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Kevat S, Mistry A, Oza N, Majmudar M, Patel N, Shah R, Ramachandran AV, Chauhan R, Haque S, Parashar NC, Tuli HS, Parashar G. Cancer Stem Cell Regulation as a Target of Therapeutic Intervention: Insights into Breast, Cervical and Lung Cancer. Cell Biochem Biophys 2025; 83:1521-1535. [PMID: 39843681 DOI: 10.1007/s12013-025-01666-w] [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] [Accepted: 01/03/2025] [Indexed: 01/24/2025]
Abstract
Cancer Stem Cells (CSCs) play an important role in the development, resistance, and recurrence of many malignancies. These subpopulations of tumor cells have the potential to self-renew, differentiate, and resist conventional therapy, highlighting their importance in cancer etiology. This review explores the regulatory mechanisms of CSCs in breast, cervical, and lung cancers, highlighting their plasticity, self-renewal, and differentiation capabilities. CD44+/CD24- cells are a known marker for breast CSCs. Markers like as CD133 and ALDH have been discovered in cervical cancer CSCs. Similarly, in lung cancer, CSCs identified by CD44, CD133, and ALDH are linked to aggressive tumor behavior and poor therapy results. The commonalities between these tumors highlight the general necessity of targeting CSCs in treatment efforts. However, the intricacies of CSC activity, such as their interaction with the tumor microenvironment and particular signaling pathways differ between cancer types, demanding specialized methods. Wnt/β-catenin, Notch, and Hedgehog pathways are one of the essential signaling pathways, targeting them, may show ameliorative effects on breast, lung and cervical carcinomas and their respective CSCs. Pre-clinical data suggests targeting specific signaling pathways can eliminate CSCs, but ongoing clinical trials are on utilizing signaling pathway inhibitors in patients. In recent studies it has been reported that CAR T based targeting of specific markers may be used as combination therapy. Ongoing research related to nanobiotechnology can also play a significant role in diagnosis and treatment purpose targeting CSCs, as nanomaterials can be used for precise targeting and identification of CSCs. Further research into the targeting of signaling pathways and its precursors could prove to be right step into directing therapies towards CSCs for cancer therapy.
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Affiliation(s)
- Sakshi Kevat
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Archie Mistry
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Naman Oza
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Mohit Majmudar
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Netra Patel
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Rushabh Shah
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - A V Ramachandran
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Ritu Chauhan
- Department of Biotechnology, Graphic Era Deemed to be University, Dehradun, Uttarakhand, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Health Sciences, Jazan University, Jazan, Saudi Arabia
- School Of Medicine, Universidad Espiritu Santo, Samborondon, Ecuador
| | | | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to be University), Ambala, Haryana, India
| | - Gaurav Parashar
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India.
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Higuchi Y, Teo JL, Yi D, Kahn M. Safely Targeting Cancer, the Wound That Never Heals, Utilizing CBP/Beta-Catenin Antagonists. Cancers (Basel) 2025; 17:1503. [PMID: 40361430 PMCID: PMC12071182 DOI: 10.3390/cancers17091503] [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: 03/25/2025] [Revised: 04/25/2025] [Accepted: 04/25/2025] [Indexed: 05/15/2025] Open
Abstract
Stem cells, both normal somatic (SSC) and cancer stem cells (CSC) exist in minimally two states, i.e., quiescent and activated. Regulation of these two states, including their reliance on different metabolic processes, i.e., FAO and glycolysis in quiescent versus activated stem cells respectively, involves the analysis of a complex array of factors (nutrient and oxygen levels, adhesion molecules, cytokines, etc.) to initiate the epigenetic changes to either depart or enter quiescence. Quiescence is a critical feature of SSC that is required to maintain the genomic integrity of the stem cell pool, particularly in long lived complex organisms. Quiescence in CSC, whether they are derived from mutations arising in SSC, aberrant microenvironmental regulation, or via dedifferentiation of more committed progenitors, is a critical component of therapy resistance and disease latency and relapse. At the beginning of vertebrate evolution, approximately 450 million years ago, a gene duplication generated the two members of the Kat3 family, CREBBP (CBP) and EP300 (p300). Despite their very high degree of homology, these two Kat3 coactivators play critical and non-redundant roles at enhancers and super-enhancers via acetylation of H3K27, thereby controlling stem cell quiescence versus activation and the cells metabolic requirements. In this review/perspective, we discuss the unique regulatory roles of CBP and p300 and how specifically targeting the CBP/β-catenin interaction utilizing small molecule antagonists, can correct lineage infidelity and safely eliminate quiescent CSC.
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Affiliation(s)
- Yusuke Higuchi
- Beckman Research Institute, City of Hope, Duarte, CA 91010, USA;
| | - Jia-Ling Teo
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; (J.-L.T.); (D.Y.)
| | - Daniel Yi
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; (J.-L.T.); (D.Y.)
| | - Michael Kahn
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; (J.-L.T.); (D.Y.)
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Luo Y, He Y, Xu Y, Wang Y, Yang L. The KDM5A/HOXA5 axis regulates osteosarcoma progression via activating the Wnt/β-catenin pathway. Eur J Med Res 2025; 30:284. [PMID: 40229896 PMCID: PMC11998425 DOI: 10.1186/s40001-025-02478-7] [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: 07/09/2024] [Accepted: 03/19/2025] [Indexed: 04/16/2025] Open
Abstract
As an oncogenic driver, lysine-specific demethylase 5A (KDM5A) participates in regulating numerous tumor progression-related processes. Moreover, KDM5A functions as a histone demethylase, modulating the expression levels of its target genes by adjusting methylation levels. However, the underlying molecular mechanism of KDM5A in osteosarcoma remains elusive. To elucidate this mechanism, specifically how the KDM5A /Homeobox A5 (HOXA5) axis regulates osteosarcoma progression, we measured the expression levels of KDM5A and HOXA5 genes using reverse transcription-quantitative real-time PCR. The correlation between HOXA5 and KDM5A was analyzed via Pearson correlation analysis and further validated through chromatin immunoprecipitation-quantitative real-time PCR. Immunohistochemistry was conducted to determine the number of KDM5A-or HOXA5-positive cells present in osteosarcoma tissues. Additionally, Western blot analysis was utilized to quantify the protein levels of KDM5A, HOXA5, di- and tri-methylation of lysine 4 on histone H3, and β-catenin. Colony formation assays, wound healing assays and flow cytometry were used to detect cell proliferation, migration and apoptosis. The factors associated with the five-year survival rate of patients were analyzed. Our results illustrated that KDM5A was up-regulated in osteosarcoma and associated with a poor prognosis; KDM5A knockdown inhibited osteosarcoma cell proliferation and migration and promotes apoptosis. Subsequently, KDM5A knockdown induced HOXA5 expression by promoting di- and tri-methylation of lysine 4 on histone H3 demethylation, and HOXA5 overexpression inhibited osteosarcoma cell proliferation and migration, and promoted apoptosis by inhibiting the Wnt/β-catenin pathway. We finally proved that HOXA5 silence weakened the inhibitory effect of sh- KDM5A on osteosarcoma proliferation and migration and promoted apoptosis via activating Wnt/β-catenin pathway in vivo and in vitro. Our study demonstrated that the KDM5A /HOXA5 axis regulates osteosarcoma progression by activating the Wnt/β-catenin pathway.
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Affiliation(s)
- Yi Luo
- Department of Spine Surgery, Hengyang Medical School, The Affiliated Changsha Central Hospital, University of South China, The No.161 of the Shaoshan South Road, Changsha City, Hunan Province, China.
| | - Youzhi He
- Department of Spine Surgery, Hengyang Medical School, The Affiliated Changsha Central Hospital, University of South China, The No.161 of the Shaoshan South Road, Changsha City, Hunan Province, China
| | - Yuxia Xu
- Department of Spine Surgery, Hengyang Medical School, The Affiliated Changsha Central Hospital, University of South China, The No.161 of the Shaoshan South Road, Changsha City, Hunan Province, China
| | - Yongfu Wang
- Department of Spine Surgery, Hengyang Medical School, The Affiliated Changsha Central Hospital, University of South China, The No.161 of the Shaoshan South Road, Changsha City, Hunan Province, China
| | - Li Yang
- Department of Spine Surgery, Hengyang Medical School, The Affiliated Changsha Central Hospital, University of South China, The No.161 of the Shaoshan South Road, Changsha City, Hunan Province, China
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Xue C, Chu Q, Shi Q, Zeng Y, Lu J, Li L. Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances. Signal Transduct Target Ther 2025; 10:106. [PMID: 40180907 PMCID: PMC11968978 DOI: 10.1038/s41392-025-02142-w] [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: 08/19/2024] [Revised: 11/13/2024] [Accepted: 12/29/2024] [Indexed: 04/05/2025] Open
Abstract
The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling's involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.
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Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yifan Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Nojima Y, Yao R, Suzuki T. Single-cell RNA sequencing and machine learning provide candidate drugs against drug-tolerant persister cells in colorectal cancer. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167693. [PMID: 39870146 DOI: 10.1016/j.bbadis.2025.167693] [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: 11/25/2024] [Revised: 12/24/2024] [Accepted: 01/22/2025] [Indexed: 01/29/2025]
Abstract
Drug resistance often stems from drug-tolerant persister (DTP) cells in cancer. These cells arise from various lineages and exhibit complex dynamics. However, effectively targeting DTP cells remains challenging. We used single-cell RNA sequencing (scRNA-Seq) data and machine learning (ML) models to identify DTP cells in patient-derived organoids (PDOs) and computationally screened candidate drugs targeting these cells in familial adenomatous polyposis (FAP), associated with a high risk of colorectal cancer. Three PDOs (benign and malignant tumor organoids and a normal organoid) were evaluated using scRNA-Seq. ML models constructed based on public scRNA-Seq data classified DTP versus non-DTP cells. Candidate drugs for DTP cells in a malignant tumor organoid were identified from public drug sensitivity data. From FAP scRNA-Seq data, a specific TC1 cell cluster in tumor organoids was identified. The ML model identified up to 36 % of TC1 cells as DTP cells, a higher proportion than those for other clusters. A viability assay using a malignant tumor organoid demonstrated that YM-155 and THZ2 exert synergistic effects with trametinib. The constructed ML model is effective for DTP cell identification based on scRNA-Seq data for FAP and provides candidate treatments. This approach may improve DTP cell targeting in the treatment of colorectal and other cancers.
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Affiliation(s)
- Yosui Nojima
- Center for Mathematical Modeling and Data Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan.
| | - Ryoji Yao
- Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
| | - Takashi Suzuki
- Center for Mathematical Modeling and Data Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan.
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Vanderheijden C, Yakkioui Y, Vaessen T, Santegoeds R, Temel Y, Hoogland G, Hovinga K. Developmental gene expression in skull-base chordomas and chondrosarcomas. J Neurooncol 2025; 172:249-256. [PMID: 39690395 PMCID: PMC11832612 DOI: 10.1007/s11060-024-04913-x] [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: 09/23/2024] [Accepted: 12/10/2024] [Indexed: 12/19/2024]
Abstract
PURPOSE Chordomas are malignant tumors of the axial spine and skull base, and they are notorious for their poor treatment response. Differentiating these tumors from comparatively less malignant chondrosarcomas is crucial for treatment and prognostication. Both tumor types differ in their developmental origin. Chordomas are considered to be derived from notochordal remnants and chondrosarcomas from mesenchymal cells. Here, we evaluated the differential expression of developmental transcription factors in these skull base tumors. METHODS Histopathologically-confirmed tumor biopsies were obtained from 12 chordoma and 7 chondrosarcoma patients. Following RNA extraction, samples were submitted to real-time quantitative PCR (RT-qPCR) for the evaluation of 32 evolutionary conserved genes that are known to associate with notochord, mesoderm, and axial spine development. Gene expression levels were normalized to housekeeping genes ACTB and RS27a. RESULTS Fifteen genes were either exclusively expressed (n = 12) or overexpressed (n = 3; 2.21-4.43 fold increase) in chordoma, compared to chondrosarcoma. Brachyury and CD24 were highly and exclusively expressed in chordoma. Other novel genes exclusive to chordomas included chordin, HOXA5 and ACAN. Vice versa, ten genes were either exclusively expressed (n = 2) or overexpressed (n = 8; 0.01-0.66 fold increase) in chondrosarcoma, compared to chordoma. CONCLUSION As chordoma patients demonstrate a worse prognosis compared to chondrosarcoma patients, the differential expression of chordin, HOXA5 and ACAN and CD24 could be relevant for the pathophysiology of chordomas and may have diagnostic and treatment value. Further study on role of these genes in tumorigenesis is therefore warranted.
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Affiliation(s)
- Cas Vanderheijden
- Department of Neurosurgery, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands
- School of Mental Health and Neuroscience, Experimental Neurosurgery, Maastricht University, Maastricht, The Netherlands
| | - Youssef Yakkioui
- School of Mental Health and Neuroscience, Experimental Neurosurgery, Maastricht University, Maastricht, The Netherlands
- Department of Neurosurgery, Noordwest Hospital, Alkmaar, The Netherlands
| | - Thomas Vaessen
- School of Mental Health and Neuroscience, Experimental Neurosurgery, Maastricht University, Maastricht, The Netherlands
- Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Remco Santegoeds
- School of Mental Health and Neuroscience, Experimental Neurosurgery, Maastricht University, Maastricht, The Netherlands
- Department of Radiology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Yasin Temel
- Department of Neurosurgery, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands
- School of Mental Health and Neuroscience, Experimental Neurosurgery, Maastricht University, Maastricht, The Netherlands
| | - Govert Hoogland
- Department of Neurosurgery, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands
- School of Mental Health and Neuroscience, Experimental Neurosurgery, Maastricht University, Maastricht, The Netherlands
| | - Koos Hovinga
- Department of Neurosurgery, Maastricht University Medical Center, P. Debyelaan 25, 6202 AZ, Maastricht, The Netherlands.
- School of Mental Health and Neuroscience, Experimental Neurosurgery, Maastricht University, Maastricht, The Netherlands.
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Kopec K, Quaranto D, DeSouza NR, Jarboe T, Islam HK, Moscatello A, Li XM, Geliebter J, Tiwari RK. The HOX Gene Family's Role as Prognostic and Diagnostic Biomarkers in Hematological and Solid Tumors. Cancers (Basel) 2025; 17:262. [PMID: 39858044 PMCID: PMC11763641 DOI: 10.3390/cancers17020262] [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: 12/11/2024] [Revised: 01/07/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
The HOX gene family encodes for regulatory transcription factors that play a crucial role in embryogenesis and differentiation of adult cells. This highly conserved family of genes consists of thirty-nine genes in humans that are located in four clusters, A-D, on different chromosomes. While early studies on the HOX gene family have been focused on embryonic development and its related disorders, research has shifted to examine aberrant expression of HOX genes and the subsequent implication in cancer prediction and progression. Due to their role of encoding master regulatory transcription factors, the abnormal expression of HOX genes has been shown to affect all stages of tumorigenesis and metastasis. This review highlights the novel role of the HOX family's clinical relevance as both prognostic and diagnostic biomarkers in hematological and solid tumors.
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Affiliation(s)
- Kaci Kopec
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
| | - Danielle Quaranto
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
| | - Nicole R. DeSouza
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
| | - Tara Jarboe
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
| | - Humayun K. Islam
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
- Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
| | - Augustine Moscatello
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
- Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
| | - Xiu-Min Li
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
- Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
- Department of Dermatology, New York Medical College, Valhalla, NY 10595, USA
| | - Jan Geliebter
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
- Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
| | - Raj K. Tiwari
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA; (K.K.); (D.Q.); (N.R.D.); (T.J.); (H.K.I.); (A.M.); (X.-M.L.); (R.K.T.)
- Department of Otolaryngology, New York Medical College, Valhalla, NY 10595, USA
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Fu Z, Wang X, Chen Z, Wang B, Huang W, Liu X. CELF6 as an Oncogene in Colorectal Cancer: Targeting Stem-Cell-Like Properties Through Modulation of HOXA5 mRNA Stability. FRONT BIOSCI-LANDMRK 2024; 29:395. [PMID: 39614437 DOI: 10.31083/j.fbl2911395] [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: 06/11/2024] [Revised: 08/15/2024] [Accepted: 08/23/2024] [Indexed: 12/01/2024]
Abstract
BACKGROUND Emerging evidence indicates the essential role of cancer stem cells (CSCs) in the development and progression of various cancers, including colorectal cancer (CRC). CELF6, a member of the cytosine-uridine-guanine-binding protein (CUG-BP), Elav-like family (CELF), has been reported to be downregulated in CRC tissues. This study aims to elucidate the role and underlying mechanisms of CELF6 in CRC progression. METHODS The expression levels and prognostic significance of CELF6, along with its association with homeobox A5 (HOXA5), were analyzed using University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN), PrognoScan, and Tumor Immune Estimation Resource (TIMER) databases. The expression of CELF6 was further assessed through quantitative real-time polymerase chain reaction (qRT-PCR), immunoblotting, and immunohistochemistry. Both in vitro and in vivo experiments were conducted to investigate the effects of CELF6 on CRC cell proliferation, stemness and tumorigenesis, and to elucidate the molecular mechanisms. RESULTS CELF6 was found to be downregulated in CRC and was associated with poor prognosis. Functional studies revealed that overexpression of CELF6 resulted in decreased CRC cell proliferation and stemness in vitro, reduced tumor growth in vivo, and induced G1 phase cell cycle arrest. Mechanistically, CELF6 regulated the expression of HOXA5 by modulating its mRNA stability. Furthermore, the knockdown of HOXA5 reversed the inhibitory effects of CELF6 on CRC cell proliferation and stemness, demonstrating that silencing HOXA5 counteracted the suppressive effects of CELF6. CONCLUSIONS This study is the first to identify CELF6 as a suppressor of stemness and a modulator of CRC progression. These findings provide new insights into the role of CELF6 in CRC and highlight its potential as a novel therapeutic target.
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Affiliation(s)
- Zhiming Fu
- Department of General Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, 570311 Haikou, Hainan, China
| | - Xiang Wang
- Department of General Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, 570311 Haikou, Hainan, China
| | - Zhiju Chen
- Department of General Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, 570311 Haikou, Hainan, China
| | - Baochun Wang
- Department of General Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, 570311 Haikou, Hainan, China
| | - Weiwei Huang
- Department of General Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, 570311 Haikou, Hainan, China
| | - Xin Liu
- Department of General Surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, 570311 Haikou, Hainan, China
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Chen XJ, Guo CH, Yang Y, Wang ZC, Liang YY, Cai YQ, Cui XF, Fan LS, Wang W. HPV16 integration regulates ferroptosis resistance via the c-Myc/miR-142-5p/HOXA5/SLC7A11 axis during cervical carcinogenesis. Cell Biosci 2024; 14:129. [PMID: 39420439 PMCID: PMC11484211 DOI: 10.1186/s13578-024-01309-2] [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] [Accepted: 10/01/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Ferroptosis, a newly identified form of regulated cell death triggered by small molecules or specific conditions, plays a significant role in virus-associated carcinogenesis. However, whether tumours arising after high-risk HPV integration are associated with ferroptosis is unexplored and remains enigmatic. METHODS High-risk HPV16 integration was analysed by high-throughput viral integration detection (HIVID). Ferroptosis was induced by erastin, and the levels of ferroptosis were assessed through the measurement of lipid-reactive oxygen species (ROS), malondialdehyde (MDA), intracellular Fe2+ level and transmission electron microscopy (TEM). Additionally, clinical cervical specimens and an in vivo xenograft model were utilized for the study. RESULTS Expression of HPV16 integration hot spot c-Myc negatively correlates with ferroptosis during the progression of cervical squamous cell carcinoma (CSCC). Further investigation revealed that the upregulated oncogene miR-142-5p in HPV16-integrated CSCC cells served as a critical downstream effector of c-Myc in its target network. Inhibiting miR-142-5p significantly decreased the ferroptosis-suppressing effect mediated by c-Myc. Through a combination of computational and experimental approaches, HOXA5 was identified as a key downstream target gene of miR-142-5p. Overexpression of miR-142-5p suppressed HOXA5 expression, leading to decreased accumulation of intracellular Fe2+ and lipid peroxides (ROS and MDA). HOXA5 increased the sensitivity of CSCC cells to erastin-induced ferroptosis via transcriptional downregulation of SLC7A11, a negative regulator of ferroptosis. Importantly, c-Myc knockdown increased the anti-tumour activity of erastin by promoting ferroptosis both in vitro and in vivo. CONCLUSIONS Collectively, these data indicate that HPV16 integration hot spot c-Myc plays a novel and indispensable role in ferroptosis resistance by regulating the miR-142-5p/HOXA5/SLC7A11 signalling axis and suggest a potential therapeutic approach for HPV16 integration-related CSCC.
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Affiliation(s)
- Xiao-Jing Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Yuexiu District, Guangzhou, 510120, People's Republic of China
- Department of Gynecology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, People's Republic of China
| | - Chu-Hong Guo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Yuexiu District, Guangzhou, 510120, People's Republic of China
| | - Yang Yang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Yuexiu District, Guangzhou, 510120, People's Republic of China
- Department of Obstetrics and Gynecology, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan, 511699, People's Republic of China
| | - Zi-Ci Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Yuexiu District, Guangzhou, 510120, People's Republic of China
| | - Yun-Yi Liang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Yuexiu District, Guangzhou, 510120, People's Republic of China
| | - Yong-Qi Cai
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Yuexiu District, Guangzhou, 510120, People's Republic of China
| | - Xiao-Feng Cui
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Yuexiu District, Guangzhou, 510120, People's Republic of China
| | - Liang-Sheng Fan
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Yuexiu District, Guangzhou, 510120, People's Republic of China.
| | - Wei Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Yuexiu District, Guangzhou, 510120, People's Republic of China.
- Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 201204, People's Republic of China.
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10
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Yadav C, Yadav R, Nanda S, Ranga S, Ahuja P, Tanwar M. Role of HOX genes in cancer progression and their therapeutical aspects. Gene 2024; 919:148501. [PMID: 38670395 DOI: 10.1016/j.gene.2024.148501] [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: 01/19/2024] [Revised: 03/28/2024] [Accepted: 04/22/2024] [Indexed: 04/28/2024]
Abstract
HOX genes constitute a family of evolutionarily conserved transcription factors that play pivotal roles in embryonic development, tissue patterning, and cell differentiation. These genes are essential for the precise spatial and temporal control of body axis formation in vertebrates. In addition to their developmental functions, HOX genes have garnered significant attention for their involvement in various diseases, including cancer. Deregulation of HOX gene expression has been observed in numerous malignancies, where they can influence tumorigenesis, progression, and therapeutic responses. This review provides an overview of the diverse roles of HOX genes in development, disease, and potential therapeutic targets, highlighting their significance in understanding biological processes and their potential clinical implications.
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Affiliation(s)
- Chetna Yadav
- Department of Genetics, Maharshi Dayanand University, Rohtak, Haryana 124001, India
| | - Ritu Yadav
- Department of Genetics, Maharshi Dayanand University, Rohtak, Haryana 124001, India.
| | - Smiti Nanda
- Retd. Senior Professor and Head, Department of Gynaecology and Obstetrics, Pt. B.D. Sharma University of Health Sciences, Rohtak 124001, India
| | - Shalu Ranga
- Department of Genetics, Maharshi Dayanand University, Rohtak, Haryana 124001, India
| | - Parul Ahuja
- Department of Genetics, Maharshi Dayanand University, Rohtak, Haryana 124001, India
| | - Mukesh Tanwar
- Department of Genetics, Maharshi Dayanand University, Rohtak, Haryana 124001, India
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11
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Wang H, Zhang L, Hu C, Li H, Jiang M. Wnt signaling and tumors (Review). Mol Clin Oncol 2024; 21:45. [PMID: 38798312 PMCID: PMC11117032 DOI: 10.3892/mco.2024.2743] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/23/2024] [Indexed: 05/29/2024] Open
Abstract
Wnt signaling is a highly conserved evolutionary pathway that plays a key role in regulation of embryonic development, as well as tissue homeostasis and regeneration. Abnormalities in Wnt signaling are associated with tumorigenesis and development, leading to poor prognosis in patients with cancer. However, the pharmacological effects and mechanisms underlying Wnt signaling and its inhibition in cancer treatment remain unclear. In addition, potential side effects of inhibiting this process are not well understood. Therefore, the present review outlines the role of Wnt signaling in tumorigenesis, development, metastasis, cancer stem cells, radiotherapy resistance and tumor immunity. The present review further identifies inhibitors that target Wnt signaling to provide a potential novel direction for cancer treatment. This may facilitate early application of safe and effective drugs targeting Wnt signaling in clinical settings. An in-depth understanding of the mechanisms underlying inhibition of Wnt signaling may improve the prognosis of patients with cancer.
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Affiliation(s)
- Huaishi Wang
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
| | - Lihai Zhang
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
| | - Chao Hu
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
| | - Hui Li
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
| | - Mingyan Jiang
- Department of Pulmonary and Critical Care Medicine, Xiangtan Central Hospital, Xiangtan, Hunan 411100, P.R. China
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12
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Xia Y, Sun M, Huang H, Jin WL. Drug repurposing for cancer therapy. Signal Transduct Target Ther 2024; 9:92. [PMID: 38637540 PMCID: PMC11026526 DOI: 10.1038/s41392-024-01808-1] [Citation(s) in RCA: 82] [Impact Index Per Article: 82.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/05/2024] [Accepted: 03/19/2024] [Indexed: 04/20/2024] Open
Abstract
Cancer, a complex and multifactorial disease, presents a significant challenge to global health. Despite significant advances in surgical, radiotherapeutic and immunological approaches, which have improved cancer treatment outcomes, drug therapy continues to serve as a key therapeutic strategy. However, the clinical efficacy of drug therapy is often constrained by drug resistance and severe toxic side effects, and thus there remains a critical need to develop novel cancer therapeutics. One promising strategy that has received widespread attention in recent years is drug repurposing: the identification of new applications for existing, clinically approved drugs. Drug repurposing possesses several inherent advantages in the context of cancer treatment since repurposed drugs are typically cost-effective, proven to be safe, and can significantly expedite the drug development process due to their already established safety profiles. In light of this, the present review offers a comprehensive overview of the various methods employed in drug repurposing, specifically focusing on the repurposing of drugs to treat cancer. We describe the antitumor properties of candidate drugs, and discuss in detail how they target both the hallmarks of cancer in tumor cells and the surrounding tumor microenvironment. In addition, we examine the innovative strategy of integrating drug repurposing with nanotechnology to enhance topical drug delivery. We also emphasize the critical role that repurposed drugs can play when used as part of a combination therapy regimen. To conclude, we outline the challenges associated with repurposing drugs and consider the future prospects of these repurposed drugs transitioning into clinical application.
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Affiliation(s)
- Ying Xia
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, PR China
- The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, PR China
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, PR China
- Division of Gastroenterology and Hepatology, Department of Medicine and, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Ming Sun
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, PR China
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, PR China
| | - Hai Huang
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, PR China.
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, 550004, PR China.
| | - Wei-Lin Jin
- Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, PR China.
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13
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Mao Y, Wang W, Yang J, Zhou X, Lu Y, Gao J, Wang X, Wen L, Fu W, Tang F. Drug repurposing screening and mechanism analysis based on human colorectal cancer organoids. Protein Cell 2024; 15:285-304. [PMID: 37345888 PMCID: PMC10984622 DOI: 10.1093/procel/pwad038] [Citation(s) in RCA: 43] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 05/22/2023] [Indexed: 06/23/2023] Open
Abstract
Colorectal cancer (CRC) is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be addressed. Here, we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original tumors. To efficiently identify repurposed drugs for CRC, we developed a robust organoid-based drug screening system. By combining the repurposed drug library and computation-based drug prediction, 335 drugs were tested and 34 drugs with anti-CRC effects were identified. More importantly, we conducted a detailed transcriptome analysis of drug responses and divided the drug response signatures into five representative patterns: differentiation induction, growth inhibition, metabolism inhibition, immune response promotion, and cell cycle inhibition. The anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft (PDOX) system in vivo. We found that fedratinib, trametinib, and bortezomib exhibited effective anticancer effects. Furthermore, the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were evaluated. Our study offers an innovative approach for drug discovery, and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC.
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Affiliation(s)
- Yunuo Mao
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
- The Research Center of Stem Cell and Regenerative Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
| | - Wei Wang
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
| | - Jingwei Yang
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
| | - Xin Zhou
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Peking University Third Hospital Cancer Center, Beijing 100871, China
| | - Yongqu Lu
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Peking University Third Hospital Cancer Center, Beijing 100871, China
| | - Junpeng Gao
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
| | - Xiao Wang
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
| | - Lu Wen
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
| | - Wei Fu
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Peking University Third Hospital Cancer Center, Beijing 100871, China
| | - Fuchou Tang
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
- Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
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14
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Gholamzad A, Khakpour N, Khosroshahi EM, Asadi S, Koohpar ZK, Matinahmadi A, Jebali A, Rashidi M, Hashemi M, Sadi FH, Gholamzad M. Cancer stem cells: The important role of CD markers, Signaling pathways, and MicroRNAs. Pathol Res Pract 2024; 256:155227. [PMID: 38490099 DOI: 10.1016/j.prp.2024.155227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 02/23/2024] [Accepted: 02/25/2024] [Indexed: 03/17/2024]
Abstract
For the first time, a subset of small cancer cells identified in acute myeloid leukemia has been termed Cancer Stem Cells (CSCs). These cells are notorious for their robust proliferation, self-renewal abilities, significant tumor-forming potential, spread, and resistance to treatments. CSCs are a global concern, as it found in numerous types of cancer, posing a real-world challenge today. Our review encompasses research on key CSC markers, signaling pathways, and MicroRNA in three types of cancer: breast, colon, and liver. These factors play a critical role in either promoting or inhibiting cancer cell growth. The reviewed studies have shown that as cells undergo malignant transformation, there can be an increase or decrease in the expression of different Cluster of Differentiation (CD) markers on their surface. Furthermore, alterations in essential signaling pathways, such as Wnt and Notch1, may impact CSC proliferation, survival, and movement, while also providing potential targets for cancer therapies. Additionally, some research has focused on MicroRNAs due to their dual role as potential therapeutic biomarkers and their ability to enhance CSCs' response to anti-cancer drugs. MicroRNAs also regulate a wide array of cellular processes, including the self-renewal and pluripotency of CSCs, and influence gene transcription. Thus, these studies indicate that MicroRNAs play a significant role in the malignancy of various tumors. Although the gathered information suggests that specific CSC markers, signaling pathways, and MicroRNAs are influential in determining the destiny of cancer cells and could be advantageous for therapeutic strategies, their precise roles and impacts remain incompletely defined, necessitating further investigation.
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Affiliation(s)
- Amir Gholamzad
- Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Niloofar Khakpour
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Zeinab Khazaei Koohpar
- Department of Cell and Molecular Biology, Faculty of Biological Sciences,Tonekabon Branch,Islamic Azad University, Tonekabon, Iran
| | - Arash Matinahmadi
- Department of Cellular and Molecular Biology, Nicolaus Copernicus,Torun,Poland
| | - Ali Jebali
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Deprtment of Medical Nanotechnology,Faculty of Advanced Sciences and Technology,Tehran Medical Sciences,Islamic Azad University, Tehran, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran.
| | | | - Mehrdad Gholamzad
- Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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15
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Ke C, Zhou H, Xia T, Xie X, Jiang B. GTP binding protein 2 maintains the quiescence, self-renewal, and chemoresistance of mouse colorectal cancer stem cells via promoting Wnt signaling activation. Heliyon 2024; 10:e27159. [PMID: 38468952 PMCID: PMC10926081 DOI: 10.1016/j.heliyon.2024.e27159] [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: 04/05/2023] [Revised: 02/19/2024] [Accepted: 02/26/2024] [Indexed: 03/13/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers and the second most deadly cancer across the globe. Colorectal cancer stem cells (CCSCs) fuel CRC growth, metastasis, relapse, and chemoresistance. A complete understanding of the modulatory mechanisms of CCSC biology is essential for developing efficacious CRC treatment. In the current study, we characterized the expression and function of GTP binding protein 2 (GTPBP2) in a chemical-induced mouse CRC model. We found that GTPBP2 was expressed at a higher level in CD133+CD44+ CCSCs compared with other CRC cells. Using a lentivirus-based Cas9/sgRNA system, GTPBP2 expression was ablated in CRC cells in vitro. GTPBP2 deficiency caused the following effects on CCSCs: 1) Significantly accelerating proliferation and increasing the proportions of cells at G1, S, and G2/M phase; 2) Impairing resistance to 5-Fluorouracil; 3) Weakening self-renewal but not impacting cell migration. In addition, GTPBP2 deficiency remarkably decreased β-catenin expression while increasing β-catenin phosphorylation in CCSCs. These effects of GTPBP2 were present in CCSCs but not in other CRC cell populations. The Wnt agonist SKL2001 completely abolished these changes in GTPBP2-deficient CCSCs. When GTPBP2-deficient CCSCs were implanted in nude mice, they exhibited consistent changes compared with GTPBP2-expressing CCSCs. Collectively, this study indicates that GTPBP2 positively modulates Wnt signaling to reinforce the quiescence, self-renewal, and chemoresistance of mouse CCSCs. Therefore, we disclose a novel mechanism underlying CCSC biology and GTPBP2 could be a therapeutic target in future CRC treatment.
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Affiliation(s)
- Chao Ke
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Wuhan Third Hospital (Tongren Hospital of Wuhan University), 241 Pengliuyang Road, Wuchang District, Wuhan, Hubei Province, 430060, China
| | - Hongjian Zhou
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Wuhan Third Hospital (Tongren Hospital of Wuhan University), 241 Pengliuyang Road, Wuchang District, Wuhan, Hubei Province, 430060, China
| | - Tian Xia
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Wuhan Third Hospital (Tongren Hospital of Wuhan University), 241 Pengliuyang Road, Wuchang District, Wuhan, Hubei Province, 430060, China
| | - Xingwang Xie
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Wuhan Third Hospital (Tongren Hospital of Wuhan University), 241 Pengliuyang Road, Wuchang District, Wuhan, Hubei Province, 430060, China
| | - Bin Jiang
- The Department of Gastrointestinal, Hernia and Abdominal Wall Surgery, Wuhan Third Hospital (Tongren Hospital of Wuhan University), 241 Pengliuyang Road, Wuchang District, Wuhan, Hubei Province, 430060, China
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16
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Yuan Y, Zhang XF, Li YC, Chen HQ, Wen T, Zheng JL, Zhao ZY, Hu QY. VX-509 attenuates the stemness characteristics of colorectal cancer stem-like cells by regulating the epithelial-mesenchymal transition through Nodal/Smad2/3 signaling. World J Stem Cells 2024; 16:207-227. [PMID: 38455101 PMCID: PMC10915959 DOI: 10.4252/wjsc.v16.i2.207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/19/2023] [Accepted: 01/16/2024] [Indexed: 02/26/2024] Open
Abstract
BACKGROUND Colorectal cancer stem cells (CCSCs) are heterogeneous cells that can self-renew and undergo multidirectional differentiation in colorectal cancer (CRC) patients. CCSCs are generally accepted to be important sources of CRC and are responsible for the progression, metastasis, and therapeutic resistance of CRC. Therefore, targeting this specific subpopulation has been recognized as a promising strategy for overcoming CRC. AIM To investigate the effect of VX-509 on CCSCs and elucidate the underlying mechanism. METHODS CCSCs were enriched from CRC cell lines by in conditioned serum-free medium. Western blot, Aldefluor, transwell and tumorigenesis assays were performed to verify the phenotypic characteristics of the CCSCs. The anticancer efficacy of VX-509 was assessed in HCT116 CCSCs and HT29 CCSCs by performing cell viability analysis, colony formation, sphere formation, flow cytometry, and western blotting assessments in vitro and tumor growth, immunohistochemistry and immunofluorescence assessments in vivo. RESULTS Compared with parental cells, sphere cells derived from HCT116 and HT29 cells presented increased expression of stem cell transcription factors and stem cell markers and were more potent at promoting migration and tumorigenesis, demonstrating that the CRC sphere cells displayed CSC features. VX-509 inhibited the tumor malignant biological behavior of CRC-stem-like cells, as indicated by their proliferation, migration and clonality in vitro, and suppressed the tumor of CCSC-derived xenograft tumors in vivo. Besides, VX-509 suppressed the CSC characteristics of CRC-stem-like cells and inhibited the progression of epithelial-mesenchymal transition (EMT) signaling in vitro. Nodal was identified as the regulatory factor of VX-509 on CRC stem-like cells through analyses of differentially expressed genes and CSC-related database information. VX-509 markedly downregulated the expression of Nodal and its downstream phosphorylated Smad2/3 to inhibit EMT progression. Moreover, VX-509 reversed the dedifferentiation of CCSCs and inhibited the progression of EMT induced by Nodal overexpression. CONCLUSION VX-509 prevents the EMT process in CCSCs by inhibiting the transcription and protein expression of Nodal, and inhibits the dedifferentiated self-renewal of CCSCs.
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Affiliation(s)
- Yun Yuan
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
| | - Xu-Fan Zhang
- Department of Nuclear Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
- College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan Province, China
| | - Yu-Chen Li
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
| | - Hong-Qing Chen
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
| | - Tian Wen
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
| | - Jia-Lian Zheng
- Department of Hepatology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, Liaoning Province, China
| | - Zi-Yi Zhao
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China
- Traditional Chinese Medicine Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu 610072, Sichuan Province, China
| | - Qiong-Ying Hu
- Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, Sichuan Province, China.
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17
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Song S, van Dijk F, Vasse GF, Liu Q, Gosselink IF, Weltjens E, Remels AHV, de Jager MH, Bos S, Li C, Stoeger T, Rehberg M, Kutschke D, van Eck GWA, Wu X, Willems SH, Boom DHA, Kooter IM, Spierings D, Wardenaar R, Cole M, Nawijn MC, Salvati A, Gosens R, Melgert BN. Inhalable Textile Microplastic Fibers Impair Airway Epithelial Differentiation. Am J Respir Crit Care Med 2024; 209:427-443. [PMID: 37971785 DOI: 10.1164/rccm.202211-2099oc] [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: 11/14/2022] [Accepted: 11/16/2023] [Indexed: 11/19/2023] Open
Abstract
Rationale: Microplastics are a pressing global concern, and inhalation of microplastic fibers has been associated with interstitial and bronchial inflammation in flock workers. However, how microplastic fibers affect the lungs is unknown. Objectives: Our aim was to assess the effects of 12 × 31 μm nylon 6,6 (nylon) and 15 × 52 μm polyethylene terephthalate (polyester) textile microplastic fibers on lung epithelial growth and differentiation. Methods: We used human and murine alveolar and airway-type organoids as well as air-liquid interface cultures derived from primary lung epithelial progenitor cells and incubated these with either nylon or polyester fibers or nylon leachate. In addition, mice received one dose of nylon fibers or nylon leachate, and, 7 days later, organoid-forming capacity of isolated epithelial cells was investigated. Measurements and Main Results: We observed that nylon microfibers, more than polyester, inhibited developing airway organoids and not established ones. This effect was mediated by components leaching from nylon. Epithelial cells isolated from mice exposed to nylon fibers or leachate also formed fewer airway organoids, suggesting long-lasting effects of nylon components on epithelial cells. Part of these effects was recapitulated in human air-liquid interface cultures. Transcriptomic analysis revealed upregulation of Hoxa5 after exposure to nylon fibers. Inhibiting Hoxa5 during nylon exposure restored airway organoid formation, confirming Hoxa5's pivotal role in the effects of nylon. Conclusions: These results suggest that components leaching from nylon 6,6 may especially harm developing airways and/or airways undergoing repair, and we strongly encourage characterization in more detail of both the hazard of and the exposure to microplastic fibers.
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Affiliation(s)
- Shanshan Song
- Department of Molecular Pharmacology
- Groningen Research Institute for Asthma and COPD
| | - Fransien van Dijk
- Department of Molecular Pharmacology
- Groningen Research Institute for Asthma and COPD
| | - Gwenda F Vasse
- Department of Molecular Pharmacology
- Groningen Research Institute for Asthma and COPD
| | - Qiongliang Liu
- Comprehensive Pneumology Center, Institute of Lung Health and Immunity, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, German Center for Lung Research (DZL), Munich, Germany
| | - Irene F Gosselink
- Department of Pharmacology and Toxicology, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Ellen Weltjens
- Department of Pharmacology and Toxicology, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Alex H V Remels
- Department of Pharmacology and Toxicology, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands
| | | | | | - Chenxi Li
- Comprehensive Pneumology Center, Institute of Lung Health and Immunity, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, German Center for Lung Research (DZL), Munich, Germany
| | - Tobias Stoeger
- Comprehensive Pneumology Center, Institute of Lung Health and Immunity, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, German Center for Lung Research (DZL), Munich, Germany
| | - Markus Rehberg
- Comprehensive Pneumology Center, Institute of Lung Health and Immunity, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, German Center for Lung Research (DZL), Munich, Germany
| | - David Kutschke
- Comprehensive Pneumology Center, Institute of Lung Health and Immunity, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, German Center for Lung Research (DZL), Munich, Germany
| | | | - Xinhui Wu
- Department of Molecular Pharmacology
- Groningen Research Institute for Asthma and COPD
| | | | - Devin H A Boom
- The Netherlands Organization for Applied Scientific Research (TNO), Utrecht, the Netherlands; and
| | - Ingeborg M Kooter
- Department of Pharmacology and Toxicology, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands
- The Netherlands Organization for Applied Scientific Research (TNO), Utrecht, the Netherlands; and
| | | | - René Wardenaar
- European Research Institute for the Biology of Ageing, and
| | - Matthew Cole
- Plymouth Marine Laboratory, Plymouth, United Kingdom
| | - Martijn C Nawijn
- Groningen Research Institute for Asthma and COPD
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Anna Salvati
- Department of Nanomedicine & Drug Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Reinoud Gosens
- Department of Molecular Pharmacology
- Groningen Research Institute for Asthma and COPD
| | - Barbro N Melgert
- Department of Molecular Pharmacology
- Groningen Research Institute for Asthma and COPD
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18
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Kaur K, Jewett A. Role of Natural Killer Cells as Cell-Based Immunotherapy in Oral Tumor Eradication and Differentiation Both In Vivo and In Vitro. Crit Rev Immunol 2024; 44:87-98. [PMID: 38618731 DOI: 10.1615/critrevimmunol.2024052389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
Despite advancements in the field of cancer therapeutics, the five-year survival rate remains low in oral cancer patients. Therefore, the effective therapeutics are needed against oral cancer. Also, several studies including ours, have shown severely suppressed function and number of NK cells in oral cancer patients. In this review, we discuss the approach to inhibit the tumor growth and metastasis by direct killing or NK cell-mediated tumor differentiation. This review also provides an overview on supercharging NK cells using osteoclasts and probiotic bacteria, and their efficacy as cancer immunotherapeutic in humanized-BLT mice.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
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19
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Wu Z, Zhang X, An Y, Ma K, Xue R, Ye G, Du J, Chen Z, Zhu Z, Shi G, Ding X, Wan M, Jiang B, Zhang P, Liu J, Bu P. CLMP is a tumor suppressor that determines all-trans retinoic acid response in colorectal cancer. Dev Cell 2023; 58:2684-2699.e6. [PMID: 37944525 DOI: 10.1016/j.devcel.2023.10.006] [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: 03/30/2023] [Revised: 08/16/2023] [Accepted: 10/11/2023] [Indexed: 11/12/2023]
Abstract
CAR-like membrane protein (CLMP) is a tight junction-associated protein whose mutation is associated with congenital short bowel syndrome (CSBS), but its functions in colorectal cancer (CRC) remain unknown. Here, we demonstrate that CLMP is rarely mutated but significantly decreased in CRC patients, and its deficiency accelerates CRC tumorigenesis, growth, and resistance to all-trans retinoic acid (ATRA). Mechanistically, CLMP recruits β-catenin to cell membrane, independent of cadherin proteins. CLMP-mediated β-catenin translocation inactivates Wnt(Wingless and INT-1)/β-catenin signaling, thereby suppressing CRC tumorigenesis and growth in ApcMin/+, azoxymethane/dextran sodium sulfate (AOM/DSS), and orthotopic CRC mouse models. As a direct target of Wnt/β-catenin, cytochrome P450 hydroxylase A1 (CYP26A1)-an enzyme that degrades ATRA to a less bioactive retinoid-is upregulated by CLMP deficiency, resulting in ATRA-resistant CRC that can be reversed by administering CYP26A1 inhibitor. Collectively, our data identify the anti-CRC role of CLMP and suggest that CYP26A1 inhibitor enable to boost ATRA's therapeutic efficiency.
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Affiliation(s)
- Zhenzhen Wu
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xuanxuan Zhang
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yunhe An
- Institute of Analysis and Testing, Beijing Academy of Science and Technology (Beijing Center for Physical & Chemical Analysis), Beijing 100089, China
| | - Kaiyue Ma
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ruixin Xue
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Gaoqi Ye
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Junfeng Du
- Department of General Surgery, the 7(th) Medical Center, Chinese PLA General Hospital, Beijing 100700, China
| | - Zhiyong Chen
- Department of Radiation Oncology Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China
| | - Zijing Zhu
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guizhi Shi
- Laboratory Animal Research Center, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Xiang Ding
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Meng Wan
- Laboratory Animal Research Center, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Bing Jiang
- Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Peng Zhang
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Rare Disease Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
| | - Jinbo Liu
- Department of Colorectal Surgery of the 1(st) Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Pengcheng Bu
- Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
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20
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Fujino S, Miyoshi N, Ito A, Hayashi R, Yasui M, Matsuda C, Ohue M, Horie M, Yachida S, Koseki J, Shimamura T, Hata T, Ogino T, Takahashi H, Uemura M, Mizushima T, Doki Y, Eguchi H. Metastases and treatment-resistant lineages in patient-derived cancer cells of colorectal cancer. Commun Biol 2023; 6:1191. [PMID: 37996567 PMCID: PMC10667365 DOI: 10.1038/s42003-023-05562-y] [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: 01/25/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023] Open
Abstract
Circulating tumor cells (CTCs) play an important role in metastasis and recurrence. However, which cells comprise the complex tumor lineages in recurrence and are key in metastasis are unknown in colorectal cancer (CRC). CRC with high expression of POU5F1 has a poor prognosis with a high incidence of liver metastatic recurrence. We aim to reveal the key cells promoting metastasis and identify treatment-resistant lineages with established EGFP-expressing organoids in two-dimensional culture (2DOs) under the POU5F1 promotor. POU5F1-expressing cells are highly present in relapsed clinical patients' blood as CTCs. Sorted POU5F1-expressing cells from 2DOs have cancer stem cell abilities and abundantly form liver metastases in vivo. Single-cell RNA sequencing of 2DOs identifies heterogeneous populations derived from POU5F1-expressing cells and the Wnt signaling pathway is enriched in POU5F1-expressing cells. Characteristic high expression of CTLA4 is observed in POU5F1-expressing cells and immunocytochemistry confirms the co-expression of POU5F1 and CTLA4. Demethylation in some CpG islands at the transcriptional start sites of POU5F1 and CTLA4 is observed. The Wnt/β-catenin pathway inhibitor, XAV939, prevents the adhesion and survival of POU5F1-expressing cells in vitro. Early administration of XAV939 also completely inhibits liver metastasis induced by POU5F1-positive cells.
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Affiliation(s)
- Shiki Fujino
- Department of Gastroenterology, Central Clinical School, Monash University, Melbourne, VIC, Australia
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan
- Innovative Oncology Research and Translational Medicine, Osaka International Cancer Institute, Chuo-ku, Osaka, Japan
| | - Norikatsu Miyoshi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
- Innovative Oncology Research and Translational Medicine, Osaka International Cancer Institute, Chuo-ku, Osaka, Japan.
| | - Aya Ito
- Innovative Oncology Research and Translational Medicine, Osaka International Cancer Institute, Chuo-ku, Osaka, Japan
| | - Rie Hayashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan
- Innovative Oncology Research and Translational Medicine, Osaka International Cancer Institute, Chuo-ku, Osaka, Japan
| | - Masayoshi Yasui
- Department of Surgery, Osaka International Cancer Institute, Chuo-ku, Osaka, 541-8567, Japan
| | - Chu Matsuda
- Department of Surgery, Osaka International Cancer Institute, Chuo-ku, Osaka, 541-8567, Japan
| | - Masayuki Ohue
- Department of Surgery, Osaka International Cancer Institute, Chuo-ku, Osaka, 541-8567, Japan
| | - Masafumi Horie
- Department of Cancer Genome Informatics, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan
| | - Shinichi Yachida
- Department of Cancer Genome Informatics, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan
| | - Jun Koseki
- Division of Systems Biology, Graduate School of Medicine, Nagoya University, Nagoya-City, Aichi, Japan
| | - Teppei Shimamura
- Division of Systems Biology, Graduate School of Medicine, Nagoya University, Nagoya-City, Aichi, Japan
| | - Tsuyoshi Hata
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan
| | - Takayuki Ogino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan
| | - Hidekazu Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan
| | - Mamoru Uemura
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan
| | - Tsunekazu Mizushima
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan
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21
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Ye J, Liu W, Yu X, Wu L, Chen Z, Yu Y, Wang J, Bai S, Zhang M. TRAF7-targeted HOXA5 acts as a tumor suppressor in prostate cancer progression and stemness via transcriptionally activating SPRY2 and regulating MEK/ERK signaling. Cell Death Discov 2023; 9:378. [PMID: 37845209 PMCID: PMC10579307 DOI: 10.1038/s41420-023-01675-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 09/23/2023] [Accepted: 10/03/2023] [Indexed: 10/18/2023] Open
Abstract
Homeobox A5 (HOXA5), a homeodomain transcription factor, is considered a tumor suppressor in cancer progression; however, its function in prostate cancer (PCa) remains unclear. This study focused on the relevance of HOXA5 in PCa progression. We identified the downregulation of HOXA5 in PCa tissues based on the TCGA database and further verified in 30-paired PCa and adjacent normal tissues. Functional studies revealed that HOXA5 upregulation impaired the stem-like characteristics and malignant behaviors of PCa cells in vitro and in vivo. Mechanistically, HOXA5 was found to be regulated by tumor necrosis factor receptor-associated factor 7 (TRAF7), a putative E3-ubiquitin ligase. We observed that TRAF7 was overexpressed in PCa and subsequently enhanced the degradation of HOXA5 protein via its ubiquitin ligase activity, contributing to the acquisition of an aggressive PCa phenotype. For its downstream mechanism, we demonstrated that sprouty RTK signaling antagonist 2 (SPRY2) served as a downstream target of HOXA5. HOXA5 could directly bind to the SPRY2 promoter, thereby regulating the SPRY2-mediated MEK/ERK signaling pathway. Silencing SPRY2 largely compromised the tumor-suppressive effect of HOXA5 in PCa progression and cancer stemness. Our findings highlight the previously-underappreciated signaling axis of TRAF7-HOXA5-SPRY2, which provides a novel prognostic and therapeutic target for PCa treatment.
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Affiliation(s)
- Jianfeng Ye
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Wangmin Liu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xueyang Yu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Lina Wu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhengjie Chen
- Department of Urology, the First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yufei Yu
- Department of Urology, the First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jianfeng Wang
- Department of Urology, the First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Song Bai
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
| | - Mo Zhang
- Department of Urology, the First Hospital of China Medical University, Shenyang, Liaoning, China.
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22
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Song C, Kim KB, Lee GS, Shin S, Kim B. Is HOXA5 a Novel Prognostic Biomarker for Uterine Corpus Endometrioid Adenocarcinoma? Int J Mol Sci 2023; 24:14758. [PMID: 37834206 PMCID: PMC10573156 DOI: 10.3390/ijms241914758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/26/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Endometrial cancer (EC) is one of the most pervasive malignancies in females worldwide. HOXA5 is a member of the homeobox (HOX) family and encodes the HOXA5 protein. HOXA5 is associated with various cancers; however, its association with EC remains unclear. This study aimed to determine the association between HOXA5 gene expression and the prognosis of endometrioid adenocarcinoma, a subtype of EC (EAEC). Microarray data of HOXA5 were collected from the Gene Expression Omnibus datasets, consisting of 79 samples from GSE17025 and 20 samples from GSE29981. RNA-sequencing, clinical, and survival data on EC were obtained from The Cancer Genome Atlas cohort. Survival analysis revealed that HOXA5 overexpression was associated with poor overall survival in patients with EAEC (p = 0.044, HR = 1.832, 95% CI = 1.006-3.334). Cox regression analysis revealed that HOXA5 was an independent risk factor for poor prognosis in EAEC. The overexpression of HOXA5 was associated with a higher histological grade of EAEC, and it was also associated with TP53 mutation or the high copy number of EC. Our findings suggest the potential of HOXA5 as a novel biomarker for predicting poor survival outcomes in patients with EAEC.
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Affiliation(s)
- Changho Song
- Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan 44033, Republic of Korea;
| | - Kyoung Bo Kim
- Department of Laboratory Medicine, Keimyung University School of Medicine, Daegu 42601, Republic of Korea;
| | - Gi Su Lee
- Department of Obstetrics and Gynecology, Keimyung University School of Medicine, Daegu 42601, Republic of Korea;
| | - Soyoung Shin
- Department of Pediatrics, Keimyung University School of Medicine, Daegu 42601, Republic of Korea;
| | - Byoungje Kim
- Department of Radiology, Keimyung University School of Medicine, Daegu 42601, Republic of Korea
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23
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Parrillo L, Spinelli R, Longo M, Zatterale F, Santamaria G, Leone A, Campitelli M, Raciti GA, Beguinot F. The Transcription Factor HOXA5: Novel Insights into Metabolic Diseases and Adipose Tissue Dysfunction. Cells 2023; 12:2090. [PMID: 37626900 PMCID: PMC10453582 DOI: 10.3390/cells12162090] [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: 06/15/2023] [Revised: 08/03/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
The transcription factor HOXA5, from the HOX gene family, has long been studied due to its critical role in physiological activities in normal cells, such as organ development and body patterning, and pathological activities in cancer cells. Nonetheless, recent evidence supports the hypothesis of a role for HOXA5 in metabolic diseases, particularly in obesity and type 2 diabetes (T2D). In line with the current opinion that adipocyte and adipose tissue (AT) dysfunction belong to the group of primary defects in obesity, linking this condition to an increased risk of insulin resistance (IR) and T2D, the HOXA5 gene has been shown to regulate adipocyte function and AT remodeling both in humans and mice. Epigenetics adds complexity to HOXA5 gene regulation in metabolic diseases. Indeed, epigenetic mechanisms, specifically DNA methylation, influence the dynamic HOXA5 expression profile. In human AT, the DNA methylation profile at the HOXA5 gene is associated with hypertrophic obesity and an increased risk of developing T2D. Thus, an inappropriate HOXA5 gene expression may be a mechanism causing or maintaining an impaired AT function in obesity and potentially linking obesity to its associated disorders. In this review, we integrate the current evidence about the involvement of HOXA5 in regulating AT function, as well as its association with the pathogenesis of obesity and T2D. We also summarize the current knowledge on the role of DNA methylation in controlling HOXA5 expression. Moreover, considering the susceptibility of epigenetic changes to reversal through targeted interventions, we discuss the potential therapeutic value of targeting HOXA5 DNA methylation changes in the treatment of metabolic diseases.
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Affiliation(s)
- Luca Parrillo
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy; (R.S.); (M.L.); (F.Z.); (A.L.); (M.C.); (G.A.R.)
| | - Rosa Spinelli
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy; (R.S.); (M.L.); (F.Z.); (A.L.); (M.C.); (G.A.R.)
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden
| | - Michele Longo
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy; (R.S.); (M.L.); (F.Z.); (A.L.); (M.C.); (G.A.R.)
| | - Federica Zatterale
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy; (R.S.); (M.L.); (F.Z.); (A.L.); (M.C.); (G.A.R.)
| | - Gianluca Santamaria
- Department of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy;
| | - Alessia Leone
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy; (R.S.); (M.L.); (F.Z.); (A.L.); (M.C.); (G.A.R.)
| | - Michele Campitelli
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy; (R.S.); (M.L.); (F.Z.); (A.L.); (M.C.); (G.A.R.)
| | - Gregory Alexander Raciti
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy; (R.S.); (M.L.); (F.Z.); (A.L.); (M.C.); (G.A.R.)
| | - Francesco Beguinot
- URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Department of Translational Medical Sciences, Federico II University of Naples, 80131 Naples, Italy; (R.S.); (M.L.); (F.Z.); (A.L.); (M.C.); (G.A.R.)
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24
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Davies A, Zoubeidi A, Beltran H, Selth LA. The Transcriptional and Epigenetic Landscape of Cancer Cell Lineage Plasticity. Cancer Discov 2023; 13:1771-1788. [PMID: 37470668 PMCID: PMC10527883 DOI: 10.1158/2159-8290.cd-23-0225] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/25/2023] [Accepted: 06/09/2023] [Indexed: 07/21/2023]
Abstract
Lineage plasticity, a process whereby cells change their phenotype to take on a different molecular and/or histologic identity, is a key driver of cancer progression and therapy resistance. Although underlying genetic changes within the tumor can enhance lineage plasticity, it is predominantly a dynamic process controlled by transcriptional and epigenetic dysregulation. This review explores the transcriptional and epigenetic regulators of lineage plasticity and their interplay with other features of malignancy, such as dysregulated metabolism, the tumor microenvironment, and immune evasion. We also discuss strategies for the detection and treatment of highly plastic tumors. SIGNIFICANCE Lineage plasticity is a hallmark of cancer and a critical facilitator of other oncogenic features such as metastasis, therapy resistance, dysregulated metabolism, and immune evasion. It is essential that the molecular mechanisms of lineage plasticity are elucidated to enable the development of strategies to effectively target this phenomenon. In this review, we describe key transcriptional and epigenetic regulators of cancer cell plasticity, in the process highlighting therapeutic approaches that may be harnessed for patient benefit.
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Affiliation(s)
- Alastair Davies
- Oncology Research Discovery, Pfizer Worldwide Research and Development, San Diego, CA, USA
| | - Amina Zoubeidi
- Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada
- Vancouver Prostate Centre, Vancouver, British Columbia, Canada
| | - Himisha Beltran
- Department of Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Luke A. Selth
- Flinders Health and Medical Research Institute and Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, South Australia, 5042 Australia
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, 5005 Australia
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25
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Hjazi A, Nasir F, Noor R, Alsalamy A, Zabibah RS, Romero-Parra RM, Ullah MI, Mustafa YF, Qasim MT, Akram SV. The pathological role of C-X-C chemokine receptor type 4 (CXCR4) in colorectal cancer (CRC) progression; special focus on molecular mechanisms and possible therapeutics. Pathol Res Pract 2023; 248:154616. [PMID: 37379710 DOI: 10.1016/j.prp.2023.154616] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 06/07/2023] [Accepted: 06/10/2023] [Indexed: 06/30/2023]
Abstract
Colorectal cancer (CRC) is comprised of transformed cells and non-malignant cells including cancer-associated fibroblasts (CAF), endothelial vasculature cells, and tumor-infiltrating cells. These nonmalignant cells, as well as soluble factors (e.g., cytokines), and the extracellular matrix (ECM), form the tumor microenvironment (TME). In general, the cancer cells and their surrounding TME can crosstalk by direct cell-to-cell contact and via soluble factors, such as cytokines (e.g., chemokines). TME not only promotes cancer progression through growth-promoting cytokines but also provides resistance to chemotherapy. Understanding the mechanisms of tumor growth and progression and the roles of chemokines in CRC will likely suggest new therapeutic targets. In this line, a plethora of reports has evidenced the critical role of chemokine receptor type 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12 or SDF-1) axis in CRC pathogenesis. In the current review, we take a glimpse into the role of the CXCR4/CXCL12 axis in CRC growth, metastasis, angiogenesis, drug resistance, and immune escape. Also, a summary of recent reports concerning targeting CXCR4/CXCL12 axis for CRC management and therapy has been delivered.
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Affiliation(s)
- Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | | | - Rabia Noor
- Amna Inayat Medical College, Lahore, Pakistan
| | - Ali Alsalamy
- College of Medical Technique, Imam Ja'afar Al-Sadiq University, Al-Muthanna 66002, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | - Muhammad Ikram Ullah
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 75471, Aljouf, Saudi Arabia
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul 41001, Iraq
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Shaik Vaseem Akram
- Uttaranchal Institute of Technology, Division of Research & Innovation, Uttaranchal University, Dehradun 248007, India
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26
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Martínez-Ramos S, Rafael-Vidal C, Malvar-Fernández B, Rodriguez-Trillo A, Veale D, Fearon U, Conde C, Conde-Aranda J, Radstake TRDJ, Pego-Reigosa JM, Reedquist KA, García S. HOXA5 is a key regulator of class 3 semaphorins expression in the synovium of rheumatoid arthritis patients. Rheumatology (Oxford) 2023; 62:2621-2630. [PMID: 36398888 PMCID: PMC10321103 DOI: 10.1093/rheumatology/keac654] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 11/08/2022] [Indexed: 07/20/2023] Open
Abstract
OBJECTIVE Class 3 semaphorins are reduced in the synovial tissue of RA patients and these proteins are involved in the pathogenesis of the disease. The aim of this study was to identify the transcription factors involved in the expression of class 3 semaphorins in the synovium of RA patients. METHODS Protein and mRNA expression in synovial tissue from RA and individuals at risk (IAR) patients, human umbilical vein endothelial cells (HUVEC) and RA fibroblast-like synoviocytes (FLS) was determined by ELISA, immunoblotting and quantitative PCR. TCF-3, EBF-1 and HOXA5 expression was knocked down using siRNA. Cell viability, migration and invasion were determined using MTT, calcein, wound closure and invasion assays, respectively. RESULTS mRNA expression of all class 3 semaphorins was significantly lower in the synovium of RA compared with IAR patients. In silico analysis suggested TCF-3, EBF-1 and HOXA5 as transcription factors involved in the expression of these semaphorins. TCF-3, EBF-1 and HOXA5 silencing significantly reduced the expression of several class 3 semaphorin members in FLS and HUVEC. Importantly, HOXA5 expression was significantly reduced in the synovium of RA compared with IAR patients and was negatively correlated with clinical disease parameters. Additionally, TNF-α down-regulated the HOXA5 expression in FLS and HUVEC. Finally, HOXA5 silencing enhanced the migratory and invasive capacities of FLS and the viability of HUVEC. CONCLUSION HOXA5 expression is reduced during the progression of RA and could be a novel therapeutic strategy for modulating the hyperplasia of the synovium, through the regulation of class 3 semaphorins expression.
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Affiliation(s)
- Sara Martínez-Ramos
- Rheumatology & Immuno-mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain
- Rheumatology Department, University Hospital Complex of Vigo, Vigo, Spain
| | - Carlos Rafael-Vidal
- Rheumatology & Immuno-mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain
- Rheumatology Department, University Hospital Complex of Vigo, Vigo, Spain
| | - Beatriz Malvar-Fernández
- Rheumatology & Immuno-mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain
- Rheumatology Department, University Hospital Complex of Vigo, Vigo, Spain
| | - Angela Rodriguez-Trillo
- Laboratorio de Reumatología Experimental y Observacional, Servicio de Reumatología, Instituto de Investigación Sanitaria de Santiago (IDIS), Hospital Clínico, Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saude (SERGAS), Santiago de Compostela, Spain
| | - Douglas Veale
- Rheumatology EULAR Centre of Excellence, St Vincent's University Hospital and University College Dublin, Dublin, Ireland
| | - Ursula Fearon
- Rheumatology EULAR Centre of Excellence, St Vincent's University Hospital and University College Dublin, Dublin, Ireland
- Department of Molecular Rheumatology, Trinity Biomedical Science Institute, Trinity College Dublin, Dublin, Ireland
| | - Carmen Conde
- Laboratorio de Reumatología Experimental y Observacional, Servicio de Reumatología, Instituto de Investigación Sanitaria de Santiago (IDIS), Hospital Clínico, Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saude (SERGAS), Santiago de Compostela, Spain
| | - Javier Conde-Aranda
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Timothy R D J Radstake
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
| | - Jose María Pego-Reigosa
- Rheumatology & Immuno-mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain
- Rheumatology Department, University Hospital Complex of Vigo, Vigo, Spain
| | - Kris A Reedquist
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
| | - Samuel García
- Correspondence to: Samuel García, Rheumatology & Immune-mediated Diseases (IRIDIS) Group, Galicia Sur Health Research Institute (IIS Galicia Sur), Hospital Álvaro Cunqueiro, Estrada Clara Campoamor No. 341, Beade, 36312 Vigo (Pontevedra), Spain. E-mail:
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Wang MY, Wang XW, Zhao WX, Li Y, Cai ML, Wang KX, Xi XM, Zhao C, Zhou HM, Shao RG, Xia GM, Zhang YF, Zhao WL. Enhanced binding of β-catenin and β-TrCP mediates LMPt's anti-CSCs activity in colorectal cancer. Biochem Pharmacol 2023; 212:115577. [PMID: 37137416 DOI: 10.1016/j.bcp.2023.115577] [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: 01/14/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/05/2023]
Abstract
Cancer stem cells (CSCs), a subpopulation of tumor cells with the features of self-renewal, tumor initiation, and insensitivity to common physical and chemical agents, are the key to cancer relapses, metastasis, and resistance. Accessible CSCs inhibitory strategies are primarily based on small molecule drugs, yet toxicity limits their application. Here, we report a liposome loaded with low toxicity and high effectiveness of miriplatin, lipo-miriplatin (LMPt) with high miriplatin loading, and robust stability, exhibiting a superior inhibitory effect on CSCs and non-CSCs. LMPt predominantly inhibits the survival of oxaliplatin-resistant (OXA-resistant) cells composed of CSCs. Furthermore, LMPt directly blocks stemness features of self-renewal, tumor initiation, unlimited proliferation, metastasis, and insensitivity. In mechanistic exploration, RNA sequencing (RNA-seq) revealed that LMPt downregulates the levels of pro-stemness proteins and that the β-catenin-mediated stemness pathway is enriched. Further research shows that either in adherent cells or 3D-spheres, the β-catenin-OCT4/NANOG axis, the vital pathway to maintain stemness, is depressed by LMPt. The consecutive activation of the β-catenin pathway induced by mutant β-catenin (S33Y) and OCT4/NANOG overexpression restores LMPt's anti-CSCs effect, elucidating the key role of the β-catenin-OCT4/NANOG axis. Further studies revealed that the strengthened binding of β-catenin and β-TrCP initiates ubiquitination and degradation of β-catenin induced by LMPt. In addition,the ApcMin/+transgenicmouse model, in which colon tumors are spontaneously formed, demonstrates LMPt's potent anti-non-CSCs activity in vivo.
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Affiliation(s)
- Meng-Yan Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Xiao-Wei Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Wen-Xia Zhao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Yang Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Mei-Lian Cai
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Ke-Xin Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Xiao-Ming Xi
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Cong Zhao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Hui-Min Zhou
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China
| | - Rong-Guang Shao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China.
| | - Gui-Min Xia
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China.
| | - Ye-Fan Zhang
- Department of Hepatobiliary Surgery/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Wu-Li Zhao
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Tiantanxili #1, Beijing 100050, P.R. China.
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28
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Bala P, Rennhack JP, Aitymbayev D, Morris C, Moyer SM, Duronio GN, Doan P, Li Z, Liang X, Hornick JL, Yurgelun MB, Hahn WC, Sethi NS. Aberrant cell state plasticity mediated by developmental reprogramming precedes colorectal cancer initiation. SCIENCE ADVANCES 2023; 9:eadf0927. [PMID: 36989360 PMCID: PMC10058311 DOI: 10.1126/sciadv.adf0927] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 02/28/2023] [Indexed: 05/12/2023]
Abstract
Cell state plasticity is carefully regulated in adult epithelia to prevent cancer. The aberrant expansion of the normally restricted capability for cell state plasticity in neoplasia is poorly defined. Using genetically engineered and carcinogen-induced mouse models of intestinal neoplasia, we observed that impaired differentiation is a conserved event preceding cancer development. Single-cell RNA sequencing (scRNA-seq) of premalignant lesions from mouse models and a patient with hereditary polyposis revealed that cancer initiates by adopting an aberrant transcriptional state characterized by regenerative activity, marked by Ly6a (Sca-1), and reactivation of fetal intestinal genes, including Tacstd2 (Trop2). Genetic inactivation of Sox9 prevented adenoma formation, obstructed the emergence of regenerative and fetal programs, and restored multilineage differentiation by scRNA-seq. Expanded chromatin accessibility at regeneration and fetal genes upon Apc inactivation was reduced by concomitant Sox9 suppression. These studies indicate that aberrant cell state plasticity mediated by unabated regenerative activity and developmental reprogramming precedes cancer development.
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Affiliation(s)
- Pratyusha Bala
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
| | - Jonathan P. Rennhack
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
| | - Daulet Aitymbayev
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
| | - Clare Morris
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sydney M. Moyer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
| | - Gina N. Duronio
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Paul Doan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Zhixin Li
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
| | - Xiaoyan Liang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jason L. Hornick
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Matthew B. Yurgelun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastrointestinal Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - William C. Hahn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
| | - Nilay S. Sethi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
- Division of Gastrointestinal Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
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29
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Hao L, Zhang J, Liu Z, Lin X, Guo J. Epitranscriptomics in the development, functions, and disorders of cancer stem cells. Front Oncol 2023; 13:1145766. [PMID: 37007137 PMCID: PMC10063963 DOI: 10.3389/fonc.2023.1145766] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 02/10/2023] [Indexed: 03/19/2023] Open
Abstract
Biomolecular modifications play an important role in the development of life, and previous studies have investigated the role of DNA and proteins. In the last decade, with the development of sequencing technology, the veil of epitranscriptomics has been gradually lifted. Transcriptomics focuses on RNA modifications that affect gene expression at the transcriptional level. With further research, scientists have found that changes in RNA modification proteins are closely linked to cancer tumorigenesis, progression, metastasis, and drug resistance. Cancer stem cells (CSCs) are considered powerful drivers of tumorigenesis and key factors for therapeutic resistance. In this article, we focus on describing RNA modifications associated with CSCs and summarize the associated research progress. The aim of this review is to identify new directions for cancer diagnosis and targeted therapy.
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Affiliation(s)
- Linlin Hao
- Department of Tumor Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Jian Zhang
- School of Life Sciences, Department of Biology, Southern University of Science and Technology, Shenzhen, China
| | - Zhongshan Liu
- Department of Tumor Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Xia Lin
- Department of Tumor Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Jie Guo
- Department of Tumor Radiotherapy, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Jie Guo,
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30
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Tímár J, Honn KV, Hendrix MJC, Marko-Varga G, Jalkanen S. Newly identified form of phenotypic plasticity of cancer: immunogenic mimicry. Cancer Metastasis Rev 2023; 42:323-334. [PMID: 36754910 PMCID: PMC10014767 DOI: 10.1007/s10555-023-10087-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 01/18/2023] [Indexed: 02/10/2023]
Abstract
Cancer plasticity is now a recognized new hallmark of cancer which is due to disturbances of cell differentiation programs. It is manifested not only in various forms like the best-known epithelial-mesenchymal transition (EMT) but also in vasculogenic and megakaryocytic mimicries regulated by EMT-specific or less-specific transcription factors such as HIF1a or STAT1/2. Studies in the past decades provided ample data that cancer plasticity can be manifested also in the expression of a vast array of immune cell genes; best-known examples are PDL1/CD274, CD47, or IDO, and we termed it immunogenic mimicry (IGM). However, unlike other types of plasticities which are epigenetically regulated, expression of IGM genes are frequently due to gene amplifications. It is important that the majority of the IGM genes are regulated by interferons (IFNs) suggesting that their protein expressions are regulated by the immune microenvironment. Most of the IGM genes have been shown to be involved in immune escape of cancers broadening the repertoire of these mechanisms and offering novel targets for immunotherapeutics.
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Affiliation(s)
- József Tímár
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, Budapest, Hungary.
| | - Kenneth V Honn
- Departments of Pathology, Oncology and Chemistry, Wayne State University, Detroit, MI, USA.,Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA
| | - Mary J C Hendrix
- Department of Biology, Shepherd University, Shepherdstown, WV, USA
| | - György Marko-Varga
- Clinical Protein Science and Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, Lund, Sweden
| | - Sirpa Jalkanen
- Medicity Research Laboratories, Turku, Finland.,InFLAMES Flagship, University of Turku, Turku, Finland
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31
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Ebrahimi N, Afshinpour M, Fakhr SS, Kalkhoran PG, Shadman-Manesh V, Adelian S, Beiranvand S, Rezaei-Tazangi F, Khorram R, Hamblin MR, Aref AR. Cancer stem cells in colorectal cancer: Signaling pathways involved in stemness and therapy resistance. Crit Rev Oncol Hematol 2023; 182:103920. [PMID: 36702423 DOI: 10.1016/j.critrevonc.2023.103920] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 12/07/2022] [Accepted: 01/20/2023] [Indexed: 01/24/2023] Open
Abstract
Colorectal cancer (CRC) is the third cause of cancer death worldwide. Although, in some cases, treatment can increase patient survival and reduce cancer recurrence, in many cases, tumors can develop resistance to therapy leading to recurrence. One of the main reasons for recurrence and therapy resistance is the presence of cancer stem cells (CSCs). CSCs possess a self-renewal ability, and their stemness properties lead to the avoidance of apoptosis, and allow a new clone of cancer cells to emerge. Numerous investigations inidicated the involvment of cellular signaling pathways in embryonic development, and growth, repair, and maintenance of tissue homeostasis, also participate in the generation and maintenance of stemness in colorectal CSCs. This review discusses the role of Wnt, NF-κB, PI3K/AKT/mTOR, Sonic hedgehog, and Notch signaling pathways in colorectal CSCs, and the possible modulating drugs that could be used in treatment for resistant CRC.
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Affiliation(s)
- Nasim Ebrahimi
- Division of Genetics, Department of cell and molecular & microbiology, Faculty of Science and technology, University of Isfahan, Isfahan, Iran
| | - Maral Afshinpour
- Department of chemistry and Biochemistry, South Dakota State University (SDSU), Brookings, SD, USA
| | - Siavash Seifollahy Fakhr
- Department of Biotechnology; Faculty of Applied Ecology, Agricultural Sciences and Biotechnology, Campus Hamar, Norway
| | - Paniz Ghasempour Kalkhoran
- Department of Cellular and Molecular Biology_Microbiology, Faculty of Advanced Science and Technology, Tehran Medical science, Islamic Azad University, Tehran, Iran
| | - Vida Shadman-Manesh
- Department of Biomedical Engineering, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Samaneh Adelian
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Sheida Beiranvand
- Department of Biotechnology, School of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa.
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Xsphera Biosciences, Translational Medicine Group, 6 Tide Street, Boston, MA 02210, USA.
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32
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López-Otín C, Pietrocola F, Roiz-Valle D, Galluzzi L, Kroemer G. Meta-hallmarks of aging and cancer. Cell Metab 2023; 35:12-35. [PMID: 36599298 DOI: 10.1016/j.cmet.2022.11.001] [Citation(s) in RCA: 237] [Impact Index Per Article: 118.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/11/2022] [Accepted: 11/07/2022] [Indexed: 01/05/2023]
Abstract
Both aging and cancer are characterized by a series of partially overlapping "hallmarks" that we subject here to a meta-analysis. Several hallmarks of aging (i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis) are very similar to specific cancer hallmarks and hence constitute common "meta-hallmarks," while other features of aging (i.e., telomere attrition and stem cell exhaustion) act likely to suppress oncogenesis and hence can be viewed as preponderantly "antagonistic hallmarks." Disabled macroautophagy and cellular senescence are two hallmarks of aging that exert context-dependent oncosuppressive and pro-tumorigenic effects. Similarly, the equivalence or antagonism between aging-associated deregulated nutrient-sensing and cancer-relevant alterations of cellular metabolism is complex. The agonistic and antagonistic relationship between the processes that drive aging and cancer has bearings for the age-related increase and oldest age-related decrease of cancer morbidity and mortality, as well as for the therapeutic management of malignant disease in the elderly.
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Affiliation(s)
- Carlos López-Otín
- Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
| | - Federico Pietrocola
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - David Roiz-Valle
- Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France; Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
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33
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Gajera KR, Fair KL, Moran GW, Hannan NRF, Huelsken J, Ordóñez-Morán P. In Vitro and in Vivo Assays for Testing Retinoids Effect on Intestinal Progenitors' Lineage Commitments. Methods Mol Biol 2023; 2650:53-61. [PMID: 37310623 DOI: 10.1007/978-1-0716-3076-1_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The intestine consists of epithelial cells surrounded by a complex environment as mesenchymal cells and the gut microbiota. With its impressive stem cell regeneration capability, the intestine is able to constantly replenish cells lost through apoptosis or abrasion by food passing through. Over the past decade, researchers have identified signaling pathways involved in stem cell homeostasis such as retinoids pathway. Retinoids are also involved in cell differentiation of healthy and cancer cells. In this study, we describe several approaches in vitro and in vivo to further investigate the effect of retinoids on stem cells, progenitors, and differentiated intestinal cells.
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Affiliation(s)
- Krishna R Gajera
- Swiss Institute for Experimental Cancer Research (ISREC), École Polytechnique Fédérale de Lausanne-(EPFL-SV), Lausanne, Switzerland
- Translational Medical Sciences Unit, School of Medicine, Centre for Cancer Sciences, Biodiscovery Institute-3, University Park, University of Nottingham, Nottingham, UK
| | - Kathryn L Fair
- Translational Medical Sciences Unit, School of Medicine, Centre for Cancer Sciences, Biodiscovery Institute-3, University Park, University of Nottingham, Nottingham, UK
| | - Gordon W Moran
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Nicholas R F Hannan
- Translational Medical Sciences Unit, School of Medicine, Centre for Cancer Sciences, Biodiscovery Institute-3, University Park, University of Nottingham, Nottingham, UK
| | - Joerg Huelsken
- Swiss Institute for Experimental Cancer Research (ISREC), École Polytechnique Fédérale de Lausanne-(EPFL-SV), Lausanne, Switzerland
| | - Paloma Ordóñez-Morán
- Translational Medical Sciences Unit, School of Medicine, Centre for Cancer Sciences, Biodiscovery Institute-3, University Park, University of Nottingham, Nottingham, UK.
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Marva G, Ünsal S, Benest AV, Bates DO, Ordóñez-Morán P. Novel Approach to Measure Transepithelial Electrical Resistance in Intestinal Cells. Methods Mol Biol 2023; 2650:35-42. [PMID: 37310621 DOI: 10.1007/978-1-0716-3076-1_3] [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] [Indexed: 06/14/2023]
Abstract
The technique electric cell-substrate impedance sensing (ECIS) can be used to detect and monitor the behavior of intestinal cells. The methodology presented was designed to achieve results within a short time frame, and it was tailored to use a colonic cancer cell line. Differentiation of intestinal cancer cells has previously been reported to be regulated by retinoic acid (RA). Here, colonic cancer cells were cultured in the ECIS array before being treated with RA, and any changes in response to RA were monitored after treatment. The ECIS recorded changes in impedance in response to the treatment and vehicle. This methodology poses as a novel way to record the behavior of colonic cells and opens new avenues for in vitro research.
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Affiliation(s)
- Gurveer Marva
- Translational Medical Sciences Unit, School of Medicine, Centre for Cancer Sciences, Biodiscovery Institute-3, University Park, University of Nottingham, Nottingham, UK
| | - Seyda Ünsal
- Department of Molecular Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Andrew V Benest
- Translational Medical Sciences Unit, School of Medicine, Centre for Cancer Sciences, Biodiscovery Institute-3, University Park, University of Nottingham, Nottingham, UK
| | - David O Bates
- Translational Medical Sciences Unit, School of Medicine, Centre for Cancer Sciences, Biodiscovery Institute-3, University Park, University of Nottingham, Nottingham, UK
| | - Paloma Ordóñez-Morán
- Translational Medical Sciences Unit, School of Medicine, Centre for Cancer Sciences, Biodiscovery Institute-3, University Park, University of Nottingham, Nottingham, UK.
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35
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Liang Y, Cen J, Huang Y, Fang Y, Wang Y, Shu G, Pan Y, Huang K, Dong J, Zhou M, Xu Y, Luo J, Liu M, Zhang J. CircNTNG1 inhibits renal cell carcinoma progression via HOXA5-mediated epigenetic silencing of Slug. Mol Cancer 2022; 21:224. [PMID: 36536414 PMCID: PMC9761964 DOI: 10.1186/s12943-022-01694-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 12/03/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Recent studies have identified that circular RNAs (circRNAs) have an important role in cancer via their well-recognized sponge effect on miRNAs, which regulates a large variety of cancer-related genes. However, only a few circRNAs have been well-studied in renal cell carcinoma (RCC) and their regulatory function remains largely elusive. METHODS Bioinformatics approaches were used to characterize the differentially expressed circRNAs in our own circRNA-sequencing dataset, as well as two public circRNA microarray datasets. CircNTNG1 (hsa_circ_0002286) was identified as a potential tumor-suppressing circRNA. Transwell assay and CCK-8 assay were used to assess phenotypic changes. RNA pull-down, luciferase reporter assays and FISH experiment were used to confirm the interactions among circNTNG1, miR-19b-3p, and HOXA5 mRNA. GSEA was performed to explore the downstream pathway regulated by HOXA5. Immunoblotting, chromatin immunoprecipitation, and methylated DNA immunoprecipitation were used to study the mechanism of HOXA5. RESULTS In all three circRNA datasets, circNTNG1, which was frequently deleted in RCC, showed significantly low expression in the tumor group. The basic properties of circNTNG1 were characterized, and phenotype studies also demonstrated the inhibitory effect of circNTNG1 on RCC cell aggressiveness. Clinically, circNTNG1 expression was associated with RCC stage and Fuhrman grade, and it also served as an independent predictive factor for both OS and RFS of RCC patients. Next, the sponge effect of circNTNG1 on miR-19b-3p and the inhibition of HOXA5 by miR-19b-3p were validated. GSEA analysis indicated that HOXA5 could inactivate the epithelial-mesenchymal transition (EMT) process, and this inactivation was mediated by HOXA5-induced SNAI2 (Slug) downregulation. Finally, it was confirmed that the Slug downregulation was caused by HOXA5, along with the DNA methyltransferase DNMT3A, binding to its promoter region and increasing the methylation level. CONCLUSIONS Based on the experimental data, in RCC, circNTNG1/miR-19b-3p/HOXA5 axis can regulate the epigenetic silencing of Slug, thus interfering EMT and metastasis of RCC. Together, our findings provide potential biomarkers and novel therapeutic targets for future study in RCC.
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Affiliation(s)
- Yanping Liang
- grid.12981.330000 0001 2360 039XDepartment of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Junjie Cen
- grid.12981.330000 0001 2360 039XDepartment of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Yong Huang
- grid.12981.330000 0001 2360 039XDepartment of Emergency, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Yong Fang
- grid.12981.330000 0001 2360 039XDepartment of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Yunfei Wang
- grid.12981.330000 0001 2360 039XDepartment of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Guannan Shu
- grid.12981.330000 0001 2360 039XDepartment of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Yihui Pan
- grid.12981.330000 0001 2360 039XDepartment of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Kangbo Huang
- grid.488530.20000 0004 1803 6191Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, 510060 China
| | - Jiaqi Dong
- grid.12981.330000 0001 2360 039XDepartment of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Mi Zhou
- grid.12981.330000 0001 2360 039XDepartment of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Yi Xu
- grid.12981.330000 0001 2360 039XDepartment of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Junhang Luo
- grid.12981.330000 0001 2360 039XDepartment of Urology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China ,grid.12981.330000 0001 2360 039XInstitute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Min Liu
- grid.12981.330000 0001 2360 039XDepartment of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
| | - Jiaxing Zhang
- grid.12981.330000 0001 2360 039XDepartment of Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 China
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Luan C, Jin S, Hu Y, Zhou X, Liu L, Li R, Ju M, Huang D, Chen K. Whole-genome identification and construction of the lncRNA-mRNA co-expression network in patients with actinic keratosis. Transl Cancer Res 2022; 11:4070-4078. [PMID: 36523309 PMCID: PMC9745357 DOI: 10.21037/tcr-22-842] [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: 03/28/2022] [Accepted: 08/17/2022] [Indexed: 08/30/2023]
Abstract
BACKGROUND Actinic keratosis (AK) is a common premalignant lesion induced by chronic exposure to ultraviolet radiation and may develop into invasive cutaneous squamous carcinoma (cSCC). The identification of specific biomarkers in AK are still unclear. Long non-coding RNAs (lncRNAs), as transcripts of more than 200 nucleotides, significantly involving in multiple biologic processes, especially in the development of tumors. METHODS In our study, we obtained data from RNA-sequencing analysis using two AK lesion tissues and three normal cutaneous tissues to comparatively analyze the differentially expressed (DE) lncRNAs and messenger RNAs (mRNAs). Firstly, we used microarray analyses to identify DE lncRNAs and DE mRNAs. Secondly, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to analyze the primary function and find out significant pathways of these DE mRNA and lncRNAs. Finally, we used the top ten DE lncRNAs to construct a lncRNA-mRNA co-expression network. RESULTS Our results showed that there were a total of 2,097 DE lncRNAs and 2,043 DE mRNAs identified. GO and KEGG analysis and the lncRNA-mRNA co-expression network (using the top 10 DE lncRNAs comprises 130 specific co-expressed mRNAs to construct) indicated that lncRNA uc011fnr.2 may negatively regulate SCIMP and Toll-like receptor 4 (TLR4) and play an important role in Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) signaling pathway of AK. CONCLUSIONS lncRNA uc011fnr.2 may play an important role in JAK-STAT3 signaling pathway of AK by modulating SCIMP, TLR4 and IL-6. Further research is required to validate the value of lncRNA uc011fnr.2 in the progression of AK.
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Affiliation(s)
- Chao Luan
- Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, China
| | - Shuang Jin
- Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, China
| | - Yu Hu
- Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, China
| | - Xuyue Zhou
- Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, China
| | - Lingxi Liu
- Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, China
| | - Rong Li
- Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, China
| | - Mei Ju
- Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, China
| | - Dan Huang
- Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, China
| | - Kun Chen
- Institute of Dermatology, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Chinese Academy of Medical Science & Peking Union Medical College, Nanjing, China
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The role of transcription factors in the acquisition of the four latest proposed hallmarks of cancer and corresponding enabling characteristics. Semin Cancer Biol 2022; 86:1203-1215. [PMID: 36244529 DOI: 10.1016/j.semcancer.2022.10.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 10/10/2022] [Accepted: 10/12/2022] [Indexed: 01/27/2023]
Abstract
With the recent description of the molecular and cellular characteristics that enable acquisition of both core and new hallmarks of cancer, the consequences of transcription factor dysregulation in the hallmarks scheme has become increasingly evident. Dysregulation or mutation of transcription factors has long been recognized in the development of cancer where alterations in these key regulatory molecules can result in aberrant gene expression and consequential blockade of normal cellular differentiation. Here, we provide an up-to-date review of involvement of dysregulated transcription factor networks with the most recently reported cancer hallmarks and enabling characteristic properties. We present some illustrative examples of the impact of dysregulated transcription factors, specifically focusing on the characteristics of phenotypic plasticity, non-mutational epigenetic reprogramming, polymorphic microbiomes, and senescence. We also discuss how new insights into transcription factor dysregulation in cancer is contributing to addressing current therapeutic challenges.
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Fan F, Mo H, Zhang H, Dai Z, Wang Z, Qu C, Liu F, Zhang L, Luo P, Zhang J, Liu Z, Cheng Q, Ding F. HOXA5: A crucial transcriptional factor in cancer and a potential therapeutic target. Biomed Pharmacother 2022; 155:113800. [PMID: 36271576 DOI: 10.1016/j.biopha.2022.113800] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/29/2022] [Accepted: 10/02/2022] [Indexed: 11/20/2022] Open
Abstract
HOX genes occupy a significant role in embryogenesis, hematopoiesis, and oncogenesis. HOXA5, a member of the A cluster of HOX genes, is essential for establishing the skeleton and normal organogenesis. As previously reported, aberrant HOXA5 expression contributes to anomalies and dysfunction of various organs, as well as affecting proliferation, differentiation, invasion, apoptosis, and other biological processes of tumor cells. Different cancers showed both downregulated and upregulated HOXA5 expression. The most common strategy for controlling HOXA5 downregulated expression may be CpG island hypermethylation. Additionally, current research demonstrated the regulatory network of HOXA5 and its connection with cancer stem cell progression and the immune microenvironment. Epigenetic modulators and upstream regulators, such as DNMTi and retinoic acid, may be beneficial for anti-tumor effects targeting HOXA5. Here, we summarize current knowledge about the HOXA5 gene, its role in various cancers, and its potential therapeutic value.
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Affiliation(s)
- Fan Fan
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China; Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China
| | - Haoyang Mo
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Hao Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ziyu Dai
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Zeyu Wang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Chunrun Qu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
| | - Fangkun Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China
| | - Liyang Zhang
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, China; Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
| | - Fengqin Ding
- Department of Clinical Laboratory, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, China.
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Brown DW, Beatty PH, Lewis JD. Molecular Targeting of the Most Functionally Complex Gene in Precision Oncology: p53. Cancers (Basel) 2022; 14:5176. [PMID: 36358595 PMCID: PMC9654076 DOI: 10.3390/cancers14215176] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/16/2022] [Accepted: 10/20/2022] [Indexed: 09/29/2023] Open
Abstract
While chemotherapy is a key treatment strategy for many solid tumors, it is rarely curative, and most tumor cells eventually become resistant. Because of this, there is an unmet need to develop systemic treatments that capitalize on the unique mutational landscape of each patient's tumor. The most frequently mutated protein in cancer, p53, has a role in nearly all cancer subtypes and tumorigenesis stages and therefore is one of the most promising molecular targets for cancer treatment. Unfortunately, drugs targeting p53 have seen little clinical success despite promising preclinical data. Most of these drug compounds target specific aspects of p53 inactivation, such as through inhibiting negative regulation by the mouse double minute (MDM) family of proteins. These treatment strategies fail to address cancer cells' adaptation mechanisms and ignore the impact that p53 loss has on the entire p53 network. However, recent gene therapy successes show that targeting the p53 network and cellular dysfunction caused by p53 inactivation is now possible and may soon translate into successful clinical responses. In this review, we discuss p53 signaling complexities in cancer that have hindered the development and use of p53-targeted drugs. We also describe several current therapeutics reporting promising preclinical and clinical results.
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Affiliation(s)
- Douglas W. Brown
- Department of Oncology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Entos Pharmaceuticals, Unit 4550, 10230 Jasper Avenue, Edmonton, AB T5J 4P6, Canada
| | - Perrin H. Beatty
- Entos Pharmaceuticals, Unit 4550, 10230 Jasper Avenue, Edmonton, AB T5J 4P6, Canada
| | - John D. Lewis
- Department of Oncology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Entos Pharmaceuticals, Unit 4550, 10230 Jasper Avenue, Edmonton, AB T5J 4P6, Canada
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40
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An X, Liu Y. HOTAIR in solid tumors: Emerging mechanisms and clinical strategies. Biomed Pharmacother 2022; 154:113594. [DOI: 10.1016/j.biopha.2022.113594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 11/02/2022] Open
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Huang Y, Zhong L, Li X, Wu P, He J, Tang C, Tang Z, Su J, Feng Z, Wang B, Ma Y, Peng H, Bai Z, Zhong Y, Liang Y, Lu W, Luo R, Li J, Li H, Deng Z, Lan X, Liu Z, Zhang K, Zhao Y. In Situ Silver-Based Electrochemical Oncolytic Bioreactor. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2109973. [PMID: 35998517 DOI: 10.1002/adma.202109973] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 07/13/2022] [Indexed: 06/15/2023]
Abstract
In this study, it is shown for the first time that a reduced graphene oxide (rGO) carrier has a 20-fold higher catalysis rate than graphene oxide in Ag+ reduction. Based on this, a tumor microenvironment-enabled in situ silver-based electrochemical oncolytic bioreactor (SEOB) which switched Ag+ prodrugs into in situ therapeutic silver nanoparticles with and above 95% transition rate is constructed to inhibit the growths of various tumors. In this SEOB-enabled intratumoral nanosynthetic medicine, intratumoral H2 O2 and rGO act as the reductant and the catalyst, respectively. Chelation of aptamers to the SEOB-unlocked prodrugs increases the production of silver nanoparticles in tumor cells, especially in the presence of Vitamin C, which is broken down in tumor cells to supply massive amounts of H2 O2 . Consequently, apoptosis and pyroptosis are induced to cooperatively contribute to the considerably-elevated anti-tumor effects on subcutaneous HepG2 and A549 tumors and orthotopic implanted HepG2 tumors in livers of nude mice. The specific aptamer targeting and intratumoral silver nanoparticle production guarantee excellent biosafety since it fails to elicit tissue damages in monkeys, which greatly increases the clinical translation potential of the SEOB system.
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Affiliation(s)
- Yong Huang
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Liping Zhong
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Xiaotong Li
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Pan Wu
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Jian He
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Chao Tang
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Zhiping Tang
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Jing Su
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Zhenbo Feng
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Bing Wang
- Department of Spine Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Yun Ma
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Hongmei Peng
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Zhihao Bai
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Yi Zhong
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Ying Liang
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Wenxi Lu
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Ruiyu Luo
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Jinghua Li
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Haiping Li
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Zhiming Deng
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Xianli Lan
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Ziqun Liu
- Department of Spine Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Kun Zhang
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
| | - Yongxiang Zhao
- National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, China
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Xiong F, Liu W, Wang X, Wu G, Wang Q, Guo T, Huang W, Wang B, Chen Y. HOXA5 inhibits the proliferation of extrahepatic cholangiocarcinoma cells by enhancing MXD1 expression and activating the p53 pathway. Cell Death Dis 2022; 13:829. [PMID: 36167790 PMCID: PMC9515223 DOI: 10.1038/s41419-022-05279-6] [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: 04/29/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 01/23/2023]
Abstract
Homeobox A5 (HOXA5) is a transcription factor in mammalian and can regulate cell differentiation, proliferation, and apoptosis as well as tumorigenesis. However, little is known on whether and how HOXA5 can regulate the malignant behaviors of cholangiocarcinoma. The methylation levels of HOXA5 were evaluated by methylation microarray and bisulfite sequencing PCR. HOXA5 expression in tissue samples was examined by immunohistochemistry and Western blot. The proliferation of tumor cells was assessed by CCK-8, EdU, and nude mouse tumorigenicity assays. The invasion, apoptosis and cell cycling of tumor cells were evaluated by Wound healing assay and flow cytometry. The interaction between HOXA5 and the MXD1 promoter was examined by CUT & Tag assay, luciferase reporter assay and chromatin immunoprecipitation. Hypermethylation in the HOXA5 promoter down-regulated HOXA5 expression in extrahepatic cholangiocarcinoma (ECCA) tissues, which was correlated with worse overall survival. HOXA5 overexpression significantly inhibited the proliferation and tumor growth. HOXA5 overexpression enhanced MXD1 expression by directly binding to the MXD1 promoter in ECCA cells. MXD1 overexpression inhibited the proliferation and tumor growth while MXD1 silencing abrogated the HOXA5-mediated proliferation inhibition. HOXA5 overexpression increased p53 protein expression in an MXD1-dependent manner. HOXA5 and MXD1 acted as tumor suppressors to inhibit the mitosis of ECCA cells by enhancing the p53 signaling. Our findings may uncover molecular mechanisms by which the HOXA5/MXD1 axis regulates the progression of ECCA, suggesting that the HOXA5/MXD1 may be therapeutic targets for ECCA.
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Affiliation(s)
- Fei Xiong
- grid.33199.310000 0004 0368 7223Department of Biliary‑Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Wenzheng Liu
- grid.33199.310000 0004 0368 7223Department of Biliary‑Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Xin Wang
- grid.33199.310000 0004 0368 7223Departement of Pediatric Surgery, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Wuhan, China
| | - Guanhua Wu
- grid.33199.310000 0004 0368 7223Department of Biliary‑Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Qi Wang
- grid.33199.310000 0004 0368 7223Department of Biliary‑Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Tong Guo
- grid.33199.310000 0004 0368 7223Department of Biliary‑Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Wenhua Huang
- grid.33199.310000 0004 0368 7223Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Bing Wang
- grid.33199.310000 0004 0368 7223Department of Biliary‑Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei China
| | - Yongjun Chen
- grid.33199.310000 0004 0368 7223Department of Biliary‑Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei China
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Transcriptome Profile Analysis of Intestinal Upper Villus Epithelial Cells and Crypt Epithelial Cells of Suckling Piglets. Animals (Basel) 2022; 12:ani12182324. [PMID: 36139183 PMCID: PMC9494997 DOI: 10.3390/ani12182324] [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: 07/26/2022] [Revised: 08/26/2022] [Accepted: 09/05/2022] [Indexed: 11/17/2022] Open
Abstract
It is well known that the small intestinal epithelial cells of mammals rapidly undergo differentiation, maturation, and apoptosis. However, few studies have defined the physiological state and gene expression changes of enterocytes along the crypt-villus axis in suckling piglets. In the present study, we obtained the intestinal upper villus epithelial cells (F1) and crypt epithelial cells (F3) of 21-day suckling piglets using the divalent chelation and precipitation technique. The activities of alkaline phosphatase, sucrase, and lactase of F1 were significantly higher (p < 0.05) than those of F3. To explore the differences at the gene transcription level, we compared the global transcriptional profiles of F1 and F3 using RNA-seq analysis technology. A total of 672 differentially expressed genes (DEGs) were identified between F1 and F3, including 224 highly expressed and 448 minimally expressed unigenes. Functional analyses indicated that some DEGs were involved in the transcriptional regulation of nutrient transportation (SLC15A1, SLC5A1, and SLC3A1), cell differentiation (LGR5, HOXA5 and KLF4), cell proliferation (PLK2 and TGFB3), transcriptional regulation (JUN, FOS and ATF3), and signaling transduction (WNT10B and BMP1), suggesting that these genes were related to intestinal epithelial cell maturation and cell renewal. Gene Ontology (GO) enrichment analysis showed that the DEGs were mainly associated with binding, catalytic activity, enzyme regulator activity, and molecular transducer activity. Furthermore, KEGG pathway analysis revealed that the DGEs were categorized into 284 significantly enriched pathways. The greatest number of DEGs enriched in signal transduction, some of which (Wnt, Hippo, TGF-beta, mTOR, PI3K-Akt, and MAPK signaling pathways) were closely related to the differentiation, proliferation, maturation and apoptosis of intestinal epithelial cells. We validated the expression levels of eight DEGs in F1 and F3 using qRT-PCR. The present study revealed temporal and regional changes in mRNA expression between F1 and F3 of suckling piglets, which provides insights into the regulatory mechanisms underlying intestinal epithelial cell renewal and the rapid repair of intestinal mucosal damage.
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Chen D, Lin Y, Zhao N, Wang Y, Li Y. Hoxa5 Inhibits the Proliferation and Induces Adipogenic Differentiation of Subcutaneous Preadipocytes in Goats. Animals (Basel) 2022; 12:ani12141859. [PMID: 35883405 PMCID: PMC9311789 DOI: 10.3390/ani12141859] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/04/2022] [Accepted: 07/19/2022] [Indexed: 11/16/2022] Open
Abstract
The homeobox a5 (Hoxa5) plays considerable roles in the differentiation and lipid metabolism of adipocytes. However, the current knowledge about the mechanistic roles and functions of Hoxa5 in goat subcutaneous preadipocyte remains unclear. Therefore, Hoxa5 loss-of-function and gain-of-function was performed to reveal its functions in adipogenesis. For differentiation, overexpression of Hoxa5 notably increased the expression of adipogenic genes (PPARγ, CEBP/α, CEBP/β, AP2, and SREBP1), as well as promoted goat subcutaneous preadipocyte lipid accumulation. Knockdown of Hoxa5 mediated by siRNA technique significantly inhibited its differentiation and suppressed the accumulation of lipid droplets. Regarding proliferation, overexpression of Hoxa5 reduced the number of cells stained with crystal violet, and inhibited mRNA expression of the marker genes including CCNE1, PCNA, CCND1, and CDK2, and also significantly reduced EdU-positive rates. Consistently, knockdown of Hoxa5 demonstrated the opposite tendency. In conclusion, these data demonstrated that Hoxa5 promotes adipogenic differentiation of goat subcutaneous preadipocyte and inhibits its proliferation in vitro.
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Affiliation(s)
- Dingshuang Chen
- College of Animal Science and Veterinary, Southwest Minzu University, Chengdu 610041, China; (D.C.); (Y.L.); (N.Z.); (Y.W.)
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Yaqiu Lin
- College of Animal Science and Veterinary, Southwest Minzu University, Chengdu 610041, China; (D.C.); (Y.L.); (N.Z.); (Y.W.)
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041, China
- Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu 610041, China
| | - Nan Zhao
- College of Animal Science and Veterinary, Southwest Minzu University, Chengdu 610041, China; (D.C.); (Y.L.); (N.Z.); (Y.W.)
| | - Yong Wang
- College of Animal Science and Veterinary, Southwest Minzu University, Chengdu 610041, China; (D.C.); (Y.L.); (N.Z.); (Y.W.)
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041, China
- Key Laboratory of Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation, Southwest Minzu University, Chengdu 610041, China
| | - Yanyan Li
- College of Animal Science and Veterinary, Southwest Minzu University, Chengdu 610041, China; (D.C.); (Y.L.); (N.Z.); (Y.W.)
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041, China
- Correspondence:
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Lacombe V, Lenaers G, Urbanski G. Diagnostic and Therapeutic Perspectives Associated to Cobalamin-Dependent Metabolism and Transcobalamins' Synthesis in Solid Cancers. Nutrients 2022; 14:2058. [PMID: 35631199 PMCID: PMC9145230 DOI: 10.3390/nu14102058] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 05/11/2022] [Indexed: 02/01/2023] Open
Abstract
Cobalamin or vitamin B12 (B12) is a cofactor for methionine synthase and methylmalonyl-CoA mutase, two enzymes implicated in key pathways for cell proliferation: methylation, purine synthesis, succinylation and ATP production. Ensuring these functions in cancer cells therefore requires important cobalamin needs and its uptake through the transcobalamin II receptor (TCII-R). Thus, both the TCII-R and the cobalamin-dependent metabolic pathways constitute promising therapeutic targets to inhibit cancer development. However, the link between cobalamin and solid cancers is not limited to cellular metabolism, as it also involves the circulating transcobalamins I and II (TCI or haptocorrin and TCII) carrier proteins, encoded by TCN1 and TCN2, respectively. In this respect, elevations of B12, TCI and TCII concentrations in plasma are associated with cancer onset and relapse, and with the presence of metastases and worse prognosis. In addition, TCN1 and TCN2 overexpressions are associated with chemoresistance and a proliferative phenotype, respectively. Here we review the involvement of cobalamin and transcobalamins in cancer diagnosis and prognosis, and as potential therapeutic targets. We further detail the relationship between cobalamin-dependent metabolic pathways in cancer cells and the transcobalamins' abundancies in plasma and tumors, to ultimately hypothesize screening and therapeutic strategies linking these aspects.
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Affiliation(s)
- Valentin Lacombe
- MitoLab Team, MitoVasc Institut, CNRS UMR6015, INSERM U1083, Angers University, 49000 Angers, France; (G.L.); (G.U.)
- Department of Internal Medicine and Clinical Immunology, Angers University Hospital, 49000 Angers, France
| | - Guy Lenaers
- MitoLab Team, MitoVasc Institut, CNRS UMR6015, INSERM U1083, Angers University, 49000 Angers, France; (G.L.); (G.U.)
- Department of Neurology, Angers University Hospital, 49000 Angers, France
| | - Geoffrey Urbanski
- MitoLab Team, MitoVasc Institut, CNRS UMR6015, INSERM U1083, Angers University, 49000 Angers, France; (G.L.); (G.U.)
- Department of Internal Medicine and Clinical Immunology, Angers University Hospital, 49000 Angers, France
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Yu PC, Liu D, Han ZX, Liang F, Hao CY, Lei YT, Guo CR, Wang WH, Li XH, Yang XN, Li CZ, Yu Y, Fan YZ. Thymopentin-Mediated Inhibition of Cancer Stem Cell Stemness Enhances the Cytotoxic Effect of Oxaliplatin on Colon Cancer Cells. Front Pharmacol 2022; 13:779715. [PMID: 35242031 PMCID: PMC8886222 DOI: 10.3389/fphar.2022.779715] [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: 09/19/2021] [Accepted: 01/31/2022] [Indexed: 12/02/2022] Open
Abstract
Thymopentin (TP5) is an immunomodulatory pentapeptide that has been widely used in malignancy patients with immunodeficiency due to radiotherapy and chemotherapy. Here, we propose that TP5 directly inhibits the stemness of colon cancer cells HCT116 and therefore enhances the cytotoxicity of oxaliplatin (OXA) in HCT116 cells. In the absence of serum, TP5 was able to induce cancer stemness reduction in cultured HCT116 cells and significantly reduced stemness-related signals, such as the expression of surface molecular markers (CD133, CD44 and CD24) and stemness-related genes (ALDH1, SOX2, Oct-4 and Nanog), and resulted in altered Wnt/β-catenin signaling. Acetylcholine receptors (AchRs) are implicated in this process. OXA is a common chemotherapeutic agent with therapeutic effects in various cancers. Although TP5 had no direct effect on the proliferation of HCT116, this pentapeptide significantly increased the sensitivity of HCT116 to OXA, where the effect of TP5 on the stemness of colon cancer cells through stimulation of AchRs may contribute to this process. Our results provide a promising strategy for increasing the sensitivity of colon cancer cells to chemotherapeutic agents by incorporating immunomodulatory peptides.
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Affiliation(s)
- Peng-Cheng Yu
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Di Liu
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Zeng-Xiang Han
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Three Departments of Oncology, Weifang Traditional Chinese Medicine Hospital, Weifang, China
| | - Fang Liang
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Cui-Yun Hao
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yun-Tao Lei
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chang-Run Guo
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wen-Hui Wang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xing-Hua Li
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiao-Na Yang
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chang-Zhu Li
- State Key Laboratory of Utilization of Woody Oil Resource, Hunan Academy of Forestry, Changsha, China
| | - Ye Yu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ying-Zhe Fan
- Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Epigenetic Dysregulation of the Homeobox A5 ( HOXA5) Gene Associates with Subcutaneous Adipocyte Hypertrophy in Human Obesity. Cells 2022; 11:cells11040728. [PMID: 35203377 PMCID: PMC8870634 DOI: 10.3390/cells11040728] [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: 01/30/2022] [Accepted: 02/14/2022] [Indexed: 12/28/2022] Open
Abstract
Along with insulin resistance and increased risk of type 2 diabetes (T2D), lean first-degree relatives of T2D subjects (FDR) feature impaired adipogenesis in subcutaneous adipose tissue (SAT) and subcutaneous adipocyte hypertrophy well before diabetes onset. The molecular mechanisms linking these events have only partially been clarified. In the present report, we show that silencing of the transcription factor Homeobox A5 (HOXA5) in human preadipocytes impaired differentiation in mature adipose cells in vitro. The reduced adipogenesis was accompanied by inappropriate WNT-signaling activation. Importantly, in preadipocytes from FDR individuals, HOXA5 expression was attenuated, with hypermethylation of the HOXA5 promoter region found responsible for its downregulation, as revealed by luciferase assay. Both HOXA5 gene expression and DNA methylation were significantly correlated with SAT adipose cell hypertrophy in FDR, whose increased adipocyte size marks impaired adipogenesis. In preadipocytes from FDR, the low HOXA5 expression negatively correlated with enhanced transcription of the WNT signaling downstream genes NFATC1 and WNT2B. In silico evidence indicated that NFATC1 and WNT2B were directly controlled by HOXA5. The HOXA5 promoter region also was hypermethylated in peripheral blood leukocytes from these same FDR individuals, which was further revealed in peripheral blood leukocytes from an independent group of obese subjects. Thus, HOXA5 controlled adipogenesis in humans by suppressing WNT signaling. Altered DNA methylation of the HOXA5 promoter contributed to restricted adipogenesis in the SAT of lean subjects who were FDR of type 2 diabetics and in obese individuals.
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48
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Shenoy US, Adiga D, Kabekkodu SP, Hunter KD, Radhakrishnan R. Molecular implications of HOX genes targeting multiple signaling pathways in cancer. Cell Biol Toxicol 2022; 38:1-30. [PMID: 34617205 PMCID: PMC8789642 DOI: 10.1007/s10565-021-09657-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 09/10/2021] [Indexed: 11/17/2022]
Abstract
Homeobox (HOX) genes encode highly conserved homeotic transcription factors that play a crucial role in organogenesis and tissue homeostasis. Their deregulation impacts the function of several regulatory molecules contributing to tumor initiation and progression. A functional bridge exists between altered gene expression of individual HOX genes and tumorigenesis. This review focuses on how deregulation in the HOX-associated signaling pathways contributes to the metastatic progression in cancer. We discuss their functional significance, clinical implications and ascertain their role as a diagnostic and prognostic biomarker in the various cancer types. Besides, the mechanism of understanding the theoretical underpinning that affects HOX-mediated therapy resistance in cancers has been outlined. The knowledge gained shall pave the way for newer insights into the treatment of cancer.
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Affiliation(s)
- U Sangeetha Shenoy
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Keith D Hunter
- Academic Unit of Oral and Maxillofacial Medicine and Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, S10 2TA, UK
| | - Raghu Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, 576104, India.
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Morgan R, Hunter K, Pandha HS. Downstream of the HOX genes: explaining conflicting tumour suppressor and oncogenic functions in cancer. Int J Cancer 2022; 150:1919-1932. [PMID: 35080776 PMCID: PMC9304284 DOI: 10.1002/ijc.33949] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/24/2021] [Accepted: 01/07/2022] [Indexed: 11/07/2022]
Abstract
The HOX genes are a highly conserved group of transcription factors that have key roles in early development, but which are also highly expressed in most cancers. Many studies have found strong associative relationships between the expression of individual HOX genes in tumours and clinical parameters including survival. For the majority of HOX genes, high tumour expression levels seem to be associated with a worse outcome for patients, and in some cases this has been shown to result from the activation of pro-oncogenic genes and pathways. However, there are also many studies that indicate a tumour suppressor role for some HOX genes, sometimes with conclusions that contradict earlier work. In this review, we have attempted to clarify the role of HOX genes in cancer by focusing on their downstream targets as identified in studies that provide experimental evidence for their activation or repression. On this basis, the majority of HOX genes would appear to have a pro-oncogenic function, with the notable exception of HOXD10, which acts exclusively as a tumour suppressor. HOX proteins regulate a wide range of target genes involved in metastasis, cell death, proliferation, and angiogenesis, and activate key cell signalling pathways. Furthermore, for some functionally related targets, this regulation is achieved by a relatively small subgroup of HOX genes.
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Affiliation(s)
- Richard Morgan
- School of Biomedical SciencesUniversity of West LondonLondonUK
| | - Keith Hunter
- Unit of Oral and Maxillofacial Pathology, School of Clinical DentistryUniversity of SheffieldSheffieldUK
| | - Hardev S. Pandha
- Faculty of Health and Medical SciencesUniversity of SurreyGuildfordUK
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50
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Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov 2022; 12:31-46. [PMID: 35022204 DOI: 10.1158/2159-8290.cd-21-1059] [Citation(s) in RCA: 4706] [Impact Index Per Article: 1568.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023]
Abstract
The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underlying principles. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refinements. Herein, the prospect is raised that phenotypic plasticity and disrupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogramming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities. Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. SIGNIFICANCE: Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Ever more powerful experimental and computational tools and technologies are providing an avalanche of "big data" about the myriad manifestations of the diseases that cancer encompasses. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimensions presented in this perspective may add value to that endeavor, to more fully understand mechanisms of cancer development and malignant progression, and apply that knowledge to cancer medicine.
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Affiliation(s)
- Douglas Hanahan
- Ludwig Institute for Cancer Research - Lausanne Branch, Lausanne, Switzerland. The Swiss Institute for Experimental Cancer Research (ISREC) within the School of Life Sciences at the Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland. The Swiss Cancer Center Leman (SCCL), Lausanne, Switzerland.
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