these proteins as biomarkers for different pathologies. Recent studies have revealed the role of these keratins in regulating keratinocyte migration, proliferation, and growth, and more recently, their nuclear functions, including their role in maintaining nuclear structure and responding to DNA damage, have also been identified. This review aims to summarize the latest research on keratins 6, 16, and 17, their regulation in the epidermis, and their potential use as biomarkers in various skin conditions.
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Affiliation(s)
| | | | | | - Peter M Kozhin
- Institute of Biomedical Chemistry, Moscow 119121, Russia
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13
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Yu B, Kruse N, Howard KM, Kingsley K. Downstream Target Analysis for miR-365 among Oral Squamous Cell Carcinomas Reveals Differential Associations with Chemoresistance. Life (Basel) 2024; 14:741. [PMID: 38929724 PMCID: PMC11205150 DOI: 10.3390/life14060741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/05/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
Expression of microRNAs, such as miR-365, is known to be dysregulated in many tumors, including oral cancers, although little is known about their role or functions. The objective of this project is to evaluate the downstream targets of miR-365 to determine any potential pathways or effects. Downstream targets for miR-365 (miRdatabase target scores > 90) were used for qPCR screening of oral cancer cell lines (SCC4, SCC9, SCC15, SCC25, CAL27). Each oral cancer cell line expressed miR-365 downstream targets molybdenum cofactor synthesis-2 (MOCS2), erythropoietin receptor (EPOR), IQ motif containing-K (IQCK), carboxypeptidase A3 (CPA3), solute carrier family 24 member-3 (SLC24A3), and coiled-coil domain containing 47 (CCDC47)-although the expression levels varied somewhat. However, differential results were observed with ubiquitin protein ligase E3 component n-recognin-3 (UBR3), nudix hydrolase-12 (NUDT12), zinc finger CCHC-type containing-14 (ZCCHC14), and homeobox and leucine zipper encoding (HOMEZ). These data suggest that many of the miR-365 targets are expressed in the oral cancers screened, with the differential expression of UBR3, ZCCHC14, HOMEZ, and NUDT12, which may be correlated with chemoresistance among two specific oral cancer cell lines (SCC25, SCC9). These results suggest this differential expression may signal potential targets for patient treatment with tumors exhibiting miR-365 and chemotherapeutic resistance.
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Affiliation(s)
- Brendon Yu
- Department of Clinical Sciences, School of Dental Medicine, University of Nevada-Las Vegas, 1700 W. Charleston Boulevard, Las Vegas, NV 89106, USA
| | - Nathaniel Kruse
- Department of Clinical Sciences, School of Dental Medicine, University of Nevada-Las Vegas, 1700 W. Charleston Boulevard, Las Vegas, NV 89106, USA
| | - Katherine M. Howard
- Department of Biomedical Sciences, School of Dental Medicine, University of Nevada-Las Vegas, 1001 Shadow Lane, Las Vegas, NV 89106, USA;
| | - Karl Kingsley
- Department of Biomedical Sciences, School of Dental Medicine, University of Nevada-Las Vegas, 1001 Shadow Lane, Las Vegas, NV 89106, USA;
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14
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Xu J, Liu M, Xue J, Lu P. Deciphering fatty acid biosynthesis-driven molecular subtypes in pancreatic ductal adenocarcinoma with prognostic insights. Cell Oncol (Dordr) 2024:10.1007/s13402-024-00953-7. [PMID: 38753153 DOI: 10.1007/s13402-024-00953-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2024] [Indexed: 06/26/2024] Open
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to its high heterogeneity and aggressiveness. Recognizing the urgency to delineate molecular subtypes, our study focused on the emerging field of lipid metabolism remodeling in PDAC, particularly exploring the prognostic potential and molecular classification associated with fatty acid biosynthesis. METHODS Gene set variation analysis (GSVA) and single-sample gene set enrichment analysis (ssGSEA) were performed to evaluate the dysregulation of lipid metabolism in PDAC. Univariate cox analysis and the LASSO module were used to build a prognostic risk score signature. The distinction of gene expression in different risk groups was explored by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The biological function of Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5), a pivotal gene within 7-hub gene signature panel, was validated through in vitro assays. RESULTS Our study identified a 7-hub gene signature associated with fatty acid biosynthesis-related genes (FRGs), providing a robust tool for prognosis prediction. The high-FRGs score group displayed a poorer prognosis, decreased immune cell infiltration, and a higher tumor mutation burden. Interestingly, this group exhibited enhanced responsiveness to various compounds according to the Genomics of Drug Sensitivity in Cancer (GDSC) database. Notably, ACSL5 was upregulated in PDAC and essential for tumor progression. CONCLUSION In conclusion, our research defined two novel fatty acid biosynthesis-based subtypes in PDAC, characterized by distinct transcriptional profiles. These subtypes not only served as prognostic indicator, but also offered valuable insights into their metastatic propensity and therapeutic potential.
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Affiliation(s)
- Junyi Xu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China
| | - Mingzhu Liu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China
| | - Jing Xue
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China.
| | - Ping Lu
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, 160 Pujian Rd, Shanghai, 200127, China.
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15
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Peng L, Jiang Y, Chen H, Wang Y, Lan Q, Chen S, Huang Z, Zhang J, Tian D, Qiu Y, Cai D, Peng J, Lu D, Yuan X, Yang X, Yin D. Transcription factor EHF interacting with coactivator AJUBA aggravates malignancy and acts as a therapeutic target for gastroesophageal adenocarcinoma. Acta Pharm Sin B 2024; 14:2119-2136. [PMID: 38799645 PMCID: PMC11120281 DOI: 10.1016/j.apsb.2024.02.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 12/24/2023] [Accepted: 02/26/2024] [Indexed: 05/29/2024] Open
Abstract
Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development. However, it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors (TFs) except for the nuclear receptor family of TFs. Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma (GEA) or the therapeutic effects of targeting TF and transcription cofactor complexes. In this study, we found that ETS homologous factor (EHF) expression is promoted by a core transcriptional regulatory circuitry (CRC), specifically ELF3-KLF5-GATA6, and interference with its expression suppressed the malignant biological behavior of GEA cells. Importantly, we identified Ajuba LIM protein (AJUBA) as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA. Furthermore, we identified KRAS signaling as a common pathway downstream of EHF and AJUBA. Applicably, dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo. In conclusion, EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway. Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.
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Affiliation(s)
- Li Peng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Yanyi Jiang
- Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
| | - Hengxing Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Yongqiang Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Qiusheng Lan
- Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Shuiqin Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Zhanwang Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Jingyuan Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Duanqing Tian
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Yuntan Qiu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Diankui Cai
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Jiangyun Peng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Daning Lu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Xiaoqing Yuan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Xianzhu Yang
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, China
| | - Dong Yin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
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Kalele K, Nyahatkar S, Mirgh D, Muthuswamy R, Adhikari MD, Anand K. Exosomes: A Cutting-Edge Theranostics Tool for Oral Cancer. ACS APPLIED BIO MATERIALS 2024; 7:1400-1415. [PMID: 38394624 DOI: 10.1021/acsabm.3c01243] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2024]
Abstract
Exosomes are a subpopulation of extracellular vesicles (EVs) secreted by cells. In cancer, they are key cellular messengers during cancer development and progression. Tumor-derived exosomes (TEXs) promote cancer progression. In oral cancer, the major complication is oral squamous cell carcinoma (OSCC). Exosomes show strong participation in several OSCC-related activities such as uncontrolled cell growth, immune suppression, angiogenesis, metastasis, and drug and therapeutic resistance. It is also a potential biomarker source for oral cancer. Some therapeutic exosome sources such as stem cells, plants (it is more effective compared to others), and engineered exosomes reduce oral cancer development. This therapeutic approach is effective because of its specificity, biocompatibility, and cell-free therapy (it reduced side effects in cancer treatment). This article highlights exosome-based theranostics signatures in oral cancer, clinical trials, challenges of exosome-based oral cancer research, and future improvements. In the future, exosomes may become an effective and affordable solution for oral cancer.
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Affiliation(s)
- Ketki Kalele
- Neuron Institute of Applied Research, Rajapeth-Irwin Square Flyover, Amravati, Maharashtra 444601, India
| | - Sidhanti Nyahatkar
- VYWS Dental College & Hospital, WQMV+7X6, Tapovan-Wadali Road, Camp Rd, SRPF Colony, Amravati, Maharashtra 444602, India
| | - Divya Mirgh
- Department of Infectious Diseases, Vaccine and Immunotherapy Center, Massachusetts General Hospital, Boston, Massachusetts 02114, United States
| | - Raman Muthuswamy
- Center for Global Health Research, Saveetha Medical College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai 602105, Tamil Nadu, India
| | - Manab Deb Adhikari
- Department of Biotechnology, University of North Bengal, Darjeeling, West Bengal 734013, India
| | - Krishnan Anand
- Department of Chemical Pathology, School of Pathology, Faculty of Health Sciences, University of the Free State, Bloemfontein 9300, South Africa
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Vastrad SJ, Ritesh G, V SS, Saraswathy GR, Augustine D, Alzahrani KJ, Alzahrani FM, Halawani IF, Ashi H, Alshahrani M, Hassan RN, Baeshen HA, Saravanan KS, Satish KS, Vutukuru P, Patil S. Panoramic view of key cross-talks underpinning the oral squamous cell carcinoma stemness - unearthing the future opportunities. Front Oncol 2023; 13:1247399. [PMID: 38170015 PMCID: PMC10759990 DOI: 10.3389/fonc.2023.1247399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 11/09/2023] [Indexed: 01/05/2024] Open
Abstract
The clinical management of oral cancer is often frequented with challenges that arise from relapse, recurrence, invasion and resistance towards the cornerstone chemo and radiation therapies. The recent conceptual advancement in oncology has substantiated the role of cancer stem cells (CSC) as a predominant player of these intricacies. CSC are a sub-group of tumor population with inherent adroitness to self-renew with high plasticity. During tumor evolution, the structural and functional reprogramming persuades the cancer cells to acquire stem-cell like properties, thus presenting them with higher survival abilities and treatment resistance. An appraisal on key features that govern the stemness is of prime importance to confront the current challenges encountered in oral cancer. The nurturing niche of CSC for maintaining its stemness characteristics is thought to be modulated by complex multi-layered components encompassing neoplastic cells, extracellular matrix, acellular components, circulatory vessels, various cascading signaling molecules and stromal cells. This review focuses on recapitulating both intrinsic and extrinsic mechanisms that impart the stemness. There are contemplating evidences that demonstrate the role of transcription factors (TF) in sustaining the neoplastic stem cell's pluripotency and plasticity alongside the miRNA in regulation of crucial genes involved in the transformation of normal oral mucosa to malignancy. This review illustrates the interplay between miRNA and various known TF of oral cancer such as c-Myc, SOX, STAT, NANOG and OCT in orchestrating the stemness and resistance features. Further, the cross-talks involved in tumor micro-environment inclusive of cytokines, macrophages, extra cellular matrix, angiogenesis leading pathways and influential factors of hypoxia on tumorigenesis and CSC survival have been elucidated. Finally, external factorial influence of oral microbiome gained due to the dysbiosis is also emphasized. There are growing confirmations of the possible roles of microbiomes in the progression of oral cancer. Given this, an attempt has been made to explore the potential links including EMT and signaling pathways towards resistance and stemness. This review provides a spectrum of understanding on stemness and progression of oral cancers at various regulatory levels along with their current therapeutic knowledge. These mechanisms could be exploited for future research to expand potential treatment strategies.
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Affiliation(s)
- Soujanya J. Vastrad
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Giri Ritesh
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Sowmya S. V
- Department of Oral Pathology and Microbiology, Faculty of Dental Sciences, MS Ramaiah University of Applied Sciences, Bengaluru, India
| | | | - Dominic Augustine
- Department of Oral Pathology and Microbiology, Faculty of Dental Sciences, MS Ramaiah University of Applied Sciences, Bengaluru, India
| | - Khalid J. Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Fuad M. Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Ibrahim F. Halawani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
- Haematology and Immunology Department, Faculty of Medicine, Umm Al-Qura University, AI Abdeyah, Makkah, Saudi Arabia
| | - Heba Ashi
- Department of Dental Public Health, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mohammed Alshahrani
- Department of Endodontic, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Reem Nabil Hassan
- Department of Biological Sciences (Genome), Faculty of Sciences, King Abdul-Aziz University, Jeddah, Saudi Arabia
| | - Hosam Ali Baeshen
- Department of Orthodontics Faculty of Dentistry, King Abdulaziz University, Bengaluru, India
| | - Kamatchi Sundara Saravanan
- Department of Pharmacognosy, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Kshreeraja S. Satish
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Pravallika Vutukuru
- Department of Pharmacy Practice, Faculty of Pharmacy, M.S. Ramaiah University of Applied Sciences, Bengaluru, India
| | - Shankargouda Patil
- College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT, United States
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Wang W, Li S, Hao Y, Cui B, Zheng X, Yan L, Yang X. MicroRNA-365-3p inhibits bone marrow mesenchymal stem cell differentiation into islet-like cell clusters via targeting Pax6 and inhibiting the MEK/ERK pathway. Minerva Endocrinol (Torino) 2023; 48:420-431. [PMID: 34160186 DOI: 10.23736/s2724-6507.21.03389-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Diabetes has severe impacts on the health of patients. The differentiation of mesenchymal stem cells (MSCs) into islet-like cell clusters (ICCs) is an effective protocol for the treatment of diabetes. microRNAs (miRs) regulate multiple cellular processes including cell differentiation. This study sought to identify the mechanism of miR-365-3p in the differentiation of bone marrow MSCs (bMSCs) into ICCs. METHODS Initially, the differentiation of bMSCs into ICCs was induced. Then, the miR-365-3p expression pattern in the bMSCs and ICCs was detected. Next, the miR-365-3p expression pattern was silenced in bMSCs to assess the effect on differentiation efficiency and measure the expressions of ICC marker genes during the differentiation of bMSCs into ICCs. The miR-365-3p downstream target genes were predicted and verified. Paired box protein 6 (Pax6) was downregulated in bMSCs with silenced miR-365-3p to evaluate the differentiation of bMSCs into ICCs. Furthermore, the Pax6 downstream pathway was evaluated. RESULTS The differentiation of bMSCs into ICCs was successfully induced. The miR-365-3p expression in bMSCs was higher than that in ICCs. miR-365-3p downregulation in bMSCs facilitated the differentiation of bMSCs into ICCs, as evidenced by elevated releases of insulin and C-peptide in ICCs and elevated expressions of ICC marker genes. Our findings denoted that miR-365-3p targeted Pax6. Inhibition of Pax6 expression annulled the promotion of miR-365-3p downregulation on the differentiation of bMSCs into ICCs. Increased phosphorylation levels of MEK and ERK were identified in ICCs after downregulation of miR-365-3p however they were decreased after downregulation of Pax6. CONCLUSIONS This study supported that miR-365-3p inhibited the differentiation of bMSCs into ICCs via targeting Pax6 and inhibiting the MEK/ERK pathway.
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Affiliation(s)
- Wenting Wang
- Department of Physiology, Mudanjiang Medical University, Mudanjiang, China
| | - Shu Li
- Department of Medical Function, Mudanjiang Medical University, Mudanjiang, China
| | - Yankun Hao
- Department of Medical Function, Mudanjiang Medical University, Mudanjiang, China
| | - Baixiang Cui
- Department of Pathology, The Second Hospital of Mudanjiang Medical University, Mudanjiang, China
| | - Xuezhi Zheng
- Department of Physiology, Mudanjiang Medical University, Mudanjiang, China
| | - Lei Yan
- Department of Histology and Embryology, Mudanjiang Medical University, Mudanjiang, China
| | - Xufang Yang
- Department of Pathophysiology, Mudanjiang Medical University, Mudanjiang, China -
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Tan Y, Wang Z, Xu M, Li B, Huang Z, Qin S, Nice EC, Tang J, Huang C. Oral squamous cell carcinomas: state of the field and emerging directions. Int J Oral Sci 2023; 15:44. [PMID: 37736748 PMCID: PMC10517027 DOI: 10.1038/s41368-023-00249-w] [Citation(s) in RCA: 208] [Impact Index Per Article: 104.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/25/2023] [Accepted: 09/04/2023] [Indexed: 09/23/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% of oral malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases were reported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by 2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ), and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oral mucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involves genetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeutic interventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCC and OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors, thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC. Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitate comprehension and provide several prospective outlooks for the fields.
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Affiliation(s)
- Yunhan Tan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
- West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Zhihan Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Mengtong Xu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Bowen Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Zhao Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Siyuan Qin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Jing Tang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China.
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
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20
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Eslami M, Khazeni S, Khanaghah XM, Asadi MH, Ansari MA, Garjan JH, Lotfalizadeh MH, Bayat M, Taghizadieh M, Taghavi SP, Hamblin MR, Nahand JS. MiRNA-related metastasis in oral cancer: moving and shaking. Cancer Cell Int 2023; 23:182. [PMID: 37635248 PMCID: PMC10463971 DOI: 10.1186/s12935-023-03022-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/06/2023] [Indexed: 08/29/2023] Open
Abstract
Across the world, oral cancer is a prevalent tumor. Over the years, both its mortality and incidence have grown. Oral cancer metastasis is a complex process involving cell invasion, migration, proliferation, and egress from cancer tissue either by lymphatic vessels or blood vessels. MicroRNAs (miRNAs) are essential short non-coding RNAs, which can act either as tumor suppressors or as oncogenes to control cancer development. Cancer metastasis is a multi-step process, in which miRNAs can inhibit or stimulate metastasis at all stages, including epithelial-mesenchymal transition, migration, invasion, and colonization, by targeting critical genes in these pathways. On the other hand, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), two different types of non-coding RNAs, can regulate cancer metastasis by affecting gene expression through cross-talk with miRNAs. We reviewed the scientific literature (Google Scholar, Scopus, and PubMed) for the period 2000-2023 to find reports concerning miRNAs and lncRNA/circRNA-miRNA-mRNA networks, which control the spread of oral cancer cells by affecting invasion, migration, and metastasis. According to these reports, miRNAs are involved in the regulation of metastasis pathways either by directly or indirectly targeting genes associated with metastasis. Moreover, circRNAs and lncRNAs can induce or suppress oral cancer metastasis by acting as competing endogenous RNAs to inhibit the effect of miRNA suppression on specific mRNAs. Overall, non-coding RNAs (especially miRNAs) could help to create innovative therapeutic methods for the control of oral cancer metastases.
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Affiliation(s)
- Meghdad Eslami
- Department of oral and maxillofacial surgery, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saba Khazeni
- Department of oral and maxillofacial surgery, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Xaniar Mohammadi Khanaghah
- Department of oral and maxillofacial surgery, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Asadi
- Department of oral and maxillofacial surgery, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohamad Amin Ansari
- Department of oral and maxillofacial surgery, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Hayati Garjan
- Department of oral and maxillofacial surgery, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mobina Bayat
- Department of Plant, Cell and Molecular Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyed Pouya Taghavi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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21
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Yen WC, Chang KP, Chen CY, Huang Y, Chen TW, Cheng HW, Yi JS, Cheng CC, Wu CC, Wang CI. MFI2 upregulation promotes malignant progression through EGF/FAK signaling in oral cavity squamous cell carcinoma. Cancer Cell Int 2023; 23:112. [PMID: 37309001 DOI: 10.1186/s12935-023-02956-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 05/26/2023] [Indexed: 06/14/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) is the predominant histological type of the head and neck squamous cell carcinoma (HNSCC). By comparing the differentially expressed genes (DEGs) in OSCC-TCGA patients with copy number variations (CNVs) that we identify in OSCC-OncoScan dataset, we herein identified 37 dysregulated candidate genes. Among these potential candidate genes, 26 have been previously reported as dysregulated proteins or genes in HNSCC. Among 11 novel candidates, the overall survival analysis revealed that melanotransferrin (MFI2) is the most significant prognostic molecular in OSCC-TCGA patients. Another independent Taiwanese cohort confirmed that higher MFI2 transcript levels were significantly associated with poor prognosis. Mechanistically, we found that knockdown of MFI2 reduced cell viability, migration and invasion via modulating EGF/FAK signaling in OSCC cells. Collectively, our results support a mechanistic understanding of a novel role for MFI2 in promoting cell invasiveness in OSCC.
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Affiliation(s)
- Wei-Chen Yen
- Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Kai-Ping Chang
- Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Cheng-Yi Chen
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yenlin Huang
- School of Medicine, National Tsing-Hua University, Hsinchu, Taiwan
- Institute of Stem Cell and Translational Cancer Research, Department of Anatomic Pathology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Ting-Wen Chen
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
- Center For Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Hsing-Wen Cheng
- Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Jui-Shan Yi
- Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chun-Chia Cheng
- Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University, Taoyuan, Taiwan
| | - Chih-Ching Wu
- Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
- Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chun-I Wang
- Department of Biochemistry, School of Medicine, China Medical University, Taichung, Taiwan.
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22
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Wang W, Zhu L, Zhou J, Liu X, Xiao M, Chen N, Huang X, Chen H, Pei X, Zhang H. Targeting the KRT16-vimentin axis for metastasis in lung cancer. Pharmacol Res 2023:106818. [PMID: 37315823 DOI: 10.1016/j.phrs.2023.106818] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 05/23/2023] [Accepted: 06/08/2023] [Indexed: 06/16/2023]
Abstract
Lung cancer is the most diagnosed malignant cancer and the leading cause of cancer-related deaths worldwide, with advanced stage and metastasis being a major issue. The mechanism leading to metastasis is not yet understood. Here, we found that KRT16 is upregulated in metastatic lung cancer tissues and correlated with poor overall survival. Knockdown of KRT16 inhibits metastasis of lung cancer both in vitro and in vivo. Mechanistically, KRT16 interacts with vimentin, and depletion of KRT16 leads to downregulation of vimentin. KRT16 acquired its oncogenic ability by stabilizing vimentin, and vimentin is required for KRT16-driven metastasis. FBXO21 mediates the polyubiquitination and degradation of KRT16, and vimentin inhibits KRT16 ubiquitination and degradation by impairing its interaction with FBXO21. Significantly, IL-15 inhibits metastasis of lung cancer in a mouse model through upregulation of FBXO21, and the level of IL-15 in circulating serum was significantly higher in nonmetastatic lung cancer patients than in metastatic patients. Our findings indicate that targeting the FBXO21/KRT16/vimentin axis may benefit lung cancer patients with metastasis.
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Affiliation(s)
- Wen Wang
- Department of Oncology, The fifth Affiliated Hospital of Sun Yat-sen University, 519000(,) Zhuhai(,) China.
| | - Lifei Zhu
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, 510515(,) Guangzhou(,) China.
| | - Jiao Zhou
- Department of Oncology, The fifth Affiliated Hospital of Sun Yat-sen University, 519000(,) Zhuhai(,) China.
| | - Xiaoli Liu
- Department of Oncology, The fifth Affiliated Hospital of Sun Yat-sen University, 519000(,) Zhuhai(,) China.
| | - Mei Xiao
- Department of Oncology, The fifth Affiliated Hospital of Sun Yat-sen University, 519000(,) Zhuhai(,) China.
| | - Nan Chen
- Department of Oncology, The fifth Affiliated Hospital of Sun Yat-sen University, 519000(,) Zhuhai(,) China.
| | - Xiaodan Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
| | - Hongtao Chen
- Department of Laboratory, The fifth Affiliated Hospital of Sun Yat-sen University, 519000(,) Zhuhai(,) China.
| | - Xiaofeng Pei
- Department of Oncology, The fifth Affiliated Hospital of Sun Yat-sen University, 519000(,) Zhuhai(,) China.
| | - Hongyu Zhang
- Department of Oncology, The fifth Affiliated Hospital of Sun Yat-sen University, 519000(,) Zhuhai(,) China; Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, 519000, Zhuhai, China.
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23
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Xie J, Lan T, Zheng DL, Ding LC, Lu YG. CDH4 inhibits ferroptosis in oral squamous cell carcinoma cells. BMC Oral Health 2023; 23:329. [PMID: 37237299 DOI: 10.1186/s12903-023-03046-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND The cadherin-4 gene (CDH4), a member of the cadherin family genes, encodes R-cadherin (R-cad); however, the function of this gene in different types of cancer remains controversial. The function of CDH4 in OSCC (oral squamous cell carcinoma) is unknown. MATERIALS AND METHODS We use the Cancer Genome Atlas (TCGA) database to find the expression of CDH4 in OSCC is more than normal tissue. Our tissue samples also confirmed that CDH4 gene was highly expressed in OSCC. The related cell function assay detected that CDH4 promotes the ability of cell proliferation, migration, self-renewal and invasion. Cell staining experiment confirmed that the change of CDH4 expression would change the cell mortality. The western blot of GPX4 (glutathione-dependent peroxidase-4), GSH (reduced glutathione) test assay and MDA(Malondialdehyde) test assay show that the expression of CDH4 may resist the sensitivity of ferropotosis in OSCC. RESULTS CDH4 was upregulated in OSCC samples and was correlation with poor survival of patients. High expression of CDH4 effectively promotes the proliferation, mobility of OSCC cells and reduce the sensitivity of OSCC cells to ferroptosis. CDH4 is positively correlated with EMT pathway genes, negatively correlated with fatty acid metabolism pathway genes and peroxisome pathway genes, and positively correlated with ferroptosis suppressor genes in OSCC. CONCLUSIONS These results indicate that CDH4 may play a positive role in tumor progression and resistance ferroptosis and may be a potential therapeutic target for OSCC.
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Affiliation(s)
- Jian Xie
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou, 350002, China
- Key Laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, 88 Jiaotong Rd, Fuzhou, 350004, China
| | - Ting Lan
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou, 350002, China
| | - Da-Li Zheng
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou, 350002, China
| | - Lin-Can Ding
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou, 350002, China.
| | - You-Guang Lu
- Department of Preventive Dentistry, School and Hospital of Stomatology, Fujian Medical University, 246 Yang Qiao Middle Road, Fuzhou, 350002, China.
- Key Laboratory of Stomatology of Fujian Province, School and Hospital of Stomatology, Fujian Medical University, 88 Jiaotong Rd, Fuzhou, 350004, China.
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24
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El-Mahdy HA, Mohamadin AM, Abulsoud AI, Khidr EG, El-Husseiny AA, Ismail A, Elsakka EGE, Mokhlis HA, El-Husseiny HM, Doghish AS. miRNAs as potential game-changers in head and neck cancer: Future clinical and medicinal uses. Pathol Res Pract 2023; 245:154457. [PMID: 37058745 DOI: 10.1016/j.prp.2023.154457] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/06/2023] [Accepted: 04/07/2023] [Indexed: 04/16/2023]
Abstract
Head and neck cancers (HNCs) are a group of heterogeneous tumors formed most frequently from epithelial cells of the larynx, lips, oropharynx, nasopharynx, and mouth. Numerous epigenetic components, including miRNAs, have been demonstrated to have an impact on HNCs characteristics like progression, angiogenesis, initiation, and resistance to therapeutic interventions. The miRNAs may control the production of numerous genes linked to HNCs pathogenesis. The roles that miRNAs play in angiogenesis, invasion, metastasis, cell cycle, proliferation, and apoptosis are responsible for this impact. The miRNAs also have an impact on crucial HNCs-related mechanistic networks like the WNT/β-catenin signaling, PTEN/Akt/mTOR pathway, TGFβ, and KRAS mutations. miRNAs may affect how the HNCs respond to treatments like radiation and chemotherapy in addition to pathophysiology. This review aims to demonstrate the relationship between miRNAs and HNCs with a particular emphasis on how miRNAs impact HNCs signaling networks.
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Affiliation(s)
- Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt.
| | - Ahmed M Mohamadin
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt
| | - Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt; Department of Biochemistry and Biotechnology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Emad Gamil Khidr
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt
| | - Ahmed A El-Husseiny
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt; Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr, Cairo 11829, Egypt
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt
| | - Elsayed G E Elsakka
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt
| | - Hamada Ahmed Mokhlis
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Nasr, Cairo 11231, Egypt
| | - Hussein M El-Husseiny
- Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai Cho, Fuchu-shi, Tokyo 183-8509, Japan; Department of Surgery, Anesthesiology, and Radiology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh, Al Qalyubia 13736, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo 11829, Egypt; Faculty of Pharmacy (Boys), Al-Azhar University, Nasr, Cairo 11231, Egypt.
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25
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Huni KC, Cheung J, Sullivan M, Robison WT, Howard KM, Kingsley K. Chemotherapeutic Drug Resistance Associated with Differential miRNA Expression of miR-375 and miR-27 among Oral Cancer Cell Lines. Int J Mol Sci 2023; 24:ijms24021244. [PMID: 36674758 PMCID: PMC9865318 DOI: 10.3390/ijms24021244] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/01/2023] [Accepted: 01/06/2023] [Indexed: 01/11/2023] Open
Abstract
Recent advances have suggested that non-coding miRNAs (such as miR-21, miR-27, miR-145, miR-155, miR-365, miR-375 and miR-494) may be involved in multiple aspects of oral cancer chemotherapeutic responsiveness. This study evaluated whether these specific miRNAs are correlated with oral cancer responsiveness to chemotherapies, including Paclitaxel, Cisplatin and Fluorouracil (5FU). Commercially available and well-characterized oral squamous cell carcinoma cell lines (SCC4, SCC9, SCC15, SCC25 and CAL27) revealed differing resistance and chemosensitivity to these agents-with SCC9 and SCC25 demonstrating the most resistance to all chemotherapeutic agents. SCC9 and SCC25 were also the only cell lines that expressed miR-375, and were the only cell lines that did not express miR-27. In addition, the expression of miR-375 was associated with the upregulation of Rearranged L-myc fusion (RLF) and the downregulation of Centriolar protein B (POC1), whereas lack of miR-27 expression was associated with Nucleophosmin 1 (NPM1) expression. These data have revealed important regulatory pathways and mechanisms associated with oral cancer proliferation and resistance that must be explored in future studies of potential therapeutic interventions.
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Affiliation(s)
- Kieran Caberto Huni
- Department of Advanced Education in Orthodontic Dentistry, School of Dental Medicine, University of Nevada-Las Vegas, 1700 W. Charleston Boulevard, Las Vegas, NV 89106, USA
| | - Jacky Cheung
- Department of Clinical Sciences, School of Dental Medicine, University of Nevada-Las Vegas, 1700 W. Charleston Boulevard, Las Vegas, NV 89106, USA
| | - Madeline Sullivan
- Department of Clinical Sciences, School of Dental Medicine, University of Nevada-Las Vegas, 1700 W. Charleston Boulevard, Las Vegas, NV 89106, USA
| | - William Taylor Robison
- Department of Clinical Sciences, School of Dental Medicine, University of Nevada-Las Vegas, 1700 W. Charleston Boulevard, Las Vegas, NV 89106, USA
| | - Katherine M. Howard
- Department of Biomedical Sciences, School of Dental Medicine, University of Nevada-Las Vegas, 1001 Shadow Lane, Las Vegas, NV 89106, USA
| | - Karl Kingsley
- Department of Biomedical Sciences, School of Dental Medicine, University of Nevada-Las Vegas, 1001 Shadow Lane, Las Vegas, NV 89106, USA
- Correspondence: ; Tel.: +1-702-774-2623
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26
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Huang C, Su L, Chen Y, Wu S, Sun R, Xu Q, Qiu X, Yang C, Kong X, Qin H, Zhao X, Jiang X, Wang K, Zhu Y, Wong PP. Ceramide kinase confers tamoxifen resistance in estrogen receptor-positive breast cancer by altering sphingolipid metabolism. Pharmacol Res 2023; 187:106558. [PMID: 36410675 DOI: 10.1016/j.phrs.2022.106558] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/12/2022] [Accepted: 11/15/2022] [Indexed: 11/23/2022]
Abstract
Dysregulated sphingolipid metabolism contributes to ER+ breast cancer progression and therapeutic response, whereas its underlying mechanism and contribution to tamoxifen resistance (TAMR) is unknown. Here, we establish sphingolipid metabolic enzyme CERK as a regulator of TAMR in breast cancer. Multi-omics analysis reveals an elevated CERK driven sphingolipid metabolic reprogramming in TAMR cells, while high CERK expression associates with worse patient prognosis in ER+ breast cancer. CERK overexpression confers tamoxifen resistance and promotes tumorigenicity in ER+ breast cancer cells. Knocking out CERK inhibits the orthotopic breast tumor growth of TAMR cells while rescuing their tamoxifen sensitivity. Mechanistically, the elevated EHF expression transcriptionally up-regulates CERK expression to prohibit tamoxifen-induced sphingolipid ceramide accumulation, which then inhibits tamoxifen-mediated repression on PI3K/AKT dependent cell proliferation and its driven p53/caspase-3 mediated apoptosis in TAMR cells. This work provides insight into the regulation of sphingolipid metabolism in tamoxifen resistance and identifies a potential therapeutic target for this disease.
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Affiliation(s)
- Cheng Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Liangping Su
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Yitian Chen
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Sangqing Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Department of Otolaryngology, Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Ruipu Sun
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Qiuping Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Xiaoyi Qiu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Ciqiu Yang
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Xiangzhan Kong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Hongquan Qin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Xinbao Zhao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Xue Jiang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Kun Wang
- Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
| | - Yinghua Zhu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Laboratory Department, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan 523000, China.
| | - Ping-Pui Wong
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
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27
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Takan I, Karakülah G, Louka A, Pavlopoulou A. "In the light of evolution:" keratins as exceptional tumor biomarkers. PeerJ 2023; 11:e15099. [PMID: 36949761 PMCID: PMC10026720 DOI: 10.7717/peerj.15099] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 02/28/2023] [Indexed: 03/19/2023] Open
Abstract
Keratins (KRTs) are the intermediate filament-forming proteins of epithelial cells, classified, according to their physicochemical properties, into "soft" and "hard" keratins. They have a key role in several aspects of cancer pathophysiology, including cancer cell invasion and metastasis, and several members of the KRT family serve as diagnostic or prognostic markers. The human genome contains both, functional KRT genes and non-functional KRT pseudogenes, arranged in two uninterrupted clusters on chromosomes 12 and 17. This characteristic renders KRTs ideal for evolutionary studies. Herein, comprehensive phylogenetic analyses of KRT homologous proteins in the genomes of major taxonomic divisions were performed, so as to fill a gap in knowledge regarding the functional implications of keratins in cancer biology among tumor-bearing species. The differential expression profiles of KRTs in diverse types of cancers were investigated by analyzing high-throughput data, as well. Several KRT genes, including the phylogenetically conserved ones, were found to be deregulated across several cancer types and to participate in a common protein-protein interaction network. This indicates that, at least in cancer-bearing species, these genes might have been under similar evolutionary pressure, perhaps to support the same important function(s). In addition, semantic relations between KRTs and cancer were detected through extensive text mining. Therefore, by applying an integrative in silico pipeline, the evolutionary history of KRTs was reconstructed in the context of cancer, and the potential of using non-mammalian species as model organisms in functional studies on human cancer-associated KRT genes was uncovered.
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Affiliation(s)
- Işıl Takan
- Izmir Biomedicine and Genome Center, Izmir, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Izmir, Turkey
| | - Gökhan Karakülah
- Izmir Biomedicine and Genome Center, Izmir, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Izmir, Turkey
| | - Aikaterini Louka
- DNA Damage Laboratory, Department of Physics, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Athens, Greece
- Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasia Pavlopoulou
- Izmir Biomedicine and Genome Center, Izmir, Turkey
- Izmir International Biomedicine and Genome Institute, Dokuz Eylül University, Izmir, Turkey
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28
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Chen F, Wang Y, Zhang X, Fang J. Five hub genes contributing to the oncogenesis and trastuzumab-resistance in gastric cancer. Gene 2023; 851:146942. [DOI: 10.1016/j.gene.2022.146942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 11/06/2022]
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Zhang J, Ma C, Qin H, Wang Z, Zhu C, Liu X, Hao X, Liu J, Li L, Cai Z. Construction and validation of a metabolic-related genes prognostic model for oral squamous cell carcinoma based on bioinformatics. BMC Med Genomics 2022; 15:269. [PMID: 36566175 PMCID: PMC9789624 DOI: 10.1186/s12920-022-01417-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 12/13/2022] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) accounts for a frequently-occurring head and neck cancer, which is characterized by high rates of morbidity and mortality. Metabolism-related genes (MRGs) show close association with OSCC development, metastasis and progression, so we constructed an MRGs-based OSCC prognosis model for evaluating OSCC prognostic outcome. METHODS This work obtained gene expression profile as well as the relevant clinical information from the The Cancer Genome Atlas (TCGA) database, determined the MRGs related to OSCC by difference analysis, screened the prognosis-related MRGs by performing univariate Cox analysis, and used such identified MRGs for constructing the OSCC prognosis prediction model through Lasso-Cox regression. Besides, we validated the model with the GSE41613 dataset based on Gene Expression Omnibus (GEO) database. RESULTS The present work screened 317 differentially expressed MRGs from the database, identified 12 OSCC prognostic MRGs through univariate Cox regression, and then established a clinical prognostic model composed of 11 MRGs by Lasso-Cox analysis. Based on the optimal risk score threshold, cases were classified as low- or high-risk group. As suggested by Kaplan-Meier (KM) analysis, survival rate was obviously different between the two groups in the TCGA training set (P < 0.001). According to subsequent univariate and multivariate Cox regression, risk score served as the factor to predict prognosis relative to additional clinical features (P < 0.001). Besides, area under ROC curve (AUC) values for patient survival at 1, 3 and 5 years were determined as 0.63, 0.70, and 0.76, separately, indicating that the prognostic model has good predictive accuracy. Then, we validated this clinical prognostic model using GSE41613. To enhance our model prediction accuracy, age, gender, risk score together with TNM stage were incorporated in a nomogram. As indicated by results of ROC curve and calibration curve analyses, the as-constructed nomogram had enhanced prediction accuracy compared with clinicopathological features alone, besides, combining clinicopathological characteristics with risk score contributed to predicting patient prognosis and guiding clinical decision-making. CONCLUSION In this study, 11 MRGs prognostic models based on TCGA database showed superior predictive performance and had a certain clinical application prospect in guiding individualized.
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Affiliation(s)
- Jingfei Zhang
- grid.440653.00000 0000 9588 091XDepartment of Stomatology, Binzhou Medical University, Yantai, 264000 Shandong China
| | - Chenxi Ma
- grid.27255.370000 0004 1761 1174Department of Human Microbiome, School and Hospital of Stomatology, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Shandong University, Jinan, 250000 Shandong China
| | - Han Qin
- grid.440653.00000 0000 9588 091XDepartment of Stomatology, Binzhou Medical University, Yantai, 264000 Shandong China
| | - Zhi Wang
- grid.415946.b0000 0004 7434 8069Department of Stomatology, Linyi People’s Hospital, Linyi, 276000 Shandong China
| | - Chao Zhu
- grid.415946.b0000 0004 7434 8069Department of Stomatology, Linyi People’s Hospital, Linyi, 276000 Shandong China
| | - Xiujuan Liu
- grid.415946.b0000 0004 7434 8069Department of Stomatology, Linyi People’s Hospital, Linyi, 276000 Shandong China
| | - Xiuyan Hao
- grid.415946.b0000 0004 7434 8069Department of Stomatology, Linyi People’s Hospital, Linyi, 276000 Shandong China
| | - Jinghua Liu
- grid.415946.b0000 0004 7434 8069Department of Hepatobiliary Surgery and Minimally Invasive Institute of Digestive Surgery and Prof. Cai’s Laboratory, Linyi People’s Hospital, Shandong University, Linyi, 264000 Shandong China
| | - Ling Li
- grid.415946.b0000 0004 7434 8069Department of Stomatology, Linyi People’s Hospital, Linyi, 276000 Shandong China
| | - Zhen Cai
- grid.415946.b0000 0004 7434 8069Department of Stomatology, Linyi People’s Hospital, Linyi, 276000 Shandong China
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Lin SC, Liao YC, Chen PM, Yang YY, Wang YH, Tung SL, Chuang CM, Sung YW, Jang TH, Chuang SE, Wang LH. Periostin promotes ovarian cancer metastasis by enhancing M2 macrophages and cancer-associated fibroblasts via integrin-mediated NF-κB and TGF-β2 signaling. J Biomed Sci 2022; 29:109. [PMID: 36550569 PMCID: PMC9784270 DOI: 10.1186/s12929-022-00888-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 11/28/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Ovarian cancer has the highest mortality among gynecological cancers due to late diagnosis and lack of effective targeted therapy. Although the study of interplay between cancer cells with their microenvironment is emerging, how ovarian cancer triggers signaling that coordinates with immune cells to promote metastasis is still elusive. METHODS Microarray and bioinformatics analysis of low and highly invasive ovarian cancer cell lines were used to reveal periostin (POSTN), a matrix protein with multifunctions in cancer, with elevated expression in the highly invasive cells. Anchorage independent assay, Western blot, RNA interference, confocal analysis and neutralizing antibody treatment were performed to analyze the effects of POSTN on tumor promotion and to explore the underlying mechanism. Chemotaxis, flow cytometry and cytokine array analyses were undertaken to analyze the involvement of POSTN in cancer-associated fibroblast (CAF) and macrophage modulation. Correlations between POSTN expression levels and clinical characteristics were analyzed using the Oncomine, commercial ovarian cancer cDNA and China Medical University Hospital patient cohort. In vivo effect of POSTN on metastasis was studied using a mouse xenograft model. RESULTS Expression of POSTN was found to be elevated in highly invasive ovarian cancer cells. We observed that POSTN was co-localized with integrin β3 and integrin β5, which was important for POSTN-mediated activation of ERK and NF-κB. Ectopic expression of POSTN enhanced whereas knockdown of POSTN decreased cancer cell migration and invasion in vitro, as well as tumor growth and metastasis in vivo. POSTN enhanced integrin/ERK/NF-κB signaling through an autocrine effect on cancer cells to produce macrophage attracting and mobilizing cytokines including MIP-1β, MCP-1, TNFα and RANTES resulting in increased chemotaxis of THP-1 monocytes and their polarization to M2 macrophages in vitro. In agreement, tumors derived from POSTN-overexpressing SKOV3 harbored more tumor-associated macrophages than the control tumors. POSTN induced TGF-β2 expression from ovarian cancer cells to promote activation of adipose-derived stromal cells to become CAF-like cells expressing alpha smooth muscle actin and fibroblast activation protein alpha. Consistently, increased CAFs were observed in POSTN overexpressing SKOV3 cells-derived metastatic tumors. In clinical relevance, we found that expression of POSTN was positively correlated with advanced-stage diseases and poor overall survival of patients. CONCLUSIONS Our study revealed a POSTN-integrin-NF-κB-mediated signaling and its involvement in enhancing M2 macrophages and CAFs, which could potentially participate in promoting tumor growth. Our results suggest that POSTN could be a useful prognosis marker and potential therapeutic target.
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Affiliation(s)
- Sheng-Chieh Lin
- grid.254145.30000 0001 0083 6092Graduate Institute of Integrated Medicine and Chinese Medicine Research Center, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 40402 Taiwan ,grid.254145.30000 0001 0083 6092Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Yi-Chu Liao
- grid.59784.370000000406229172Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan
| | - Po-Ming Chen
- grid.254145.30000 0001 0083 6092Graduate Institute of Integrated Medicine and Chinese Medicine Research Center, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 40402 Taiwan ,grid.452796.b0000 0004 0634 3637Research Assistant Center, Show Chwan Memorial Hospital, Changhua, Taiwan
| | - Ya-Yu Yang
- grid.59784.370000000406229172National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
| | - Yi-Hsiang Wang
- grid.59784.370000000406229172Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan ,grid.38348.340000 0004 0532 0580Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Shiao-Lin Tung
- Department of Hematology and Oncology, Ton-Yen General Hospital, Hsinchu, Taiwan ,Department of Nursing, Hsin Sheng Junior College of Medical Care and Management, Taoyuan, Taiwan
| | - Chi-Mu Chuang
- grid.278247.c0000 0004 0604 5314Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan ,grid.260539.b0000 0001 2059 7017School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yu-Wen Sung
- grid.254145.30000 0001 0083 6092Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan ,grid.411508.90000 0004 0572 9415Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan
| | - Te-Hsuan Jang
- grid.59784.370000000406229172National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan ,grid.38348.340000 0004 0532 0580Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Shuang-En Chuang
- grid.59784.370000000406229172National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
| | - Lu-Hai Wang
- grid.254145.30000 0001 0083 6092Graduate Institute of Integrated Medicine and Chinese Medicine Research Center, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 40402 Taiwan ,grid.59784.370000000406229172Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan ,grid.38348.340000 0004 0532 0580Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan
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Bernstein MN, Ni Z, Prasad A, Brown J, Mohanty C, Stewart R, Newton MA, Kendziorski C. SpatialCorr identifies gene sets with spatially varying correlation structure. CELL REPORTS METHODS 2022; 2:100369. [PMID: 36590683 PMCID: PMC9795364 DOI: 10.1016/j.crmeth.2022.100369] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 09/26/2022] [Accepted: 11/21/2022] [Indexed: 12/15/2022]
Abstract
Recent advances in spatially resolved transcriptomics technologies enable both the measurement of genome-wide gene expression profiles and their mapping to spatial locations within a tissue. A first step in spatial transcriptomics data analysis is identifying genes with expression that varies spatially, and robust statistical methods exist to address this challenge. While useful, these methods do not detect spatial changes in the coordinated expression within a group of genes. To this end, we present SpatialCorr, a method for identifying sets of genes with spatially varying correlation structure. Given a collection of gene sets pre-defined by a user, SpatialCorr tests for spatially induced differences in the correlation of each gene set within tissue regions, as well as between and among regions. An application to cutaneous squamous cell carcinoma demonstrates the power of the approach for revealing biological insights not identified using existing methods.
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Affiliation(s)
| | - Zijian Ni
- Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Aman Prasad
- Department of Dermatology, University of Wisconsin-Madison, Madison, WI 53715, USA
| | - Jared Brown
- Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Chitrasen Mohanty
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Ron Stewart
- Morgridge Institute for Research, Madison, WI 53715, USA
| | - Michael A. Newton
- Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706, USA
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Christina Kendziorski
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53792, USA
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An J, Nagaki Y, Motoyama S, Kuze Y, Hoshizaki M, Kemuriyama K, Yamaguchi T, Ebihara T, Minamiya Y, Suzuki Y, Imai Y, Kuba K. Identification of Galectin-7 as a crucial metastatic enhancer of squamous cell carcinoma associated with immunosuppression. Oncogene 2022; 41:5319-5330. [PMID: 36335283 DOI: 10.1038/s41388-022-02525-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 10/18/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022]
Abstract
Metastasis predicts poor prognosis in cancer patients. It has been recognized that specific tumor microenvironment defines cancer cell metastasis, whereas the underlying mechanisms remain elusive. Here we show that Galectin-7 is a crucial mediator of metastasis associated with immunosuppression. In a syngeneic mouse squamous cell carcinoma (SCC) model of NR-S1M cells, we isolated metastasized NR-S1M cells from lymph nodes in tumor-bearing mice and established metastatic NR-S1M cells in in vitro culture. RNA-seq analysis revealed that interferon gene signature was markedly downregulated in metastatic NR-S1M cells compared with parental cells, and in vivo NR-S1M tumors heterogeneously developed focal immunosuppressive areas featured by deficiency of anti-tumor immune cells. Spatial transcriptome analysis (Visium) for the NR-S1M tumors revealed that various pro-metastatic genes were significantly upregulated in immunosuppressive areas when compared to immunocompetent areas. Notably, Galectin-7 was identified as a novel metastasis-driving factor. Galectin-7 expression was induced during tumorigenesis particularly in the microenvironment of immunosuppression, and extracellularly released at later stage of tumor progression. Deletion of Galectin-7 in NR-S1M cells significantly suppressed lymph node and lung metastasis without affecting primary tumor growth. Therefore, Galectin-7 is a crucial mediator of tumor metastasis of SCC, which is educated in the immune-suppressed tumor areas, and may be a potential target of cancer immunotherapy.
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Affiliation(s)
- Jianbo An
- Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Yushi Nagaki
- Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.,Department of Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Satoru Motoyama
- Department of Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Yuta Kuze
- Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, 277-8562, Japan
| | - Midori Hoshizaki
- Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.,Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan
| | - Kohei Kemuriyama
- Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.,Department of Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Tomokazu Yamaguchi
- Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Takashi Ebihara
- Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan
| | - Yoshihiro Minamiya
- Department of Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Yutaka Suzuki
- Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, 277-8562, Japan
| | - Yumiko Imai
- Laboratory of Regulation of Intractable Infectious Diseases, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, 567-0085, Japan
| | - Keiji Kuba
- Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan. .,Department of Pharmacology, Kyushu University Graduate School of Medical Sciences, Fukuoka, 812-8582, Japan.
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33
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Wang Y, Li Q, Wang S, Wang BJ, Jin Y, Hu H, Fu QS, Wang JW, Wu Q, Qian L, Cao TT, Xia YB, Huang XX, Xu L. The role of noncoding RNAs in cancer lipid metabolism. Front Oncol 2022; 12:1026257. [PMID: 36452489 PMCID: PMC9704363 DOI: 10.3389/fonc.2022.1026257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/20/2022] [Indexed: 12/03/2023] Open
Abstract
Research on noncoding ribonucleic acids (ncRNAs) is mostly and broadly focused on microRNAs (miRNAs), cyclic RNAs (circRNAs), and long ncRNAs (lncRNAs), which have been confirmed to play important roles in tumor cell proliferation, invasion, and migration. Specifically, recent studies have shown that ncRNAs contribute to tumorigenesis and tumor development by mediating changes in enzymes related to lipid metabolism. The purpose of this review is to discuss the characterized ncRNAs involved in the lipid metabolism of tumors to highlight ncRNA-mediated lipid metabolism-related enzyme expression in malignant tumors and its importance to tumor development. In this review, we describe the types of ncRNA and the mechanism of tumor lipid metabolism and analyze the important role of ncRNA in tumor lipid metabolism and its future prospects from the perspectives of ncRNA biological function and lipid metabolic enzyme classification. However, several critical issues still need to be resolved. Because ncRNAs can affect tumor processes by regulating lipid metabolism enzymes, in the future, we can study the unique role of ncRNAs from four aspects: disease prevention, detection, diagnosis, and treatment. Therefore, in the future, the development of ncRNA-targeted therapy will become a hot direction and shoulder a major task in the medical field.
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Affiliation(s)
- Ye Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, Anhui, China
- Non-coding RNA Research Center of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
| | - Qian Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, Anhui, China
- Non-coding RNA Research Center of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
| | - Song Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, Anhui, China
- Non-coding RNA Research Center of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
| | - Bi-jun Wang
- Department of Clinical Medicine, Clinical College of Anhui Medical University, Hefei, Anhui, China
| | - Yan Jin
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, Anhui, China
- Non-coding RNA Research Center of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
| | - Hao Hu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, Anhui, China
- Non-coding RNA Research Center of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
| | - Qing-sheng Fu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, Anhui, China
- Non-coding RNA Research Center of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
| | - Jia-wei Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, Anhui, China
- Non-coding RNA Research Center of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
| | - Qing Wu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, Anhui, China
- Non-coding RNA Research Center of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
| | - Long Qian
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, Anhui, China
- Non-coding RNA Research Center of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
| | - Ting-ting Cao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, Anhui, China
- Non-coding RNA Research Center of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
| | - Ya-bin Xia
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, Anhui, China
- Non-coding RNA Research Center of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
| | - Xiao-xu Huang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, Anhui, China
- Non-coding RNA Research Center of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
| | - Li Xu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wuhu, Anhui, China
- Non-coding RNA Research Center of Wannan Medical College, Yijishan Hospital, Wuhu, Anhui, China
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Li Y, Wang D, Ge H, Güngör C, Gong X, Chen Y. Cytoskeletal and Cytoskeleton-Associated Proteins: Key Regulators of Cancer Stem Cell Properties. Pharmaceuticals (Basel) 2022; 15:1369. [PMID: 36355541 PMCID: PMC9698833 DOI: 10.3390/ph15111369] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/02/2022] [Accepted: 11/06/2022] [Indexed: 08/08/2023] Open
Abstract
Cancer stem cells (CSCs) are a subpopulation of cancer cells possessing stemness characteristics that are closely associated with tumor proliferation, recurrence and resistance to therapy. Recent studies have shown that different cytoskeletal components and remodeling processes have a profound impact on the behavior of CSCs. In this review, we outline the different cytoskeletal components regulating the properties of CSCs and discuss current and ongoing therapeutic strategies targeting the cytoskeleton. Given the many challenges currently faced in targeted cancer therapy, a deeper comprehension of the molecular events involved in the interaction of the cytoskeleton and CSCs will help us identify more effective therapeutic strategies to eliminate CSCs and ultimately improve patient survival.
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Affiliation(s)
- Yuqiang Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
- NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Dan Wang
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Heming Ge
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Cenap Güngör
- Department of General Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Xuejun Gong
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yongheng Chen
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
- NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha 410008, China
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35
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Kurtović M, Piteša N, Bartoniček N, Ozretić P, Musani V, Čonkaš J, Petrić T, King C, Sabol M. RNA-seq and ChIP-seq Identification of Unique and Overlapping Targets of GLI Transcription Factors in Melanoma Cell Lines. Cancers (Basel) 2022; 14:4540. [PMID: 36139698 PMCID: PMC9497141 DOI: 10.3390/cancers14184540] [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: 08/11/2022] [Revised: 09/05/2022] [Accepted: 09/14/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Despite significant progress in therapy, melanoma still has a rising incidence worldwide, and novel treatment strategies are needed. Recently, researchers have recognized the involvement of the Hedgehog-GLI (HH-GLI) signaling pathway in melanoma and its consistent crosstalk with the MAPK pathway. In order to further investigate the link between the two pathways and to find new target genes that could be considered for combination therapy, we set out to find transcriptional targets of all three GLI proteins in melanoma. METHODS We performed RNA sequencing on three melanoma cell lines (CHL-1, A375, and MEL224) with overexpressed GLI1, GLI2, and GLI3 and combined them with the results of ChIP-sequencing on endogenous GLI1, GLI2, and GLI3 proteins. After combining these results, 21 targets were selected for validation by qPCR. RESULTS RNA-seq revealed a total of 808 differentially expressed genes (DEGs) for GLI1, 941 DEGs for GLI2, and 58 DEGs for GLI3. ChIP-seq identified 527 genes that contained GLI1 binding sites in their promoters, 1103 for GLI2 and 553 for GLI3. A total of 15 of these targets were validated in the tested cell lines, 6 of which were detected by both RNA-seq and ChIP-seq. CONCLUSIONS Our study provides insight into the unique and overlapping transcriptional output of the GLI proteins in melanoma. We suggest that our findings could provide new potential targets to consider while designing melanoma-targeted therapy.
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Affiliation(s)
- Matea Kurtović
- Division of Molecular Medicine, Ruđer Bošković Institute, 10 000 Zagreb, Croatia
| | - Nikolina Piteša
- Division of Molecular Medicine, Ruđer Bošković Institute, 10 000 Zagreb, Croatia
| | - Nenad Bartoniček
- The Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia
- The Kinghorn Centre for Clinical Genomics, 370 Victoria St., Darlinghurst, NSW 2010, Australia
| | - Petar Ozretić
- Division of Molecular Medicine, Ruđer Bošković Institute, 10 000 Zagreb, Croatia
| | - Vesna Musani
- Division of Molecular Medicine, Ruđer Bošković Institute, 10 000 Zagreb, Croatia
| | - Josipa Čonkaš
- Division of Molecular Medicine, Ruđer Bošković Institute, 10 000 Zagreb, Croatia
| | - Tina Petrić
- Division of Molecular Medicine, Ruđer Bošković Institute, 10 000 Zagreb, Croatia
| | - Cecile King
- School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW 2052, Australia
| | - Maja Sabol
- Division of Molecular Medicine, Ruđer Bošković Institute, 10 000 Zagreb, Croatia
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Patel A, Patel S, Patel P, Mandlik D, Patel K, Tanavde V. Salivary Exosomal miRNA-1307-5p Predicts Disease Aggressiveness and Poor Prognosis in Oral Squamous Cell Carcinoma Patients. Int J Mol Sci 2022; 23:ijms231810639. [PMID: 36142544 PMCID: PMC9505291 DOI: 10.3390/ijms231810639] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/07/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Salivary exosomal miRNAs as biomarkers facilitate repeated sampling, real-time disease monitoring and assessment of therapeutic response. This study identifies a single salivary exosomal miRNA prognosticator that will aid in improved patient outcome using a liquid biopsy approach. Method: Small RNA and transcriptome sequencing profiles of tumour tissues (n = 12) and salivary exosomes (n = 8) from oral cancer patients were compared to their non-cancerous counterparts. We validated these results using The Cancer Genome Atlas database and performing Real-time PCR on a large patient cohort (n = 19 tissue samples; n = 12 salivary exosomes). Potential target genes and the miRNA–mRNA networks and enriched biological pathways regulated by this microRNA were identified using computational tools. Results: Salivary exosomes (size: 30–50 nm) demonstrated a strong expression of CD47 and detectable expression of tetraspanins CD63, CD81 and CD9 by flow cytometry. miR-1307-5p was exclusively overexpressed in tissues and salivary exosomes of oral cancer patients compared to their non-cancerous counterparts. Enhanced expression of miR-1307-5p clinically correlated with poor patient survival, disease progression, aggressiveness and chemo-resistance. Transcriptome analysis suggested that miRNA-1307-5p could promote oral cancer progression by suppressing THOP1, EHF, RNF4, GET4 and RNF114. Conclusions: Salivary exosomal miRNA-1307-5p is a potential prognosticator for predicting poor survival and poor patient outcome in oral cancers.
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Affiliation(s)
- Aditi Patel
- Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Ahmedabad 380009, India
| | - Shanaya Patel
- Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Ahmedabad 380009, India
| | - Parina Patel
- Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Ahmedabad 380009, India
| | - Dushyant Mandlik
- Department of Head and Neck Oncology, HCG Cancer Centre, Ahmedabad 380060, India
| | - Kaustubh Patel
- Department of Head and Neck Oncology, HCG Cancer Centre, Ahmedabad 380060, India
| | - Vivek Tanavde
- Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Ahmedabad 380009, India
- Bioinformatics Institute, Agency for Science Technology and Research (A*STAR), Singapore 138671, Singapore
- Correspondence:
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Hua X, Xiang D, Guo M, Qian X, Chen R, Li T, Tian Z, Xu J, Huang C, Xie Q, Huang C. Induction of RAC1 protein translation and MKK7/JNK-dependent autophagy through dicer/miR-145/SOX2/miR-365a axis contributes to isorhapontigenin (ISO) inhibition of human bladder cancer invasion. Cell Death Dis 2022; 13:753. [PMID: 36045117 PMCID: PMC9433410 DOI: 10.1038/s41419-022-05205-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 08/18/2022] [Accepted: 08/22/2022] [Indexed: 01/21/2023]
Abstract
Although our previous studies have identified that isorhapontigenin (ISO) is able to initiate autophagy in human bladder cancer (BC) cells by activating JNK/C-Jun/SESN2 axis and possesses an inhibitory effect on BC cell growth, association of autophagy directly with inhibition of BC invasion has never been explored. Also, upstream cascade responsible for ISO activating JNK remains unknown. Thus, we explored both important questions in the current study and discovered that ISO treatment initiated RAC1 protein translation, and its downstream kinase MKK7/JNK phosphorylation/activation, and in turn promoted autophagic responses in human BC cells. Inhibition of autophagy abolished ISO inhibition of BC invasion, revealing that autophagy inhibition was crucial for ISO inhibition of BC invasion. Consistently, knockout of RAC1 also attenuated induction of autophagy and inhibition of BC invasion by ISO treatment. Mechanistic studies showed that upregulation of RAC1 translation was due to ISO inhibition of miR-365a transcription, which reduced miR-365a binding to the 3'-UTR of RAC1 mRNA. Further study indicated that inhibition of miR-365a transcription was caused by downregulation of its transcription factor SOX2, while ISO-promoted Dicer protein translation increased miR-145 maturation, and consequently downregulating SOX2 expression. These findings not only provide a novel insight into the understanding association of autophagy induction with BC invasion inhibition by ISO, but also identify an upstream regulatory cascade, Dicer/miR145/SOX2/miR365a/RAC1, leading to MKK7/JNKs activation and autophagy induction.
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Affiliation(s)
- Xiaohui Hua
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China ,grid.186775.a0000 0000 9490 772XDepartment of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032 China
| | - Daimin Xiang
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127 China
| | - Mengxin Guo
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Xiaohui Qian
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Ruifan Chen
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Tengda Li
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Zhongxian Tian
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Jiheng Xu
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Chao Huang
- grid.33199.310000 0004 0368 7223Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China
| | - Qipeng Xie
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
| | - Chuanshu Huang
- grid.268099.c0000 0001 0348 3990Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035 China
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Chu PY, Huang WC, Tung SL, Tsai CY, Chen CJ, Liu YC, Lee CW, Lin YH, Lin HY, Chen CY, Yeh CT, Lin KH, Chi HC. IFITM3 promotes malignant progression, cancer stemness and chemoresistance of gastric cancer by targeting MET/AKT/FOXO3/c-MYC axis. Cell Biosci 2022; 12:124. [PMID: 35941699 PMCID: PMC9361616 DOI: 10.1186/s13578-022-00858-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 07/22/2022] [Indexed: 12/09/2022] Open
Abstract
Background Targeting the HGF/MET signaling pathway has been a viable therapeutic strategy for various cancer types due to hyperactivation of HGF/MET axis occurs frequently that leads to detrimental cancer progression and recurrence. Deciphering novel molecule mechanisms underlying complex HGF/MET signaling network is therefore critical to development of effective therapeutics for treating MET-dependent malignancies. Results Using isobaric mass tag-based quantitative proteomics approach, we identified IFITM3, an interferon-induced transmembrane protein that was highly expressed in micro-dissected gastric cancer (GC) tumor regions relative to adjacent non-tumor epithelia. Analyses of GC clinical specimens revealed that expression IFITM3 was closely correlated to advanced pathological stages. IFITM3 has been reported as a PIP3 scaffold protein that promotes PI3K signaling. In present study, we unprecedentedly unraveled that IFITM3 associated with MET and AKT to facilitate HGF/MET mediated AKT signaling crosstalk in suppressing FOXO3, consequently leading to c-MYC mediated GC progression. In addition, gene ontology analyses of the clinical GC cohort revealed significant correlation between IFITM3-associated genes and targets of c-MYC, which is a crucial downstream effector of HGF/MET pathway in cancer progression. Moreover, we demonstrated ectopic expression of IFITM3 suppressed FOXO3 expression, consequently led to c-MYC induction to promote tumor growth, cell metastasis, cancer stemness as well as chemoresistance. Conversely, depletion of IFITM3 resulted in suppression of HGF triggered cellular growth and migration via inhibition of AKT/c-MYC signaling in GC. Conclusions In summary, our present study unveiled a novel regulatory mechanism for c-MYC-driven oncogenesis underlined by IFITM3-mediated signaling crosstalk between MET associated AKT signaling cascade. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00858-8.
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Khatoon E, Hegde M, Kumar A, Daimary UD, Sethi G, Bishayee A, Kunnumakkara AB. The multifaceted role of STAT3 pathway and its implication as a potential therapeutic target in oral cancer. Arch Pharm Res 2022; 45:507-534. [PMID: 35987863 DOI: 10.1007/s12272-022-01398-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 07/20/2022] [Indexed: 12/20/2022]
Abstract
Oral cancer is one of the leading causes of cancer-related deaths, and it has become a matter of serious concern due to the alarming rise in its incidence rate worldwide. Despite recent advancements in oral cancer treatment strategies, there are no significant improvements in patient's survival rate. Among the numerous cell signaling pathways involved in oral cancer development and progression, STAT3 is known to play a multifaceted oncogenic role in shaping the tumor pathophysiology. STAT3 hyperactivation in oral cancer contributes to survival, proliferation, invasion, epithelial to mesenchymal transition, metastasis, immunosuppression, chemoresistance, and poor prognosis. A plethora of pre-clinical and clinical studies have documented the role of STAT3 in the initiation and development of oral cancer and showed that STAT3 inhibition holds significant potential in the prevention and treatment of this cancer. However, to date, targeting STAT3 activation mainly involves inhibiting the upstream signaling molecules such as JAK and IL-6 receptors. The major challenge in targeting STAT3 lies in the complexity of its phosphorylation- and dimerization-independent functions, which are not affected by disrupting the upstream regulators. The present review delineates the significance of the STAT3 pathway in regulating various hallmarks of oral cancer. In addition, it highlights the STAT3 inhibitors identified to date through various preclinical and clinical studies that can be employed for the therapeutic intervention in oral cancer treatment.
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Affiliation(s)
- Elina Khatoon
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India
| | - Aviral Kumar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India
| | - Uzini Devi Daimary
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India. .,DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Indian Institute of Technology (IIT) Guwahati, Guwahati, 781 039, Assam, India.
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Jang TH, Huang WC, Tung SL, Lin SC, Chen PM, Cho CY, Yang YY, Yen TC, Lo GH, Chuang SE, Wang LH. MicroRNA-485-5p targets keratin 17 to regulate oral cancer stemness and chemoresistance via the integrin/FAK/Src/ERK/β-catenin pathway. J Biomed Sci 2022; 29:42. [PMID: 35706019 PMCID: PMC9202219 DOI: 10.1186/s12929-022-00824-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 06/07/2022] [Indexed: 01/21/2023] Open
Abstract
Background The development of drug resistance in oral squamous cell carcinoma (OSCC) that frequently leads to recurrence and metastasis after initial treatment remains an unresolved challenge. Presence of cancer stem cells (CSCs) has been increasingly reported to be a critical contributing factor in drug resistance, tumor recurrence and metastasis. Thus, unveiling of mechanisms regulating CSCs and potential targets for developing their inhibitors will be instrumental for improving OSCC therapy. Methods siRNA, shRNA and miRNA that specifically target keratin 17 (KRT17) were used for modulation of gene expression and functional analyses. Sphere-formation and invasion/migration assays were utilized to assess cancer cell stemness and epithelial mesenchymal transition (EMT) properties, respectively. Duolink proximity ligation assay (PLA) was used to examine molecular proximity between KRT17 and plectin, which is a large protein that binds cytoskeleton components. Cell proliferation assay was employed to evaluate growth rates and viability of oral cancer cells treated with cisplatin, carboplatin or dasatinib. Xenograft mouse tumor model was used to evaluate the effect of KRT17- knockdown in OSCC cells on tumor growth and drug sensitization. Results Significantly elevated expression of KRT17 in highly invasive OSCC cell lines and advanced tumor specimens were observed and high KRT17 expression was correlated with poor overall survival. KRT17 gene silencing in OSCC cells attenuated their stemness properties including markedly reduced sphere forming ability and expression of stemness and EMT markers. We identified a novel signaling cascade orchestrated by KRT17 where its association with plectin resulted in activation of integrin β4/α6, increased phosphorylation of FAK, Src and ERK, as well as stabilization and nuclear translocation of β-catenin. The activation of this signaling cascade was correlated with enhanced OSCC cancer stemness and elevated expression of CD44 and epidermal growth factor receptor (EGFR). We identified and demonstrated KRT17 to be a direct target of miRNA-485-5p. Ectopic expression of miRNA-485-5p inhibited OSCC sphere formation and caused sensitization of cancer cells towards cisplatin and carboplatin, which could be significantly rescued by KRT17 overexpression. Dasatinib treatment that inhibited KRT17-mediated Src activation also resulted in OSCC drug sensitization. In OSCC xenograft mouse model, KRT17 knockdown significantly inhibited tumor growth, and combinatorial treatment with cisplatin elicited a greater tumor inhibitory effect. Consistently, markedly reduced levels of integrin β4, active β-catenin, CD44 and EGFR were observed in the tumors induced by KRT17 knockdown OSCC cells. Conclusions A novel miRNA-485-5p/KRT17/integrin/FAK/Src/ERK/β-catenin signaling pathway is unveiled to modulate OSCC cancer stemness and drug resistance to the common first-line chemotherapeutics. This provides a potential new therapeutic strategy to inhibit OSCC stem cells and counter chemoresistance. Supplementary Information The online version contains supplementary material available at 10.1186/s12929-022-00824-z.
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Affiliation(s)
- Te-Hsuan Jang
- Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan.,National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.,Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Wei-Chieh Huang
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.,Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Shiao-Lin Tung
- Department of Hematology and Oncology, Ton-Yen General Hospital, Zhubei City, Hsinchu County, Taiwan.,Department of Nursing, Hsin Sheng Junior College of Medical Care and Management, Taoyuan City, Taiwan
| | - Sheng-Chieh Lin
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Po-Ming Chen
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Chun-Yu Cho
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
| | - Ya-Yu Yang
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan
| | - Tzu-Chen Yen
- Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
| | - Guo-Hsuen Lo
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Shuang-En Chuang
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
| | - Lu-Hai Wang
- Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan. .,Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan. .,Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
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Oyelakin A, Nayak KB, Glathar AR, Gluck C, Wrynn T, Tugores A, Romano RA, Sinha S. EHF is a novel regulator of cellular redox metabolism and predicts patient prognosis in HNSCC. NAR Cancer 2022; 4:zcac017. [PMID: 35664541 PMCID: PMC9155246 DOI: 10.1093/narcan/zcac017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 04/28/2022] [Accepted: 05/18/2022] [Indexed: 12/13/2022] Open
Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC) is a heterogeneous disease with relatively high morbidity and mortality rates. The lack of effective therapies, high recurrence rates and drug resistance driven in part, by tumor heterogeneity, contribute to the poor prognosis for patients diagnosed with this cancer. This problem is further exacerbated by the fact that key regulatory factors contributing to the disease diversity remains largely elusive. Here, we have identified EHF as an important member of the ETS family of transcription factors that is highly expressed in normal oral tissues, but lost during HNSCC progression. Interestingly, HNSCC tumors and cell lines exhibited a dichotomy of high and low EHF expression, and patients whose tumors retained EHF expression showed significantly better prognosis, suggesting a potential tumor suppressive role for EHF. To address this, we have performed gain and loss of function studies and leveraged bulk and single-cell cancer genomic datasets to identify global EHF targets by RNA-sequencing (RNA-seq) and Chromatin Immunoprecipitation and next generation sequencing (ChIP-seq) experiments of HNSCC cell lines. These mechanistic studies have revealed that EHF, acts as a regulator of a broad spectrum of metabolic processes, specifically targeting regulators of redox homeostasis such as NRF2 and SOX2. Our immunostaining results confirm the mutually exclusive expression patterns of EHF and SOX2 in HNSCC tumors and suggest a possible role for these two factors in establishing discrete metabolic states within the tumor microenvironment. Taken together, EHF may serve as a novel prognostic marker for classifying HNSCC patients for actionable and targeted therapeutic intervention.
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Affiliation(s)
- Akinsola Oyelakin
- Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, Buffalo, NY, USA
| | - Kasturi Bala Nayak
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Alexandra Ruth Glathar
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Christian Gluck
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Theresa Wrynn
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
| | - Antonio Tugores
- Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno Infantil Avda Maritima del Sur, Las Palmas de Gran Canaria, Spain
| | - Rose-Anne Romano
- Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, Buffalo, NY, USA
| | - Satrajit Sinha
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA
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Du L, Liu Y, Li C, Deng J, Sang Y. The interaction between ETS transcription factor family members and microRNAs: A novel approach to cancer therapy. Biomed Pharmacother 2022; 150:113069. [PMID: 35658214 DOI: 10.1016/j.biopha.2022.113069] [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: 03/08/2022] [Revised: 04/26/2022] [Accepted: 04/28/2022] [Indexed: 11/18/2022] Open
Abstract
In cancer biology, ETS transcription factors promote tumorigenesis by mediating transcriptional regulation of numerous genes via the conserved ETS DNA-binding domain. MicroRNAs (miRNAs) act as posttranscriptional regulators to regulate various tumor-promoting or tumor-suppressing factors. Interactions between ETS factors and miRNAs regulate complex tumor-promoting and tumor-suppressing networks. This review discusses the progress of ETS factors and miRNAs in cancer research in detail. We focused on characterizing the interaction of the miRNA/ETS axis with competing endogenous RNAs (ceRNAs) and its regulation in posttranslational modifications (PTMs) and the tumor microenvironment (TME). Finally, we explore the prospect of ETS factors and miRNAs in therapeutic intervention. Generally, interactions between ETS factors and miRNAs provide fresh perspectives into tumorigenesis and development and novel therapeutic approaches for malignant tumors.
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Affiliation(s)
- Liwei Du
- Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, Department of Center Laboratory, The Third Affiliated Hospital of Nanchang University & The First Hospital of Nanchang, Nanchang 330008, China
| | - Yuchen Liu
- Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, Department of Center Laboratory, The Third Affiliated Hospital of Nanchang University & The First Hospital of Nanchang, Nanchang 330008, China; Stomatology College of Nanchang University, Nanchang, China
| | - Chenxi Li
- Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, Department of Center Laboratory, The Third Affiliated Hospital of Nanchang University & The First Hospital of Nanchang, Nanchang 330008, China
| | - Jinkuang Deng
- Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, Department of Center Laboratory, The Third Affiliated Hospital of Nanchang University & The First Hospital of Nanchang, Nanchang 330008, China
| | - Yi Sang
- Jiangxi Key Laboratory of Cancer Metastasis and Precision Treatment, Department of Center Laboratory, The Third Affiliated Hospital of Nanchang University & The First Hospital of Nanchang, Nanchang 330008, China.
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Wang H, Man Q, Huo F, Gao X, Lin H, Li S, Wang J, Su F, Cai, L, Shi Y, Liu, B, Bu L. STAT3 pathway in cancers: Past, present, and future. MedComm (Beijing) 2022; 3:e124. [PMID: 35356799 PMCID: PMC8942302 DOI: 10.1002/mco2.124] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/13/2022] [Accepted: 02/21/2022] [Indexed: 12/13/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, discovered in the cytoplasm of almost all types of mammalian cells, plays a significant role in biological functions. The duration of STAT3 activation in normal tissues is a transient event and is strictly regulated. However, in cancer tissues, STAT3 is activated in an aberrant manner and is induced by certain cytokines. The continuous activation of STAT3 regulates the expression of downstream proteins associated with the formation, progression, and metastasis of cancers. Thus, elucidating the mechanisms of STAT3 regulation and designing inhibitors targeting the STAT3 pathway are considered promising strategies for cancer treatment. This review aims to introduce the history, research advances, and prospects concerning the STAT3 pathway in cancer. We review the mechanisms of STAT3 pathway regulation and the consequent cancer hallmarks associated with tumor biology that are induced by the STAT3 pathway. Moreover, we summarize the emerging development of inhibitors that target the STAT3 pathway and novel drug delivery systems for delivering these inhibitors. The barriers against targeting the STAT3 pathway, the focus of future research on promising targets in the STAT3 pathway, and our perspective on the overall utility of STAT3 pathway inhibitors in cancer treatment are also discussed.
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Affiliation(s)
- Han‐Qi Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Qi‐Wen Man
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
- Department of Oral & Maxillofacial Head Neck OncologySchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Fang‐Yi Huo
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Xin Gao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Hao Lin
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Su‐Ran Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Jing Wang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Fu‐Chuan Su
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Lulu Cai,
- Personalized Drug Therapy Key Laboratory of Sichuan ProvinceDepartment of PharmacySchool of MedicineSichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Yi Shi
- Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory MedicineSichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengduChina
| | - Bing Liu,
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
- Department of Oral & Maxillofacial Head Neck OncologySchool & Hospital of StomatologyWuhan UniversityWuhanChina
| | - Lin‐Lin Bu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of EducationSchool & Hospital of StomatologyWuhan UniversityWuhanChina
- Department of Oral & Maxillofacial Head Neck OncologySchool & Hospital of StomatologyWuhan UniversityWuhanChina
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Zhang W, Lan X, Zhu J, Zhang C, Huang Y, Mo K, Tan J, Guo H, Huang H, Li M, Ouyang H, Wang L. Healing Ability of Central Corneal Epithelium in Rabbit Ocular Surface Injury Models. Transl Vis Sci Technol 2022; 11:28. [PMID: 35771535 PMCID: PMC9251814 DOI: 10.1167/tvst.11.6.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Purpose Wound healing of the corneal epithelium mainly involves two types of cells: limbal stem/progenitor cells (LSCs) and differentiated central corneal epithelial cells (CECs). The healing ability of CECs is still debatable, and its correlated transcriptomic alterations during wound healing are yet to be elucidated. This study aimed to determine the healing ability and mechanisms underlying the actions of CECs using rabbit ocular surface injury models. Methods A central corneal ring-like residual epithelium model was used to investigate the healing ability of CECs. Uninjured and injury-stimulated LSCs and CECs were collected for transcriptomic analysis. The analysis results were verified by quantitative reverse transcriptase polymerase chain reaction, immunofluorescence staining, and two types of rabbit corneal injury models. Results During wound healing, the upregulated genes in LSCs were mostly enriched in the mitotic cell cycle–related processes, but those in CECs were mostly enriched in cell adhesion and migration. CECs could repair the epithelial defects successfully at one-time injuries. However, after repetitive injuries, the CECs repaired notably slower and failed to completely heal the defect, but the LSCs repaired even faster than the one-time injury. Conclusions Our results indicated rabbit CECs repair the epithelial defect mainly depending on migration and its proliferative ability is limited, and LSCs are the main source of regenerative epithelial cells. Translational Relevance This study provides information on gene expression in the corneal epithelium during wound healing, indicating that regulation of the cell cycle, cell adhesion, and migration may be the basis for future treatment strategies for corneal wound healing.
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Affiliation(s)
- Wang Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Xihong Lan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Jin Zhu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Canwei Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Ying Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Kunlun Mo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Jieying Tan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Huizhen Guo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Huaxing Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Mingsen Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Hong Ouyang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Li Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
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Yang C, Mai Z, Liu C, Yin S, Cai Y, Xia C. Natural Products in Preventing Tumor Drug Resistance and Related Signaling Pathways. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27113513. [PMID: 35684449 PMCID: PMC9181879 DOI: 10.3390/molecules27113513] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 12/13/2022]
Abstract
Drug resistance is still an obstacle in cancer therapy, leading to the failure of tumor treatment. The emergence of tumor drug resistance has always been a main concern of oncologists. Therefore, overcoming tumor drug resistance and looking for new strategies for tumor treatment is a major focus in the field of tumor research. Natural products serve as effective substances against drug resistance because of their diverse chemical structures and pharmacological effects. We reviewed the signaling pathways involved in the development of tumor drug resistance, including Epidermal growth factor receptor (EGFR), Renin-angiotensin system (Ras), Phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), Wnt, Notch, Transforming growth factor-beta (TGF-β), and their specific signaling pathway inhibitors derived from natural products. This can provide new ideas for the prevention of drug resistance in cancer therapy.
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Affiliation(s)
- Chuansheng Yang
- Department of Head-Neck and Breast Surgery, Yuebei People’s Hospital of Shantou University, Shaoguan 512027, China;
| | - Zhikai Mai
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Can Liu
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Shuanghong Yin
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Yantao Cai
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- Correspondence: (Y.C.); (C.X.)
| | - Chenglai Xia
- Affiliated Foshan Maternity and Chlid Healthcare Hospital, Southern Medical University, Foshan 528000, China; (Z.M.); (C.L.); (S.Y.)
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
- Correspondence: (Y.C.); (C.X.)
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Huang WC, Yen JH, Sung YW, Tung SL, Chen PM, Chu PY, Shih YC, Chi HC, Huang YC, Huang SJ, Wang LH. Novel function of THEMIS2 in the enhancement of cancer stemness and chemoresistance by releasing PTP1B from MET. Oncogene 2022; 41:997-1010. [PMID: 34974522 PMCID: PMC8837547 DOI: 10.1038/s41388-021-02136-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 11/16/2021] [Accepted: 11/24/2021] [Indexed: 12/11/2022]
Abstract
Triple negative breast cancer (TNBC) possesses poor prognosis mainly due to lack of effective endocrine or targeted therapies, aggressive nature and high rate of chemoresistance. Cancer stem cells (CSCs) are considered to play critical roles in cancer recurrence and chemoresistance. THEMIS2 was identified as the sole common elevated gene in three triple negative breast cancer (TNBC) and two ovarian CSC lines. We discovered an intrinsic signaling scaffold function of THEMIS2, which acts as a novel regulator of cancer stemness in promoting multiple cancer stemness properties including sphere formation, stemness markers expression, chemoresistance and tumorigenicity with low numbers of cancer cells implantation. For the first time, we demonstrated that THEMIS2 specifically enhanced MET activating phosphorylation by suppressing the association of protein-tyrosine phosphatases 1B (PTP1B) with p-MET and MET, which accounted mainly for THEMIS2-mediated effect on cancer stemness and chemoresistance. Increased THEMIS2 expression was associated with poor survival in TNBC patients and in patients from our breast cancer cohort. We found that non-cytotoxic dosages of cryptotanshinone (CPT) could potently inhibit cancer stemness, chemoresistance and tumorigenicity by suppressing expression of THEMIS2. Notably, stable overexpression of THEMIS2 is associated with enhanced sensitivity toward Capmatinib and CPT treatment. Expression levels of THEMIS2 and p-MET protein were positively correlated in the 465 breast cancer specimens. Our study revealed the novel oncogenic role of THEMIS2 and its underlying mechanism via suppressing PTP1B association with MET and thus leading to its activation. Our findings suggest that THEMIS2 could be a biomarker for MET targeted therapy and also provide a potential clinical application using low dosages of CPT for treatment of THEMIS2 positive TNBC.
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Affiliation(s)
- Wei-Chieh Huang
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Jia-Hau Yen
- Research Cancer Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
| | - Yu-Wen Sung
- Department of Obstetrics and Gynecologics, China Medical University Hospital, Taichung City, Taiwan
| | - Shiao-Lin Tung
- Department of Hematology and Oncology, Ton-Yen General Hospital, Hsinchu County, Taiwan
- Department of Nursing, Hsin Sheng Junior College of Medical Care and Management, Taoyuan City, Taiwan
| | - Po-Ming Chen
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Pei-Yi Chu
- Department of Pathology, Show Chwan Memorial Hospital, Chung-Shang Road, Changhua County, Taiwan
| | - Ya-Chi Shih
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Hsiang-Cheng Chi
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Yi-Ching Huang
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Shih-Jei Huang
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Lu-Hai Wang
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
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Lu Z, Peng H, Li R, Xu X, Peng J. BarH-like homeobox 2 represses the transcription of keratin 16 and affects Ras signaling pathway to suppress nasopharyngeal carcinoma progression. Bioengineered 2022; 13:3122-3136. [PMID: 35037835 PMCID: PMC8974228 DOI: 10.1080/21655979.2022.2026549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Nasopharyngeal carcinoma (NPC) refers to a malignancy initiating from the superior mucosal epithelium of the nasopharynx. Optimal therapies for NPC are still needed. In this investigation, we attempted to explore whether BarH-like homeobox 2 (BARX2), a well-known tumor suppressor, had anti-cancer properties on NPC, and the possible mechanisms. After searching for NPC-related databases, we determined BARX2 as one of the core genes in NPC. The results of RT-qPCR and immunohistochemistry or Western blot demonstrated that BARX2 was reduced in NPC patients and cells. Ectopic expression of BARX2 reverted the malignant phenotype of NPC cells. Mechanistically, BARX2 bound to the keratin 16 (KRT16) promoter to downregulate its expression. In addition, BARX2 was found to reduce the phosphorylation levels of MEK and ERK. Further KRT16 upregulation in cells overexpressing BARX2 promoted malignant aggressiveness of C666-1 and HNE3 cells and activated the Ras signaling pathway. BARX2 inhibited the growth and metastasis of tumors and suppressed the Ras signaling pathway in vivo. In conclusion, our findings indicate that BARX2 reverts malignant phenotypes of NPC cells by downregulating KRT16 in a Ras-dependent fashion. BARX2 might act as a possible therapeutic regulator for NPC.
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Affiliation(s)
- Zhibing Lu
- Department of Oncology, Jiangxi Pingxiang People's Hospital, Pingxiang, P.R. China
| | - Hui Peng
- Department of Oncology, Jiangxi Pingxiang People's Hospital, Pingxiang, P.R. China
| | - Ruijuan Li
- Department of Oncology, Jiangxi Pingxiang People's Hospital, Pingxiang, P.R. China
| | - Xinyan Xu
- Department of Oncology, Jiangxi Pingxiang People's Hospital, Pingxiang, P.R. China
| | - Jiyong Peng
- Department of Oncology, Jiangxi Pingxiang People's Hospital, Pingxiang, P.R. China
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Tao X, Zhang X, Feng F. <i>Astragalus </i>polysaccharide suppresses cell proliferation and invasion by up-regulation of miR-195-5p in non-small cell lung cancer. Biol Pharm Bull 2022; 45:553-560. [DOI: 10.1248/bpb.b21-00634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Xingkui Tao
- School of Biological and Food Engineering, Suzhou University
| | - Xingtao Zhang
- School of Biological and Food Engineering, Suzhou University
| | - Fan Feng
- School of Biological and Food Engineering, Suzhou University
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Stanislovas J, Kermorgant S. c-Met-integrin cooperation: Mechanisms, tumorigenic effects, and therapeutic relevance. Front Cell Dev Biol 2022; 10:994528. [PMID: 36330337 PMCID: PMC9624249 DOI: 10.3389/fcell.2022.994528] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
c-Met is a receptor tyrosine kinase which upon activation by its ligand, the hepatocyte growth factor, mediates many important signalling pathways that regulate cellular functions such as survival, proliferation, and migration. Its oncogenic and tumorigenic signalling mechanisms, greatly contributing to cancer development and progression, are well documented. Integrins, heterogeneous adhesion receptors which facilitate cell-extracellular matrix interactions, are important in biomechanically sensitive cell adhesion and motility but also modulate diverse cell behaviour. Here we review the studies which reported cooperation between c-Met and several integrins, particularly β1 and β4, in various cell models including many tumour cell types. From the various experimental models and results analysed, we propose that c-Met-integrin cooperation occurs via inside-out or outside-in signalling. Thus, either c-Met activation triggers integrin activation and cell adhesion or integrin adhesion to its extracellular ligand triggers c-Met activation. These two modes of cooperation require the adhesive function of integrins and mostly lead to cell migration and invasion. In a third, less conventional, mode of cooperation, the integrin plays the role of a signalling adaptor for c-Met, independently from its adhesive property, leading to anchorage independent survival. Recent studies have revealed the influence of endocytic trafficking in c-Met-integrin cooperation including the adaptor function of integrin occurring on endomembranes, triggering an inside-in signalling, believed to promote survival of metastatic cells. We present the evidence of the cooperation in vivo and in human tissues and highlight its therapeutic relevance. A better understanding of the mechanisms regulating c-Met-integrin cooperation in cancer progression could lead to the design of new therapies targeting this cooperation, providing more effective therapeutic approaches than c-Met or integrin inhibitors as monotherapies used in the clinic.
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Affiliation(s)
- Justas Stanislovas
- Spatial Signalling Group, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Stéphanie Kermorgant
- Spatial Signalling Group, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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Shen Y, Sun C, Zhao B, Guo H, Li J, Xia Y, Liu M, Piao S, Saiyin W. miR-34c-5p mediates the cellular malignant behaviors of oral squamous cell carcinoma through targeted binding of TRIM29. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1537. [PMID: 34790743 PMCID: PMC8576676 DOI: 10.21037/atm-21-4679] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 10/21/2021] [Indexed: 12/23/2022]
Abstract
Background This investigation examined the effects of the microRNA miR-34c-5p on the proliferation, migration, and invasion of oral squamous cell carcinoma (OSCC) and the mechanisms involved. Methods The Gene Expression Omnibus (GEO) database was used to filter the chips, and the GEO2R software (https://www.ncbi.nlm.nih.gov/geo/geo2r/) was used to analyze the microarray data (GSE28100 and GSE45238). Gene set enrichment analysis (GSEA) was used to study the relationship between the expression of miR-34c-5p and the distant metastasis and pathological grade of OSCC. The correlation between TRIM29 (tripartite motif containing 29) expression and the malignant clinical phenotype of OSCC was also examined. The mRNA and protein expression levels of miR-34c-5p and TRIM29 were measured by real time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot analysis. The proliferation, migration, invasion and apoptosis of the human oral squamous carcinoma cell lines CAL-27 and Tca8113 was assessed by performing cell-counting kit-8 (CCK-8) assays, colony formation assays, transwell tests, wound scratch tests and flow cytometry. Luciferase reporter assays were used to predict the relationship between miR-34c-5p and TRIM29. A xenograft nude model was established and used to evaluate the effect of miR-34c-5p on tumor growth in female BALB/c mice. Results The expression of miR-34c-5p was significantly correlated with the proliferation, migration, and metastasis of OSCC. Overexpression of miR-34c-5p promoted the proliferation, migration, and invasion of CAL-27 and Tca8113 cells, and suppressed their apoptosis. Inversely, low expression of miR-34c-5p suppressed the proliferation, migration, and invasion of CAL-27 and Tca8113 cells, and promoted their apoptosis. Overexpression of miR-34c-5p promoted tumor growth in the xenograft nude mice model. The expression of TRIM29 was related to malignant clinical phenotype of OSCC. Overexpression of TRIM29 inhibited the proliferation, migration and invasion of CAL-27 and Tca8113 cell, and induced their apoptosis. TRIM29 knockout had just the opposite effect. Importantly, miR-34c-5p binds to TRIM29 and inhibited TRIM29 expression. Conclusions MiR-34c-5p regulates the proliferation, migration, invasion, and apoptosis of OSCC through targeted binding of TRIM29. This may represent a novel therapeutic target for the treatment of patients with OSCC.
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Affiliation(s)
- Yuchen Shen
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,School of Stomatology, Harbin Medical University, Harbin, China
| | - Changsheng Sun
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,School of Stomatology, Harbin Medical University, Harbin, China
| | - Bowen Zhao
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,School of Stomatology, Harbin Medical University, Harbin, China
| | - Haobing Guo
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,School of Stomatology, Harbin Medical University, Harbin, China
| | - Jianhao Li
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,School of Stomatology, Harbin Medical University, Harbin, China
| | - Yanyun Xia
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,School of Stomatology, Harbin Medical University, Harbin, China
| | - Miaomiao Liu
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,School of Stomatology, Harbin Medical University, Harbin, China
| | - Songlin Piao
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,School of Stomatology, Harbin Medical University, Harbin, China
| | - Wuliji Saiyin
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,School of Stomatology, Harbin Medical University, Harbin, China
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