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Haydo A, Schmidt J, Crider A, Kögler T, Ertl J, Hehlgans S, Hoffmann ME, Rathore R, Güllülü Ö, Wang Y, Zhang X, Herold-Mende C, Pampaloni F, Tegeder I, Dikic I, Dai M, Rödel F, Kögel D, Linder B. BRAT1 - a new therapeutic target for glioblastoma. Cell Mol Life Sci 2025; 82:52. [PMID: 39833546 PMCID: PMC11747058 DOI: 10.1007/s00018-024-05553-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 12/13/2024] [Accepted: 12/16/2024] [Indexed: 01/22/2025]
Abstract
Glioblastoma (GBM), the most malignant primary brain tumor in adults, has poor prognosis irrespective of therapeutic advances due to its radio-resistance and infiltrative growth into brain tissue. The present study assessed functions and putative druggability of BRCA1-associated ATM activator 1 (BRAT1) as a crucial factor driving key aspects of GBM, including enhanced DNA damage response and tumor migration. By a stable depletion of BRAT1 in GBM and glioma stem-like (GSC) cell lines, we observed a delay in DNA double-strand break repair and increased sensitivity to radiation treatment, corroborated by in vitro and in vivo studies demonstrating impaired tumor growth and invasion. Proteomic and phosphoproteomic analyses further emphasize the role of BRAT1's cell migration and invasion capacity, with a notable proportion of downregulated proteins associated with these processes. In line with the genetic manipulation, we found that treatment with the BRAT1 inhibitor Curcusone D (CurD) significantly reduced GSC migration and invasion in an ex vivo slice culture model, particularly when combined with irradiation, resulting in a synergistic inhibition of tumor growth and infiltration. Our results reveal that BRAT1 contributes to GBM growth and invasion and suggest that therapeutic inhibition of BRAT1 with CurD or similar compounds might constitute a novel approach for anti-GBM directed treatments.
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Affiliation(s)
- Alicia Haydo
- Experimental Neurosurgery, Department of Neurosurgery, Neuroscience Center, Goethe University Hospital, Goethe University Frankfurt, 60528, Frankfurt am Main, Germany.
| | - Jennifer Schmidt
- Experimental Neurosurgery, Department of Neurosurgery, Neuroscience Center, Goethe University Hospital, Goethe University Frankfurt, 60528, Frankfurt am Main, Germany
| | - Alisha Crider
- Experimental Neurosurgery, Department of Neurosurgery, Neuroscience Center, Goethe University Hospital, Goethe University Frankfurt, 60528, Frankfurt am Main, Germany
| | - Tim Kögler
- Experimental Neurosurgery, Department of Neurosurgery, Neuroscience Center, Goethe University Hospital, Goethe University Frankfurt, 60528, Frankfurt am Main, Germany
| | - Johanna Ertl
- Experimental Neurosurgery, Department of Neurosurgery, Neuroscience Center, Goethe University Hospital, Goethe University Frankfurt, 60528, Frankfurt am Main, Germany
- Radiation Biology and DNA Repair, Darmstadt, TU, Germany
| | - Stephanie Hehlgans
- Department of Radiotherapy and Oncology, Goethe University Hospital, 60590, Frankfurt am Main, Germany
| | - Marina E Hoffmann
- Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany
| | - Rajeshwari Rathore
- Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany
| | - Ömer Güllülü
- Department of Radiotherapy and Oncology, Goethe University Hospital, 60590, Frankfurt am Main, Germany
- Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, USA
| | - Yecheng Wang
- Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA
| | - Xiangke Zhang
- Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA
| | - Christel Herold-Mende
- Division of Experimental Neurosurgery, Department of Neurosurgery, University Hospital Heidelberg, 69120, Heidelberg, Germany
| | - Francesco Pampaloni
- Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, 60438, Frankfurt am Main, Germany
| | - Irmgard Tegeder
- Institute for Clinical Pharmacology, Faculty of Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Ivan Dikic
- Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany
- Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, 60438, Frankfurt am Main, Germany
- Cardio-Pulmonary Institute, 60590, Frankfurt am Main, Germany
- Frankfurt Cancer Institute, Goethe University, 60590, Frankfurt am Main, Germany
| | - Mingji Dai
- Department of Chemistry and Winship Cancer Institute, Emory University, Atlanta, GA, 30022, USA
| | - Franz Rödel
- Department of Radiotherapy and Oncology, Goethe University Hospital, 60590, Frankfurt am Main, Germany
- Frankfurt Cancer Institute, Goethe University, 60590, Frankfurt am Main, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt, 60590, Frankfurt am Main, Germany
- German Cancer Research Center DKFZ, 69120, Heidelberg, Germany
| | - Donat Kögel
- Experimental Neurosurgery, Department of Neurosurgery, Neuroscience Center, Goethe University Hospital, Goethe University Frankfurt, 60528, Frankfurt am Main, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt, 60590, Frankfurt am Main, Germany
- German Cancer Research Center DKFZ, 69120, Heidelberg, Germany
| | - Benedikt Linder
- Experimental Neurosurgery, Department of Neurosurgery, Neuroscience Center, Goethe University Hospital, Goethe University Frankfurt, 60528, Frankfurt am Main, Germany
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Alamdar N, Farivar S, Baghaei K, Hamidieh AA, Soltaninejad H, Aghdaei HA, Zali MR, Saltanatpour Z. Effect of Pioglitazone and Cetuximab on Colon Cancer Stem-like Cell (CCSLCs) Properties. Curr Stem Cell Res Ther 2025; 20:83-90. [PMID: 38303523 DOI: 10.2174/011574888x283318240118111822] [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: 09/26/2023] [Revised: 12/26/2023] [Accepted: 12/29/2023] [Indexed: 02/03/2024]
Abstract
BACKGROUND One of the main reasons for cancer resistance to chemotherapy is the presence of cancer stem cells (CSCs) in cancer tissues. It is also believed that CSCs are the unique originators of all tumor cells. On the other hand, the Epithelial-Mesenchymal Transition pathway (EMT) can act as the main agent of metastasis. Therefore, it is possible that targeting CSCs as well as the EMT pathway could help in cancer therapy. Considering that CSCs constitute only a small percentage of the total tumor mass, enrichment before study is necessary. In our previous study, CSCs were enriched in the human colon cancer cell line HT29 by induction of EMT. These CSC-enriched HT29 cells with mesenchymal morphology were named "HT29-shE". In the present study, these cells were used to investigate the effect of Pioglitazone (Pio) and Cetuximab (Cet) in order to find CSC and EMT targeting agents. METHODS The viability and IC50 rate of cells treated with different concentrations of Pio and Cet were evaluated using the MTT test. EMT and CSC markers and cell morphology were assessed in Pio and Cet treated and untreated HT29-shE cells using flow cytometry, realtime PCR, immunocytochemistry, and microscopic monitoring. RESULTS The findings showed that Pio and Cet at concentrations of 250 μM and 40 μg/ml, respectively, decrease cell viability by 50%. Also, they were able to reduce the expression of CSC markers (CD133 and CD44) in the CSC enriched HT29 cell line. Furthermore, Pio and Cet could efficiently reduce the expression of vimentin as a mesenchymal marker and significantly upregulate the expression of E-cadherin as an epidermal marker of EMT and its reverse mesenchymal- toepithelial transition (MET). In addition, the mesenchymal morphology of HT29-shE changed into epithelial morphology after Cet treatment. CONCLUSION Pio and Cet could inhibit EMT and reduce CSC markers in the EMT induced/CSC enriched cell line. We expect that focus on finding EMT/CSC-targeting agents like these drugs can be helpful for cancer treatment.
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Affiliation(s)
- Nasim Alamdar
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Shirin Farivar
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorder Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Science, Tehran, Iran
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Ali Hamidieh
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Stem Cell and Regenerative Medicine Innovation Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Soltaninejad
- Department of Stem Cells Technology and Tissue Regeneration, Faculty of Interdisciplinary Science and Technologies, Tarbiat Modares University, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorder Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Science, Tehran, Iran
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zohreh Saltanatpour
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Janakiraman H, Gao Z, Zhu Y, Dong J, Becker SA, Janneh A, Ogretmen B, Camp ER. Targeting SNAI1-Mediated Colorectal Cancer Chemoresistance and Stemness by Sphingosine Kinase 2 Inhibition. World J Oncol 2024; 15:744-757. [PMID: 39328328 PMCID: PMC11424120 DOI: 10.14740/wjon1890] [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: 05/03/2024] [Accepted: 07/30/2024] [Indexed: 09/28/2024] Open
Abstract
Background Epithelial-to-mesenchymal transition (EMT), cancer stem cells (CSCs), and colorectal cancer (CRC) therapy resistance are closely associated. Prior reports have demonstrated that sphingosine-1-phosphate (S1P) supports stem cells and maintains the CSC phenotype. We hypothesized that the EMT inducer SNAI1 drives S1P signaling to amplify CSC self-renewal capacity and chemoresistance. Methods CRC cell lines with or without ectopic expression of SNAI1 were used to study the role of S1P signaling as mediators of cancer stemness and 5-fluorouracil (5FU) chemoresistance. The therapeutic ability of sphingosine kinase 2 (SPHK2) was assessed using siRNA and ABC294640, a SPHK2 inhibitor. CSCs were isolated from patient-derived xenografts (PDXs) and assessed for SPHK2 and SNAI1 expression. Results Ectopic SNAI1 expressing cell lines demonstrated elevated SPHK2 expression and increased SPHK2 promoter activity. SPHK2 inhibition with siRNA or ABC294640 ablated in vitro self-renewal and sensitized cells to 5FU. CSCs isolated from CRC PDXs express increased SPHK2 relative to the non-CSC population. Combination ABC294640/5FU therapy significantly inhibited tumor growth in mice and enhanced 5FU response in therapy-resistant CRC patient-derived tumor organoids (PDTOs). Conclusions SNAI1/SPHK2 signaling mediates cancer stemness and 5FU resistance, implicating S1P as a therapeutic target for CRC. The S1P inhibitor ABC294640 holds potential as a therapeutic agent to target CSCs in therapy refractory CRC.
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Affiliation(s)
| | - Zachary Gao
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yun Zhu
- MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jiangling Dong
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
| | - Scott A Becker
- Molecular and Systems Pharmacology, Emory University, Atlanta, GA 30322, USA
| | - Alhaji Janneh
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Besim Ogretmen
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - E Ramsay Camp
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA
- Dan L. Duncan Comprehensive Cancer Center, Houston, TX 77030, USA
- Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA
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Hutasoit GA, Miskad UA, Akil F, Cangara MH, Dahlan H, Yamin A, Mardiati M. Snail Expression as a Prognostic Factor in Colorectal Adenocarcinoma. Asian Pac J Cancer Prev 2024; 25:3143-3149. [PMID: 39342593 DOI: 10.31557/apjcp.2024.25.9.3143] [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: 04/08/2024] [Indexed: 10/01/2024] Open
Abstract
OBJECTIVE The aim of this study was to analyze the expression of Snail in the colorectal adenocarcinoma. METHODS This study used a cross-sectional design. Seventy four paraffin embedded block of Colorectal Adenocarcinoma were assessed using Snail rabbit polyclonal antibody and their expression were performed using Olympus CX-43 light microscope. The relationship between Snail expression with histopathological grading, tumor budding grading, lymphovascular invasion and metastases of colorectal adenocarcinoma ability were statistically analyzed by Mann Whitney tests and presented in tables using SPSS 27. RESULT From 74 samples examined, in samples with low grade tumor budding (n=11), there were 9 samples (81.8%) with weak expression, while those with strong expression were 2 samples (18.2%). In samples with intermediate grade tumor budding (n=28), there were 17 samples (60.7%) with weak expression, while those with strong expression were 11 samples (39.3%). In samples with high grade tumor budding (n=35), there were 13 samples (37.1%) with weak expression, while those with strong expression were 22 samples (62.9%). In samples with lymphovascular invasion (n=14), there were 10 samples (71.4%) with strong expression, while those with weak expression were 4 samples (28.6%). In samples with metastases (n=23), there were 16 samples (69.6%) with strong expression, while those with weak expression were 7 samples (30.4%). There was a significant relationship between the expression of Snail with tumor budding grade (p=0.003), lymphovascular invasion and metastases (p=<0.001), but there was no significant relationship with histopathological grade (p=0.942). CONCLUSION The Snail expression can be used as a prognostic factor in colorectal adenocarcinoma.
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Affiliation(s)
- Gina Andyka Hutasoit
- Department of Anatomical Pathology, Faculty of Medicine, Hasanuddin University, Indonesia
- Department of Anatomical Pathology, Faculty of Medicine, Tadulako University, Indonesia
| | - Upik Anderiani Miskad
- Department of Anatomical Pathology, Faculty of Medicine, Hasanuddin University, Indonesia
- Anatomical Pathology Laboratory, Hasanuddin University Hospital, Indonesia
| | - Fardah Akil
- Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Indonesia
| | - Muhammad Husni Cangara
- Department of Anatomical Pathology, Faculty of Medicine, Hasanuddin University, Indonesia
- Anatomical Pathology Laboratory, Hasanuddin University Hospital, Indonesia
| | - Haslindah Dahlan
- Department of Anatomical Pathology, Faculty of Medicine, Hasanuddin University, Indonesia
- Anatomical Pathology Laboratory, Hasanuddin University Hospital, Indonesia
| | - Amalia Yamin
- Department of Anatomical Pathology, Faculty of Medicine, Hasanuddin University, Indonesia
- Anatomical Pathology Laboratory, dr. Wahidin Sudirohusodo Hospital, Indonesia
| | - Mardiati Mardiati
- Anatomical Pathology Laboratory, Hasanuddin University Hospital, Indonesia
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Cianciosi D, Forbes-Hernandez T, Armas Diaz Y, Elexpuru-Zabaleta M, Quiles JL, Battino M, Giampieri F. Manuka honey's anti-metastatic impact on colon cancer stem-like cells: unveiling its effects on epithelial-mesenchymal transition, angiogenesis and telomere length. Food Funct 2024; 15:7200-7213. [PMID: 38896046 DOI: 10.1039/d4fo00943f] [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: 06/21/2024]
Abstract
Colorectal cancer often leads to metastasis, with cancer stem cells (CSCs) playing a pivotal role in this process. Two closely linked mechanisms, epithelial-mesenchymal transition and angiogenesis, contribute to metastasis and recent research has also highlighted the impact of telomere replication on this harmful tumor progression. Standard chemotherapy alone can inadvertently promote drug-resistant CSCs, posing a challenge. Combining chemotherapy with other compounds, including natural ones, shows promise in enhancing effectiveness while minimizing side effects. This study investigated the anti-metastatic potential of Manuka honey, both alone and in combination with 5-fluorouracil, using a 3D model of colonospheres enriched with CSC-like cells. In summary, it was observed that the treatment reduced migration ability by downregulating the transcription factors Slug, Snail, and Twist, which are key players in epithelial-mesenchymal transition. Additionally, Manuka honey downregulated pro-angiogenic factors and shortened CSC telomeres by downregulating c-Myc - demonstrating an effective anti-metastatic potential. This study suggests new research opportunities for studying the impact of natural compounds when combined with pharmaceuticals, with the potential to enhance effectiveness and reduce side effects.
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Affiliation(s)
- Danila Cianciosi
- Department of Clinical Sciences, Polytechnic University of Marche, Via Pietro Ranieri 65, Ancona, 60131, Italy.
| | - Tamara Forbes-Hernandez
- Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Centre, University of Granada, Armilla, 18016, Spain
| | - Yasmany Armas Diaz
- Department of Clinical Sciences, Polytechnic University of Marche, Via Pietro Ranieri 65, Ancona, 60131, Italy.
| | - Maria Elexpuru-Zabaleta
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Isabel Torres 21, Santander, 39011, Spain
- Joint Laboratory on Food Science, Nutrition, and Intelligent Processing of Foods, Polytechnic University of Marche, Italy, Universidad Europea del Atlántico Spain and Jiangsu University, China
| | - José L Quiles
- Department of Physiology, Institute of Nutrition and Food Technology "José Mataix Verdú", Biomedical Research Centre, University of Granada, Armilla, 18016, Spain
| | - Maurizio Battino
- Department of Clinical Sciences, Polytechnic University of Marche, Via Pietro Ranieri 65, Ancona, 60131, Italy.
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Isabel Torres 21, Santander, 39011, Spain
- Joint Laboratory on Food Science, Nutrition, and Intelligent Processing of Foods, Polytechnic University of Marche, Italy, Universidad Europea del Atlántico Spain and Jiangsu University, China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-Products Processing, Jiangsu University, Zhenjiang, 212013, China
| | - Francesca Giampieri
- Department of Clinical Sciences, Polytechnic University of Marche, Via Pietro Ranieri 65, Ancona, 60131, Italy.
- Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Isabel Torres 21, Santander, 39011, Spain
- Joint Laboratory on Food Science, Nutrition, and Intelligent Processing of Foods, Polytechnic University of Marche, Italy, Universidad Europea del Atlántico Spain and Jiangsu University, China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-Products Processing, Jiangsu University, Zhenjiang, 212013, China
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Khan AQ, Hasan A, Mir SS, Rashid K, Uddin S, Steinhoff M. Exploiting transcription factors to target EMT and cancer stem cells for tumor modulation and therapy. Semin Cancer Biol 2024; 100:1-16. [PMID: 38503384 DOI: 10.1016/j.semcancer.2024.03.002] [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: 12/20/2023] [Revised: 03/15/2024] [Accepted: 03/15/2024] [Indexed: 03/21/2024]
Abstract
Transcription factors (TFs) are essential in controlling gene regulatory networks that determine cellular fate during embryogenesis and tumor development. TFs are the major players in promoting cancer stemness by regulating the function of cancer stem cells (CSCs). Understanding how TFs interact with their downstream targets for determining cell fate during embryogenesis and tumor development is a critical area of research. CSCs are increasingly recognized for their significance in tumorigenesis and patient prognosis, as they play a significant role in cancer initiation, progression, metastasis, and treatment resistance. However, traditional therapies have limited effectiveness in eliminating this subset of cells, allowing CSCs to persist and potentially form secondary tumors. Recent studies have revealed that cancer cells and tumors with CSC-like features also exhibit genes related to the epithelial-to-mesenchymal transition (EMT). EMT-associated transcription factors (EMT-TFs) like TWIST and Snail/Slug can upregulate EMT-related genes and reprogram cancer cells into a stem-like phenotype. Importantly, the regulation of EMT-TFs, particularly through post-translational modifications (PTMs), plays a significant role in cancer metastasis and the acquisition of stem cell-like features. PTMs, including phosphorylation, ubiquitination, and SUMOylation, can alter the stability, localization, and activity of EMT-TFs, thereby modulating their ability to drive EMT and stemness properties in cancer cells. Although targeting EMT-TFs holds potential in tackling CSCs, current pharmacological approaches to do so directly are unavailable. Therefore, this review aims to explore the role of EMT- and CSC-TFs, their connection and impact in cellular development and cancer, emphasizing the potential of TF networks as targets for therapeutic intervention.
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Affiliation(s)
- Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
| | - Adria Hasan
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow 226026, India; Department of Bioengineering, Faculty of Engineering, Integral University, Kursi Road, Lucknow 226026, India
| | - Snober S Mir
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow 226026, India; Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow 226026, India
| | - Khalid Rashid
- Department of Urology,Feinberg School of Medicine, Northwestern University, 303 E Superior Street, Chicago, IL 60611, USA
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow 226026, India; Laboratory Animal Research Center, Qatar University, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
| | - Martin Steinhoff
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar; Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; College of Medicine, Qatar University, Doha 2713, Qatar
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Brockmueller A, Sajeev A, Koklesova L, Samuel SM, Kubatka P, Büsselberg D, Kunnumakkara AB, Shakibaei M. Resveratrol as sensitizer in colorectal cancer plasticity. Cancer Metastasis Rev 2024; 43:55-85. [PMID: 37507626 PMCID: PMC11016130 DOI: 10.1007/s10555-023-10126-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023]
Abstract
Despite tremendous medical treatment successes, colorectal cancer (CRC) remains a leading cause of cancer deaths worldwide. Chemotherapy as monotherapy can lead to significant side effects and chemoresistance that can be linked to several resistance-activating biological processes, including an increase in inflammation, cellular plasticity, multidrug resistance (MDR), inhibition of the sentinel gene p53, and apoptosis. As a consequence, tumor cells can escape the effectiveness of chemotherapeutic agents. This underscores the need for cross-target therapeutic approaches that are not only pharmacologically safe but also modulate multiple potent signaling pathways and sensitize cancer cells to overcome resistance to standard drugs. In recent years, scientists have been searching for natural compounds that can be used as chemosensitizers in addition to conventional medications for the synergistic treatment of CRC. Resveratrol, a natural polyphenolic phytoalexin found in various fruits and vegetables such as peanuts, berries, and red grapes, is one of the most effective natural chemopreventive agents. Abundant in vitro and in vivo studies have shown that resveratrol, in interaction with standard drugs, is an effective chemosensitizer for CRC cells to chemotherapeutic agents and thus prevents drug resistance by modulating multiple pathways, including transcription factors, epithelial-to-mesenchymal transition-plasticity, proliferation, metastasis, angiogenesis, cell cycle, and apoptosis. The ability of resveratrol to modify multiple subcellular pathways that may suppress cancer cell plasticity and reversal of chemoresistance are critical parameters for understanding its anti-cancer effects. In this review, we focus on the chemosensitizing properties of resveratrol in CRC and, thus, its potential importance as an additive to ongoing treatments.
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Affiliation(s)
- Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany
| | - Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Lenka Koklesova
- Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 03601, Martin, Slovakia
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, 03601, Martin, Slovakia
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany.
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Tavlas P, Nikou S, Geramoutsou C, Bosgana P, Tsaniras SC, Melachrinou M, Maroulis I, Bravou V. CUL4A Ubiquitin Ligase Is an Independent Predictor of Overall Survival in Pancreatic Adenocarcinoma. Cancer Genomics Proteomics 2024; 21:166-177. [PMID: 38423594 PMCID: PMC10905276 DOI: 10.21873/cgp.20438] [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: 11/27/2023] [Revised: 01/22/2024] [Accepted: 02/06/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND/AIM Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with dismal prognosis. Genomic instability due to defects in cell-cycle regulation/mitosis or deficient DNA-damage repair is a major driver of PDAC progression with clinical relevance. Deregulation of licensing of DNA replication leads to DNA damage and genomic instability, predisposing cells to malignant transformation. While overexpression of DNA replication-licensing factors has been reported in several human cancer types, their role in PDAC remains largely unknown. We aimed here to examine the expression and prognostic significance of the DNA replication-licensing factors chromatin licensing and DNA replication factor 1 (CDT1), cell-division cycle 6 (CDC6), minichromosome maintenance complex component 7 (MCM7) and also of the ubiquitin ligase regulator of CDT1, cullin 4A (CUL4A), in PDAC. MATERIALS AND METHODS Expression levels of CUL4, CDT1, CDC6 and MCM7 were evaluated by immunohistochemistry in 76 formalin-fixed paraffin-embedded specimens of PDAC patients in relation to DNA-damage response marker H2AX, clinicopathological parameters and survival. We also conducted bioinformatics analysis of data from online available databases to corroborate our findings. RESULTS CUL4A and DNA replication-licensing factors were overexpressed in patients with PDAC and expression of CDT1 positively correlated with H2AX. Expression of CUL4A and CDT1 positively correlated with lymph node metastasis. Importantly, elevated CUL4A expression was associated with reduced overall survival and was an independent indicator of poor prognosis on multivariate analysis. CONCLUSION Our findings implicate CUL4A, CDT1, CDC6 and MCM7 in PDAC progression and identify CUL4A as an independent prognostic factor for this disease.
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Affiliation(s)
- Panagiotis Tavlas
- Department of Anatomy-Histology-Embryology, Medical School, University of Patras, Patras, Greece
- Department of Surgery, University General Hospital of Patras, Patras, Greece
| | - Sofia Nikou
- Department of Anatomy-Histology-Embryology, Medical School, University of Patras, Patras, Greece
| | - Christina Geramoutsou
- Department of Anatomy-Histology-Embryology, Medical School, University of Patras, Patras, Greece
| | - Pinelopi Bosgana
- Department of Pathology, School of Medicine, University of Patras, Patras, Greece
| | - Spyridon Champeris Tsaniras
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, U.S.A
- International Institute of Anticancer Research, Kapandriti, Greece
| | - Maria Melachrinou
- Department of Pathology, School of Medicine, University of Patras, Patras, Greece
| | - Ioannis Maroulis
- Department of Surgery, University General Hospital of Patras, Patras, Greece
| | - Vasiliki Bravou
- Department of Anatomy-Histology-Embryology, Medical School, University of Patras, Patras, Greece;
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9
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Mukerjee N, Nag S, Bhattacharya B, Alexiou A, Mirgh D, Mukherjee D, Adhikari MD, Anand K, Muthusamy R, Gorai S, Thorat N. Clinical impact of epithelial–mesenchymal transition for cancer therapy. CLINICAL AND TRANSLATIONAL DISCOVERY 2024; 4. [DOI: 10.1002/ctd2.260] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 12/26/2023] [Indexed: 01/03/2025]
Abstract
AbstractThe epithelial–mesenchymal transition (EMT) represents a pivotal frontier in oncology, playing a central role in the metastatic cascade of cancer—a leading global health challenge. This comprehensive review delves into the complexities of EMT, a process where cancer cells gain exceptional mobility, facilitating their invasion into distant organs and the establishment of secondary malignancies. We thoroughly examine the myriad of factors influencing EMT, encompassing transcription factors, signalling pathways, metabolic alterations, microRNAs, long non‐coding RNAs, epigenetic changes, exosomal interactions and the intricate dynamics of the tumour microenvironment. Particularly, the review emphasises the advanced stages of EMT, crucial for the development of highly aggressive cancer phenotypes. During this phase, cancer cells penetrate the vascular barrier and exploit the bloodstream to propagate life‐threatening metastases through the mesenchymal–epithelial transition. We also explore EMT's significant role in fostering tumour dormancy, senescence, the emergence of cancer stem cells and the formidable challenge of therapeutic resistance. Our review transcends a mere inventory of EMT‐inducing elements; it critically assesses the current state of EMT‐focused clinical trials, revealing both the hurdles and significant breakthroughs. Highlighting the potential of EMT research, we project its transformative impact on the future of cancer therapy. This exploration is aimed at paving the way towards an era of effectively managing this relentless disease, positioning EMT at the forefront of innovative cancer research strategies.
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Affiliation(s)
- Nobendu Mukerjee
- Department of Microbiology West Bengal State University, Barasat Kolkata India
| | - Sagnik Nag
- Department of Bio‐Sciences School of Biosciences & Technology Vellore Institute of Technology Vellore Tamil Nadu India
| | - Bikramjit Bhattacharya
- Department of Applied Microbiology School of Biosciences and Technology Vellore Institute of Technology Vellore Tamil Nadu India
| | - Athanasios Alexiou
- Department of Science and Engineering Novel Global Community Educational Foundation Hebersham New South Wales Australia
| | - Divya Mirgh
- Vaccine and Immunotherapy Canter Massachusetts General Hospital Boston Massachusetts USA
| | | | - Manab Deb Adhikari
- Department of Biotechnology University of North Bengal Darjeeling West Bengal India
| | - Krishnan Anand
- Department of Chemical Pathology School of Pathology Faculty of Health Sciences University of the Free State Bloemfontein South Africa
| | - Raman Muthusamy
- Center for Global Health Research Saveetha Medical College & Hospitals, Saveetha Institute of Medical and Technical Sciences Chennai Tamil Nadu India
| | | | - Nanasaheb Thorat
- Limerick Digital Cancer Research Centre and Department of Physics Bernal Institute University of Limerick, Castletroy Limerick Ireland
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10
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Hassani I, Anbiah B, Moore AL, Abraham PT, Odeniyi IA, Habbit NL, Greene MW, Lipke EA. Establishment of a tissue-engineered colon cancer model for comparative analysis of cancer cell lines. J Biomed Mater Res A 2024; 112:231-249. [PMID: 37927200 DOI: 10.1002/jbm.a.37611] [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: 11/10/2022] [Revised: 08/13/2023] [Accepted: 08/30/2023] [Indexed: 11/07/2023]
Abstract
To overcome the limitations of in vitro two-dimensional (2D) cancer models in mimicking the complexities of the native tumor milieu, three-dimensional (3D) engineered cancer models using biomimetic materials have been introduced to more closely recapitulate the key attributes of the tumor microenvironment. Specifically, for colorectal cancer (CRC), a few studies have developed 3D engineered tumor models to investigate cell-cell interactions or efficacy of anti-cancer drugs. However, recapitulation of CRC cell line phenotypic differences within a 3D engineered matrix has not been systematically investigated. Here, we developed an in vitro 3D engineered CRC (3D-eCRC) tissue model using the natural-synthetic hybrid biomaterial PEG-fibrinogen and three CRC cell lines, HCT 116, HT-29, and SW480. To better recapitulate native tumor conditions, our 3D-eCRC model supported higher cell density encapsulation (20 × 106 cells/mL) and enabled longer term maintenance (29 days) as compared to previously reported in vitro CRC models. The 3D-eCRCs formed using each cell line demonstrated line-dependent differences in cellular and tissue properties, including cellular growth and morphology, cell subpopulations, cell size, cell granularity, migration patterns, tissue growth, gene expression, and tissue stiffness. Importantly, these differences were found to be most prominent from Day 22 to Day 29, thereby indicating the importance of long-term culture of engineered CRC tissues for recapitulation and investigation of mechanistic differences and drug response. Our 3D-eCRC tissue model showed high potential for supporting future in vitro comparative studies of disease progression, metastatic mechanisms, and anti-cancer drug candidate response in a CRC cell line-dependent manner.
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Affiliation(s)
- Iman Hassani
- Department of Chemical Engineering, Auburn University, Auburn, Alabama, USA
- Department of Chemical Engineering, Tuskegee University, Tuskegee, Alabama, USA
| | - Benjamin Anbiah
- Department of Chemical Engineering, Auburn University, Auburn, Alabama, USA
| | - Andrew L Moore
- Department of Chemical Engineering, Auburn University, Auburn, Alabama, USA
| | - Peter T Abraham
- Department of Chemical Engineering, Auburn University, Auburn, Alabama, USA
| | - Ifeoluwa A Odeniyi
- Department of Nutritional Sciences, Auburn University, Auburn, Alabama, USA
| | - Nicole L Habbit
- Department of Chemical Engineering, Auburn University, Auburn, Alabama, USA
| | - Michael W Greene
- Department of Nutritional Sciences, Auburn University, Auburn, Alabama, USA
| | - Elizabeth A Lipke
- Department of Chemical Engineering, Auburn University, Auburn, Alabama, USA
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11
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Said R, Hernández-Losa J, Moline T, de Haro RSL, Zouari S, Blel A, Rammeh S, Derouiche A, Ouerhani S. Co-expression of Twist and Snai1: predictor of poor prognosis and biomarker of treatment resistance in untreated prostate cancer. Mol Biol Rep 2024; 51:226. [PMID: 38281235 DOI: 10.1007/s11033-023-09167-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] [Received: 09/30/2023] [Accepted: 12/15/2023] [Indexed: 01/30/2024]
Abstract
BACKGROUND Prostate cancer (PCa) remains one of the most complex tumors in men. The assessment of gene expression is expected to have a profound impact on cancer diagnosis, prognosis, and treatment decisions. The aim of this study was to determine the utility of the epithelial-mesenchymal transition (EMT) transcription factors Twist and Snai1 in the treatment of naïve prostate cancer. METHODS AND RESULTS We analyzed formalin-fixed paraffin-embedded (FFPE) prostate tissues from 108 PCa patients and 20 control biopsies using real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and 2-ΔΔCt methods for Twist and Snail gene expression. The expression of Twist and Snai1 mRNA was significantly overexpressed in primary tissues of PCa patients compared with controls using ROC curve. Statistical analysis showed that the mRNAs of these two genes expression Snai1 and Twist were positively correlated with tumor development and prognostic parameters as Gleason score (p < 0.001; r = 0.707) and (p < 0.001; r = 0.627) respectively. The results of Kaplan-Meier analysis showed that mRNA expression of Snai1 and Twist genes expression were significant predictors of poor overall survival (OS) (Log rank p < 0.001) and progression-free survival (PFS) of patients (Log rank p < 0.001). Furthermore, our results showed that the expression of Snai1 and Twist genes expression in primary tissues of PCa patients could predict resistance to androgen deprivation therapy (p < 0.001) and resistance to the acidic drugs abiraterone or enzalutamide (p < 0.001). However, these two transcription factors failed to predict taxanes resistance at the time of diagnosis (p > 0.05). CONCLUSION These results suggest that Snai1 and Twist are overexpressed during the onset and progression of PCa malignancies and may be theranostic markers of resistance to ADT, abiraterone, or enzalutamide therapy.
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Affiliation(s)
- Rahma Said
- Laboratory of Protein Engineering and Bio-Active Molecules, National Institute of Applied Science and Technology - University of Carthage, Tunis, Tunisia.
- Molecular Biology Laboratory, Department of Pathology, Hospital Universitari Vall d'Hebron, Passeig Vall d´Hebron, 119-129, 08035, Barcelona, Spain.
- Institute of Biotechnology of Béja, Jendouba University, Jendouba, Tunisia.
| | - Javier Hernández-Losa
- Molecular Biology Laboratory, Department of Pathology, Hospital Universitari Vall d'Hebron, Passeig Vall d´Hebron, 119-129, 08035, Barcelona, Spain
| | - Teresa Moline
- Molecular Biology Laboratory, Department of Pathology, Hospital Universitari Vall d'Hebron, Passeig Vall d´Hebron, 119-129, 08035, Barcelona, Spain
| | - Rosa Somoza Lopez de Haro
- Molecular Biology Laboratory, Department of Pathology, Hospital Universitari Vall d'Hebron, Passeig Vall d´Hebron, 119-129, 08035, Barcelona, Spain
| | - Skander Zouari
- Urology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Ahlem Blel
- Pathology Anatomy and Cytology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Soumaya Rammeh
- Pathology Anatomy and Cytology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Amine Derouiche
- Urology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Slah Ouerhani
- Laboratory of Protein Engineering and Bio-Active Molecules, National Institute of Applied Science and Technology - University of Carthage, Tunis, Tunisia
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12
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Hussein ZH, Hassawi BA, Ibraheem Q. Aberrant β-Catenin Expression and Its Association With Epithelial-Mesenchymal Transition and Clinical Outcomes of Colorectal Cancer. Cureus 2024; 16:e53104. [PMID: 38414697 PMCID: PMC10897760 DOI: 10.7759/cureus.53104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2024] [Indexed: 02/29/2024] Open
Abstract
Background Colorectal cancer (CRC) is a significant global health challenge with high mortality rates. Dysregulation of β-catenin, epithelial-mesenchymal transition (EMT), and adenomatous polyposis coli (APC) are crucial in CRC development. Mutations in the APC gene lead to aberrant β-catenin expression, a key player in CRC pathogenesis. β-catenin not only influences canonical Wnt signaling but also regulates EMT. This study investigated the correlation between APC mutations, β-catenin dysregulation, and EMT induction in CRC. Methodology Tissue samples from 96 CRC patients and 40 para-cancerous normal tissues were collected and subjected to immunohistochemistry to assess β-catenin, E-cadherin, ZEB1, Snail, and vimentin expression. Genomic DNA was extracted and analyzed for APC mutations. Next-generation sequencing was employed for data analysis. Results Aberrant β-catenin expression was found in 82.3% of CRC cases and correlated with advanced clinicopathological factors. Aberrant β-catenin expression was associated with age (p=0.01), tumor invasion depth (p=0.03), nodal/distant metastasis (p=0.001 and 0.004), and vascular invasion (p=0.001). Aberrant β-catenin was correlated with EMT status. A positive correlation was observed between aberrant β-catenin expression and ZEB1 (p=0.001), Snail (p=0.001), vimentin (p=0.001), and loss of membranous E-cadherin (p=0001). Coexistence of aberrant β-catenin and EMT markers was associated with advanced CRC progression. Cancerous tissues displayed higher aberrant β-catenin and EMT markers expression than para-cancerous tissues. APC mutations were present in 59.3% of cases, with 91.2% of mutated APC cases showing aberrant β-catenin expression. The coexistence of APC mutation and aberrant β-catenin expression was correlated with the clinical outcomes of CRC patients. Mutated APC cases exhibited significantly increased EMT marker expression. Conclusion This study underscores the importance of aberrant β-catenin expression in CRC progression, linked to APC mutations and EMT induction. Understanding these relationships could aid in developing targeted therapies for CRC.
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Affiliation(s)
- Zihel H Hussein
- Department of Anatomy, Biology, and Histology, College of Medicine, University of Duhok, Duhok, IRQ
| | - Bashar Al Hassawi
- Department of Anatomy, Biology, and Histology, College of Medicine, University of Duhok, Duhok, IRQ
| | - Qais Ibraheem
- Department of Anatomy, Biology, and Histology, College of Medicine, University of Duhok, Duhok, IRQ
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13
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Chałaśkiewicz K, Karaś K, Zakłos-Szyda M, Karwaciak I, Pastwińska J, Koziołkiewicz M, Ratajewski M. Trichostatin a inhibits expression of the human SLC2A5 gene via SNAI1/SNAI2 transcription factors and sensitizes colon cancer cells to platinum compounds. Eur J Pharmacol 2023; 949:175728. [PMID: 37062501 DOI: 10.1016/j.ejphar.2023.175728] [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: 12/24/2022] [Revised: 03/29/2023] [Accepted: 04/14/2023] [Indexed: 04/18/2023]
Abstract
GLUT5, a key protein encoded by the SLC2A5 gene, is involved in the uptake of fructose from the intestine. Currently, with the increased consumption of this sugar and the associated increased incidence of obesity, diabetes and cancer, GLUT5 may represent an important molecular target in the prevention and treatment of these diseases. Here, we demonstrate that overexpression of the SNAI1 and SNAI2 transcription factors in cells expressing high levels of SLC2A5 mRNA reduced SLC2A5 gene expression. Furthermore, a histone deacetylase inhibitor, trichostatin A, which induces SNAI1 and SNAI2 expression, inhibits SLC2A5/GLUT5 expression and sensitizes colon cancer cells to cisplatin and oxaliplatin. This finding might have potential relevance for the development of therapeutic treatments aimed at modulating fructose transport or genes involved in this process for use with certain cancers.
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Affiliation(s)
- Katarzyna Chałaśkiewicz
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232, Lodz, Poland; Faculty of Biotechnology and Food Sciences, Institute of Molecular and Industrial Biotechnology, Lodz University of Technology, Stefanowskiego 2/22, 90-537, Lodz, Poland
| | - Kaja Karaś
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232, Lodz, Poland
| | - Małgorzata Zakłos-Szyda
- Faculty of Biotechnology and Food Sciences, Institute of Molecular and Industrial Biotechnology, Lodz University of Technology, Stefanowskiego 2/22, 90-537, Lodz, Poland
| | - Iwona Karwaciak
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232, Lodz, Poland
| | - Joanna Pastwińska
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232, Lodz, Poland
| | - Maria Koziołkiewicz
- Faculty of Biotechnology and Food Sciences, Institute of Molecular and Industrial Biotechnology, Lodz University of Technology, Stefanowskiego 2/22, 90-537, Lodz, Poland
| | - Marcin Ratajewski
- Laboratory of Epigenetics, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232, Lodz, Poland.
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14
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Zamani B, Ramazani A, Saberzadeh J, Rostampour P, Takhshid MA. The effect of Annexin A5 overexpression on invasiveness and expression of the genes involved in epithelial-mesenchymal transition of HCT 116 cell line. MOLECULAR BIOLOGY RESEARCH COMMUNICATIONS 2023; 12:77-85. [PMID: 37520464 PMCID: PMC10382902 DOI: 10.22099/mbrc.2023.47160.1823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/01/2023]
Abstract
Epithelial-to-mesenchymal transition (EMT) plays a critical role in colorectal cancer (CRC) metastasis. In the present study, we evaluated the effects of annexin A5 (ANXA5) overexpression on invasiveness as well as the expression of genes involved in EMT of HCT 116 cell line. PCMV6-AC-IRES-GFP plasmid harboring ANXA5 cDNA was constructed. HCT 116 cell line was transfected with recombinant plasmids using Lipofectamine 3000. Fluorescent microscopy was used to determine the efficiency of plasmid transfection. Cell viability was determined using the MTT assay. HCT 116 cell migration was evaluated using wound healing assay and transwell migration assay. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to measure the expression of genes involved in EMT. The results of RT-qPCR showed overexpression of ANXA5 compared to the control group. ANXA5 overexpression had no significant effects on cell viability but significantly decreased the rate of wound closure in the wound healing assay as well as the number of migrated cells in transwell assay. Furthermore, ANXA5 overexpression decreased the expression of N-cadherin, Snail, Slug, MMP-2, and MMP-9 while the expression of E-cadherin increased following ANXA5 overexpression. However, VEGF expression did not significantly change after ANXA5 overexpression. Results of the present study suggest that ANXA5 overexpression might have inhibitory effects on the metastasis of CRC through modulating the expression of EMT- related genes.
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Affiliation(s)
- Bahareh Zamani
- Division of Medical Biotechnology, Department of Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amin Ramazani
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Science, Shiraz, Iran
| | - Jamileh Saberzadeh
- Division of Medical Biotechnology, Department of Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Puria Rostampour
- Division of Medical Biotechnology, Department of Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Ali Takhshid
- Division of Medical Biotechnology, Department of Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
- Diagnostic Laboratory Sciences and Technology Research Center, Paramedical School, Shiraz University of Medical Science, Shiraz, Iran
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15
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Ghazi B, El Ghanmi A, Kandoussi S, Ghouzlani A, Badou A. CAR T-cells for colorectal cancer immunotherapy: Ready to go? Front Immunol 2022; 13:978195. [PMID: 36458008 PMCID: PMC9705989 DOI: 10.3389/fimmu.2022.978195] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 10/14/2022] [Indexed: 08/12/2023] Open
Abstract
Chimeric antigen receptor (CAR) T-cells represent a new genetically engineered cell-based immunotherapy tool against cancer. The use of CAR T-cells has revolutionized the therapeutic approach for hematological malignancies. Unfortunately, there is a long way to go before this treatment can be developed for solid tumors, including colorectal cancer. CAR T-cell therapy for colorectal cancer is still in its early stages, and clinical data are scarce. Major limitations of this therapy include high toxicity, relapses, and an impermeable tumor microenvironment for CAR T-cell therapy in colorectal cancer. In this review, we summarize current knowledge, highlight challenges, and discuss perspectives regarding CAR T-cell therapy in colorectal cancer.
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Affiliation(s)
- Bouchra Ghazi
- Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
| | - Adil El Ghanmi
- Mohammed VI International University Hospital, Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
| | - Sarah Kandoussi
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Amina Ghouzlani
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
| | - Abdallah Badou
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco
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16
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Snail maintains the stem/progenitor state of skin epithelial cells and carcinomas through the autocrine effect of matricellular protein Mindin. Cell Rep 2022; 40:111390. [PMID: 36130502 DOI: 10.1016/j.celrep.2022.111390] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 06/11/2022] [Accepted: 08/30/2022] [Indexed: 12/22/2022] Open
Abstract
Preservation of a small population of cancer stem cells (CSCs) within a heterogeneous carcinoma serves as a paradigm to understand how select cells in a tissue maintain their undifferentiated status. In both embryogenesis and cancer, Snail has been correlated with stemness, but the molecular underpinning of this phenomenon remains largely ill-defined. In models of cutaneous squamous cell carcinoma (cSCC), we discovered a non-epithelial-mesenchymal transition function for the transcription factor Snail in maintaining the stemness of epidermal keratinocytes. Snail-expressing cells secrete the matricellular protein Mindin, which functions in an autocrine fashion to activate a Src-STAT3 pathway to reinforce their stem/progenitor phenotype. This pathway is activated by the engagement of Mindin with the leukocyte-specific integrin, CD11b (ITGAM), which is also unexpectedly expressed by epidermal keratinocytes. Interestingly, disruption of this signaling module in human cSCC attenuates tumorigenesis, suggesting that targeting Mindin would be a promising therapeutic approach to hinder cancer recurrence.
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17
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Bhavani GS, Palanisamy A. SNAIL driven by a feed forward loop motif promotes TGF βinduced epithelial to mesenchymal transition. Biomed Phys Eng Express 2022; 8. [PMID: 35700712 DOI: 10.1088/2057-1976/ac7896] [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: 01/26/2022] [Accepted: 06/14/2022] [Indexed: 11/12/2022]
Abstract
Epithelial to Mesenchymal Transition (EMT) plays an important role in tissue regeneration, embryonic development, and cancer metastasis. Several signaling pathways are known to regulate EMT, among which the modulation of TGFβ(Transforming Growth Factor-β) induced EMT is crucial in several cancer types. Several mathematical models were built to explore the role of core regulatory circuit of ZEB/miR-200, SNAIL/miR-34 double negative feedback loops in modulating TGFβinduced EMT. Different emergent behavior including tristability, irreversible switching, existence of hybrid EMT states were inferred though these models. Some studies have explored the role of TGFβreceptor activation, SMADs nucleocytoplasmic shuttling and complex formation. Recent experiments have revealed that MDM2 along with SMAD complex regulates SNAIL expression driven EMT. Encouraged by this, in the present study we developed a mathematical model for p53/MDM2 dependent TGFβinduced EMT regulation. Inclusion of p53 brings in an additional mechanistic perspective in exploring the EM transition. The network formulated comprises a C1FFL moderating SNAIL expression involving MDM2 and SMAD complex, which functions as a noise filter and persistent detector. The C1FFL was also observed to operate as a coincidence detector driving the SNAIL dependent downstream signaling into phenotypic switching decision. Systems modelling and analysis of the devised network, displayed interesting dynamic behavior, systems response to various inputs stimulus, providing a better understanding of p53/MDM2 dependent TGF-βinduced Epithelial to Mesenchymal Transition.
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18
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Ma X, Qi W, Yang F, Pan H. Deubiquitinase JOSD1 promotes tumor progression via stabilizing Snail in lung adenocarcinoma. Am J Cancer Res 2022; 12:2323-2336. [PMID: 35693075 PMCID: PMC9185601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/30/2022] [Indexed: 06/15/2023] Open
Abstract
Accumulating evidence suggests that the deubiquitinase JOSD1 accounts for aggressiveness and unfavorable prognosis in multiple human cancers. But, the significance of JOSD1 in lung adenocarcinoma (LUAD) is elusive. We established that JOSD1 was aberrantly overexpressed in LUAD tissues, relative to normal tissues. Elevated JOSD1 levels in LUAD tissues positively related to advanced clinicopathological characteristics and poor overall survival (OS) in LUAD patients. Furthermore, we found that JOSD1 knockdown suppressed tumor cell proliferation and metastasis, whereas overexpression of JOSD1 led to opposite phenotypes. Mechanistically, JOSD1 stabilized Snail protein through deubiquitination, which promotes the epithelial-to-mesenchymal transition (EMT) process. Indeed, JOSD1 promoted tumor cell invasion as well as metastasis on the dependence of Snail. The protein expression analysis of LUAD tissues indicated that JOSD1 positively correlated with Snail. Moreover, JOSD1 and Snail co-overexpression had the worst prognosis in LUAD patients. Overall, these results demonstrated that JOSD1 was significantly overexpressed in LUAD and stabilized Snail via deubiquitination to promote LUAD metastasis.
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Affiliation(s)
- Xingjie Ma
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Jiaxing UniversityJiaxing 314001, Zhejiang, China
| | - Weibo Qi
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Jiaxing UniversityJiaxing 314001, Zhejiang, China
| | - Fan Yang
- Department of Cardiothoracic Surgery, First Affiliated Hospital of Jiaxing UniversityJiaxing 314001, Zhejiang, China
| | - Huan Pan
- Department of Central Laboratory, First Affiliated Hospital of Jiaxing UniversityJiaxing 314001, Zhejiang, China
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19
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Pavlič A, Hauptman N, Boštjančič E, Zidar N. Long Non-Coding RNAs as Potential Regulators of EMT-Related Transcription Factors in Colorectal Cancer—A Systematic Review and Bioinformatics Analysis. Cancers (Basel) 2022; 14:cancers14092280. [PMID: 35565409 PMCID: PMC9105237 DOI: 10.3390/cancers14092280] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/29/2022] [Accepted: 04/30/2022] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Emerging evidence highlights long non-coding RNAs as important regulators of epithelial–mesenchymal transition. Numerous studies have attempted to define their possible diagnostic, prognostic and therapeutic values in various human cancers. The aim of this review is to summarize long non-coding RNAs involved in the regulation of epithelial–mesenchymal transition in colorectal carcinoma. Additional candidate long non-coding RNAs are identified through a bioinformatics analysis. Abstract Epithelial–mesenchymal transition (EMT) plays a pivotal role in carcinogenesis, influencing cancer progression, metastases, stemness, immune evasion, metabolic reprogramming and therapeutic resistance. EMT in most carcinomas, including colorectal carcinoma (CRC), is only partial, and can be evidenced by identification of the underlying molecular drivers and their regulatory molecules. During EMT, cellular reprogramming is orchestrated by core EMT transcription factors (EMT-TFs), namely ZEB1/2, TWIST1/2, SNAI1 (SNAIL) and SNAI2 (SLUG). While microRNAs have been clearly defined as regulators of EMT, the role of long non-coding RNAs (lncRNAs) in EMT is poorly defined and controversial. Determining the role of lncRNAs in EMT remains a challenge, because they are involved in a number of cellular pathways and are operating through various mechanisms. Adding to the complexity, some lncRNAs have controversial functions across different tumor types, acting as EMT promotors in some tumors and as EMT suppressors in others. The aim of this review is to summarize the role of lncRNAs involved in the regulation of EMT-TFs in human CRC. Additional candidate lncRNAs were identified through a bioinformatics analysis.
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20
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Qiao L, Chen Y, Liang N, Xie J, Deng G, Chen F, Wang X, Liu F, Li Y, Zhang J. Targeting Epithelial-to-Mesenchymal Transition in Radioresistance: Crosslinked Mechanisms and Strategies. Front Oncol 2022; 12:775238. [PMID: 35251963 PMCID: PMC8888452 DOI: 10.3389/fonc.2022.775238] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Radiotherapy exerts a crucial role in curing cancer, however, its treatment efficiency is mostly limited due to the presence of radioresistance. Epithelial-to-mesenchymal transition (EMT) is a biological process that endows the cancer cells with invasive and metastatic properties, as well as radioresistance. Many potential mechanisms of EMT-related radioresistance being reported have broaden our cognition, and hint us the importance of an overall understanding of the relationship between EMT and radioresistance. This review focuses on the recent progresses involved in EMT-related mechanisms in regulating radioresistance, irradiation-mediated EMT program, and the intervention strategies to increase tumor radiosensitivity, in order to improve radiotherapy efficiency and clinical outcomes of cancer patients.
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Affiliation(s)
- Lili Qiao
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Yanfei Chen
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Ning Liang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Jian Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Guodong Deng
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Fangjie Chen
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Xiaojuan Wang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Fengjun Liu
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
| | - Yupeng Li
- Department of Oncology, Shandong First Medical University, Jinan, China.,Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China
| | - Jiandong Zhang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Province Qianfoshan Hospital, Shandong Lung Cancer Institute, Jinan, China.,Department of Oncology, Shandong First Medical University, Jinan, China
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21
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Chen Y, Jiang Z, Guan X, Li H, Li C, Tang C, Lei Y, Dang Y, Song B, Long L. The value of multi-parameter diffusion and perfusion magnetic resonance imaging for evaluating epithelial-mesenchymal transition in rectal cancer. Eur J Radiol 2022; 150:110245. [DOI: 10.1016/j.ejrad.2022.110245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 02/15/2022] [Accepted: 03/07/2022] [Indexed: 11/17/2022]
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22
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Comparison of Colorectal Cancer Stem Cells and Oxaliplatin-Resistant Cells Unveils Functional Similarities. Cells 2022; 11:cells11030511. [PMID: 35159320 PMCID: PMC8833894 DOI: 10.3390/cells11030511] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/27/2022] [Accepted: 01/29/2022] [Indexed: 02/01/2023] Open
Abstract
Colorectal cancer is the second most common cancer in women, the third in men, and an important cause of cancer-related mortality. Recurrence and the development of chemotherapy resistance are major hindrances for patients’ treatment. The presence of cancer stem cells with chemotherapy resistance able to generate proliferating tumor cells contributes to tumor recurrence and resistance. In addition, tumor cells can develop chemoresistance through adaptation mechanisms. In this article, cancer stem cells were isolated from HT29 and SW620 colorectal cancer cell lines. Oxaliplatin resistance was induced by a single drug treatment simulating the usual guidelines of patient treatment. A comparison of these two populations showed similarities since cancer stem cells presented increased oxaliplatin resistance, and resistant cells contained an increased number of cancer stem cells. Cancer stem cells isolated from resistant cells showed increased oxaliplatin resistance. Cell invasion capacity and epithelial-mesenchymal transition were increased both in cancer stem cells and oxaliplatin-resistant cells. mRNA expression analysis showed that both cell types shared a significant proportion of commonly regulated genes. In summary, the data presented indicate that colorectal cancer stem cells and oxaliplatin-resistant cells are highly related cell populations that might have interesting implications in the development of tumor recurrence and resistance to chemotherapy.
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23
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Jeon HD, Han YH, Mun JG, Yoon DH, Lee YG, Kee JY, Hong SH. Dehydroevodiamine inhibits lung metastasis by suppressing survival and metastatic abilities of colorectal cancer cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 96:153809. [PMID: 34782203 DOI: 10.1016/j.phymed.2021.153809] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 10/05/2021] [Accepted: 10/17/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Despite the rising 5-year survival rate of colorectal cancer (CRC) patients, the survival rate decreases as the stage progress, and a low survival rate is highly associated with metastasis. PURPOSE The purpose of our study is to investigate the effect of dehydroevodiamine (DHE) on the lung metastasis of CRC and the proliferation of CRC cells. STUDY DESIGN Cell death was confirmed after DHE treatment on several CRC cell lines. The mechanism of cell cytotoxicity was found using flow cytometry. After that, the expression of the proteins or mRNAs related to the cell cytotoxicity was confirmed. Also, anti-metastatic ability of DHE in CRC cells was measured by checking the expression of Epithelial to Mesenchymal Transition (EMT) markers. Lung metastasis mouse model was established, and DHE was administered orally for 14 days. RESULTS DHE suppressed the viability of HCT116, CT26, SW480, and LoVo cells. DHE treatment led to G2/M arrest via a reduction of cyclin B1/CDK1 and caspase-dependent apoptosis. It also induced autophagy by regulating LC3-II and beclin-1 expression. Additionally, migration and invasion of CRC cells were decreased by DHE through regulation of the expression of EMT markers. Oral administration of DHE could inhibit the lung metastasis of CT26 cells in an in vivo model. CONCLUSION Our study demonstrated that DHE has a potential therapeutic effect on colorectal cancer metastasis.
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Affiliation(s)
- Hee Dong Jeon
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk 54538, South Korea
| | - Yo-Han Han
- Department of Clinical and Administrative Pharmacy, College of Pharmacy, University of Georgia, Augusta, GA 30901, United States.
| | - Jeong-Geon Mun
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk 54538, South Korea.
| | - Dae Hwan Yoon
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk 54538, South Korea
| | - Yeong Gyeong Lee
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk 54538, South Korea.
| | - Ji-Ye Kee
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk 54538, South Korea.
| | - Seung-Heon Hong
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Jeonbuk 54538, South Korea.
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24
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Ciszewski WM, Włodarczyk J, Chmielewska-Kassassir M, Fichna J, Wozniak LA, Sobierajska K. Evening primrose seed extract rich in polyphenols modulates the invasiveness of colon cancer cells by regulating the TYMS expression. Food Funct 2022; 13:10994-11007. [DOI: 10.1039/d2fo01737g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Natural polyphenols are plant metabolites exhibiting a broad range of biological activities.
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Affiliation(s)
- Wojciech M. Ciszewski
- Department of Molecular Cell Mechanisms, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland
| | - Jakub Włodarczyk
- Department of Biochemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland
| | | | - Jakub Fichna
- Department of Biochemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland
| | - Lucyna A. Wozniak
- Department of Structural Biology, Medical University of Lodz, Zeligowskiego 7/9, 90-752, Lodz, Poland
| | - Katarzyna Sobierajska
- Department of Molecular Cell Mechanisms, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland
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25
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Zhao W, Dai S, Yue L, Xu F, Gu J, Dai X, Qian X. Emerging mechanisms progress of colorectal cancer liver metastasis. Front Endocrinol (Lausanne) 2022; 13:1081585. [PMID: 36568117 PMCID: PMC9772455 DOI: 10.3389/fendo.2022.1081585] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignancy and the second most common cause of cancer-related mortality worldwide. A total of 20% of CRC patients present with distant metastasis. The hepatic portal venous system, responsible for collecting most intestinal blood, makes the liver the most common site of CRC metastasis. The formation of liver metastases from colorectal cancer is a long and complex process. It involves the maintenance of primary tumors, vasculature invasion, distant colonization, and metastasis formation. In this review, we serve on how the CRC cells acquire stemness, invade the vascular, and colonize the liver. In addition, we highlight how the resident cells of the liver and immune cells interact with CRC cells. We also discuss the current immunotherapy approaches and challenges we face, and finally, we look forward to finding new therapeutic targets based on novel sequencing technologies.
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26
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Tang X, Sui X, Weng L, Liu Y. SNAIL1: Linking Tumor Metastasis to Immune Evasion. Front Immunol 2021; 12:724200. [PMID: 34917071 PMCID: PMC8669501 DOI: 10.3389/fimmu.2021.724200] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
The transcription factor Snail1, a key inducer of epithelial-mesenchymal transition (EMT), plays a critical role in tumor metastasis. Its stability is strictly controlled by multiple intracellular signal transduction pathways and the ubiquitin-proteasome system (UPS). Increasing evidence indicates that methylation and acetylation of Snail1 also affects tumor metastasis. More importantly, Snail1 is involved in tumor immunosuppression by inducing chemokines and immunosuppressive cells into the tumor microenvironment (TME). In addition, some immune checkpoints potentiate Snail1 expression, such as programmed death ligand 1 (PD-L1) and T cell immunoglobulin 3 (TIM-3). This mini review highlights the pathways and molecules involved in maintenance of Snail1 level and the significance of Snail1 in tumor immune evasion. Due to the crucial role of EMT in tumor metastasis and tumor immunosuppression, comprehensive understanding of Snail1 function may contribute to the development of novel therapeutics for cancer.
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Affiliation(s)
- Xiaolong Tang
- Department of Laboratory Medicine, Binzhou Medical University, Binzhou, China
| | - Xue Sui
- Department of Laboratory Medicine, Binzhou Medical University, Binzhou, China
| | - Liang Weng
- Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China.,Key Laboratory of Molecular Radiation Oncology Hunan Province, Xiangya Hospital, Central South University, Changsha, China.,Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Xiangya Hospital, Central South University, Changsha, China.,Hunan Provincial Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South University, Changsha, China.,Institute of Gerontological Cancer Research, National Clinical Research Center for Gerontology, Changsha, China.,Center for Molecular Imaging of Central South University, Xiangya Hospital, Changsha, China
| | - Yongshuo Liu
- Department of Clinical Laboratory, Binzhou Medical University Hospital, Binzhou, China.,Biomedical Pioneering Innovation Center (BIOPIC), Beijing Advanced Innovation Center for Genomics, Peking-Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
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27
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Liu M, Yang J, Xu B, Zhang X. Tumor metastasis: Mechanistic insights and therapeutic interventions. MedComm (Beijing) 2021; 2:587-617. [PMID: 34977870 PMCID: PMC8706758 DOI: 10.1002/mco2.100] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/01/2021] [Accepted: 11/03/2021] [Indexed: 12/18/2022] Open
Abstract
Cancer metastasis is responsible for the vast majority of cancer-related deaths worldwide. In contrast to numerous discoveries that reveal the detailed mechanisms leading to the formation of the primary tumor, the biological underpinnings of the metastatic disease remain poorly understood. Cancer metastasis is a complex process in which cancer cells escape from the primary tumor, settle, and grow at other parts of the body. Epithelial-mesenchymal transition and anoikis resistance of tumor cells are the main forces to promote metastasis, and multiple components in the tumor microenvironment and their complicated crosstalk with cancer cells are closely involved in distant metastasis. In addition to the three cornerstones of tumor treatment, surgery, chemotherapy, and radiotherapy, novel treatment approaches including targeted therapy and immunotherapy have been established in patients with metastatic cancer. Although the cancer survival rate has been greatly improved over the years, it is still far from satisfactory. In this review, we provided an overview of the metastasis process, summarized the cellular and molecular mechanisms involved in the dissemination and distant metastasis of cancer cells, and reviewed the important advances in interventions for cancer metastasis.
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Affiliation(s)
- Mengmeng Liu
- Melanoma and Sarcoma Medical Oncology UnitState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Jing Yang
- Melanoma and Sarcoma Medical Oncology UnitState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Bushu Xu
- Melanoma and Sarcoma Medical Oncology UnitState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Xing Zhang
- Melanoma and Sarcoma Medical Oncology UnitState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
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28
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Stemness, Inflammation and Epithelial-Mesenchymal Transition in Colorectal Carcinoma: The Intricate Network. Int J Mol Sci 2021; 22:ijms222312891. [PMID: 34884696 PMCID: PMC8658015 DOI: 10.3390/ijms222312891] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/22/2021] [Accepted: 11/25/2021] [Indexed: 02/07/2023] Open
Abstract
In global cancer statistics, colorectal carcinoma (CRC) ranks third by incidence and second by mortality, causing 10.0% of new cancer cases and 9.4% of oncological deaths worldwide. Despite the development of screening programs and preventive measures, there are still high numbers of advanced cases. Multiple problems compromise the treatment of metastatic colorectal cancer, one of these being cancer stem cells—a minor fraction of pluripotent, self-renewing malignant cells capable of maintaining steady, low proliferation and exhibiting an intriguing arsenal of treatment resistance mechanisms. Currently, there is an increasing body of evidence for intricate associations between inflammation, epithelial–mesenchymal transition and cancer stem cells. In this review, we focus on inflammation and its role in CRC stemness development through epithelial–mesenchymal transition.
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29
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Miao D, Wang Y, Jia Y, Tong J, Jiang S, Liu L. ZRANB1 enhances stem-cell-like features and accelerates tumor progression by regulating Sox9-mediated USP22/Wnt/β-catenin pathway in colorectal cancer. Cell Signal 2021; 90:110200. [PMID: 34798260 DOI: 10.1016/j.cellsig.2021.110200] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 11/08/2021] [Accepted: 11/13/2021] [Indexed: 12/18/2022]
Abstract
The pathogenesis of colorectal cancer (CRC) is a multistep process characterized by the accumulation of gene mutations and epigenetic alterations. Tumor necrosis factor receptor-associated factor-binding protein domain (ZRANB1) is a deubiquitinase that mediates tumor growth and metastasis by deubiquitinating target proteins. In this study, we examined the regulatory effects of ZRANB1 on the maintenance of cancer stem cell (CSC) properties and tumor growth in CRC. Human CRC tissue samples and matched normal tissues were collected for the analysis of ZRANB1 expression. ZRANB1 was upregulated in CRC human tissues and cell lines, and its expression was positively correlated with advanced tumor stage and poor survival of CRC patients. The overexpression of ZRANB1 also induced the expression of CSC markers in CRC cells. Then, a xenograft model was established by inoculating BALB/c mice with CRC cells. The upregulation of ZRANB1 promoted tumorigenesis in vivo. Sox9 is a transcription factor that acts as an oncogene in human cancers. ZRANB1 increased the stability of Sox9 in CRC cells by decelerating its ubiquitination. Further analysis revealed that Sox9 regulated the transcription activity of USP22 by binding to its promoter. Moreover, ZRANB1 enhances stem-cell-like features of CRC cells and activated the Wnt/β-catenin pathway through USP22. Our results highlighted the role of ZRANB1 as a molecular target for CRC treatment, which may contribute to the development of novel therapies with better efficacy.
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Affiliation(s)
- Dazhuang Miao
- Colorectal Cancer Surgical Ward 2, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150081, China
| | - Yan Wang
- Colorectal Cancer Surgical Ward 2, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150081, China
| | - Yunhe Jia
- Colorectal Cancer Surgical Ward 2, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150081, China.
| | - Jinxue Tong
- Colorectal Cancer Surgical Ward 2, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150081, China.
| | - Shixiong Jiang
- Colorectal Cancer Surgical Ward 2, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150081, China
| | - Lixiu Liu
- Colorectal Cancer Surgical Ward 2, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150081, China
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30
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Guo Y, Wang S, Zhao ZY, Li JN, Shang A, Li DL, Wang M. Skeletal muscle metastasis with bone metaplasia from colon cancer: A case report and review of the literature. World J Clin Cases 2021; 9:9285-9294. [PMID: 34786415 PMCID: PMC8567510 DOI: 10.12998/wjcc.v9.i30.9285] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/30/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colon cancer is a common malignant disease of the gastrointestinal tract and usually occurs at the junction of the rectum and sigmoid colon. Lymphatic and hematogenous metastases occur frequently in colon cancer and the most common metastatic sites include the liver, lung, peritoneum, bone, and lymph nodes. As a manifestation of advanced tumor spread and metastasis, soft tissue metastasis, especially skeletal muscle metastasis with bone metaplasia caused by colon cancer, is rare, accounting for less than 1% of metastases.
CASE SUMMARY A 43-year-old male patient developed skeletal muscle metastasis with bone metaplasia of the right proximal thigh 5 mo after colon cancer was diagnosed. The patient was admitted to the hospital because of pain caused by a local mass on his right thigh. Positron emission tomography-computed tomography showed many enlarged lymph nodes around the abdominal aorta but no signs of lung or liver metastases. Color ultrasound revealed a mass located in the skeletal muscle and the results of histological biopsy revealed a poorly differentiated adenocarcinoma suspected to be distant metastases from colon cancer. Immunohistochemistry showed small woven bone components that were considered to be ossified.
CONCLUSION This case reminds us that for patients with advanced colorectal tumors, we should be alert to the possibility of unconventional metastasis.
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Affiliation(s)
- Yu Guo
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Shuang Wang
- Department of Dermatology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Ze-Yun Zhao
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Jian-Nan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - An Shang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Dong-Lin Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Min Wang
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
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Yao J, Yang J, Yang Z, Wang XP, Yang T, Ji B, Zhang ZY. FBXW11 contributes to stem-cell-like features and liver metastasis through regulating HIC1-mediated SIRT1 transcription in colorectal cancer. Cell Death Dis 2021; 12:930. [PMID: 34642302 PMCID: PMC8511012 DOI: 10.1038/s41419-021-04185-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 09/02/2021] [Accepted: 09/15/2021] [Indexed: 01/10/2023]
Abstract
Colorectal tumorigenesis is a heterogeneous disease driven by multiple genetic and epigenetic alterations. F-box and WD repeat domain containing 11 (FBXW11) is a member of the F-box protein family that regulates the ubiquitination of key factors associated with tumor growth and aggressiveness. Our study aimed to explore the role of FBXW11 in the development and metastasis of colorectal cancer (CRC). FBXW11 was overexpressed in colorectal tumor tissues and its overexpression was associated with a poor prognosis of CRC patients. The upregulation of FBXW11 not only promoted cell proliferation, invasion, and migration, but also contributed to maintaining stem-cell features in colorectal tumor cells. Further analysis revealed that FBXW11 targeted hypermethylated in cancer 1 (HIC1) and reduced its stability in CRC cells through ubiquitination. Moreover, the expression of sirtuin 1 (SIRT1), a deacetylase in tumor cells was upregulated by FBXW11 via regulating HIC1 expression. The mouse xenograft models of CRC confirmed that FBXW11 knockdown impeded colorectal tumor growth and liver metastasis in vivo. In summary, our study identified FBXW11 as an oncogenic factor that contributed to stem-cell-like properties and liver metastasis in CRC via regulating HIC1-mediated SIRT1 expression. These results provide a rationale for the development of FBXW11-targeting drugs for CRC patients.
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Affiliation(s)
- Jing Yao
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai City, 200233, China
| | - Jun Yang
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai City, 200233, China
| | - Zhe Yang
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai City, 200233, China
| | - Xin-Ping Wang
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai City, 200233, China
| | - Tong Yang
- Department of Internal Medicine, Huzhou Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Huzhou City, Zhejiang Province, 313000, China
| | - Bing Ji
- Department of Internal Medicine, Huzhou Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, Huzhou City, Zhejiang Province, 313000, China.
| | - Zheng-Yun Zhang
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai City, 200233, China.
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32
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Loo SY, Toh LP, Xie WH, Pathak E, Tan W, Ma S, Lee MY, Shatishwaran S, Yeo JZZ, Yuan J, Ho YY, Peh EKL, Muniandy M, Torta F, Chan J, Tan TJ, Sim Y, Tan V, Tan B, Madhukumar P, Yong WS, Ong KW, Wong CY, Tan PH, Yap YS, Deng LW, Dent R, Foo R, Wenk MR, Lee SC, Ho YS, Lim EH, Tam WL. Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer. SCIENCE ADVANCES 2021; 7:eabh2443. [PMID: 34613780 PMCID: PMC8494440 DOI: 10.1126/sciadv.abh2443] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of lipid metabolism. Retinoids bind cognate nuclear receptors, which target lipid metabolism genes, thereby redirecting fatty acids for β-oxidation in the mesenchymal cell state towards lipid storage in the epithelial cell state. Disruptions of key metabolic enzymes mediating this flux inhibit MET. Conversely, perturbations to fatty acid oxidation (FAO) rechannel fatty acid flux and promote a more epithelial cell phenotype, blocking EMT-driven breast cancer metastasis in animal models. FAO impinges on the epigenetic control of EMT through acetyl-CoA-dependent regulation of histone acetylation on EMT genes, thus determining cell states.
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Affiliation(s)
- Ser Yue Loo
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore
| | - Li Ping Toh
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore
| | - William Haowei Xie
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore
| | - Elina Pathak
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore
| | - Wilson Tan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore
| | - Siming Ma
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore
| | - May Yin Lee
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore
| | - S. Shatishwaran
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore
| | - Joanna Zhen Zhen Yeo
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Ju Yuan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore
| | - Yin Ying Ho
- Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Singapore 138668, Singapore
| | - Esther Kai Lay Peh
- Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Singapore 138668, Singapore
| | - Magendran Muniandy
- Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore
| | - Federico Torta
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore
- Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore
- Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore
| | - Jack Chan
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
| | - Tira J. Tan
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
- Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
| | - Yirong Sim
- Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
| | - Veronique Tan
- Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
| | - Benita Tan
- Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
| | - Preetha Madhukumar
- Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
| | - Wei Sean Yong
- Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
| | - Kong Wee Ong
- Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
| | - Chow Yin Wong
- Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
| | - Puay Hoon Tan
- Division of Pathology, Singapore General Hospital, 20 College Rd., Singapore 169856, Singapore
| | - Yoon Sim Yap
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
- Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
| | - Lih-Wen Deng
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore
| | - Rebecca Dent
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
| | - Roger Foo
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore
| | - Markus R. Wenk
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore
- Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore
- Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore
| | - Soo Chin Lee
- Department of Haematology-Oncology, National University Cancer Institute, National University Health System, 5 Lower Kent Ridge Road, Singapore 119074, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore
| | - Ying Swan Ho
- Bioprocessing Technology Institute, Agency for Science, Technology and Research (A*STAR), 20 Biopolis Way, Singapore 138668, Singapore
| | - Elaine Hsuen Lim
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore 169610, Singapore
- Corresponding author. (E.H.L.); (W.L.T.)
| | - Wai Leong Tam
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Singapore 138672, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University Singapore, 14 Medical Drive, Singapore 117599, Singapore
- Corresponding author. (E.H.L.); (W.L.T.)
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Afshar-Khamseh R, Javeri A, Taha MF. MiR-146a suppresses the expression of CXCR4 and alters survival, proliferation and migration rate in colorectal cancer cells. Tissue Cell 2021; 73:101654. [PMID: 34601384 DOI: 10.1016/j.tice.2021.101654] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 12/14/2022]
Abstract
CXCR4 plays an important role in colorectal cancer (CRC) development and metastasis. Some previous studies have indicated CXCR4 as a therapeutic target in cancer. CXCR4 is known as a direct target of miR-146a. The present study aimed to investigate how exogenous induction of miR-146a affects CXCR4 gene and protein expression and also proliferation, apoptosis and migration of CRC cells. Transfection of Caco-2 and SW480 cells by a synthetic miR-146a mimic led to downregulation of CXCR4 expression at both gene and protein levels. It also downregulated expression of several miR-146a targets, including GSK3B, IRAK1, TRAF6, AKT2, SMAD4, EGFR and NFKB1, mostly in SW480 cells. Overexpression of miR-146a resulted in a partial cell cycle arrest in the both cell lines, while the apoptotic rate was also decreased. In regards to epithelial-mesenchymal transition factors, VIM was downregulated in the both cell lines, but SNAI1 was upregulated in Caco-2 cells. The wound closure assay showed a reduction in cell migration in SW480 cells, but an opposite effect was detected in Caco-2 cells following transfection with miR-146a mimic. Therefore, our results are indicating that overexpression of miR-146a, despite downregulation of oncogenic CXCR4, may not lead to a universal tumor suppressive effect in all CRC cells, and this is possibly due to differences in miR-146a effects on signaling pathways in each cell type. Selection of miR-146a for tumor suppression requires enough details regarding the signaling profile of cancer cells otherwise it may produce unexpected outcome.
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Affiliation(s)
- Reyhaneh Afshar-Khamseh
- Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Box: 14965-161, Tehran, Iran
| | - Arash Javeri
- Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Box: 14965-161, Tehran, Iran.
| | - Masoumeh Fakhr Taha
- Department of Stem Cells and Regenerative Medicine, Institute for Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Box: 14965-161, Tehran, Iran.
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Zaitceva V, Kopeina GS, Zhivotovsky B. Anastasis: Return Journey from Cell Death. Cancers (Basel) 2021; 13:3671. [PMID: 34359573 PMCID: PMC8345212 DOI: 10.3390/cancers13153671] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/16/2021] [Accepted: 07/17/2021] [Indexed: 12/12/2022] Open
Abstract
For over 20 years, it has been a dogma that once the integrity of mitochondria is disrupted and proapoptotic proteins that are normally located in the intermembrane space of mitochondria appeared in the cytoplasm, the process of cell death becomes inevitable. However, it has been recently shown that upon removal of the death signal, even at the stage of disturbance in the mitochondria, cells can recover and continue to grow. This phenomenon was named anastasis. Here, we will critically discuss the present knowledge concerning the mechanisms of cell death reversal, or development of anastasis, methods for its detection, and what role signaling from different intracellular compartments plays in anastasis stimulation.
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Affiliation(s)
- Victoria Zaitceva
- Faculty of Medicine, MV Lomonosov Moscow State University, 119991 Moscow, Russia; (V.Z.); (G.S.K.)
| | - Gelina S. Kopeina
- Faculty of Medicine, MV Lomonosov Moscow State University, 119991 Moscow, Russia; (V.Z.); (G.S.K.)
| | - Boris Zhivotovsky
- Faculty of Medicine, MV Lomonosov Moscow State University, 119991 Moscow, Russia; (V.Z.); (G.S.K.)
- Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, 17177 Stockholm, Sweden
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Ghaderi F, Jokar N, Gholamrezanezhad A, Assadi M, Ahmadzadehfar H. Toward radiotheranostics in cancer stem cells: a promising initial step for tumour eradication. Clin Transl Imaging 2021. [DOI: 10.1007/s40336-021-00444-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Özerkan D, Erol A, Altuner EM, Canlı K, Kuruca DS. Some Bryophytes Trigger Cytotoxicity of Stem Cell-like Population in 5-Fluorouracil Resistant Colon Cancer Cells. Nutr Cancer 2021; 74:1012-1022. [PMID: 34151658 DOI: 10.1080/01635581.2021.1933098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Colorectal cancer is the third most common cancer worldwide. Cancer stem cells are known to play an important role in relapse, and metastases of the disease after chemotherapy. Investigation of new drugs, and their combinations targeting these cells and thus eliminating cancer is one of the most urgent needs of today's chemotherapy. The aim of the present study was to evaluate the effects of Bryophytes like Abietinella abietina (AA), Homolothecium sericeum (HS), Tortella tortuosa (TT), Syntrichia ruralis (SR), and Bryoerythrophyllum rubrum (BR) species extracted with ethyl alcohol on 5-fluorouracil(5-FU) resistant colorectal cancer cell lines (HCT116 and HT29). After extraction, stock solutions of bryophytes were prepared, and IC50 values were detected in drug-resistant cells obtained with 5-FU application. CD24+, CD44+/CD133+ surface markers and P-glycoprotein (P-gp) mediated efflux were isolated from both 5-FU treated cells and analyzed using the flow cytometry. In all bryophyte-treated groups, the binding Rho123low (low Rho fluorescence) and Rhohigh (high Rho fluorescence) were sorted from 5-FU resistant HCT116, and HT-29 cells. All types of bryophytes were found cytotoxic. Bryophyte extract reduced the percentage of Rholow cells in cultures incubated with 5-FU. In summary, the implementation of these bryophytes might be regarded as an effective approach for treatment of colorectal cancer due to their cytotoxic effect that decreases the recurrence of the disease.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.1933098.
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Affiliation(s)
- Dilşad Özerkan
- Faculty of Health Sciences, Molecular Cancer Research Center, İstinye University, İstanbul, Turkey
| | - Ayşe Erol
- Department of Medical Biology, Faculty of Medicine, İstanbul University, İstanbul, Turkey
| | - Ergin Murat Altuner
- Department of Biology, Faculty of Science and Literature, Kastamonu University, Kastamonu, Turkey
| | - Kerem Canlı
- Department of Biology, Faculty of Sciences, Dokuz Eylül University, İzmir, Turkey
| | - Dürdane Serap Kuruca
- Department of Physiology, Faculty of Medicine, Istanbul University, İstanbul, Turkey
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Wieczorek-Szukala K, Lewinski A. The Role of Snail-1 in Thyroid Cancer-What We Know So Far. J Clin Med 2021; 10:2324. [PMID: 34073413 PMCID: PMC8197874 DOI: 10.3390/jcm10112324] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/24/2021] [Accepted: 05/25/2021] [Indexed: 12/12/2022] Open
Abstract
Thyroid carcinomas, despite the usually indolent behaviour and relatively good overall prognosis, show a high tendency to gain invasive phenotype and metastasise in some cases. However, due to a relatively slow progression, the exact mechanisms governing the metastatic process of thyroid carcinomas, including the epithelial-to-mesenchymal transition (EMT), are poorly described. One of the best-known regulators of cancer invasiveness is Snail-1-a zinc-finger transcription factor that plays a key role as an EMT inducer. More and more attention is being paid to the role of Snail with regard to thyroid cancer development. Apart from the obvious implications in the EMT process, Snail-1 plays an important role in the regulation of chemoresistance of the thyroid cells and cancer stem cell (CSC) formation, and it also interacts with miRNA specific to the thyroid gland. The aim of this review was to summarise the knowledge on Snail-1, especially in the context of thyroid oncogenesis.
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Affiliation(s)
| | - Andrzej Lewinski
- Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, 93-338 Lodz, Poland;
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Alimoradi N, Firouzabadi N, Fatehi R. How metformin affects various malignancies by means of microRNAs: a brief review. Cancer Cell Int 2021; 21:207. [PMID: 33849540 PMCID: PMC8045276 DOI: 10.1186/s12935-021-01921-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/07/2021] [Indexed: 12/15/2022] Open
Abstract
Metformin known as the first-line orally prescribed drug for lowering blood glucose in type II diabetes (T2DM) has recently found various therapeutic applications including in cancer. Metformin has been studied for its influences in prevention and treatment of cancer through multiple mechanisms such as microRNA (miR) regulation. Alteration in the expression of miRs by metformin may play an important role in the treatment of various cancers. MiRs are single-stranded RNAs that are involved in gene regulation. By binding to the 3'UTR of target mRNAs, miRs influence protein levels. Irregularities in the expression of miRs that control the expression of oncogenes and tumor suppressor genes are associated with the onset and progression of cancer. Metformin may possess an effect on tumor prevention and progression by modifying miR expression and downstream pathways. Here, we summarize the effect of metformin on different types of cancer by regulating the expression of various miRs and the associated downstream molecules.
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Affiliation(s)
- Nahid Alimoradi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Firouzabadi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Reihaneh Fatehi
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
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Poturnajova M, Furielova T, Balintova S, Schmidtova S, Kucerova L, Matuskova M. Molecular features and gene expression signature of metastatic colorectal cancer (Review). Oncol Rep 2021; 45:10. [PMID: 33649827 PMCID: PMC7876998 DOI: 10.3892/or.2021.7961] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Accepted: 12/04/2020] [Indexed: 12/13/2022] Open
Abstract
Uncontrollable metastatic outgrowth process is the leading cause of mortality worldwide, even in the case of colorectal cancer. Colorectal cancer (CRC) accounts for approximately 10% of all annually diagnosed cancers and 50% of CRC patients will develop metastases in the course of disease. Most patients with metastatic CRC have incurable disease. Even if patients undergo resection of liver metastases, the 5‑year survival rate ranges from 25 to 58%. Next‑generation sequencing of tumour specimens from large colorectal cancer patient cohorts has led to major advances in elucidating the genomic landscape of these tumours and paired metastases. The expression profiles of primary CRC and their metastatic lesions at both the gene and pathway levels were compared and led to the selection of early driver genes responsible for carcinogenesis and metastasis‑specific genes that increased the metastatic process. The genetic, transcriptional and epigenetic alteration encoded by these genes and their combination influence many pivotal signalling pathways, enabling the dissemination and outgrowth in distant organs. Therapeutic regimens affecting several different active pathways may have important implications for therapeutic efficacy.
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Affiliation(s)
- Martina Poturnajova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, University Science Park for Biomedicine, 84505 Bratislava, Slovakia
| | - Tatiana Furielova
- Department of Genetics, Faculty of Natural Sciences, Comenius University, 84215 Bratislava, Slovakia
| | - Sona Balintova
- Department of Genetics, Faculty of Natural Sciences, Comenius University, 84215 Bratislava, Slovakia
| | - Silvia Schmidtova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, University Science Park for Biomedicine, 84505 Bratislava, Slovakia
- Translational Research Unit, Faculty of Medicine, Comenius University, 81499 Bratislava, Slovakia
| | - Lucia Kucerova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, University Science Park for Biomedicine, 84505 Bratislava, Slovakia
| | - Miroslava Matuskova
- Department of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of Slovak Academy of Sciences, University Science Park for Biomedicine, 84505 Bratislava, Slovakia
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Genetic and Non-Genetic Mechanisms Underlying Cancer Evolution. Cancers (Basel) 2021; 13:cancers13061380. [PMID: 33803675 PMCID: PMC8002988 DOI: 10.3390/cancers13061380] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 03/10/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Our manuscript summarizes the up-to-date data on the complex and dynamic nature of adaptation mechanisms and evolutionary processes taking place during cancer initiation, development and progression. Although for decades cancer has been viewed as a process governed by genetic mechanisms, it is becoming more and more clear that non-genetic mechanisms may play an equally important role in cancer evolution. In this review, we bring together these fundamental concepts and discuss how those tightly interconnected mechanisms lead to the establishment of highly adaptive quickly evolving cancers. Furthermore, we argue that in depth understanding of cancer progression from the evolutionary perspective may allow the prediction and direction of the evolutionary path of cancer populations towards drug sensitive phenotypes and thus facilitate the development of more effective anti-cancer approaches. Abstract Cancer development can be defined as a process of cellular and tissular microevolution ultimately leading to malignancy. Strikingly, though this concept has prevailed in the field for more than a century, the precise mechanisms underlying evolutionary processes occurring within tumours remain largely uncharacterized and rather cryptic. Nevertheless, although our current knowledge is fragmentary, data collected to date suggest that most tumours display features compatible with a diverse array of evolutionary paths, suggesting that most of the existing macro-evolutionary models find their avatar in cancer biology. Herein, we discuss an up-to-date view of the fundamental genetic and non-genetic mechanisms underlying tumour evolution with the aim of concurring into an integrated view of the evolutionary forces at play throughout the emergence and progression of the disease and into the acquisition of resistance to diverse therapeutic paradigms. Our ultimate goal is to delve into the intricacies of genetic and non-genetic networks underlying tumour evolution to build a framework where both core concepts are considered non-negligible and equally fundamental.
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Angius A, Scanu AM, Arru C, Muroni MR, Rallo V, Deiana G, Ninniri MC, Carru C, Porcu A, Pira G, Uva P, Cossu-Rocca P, De Miglio MR. Portrait of Cancer Stem Cells on Colorectal Cancer: Molecular Biomarkers, Signaling Pathways and miRNAome. Int J Mol Sci 2021; 22:1603. [PMID: 33562604 PMCID: PMC7915330 DOI: 10.3390/ijms22041603] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer death worldwide, and about 20% is metastatic at diagnosis and untreatable. Increasing evidence suggests that the heterogeneous nature of CRC is related to colorectal cancer stem cells (CCSCs), a small cells population with stemness behaviors and responsible for tumor progression, recurrence, and therapy resistance. Growing knowledge of stem cells (SCs) biology has rapidly improved uncovering the molecular mechanisms and possible crosstalk/feedback loops between signaling pathways that directly influence intestinal homeostasis and tumorigenesis. The generation of CCSCs is probably connected to genetic changes in members of signaling pathways, which control self-renewal and pluripotency in SCs and then establish function and phenotype of CCSCs. Particularly, various deregulated CCSC-related miRNAs have been reported to modulate stemness features, controlling CCSCs functions such as regulation of cell cycle genes expression, epithelial-mesenchymal transition, metastasization, and drug-resistance mechanisms. Primarily, CCSC-related miRNAs work by regulating mainly signal pathways known to be involved in CCSCs biology. This review intends to summarize the epigenetic findings linked to miRNAome in the maintenance and regulation of CCSCs, including their relationships with different signaling pathways, which should help to identify specific diagnostic, prognostic, and predictive biomarkers for CRC, but also develop innovative CCSCs-targeted therapies.
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Affiliation(s)
- Andrea Angius
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
| | - Antonio Mario Scanu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Caterina Arru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Maria Rosaria Muroni
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Vincenzo Rallo
- Institute of Genetic and Biomedical Research (IRGB), CNR, Cittadella Universitaria di Cagliari, 09042 Monserrato, Italy;
| | - Giulia Deiana
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Maria Chiara Ninniri
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Alberto Porcu
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
| | - Giovanna Pira
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; (C.A.); (C.C.); (G.P.)
| | - Paolo Uva
- IRCCS G. Gaslini, 16147 Genoa, Italy;
| | - Paolo Cossu-Rocca
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
- Department of Diagnostic Services, “Giovanni Paolo II” Hospital, ASSL Olbia-ATS Sardegna, 07026 Olbia, Italy
| | - Maria Rosaria De Miglio
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Via P. Manzella, 4, 07100 Sassari, Italy; (A.M.S.); (M.R.M.); (G.D.); (M.C.N.); (A.P.); (P.C.-R.)
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Cancer Stem Cells and Nucleolin as Drivers of Carcinogenesis. Pharmaceuticals (Basel) 2021; 14:ph14010060. [PMID: 33451077 PMCID: PMC7828541 DOI: 10.3390/ph14010060] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/05/2021] [Accepted: 01/11/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer, one of the most mortal diseases worldwide, is characterized by the gain of specific features and cellular heterogeneity. Clonal evolution is an established theory to explain heterogeneity, but the discovery of cancer stem cells expanded the concept to include the hierarchical growth and plasticity of cancer cells. The activation of epithelial-to-mesenchymal transition and its molecular players are widely correlated with the presence of cancer stem cells in tumors. Moreover, the acquisition of certain oncological features may be partially attributed to alterations in the levels, location or function of nucleolin, a multifunctional protein involved in several cellular processes. This review aims at integrating the established hallmarks of cancer with the plasticity of cancer cells as an emerging hallmark; responsible for tumor heterogeneity; therapy resistance and relapse. The discussion will contextualize the involvement of nucleolin in the establishment of cancer hallmarks and its application as a marker protein for targeted anticancer therapies
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Chen X, Liang R, Lin H, Chen K, Chen L, Tian G, Zhu X. CD166 promotes cancer stem cell-like phenotype via the EGFR/ERK1/2 pathway in the nasopharyngeal carcinoma cell line CNE-2R. Life Sci 2020; 267:118983. [PMID: 33383046 DOI: 10.1016/j.lfs.2020.118983] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/30/2020] [Accepted: 12/21/2020] [Indexed: 12/24/2022]
Abstract
AIMS The present study aimed to investigate the role and underlying mechanisms of CD166 in cancer stem cell-like (CSCs) phenotype of the radioresistant nasopharyngeal carcinoma cell CNE-2R. MAIN METHODS Established CD166-shRNA- CNE-2R cell line by lentivirus-mediated silencing CD166. Then, CSC-related genes mRNAs and proteins, and EGFR/ERK1/2 signaling pathway were detected using RT-PCR and western blot. Sphere formation assay was performed to evaluate the sphere formation capacity in CD166-shRNA- CNE-2R cells. The tumorigenesis ability in vivo was examined in nude mice mode. KEY FINDINGS Downregulation of CD166 inhibited the expression of the CSC-related genes, pEGFR and pERK in vitro and vivo. The capacity to form spheres and tumorigenesis was significantly decreased in CD166-shRNA cells. Furthermore, EGF-stimulated CD166-shRNA cells exhibited an increase in CSC-like traits by activating EGFR/ERK1/2 signaling. SIGNIFICANCE CD166 induced CSCs formation by activating the EGFR/ERK1/2 signaling pathway in nasopharyngeal carcinoma, which may serve as a critical molecular target for NPC therapeutic strategies.
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Affiliation(s)
- Xishan Chen
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, PR China; Department of Oncology, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi 545000, PR China
| | - Renba Liang
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, PR China
| | - Huan Lin
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, PR China; Department of Oncology, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi 545000, PR China
| | - Kaihua Chen
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, PR China
| | - Li Chen
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, PR China
| | - Ge Tian
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, PR China
| | - Xiaodong Zhu
- Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, PR China; Wuming Hospital of Guangxi Medical University, Nanning, Guangxi, PR China; Key Laboratory of Early Prevention and Treatment for Regional High-Incidence-Tumor, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, PR China.
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McCabe EM, Rasmussen TP. lncRNA involvement in cancer stem cell function and epithelial-mesenchymal transitions. Semin Cancer Biol 2020; 75:38-48. [PMID: 33346133 DOI: 10.1016/j.semcancer.2020.12.012] [Citation(s) in RCA: 176] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 10/14/2020] [Accepted: 12/12/2020] [Indexed: 02/06/2023]
Abstract
Epithelial to mesenchymal transition (EMT) is a cellular process in which cells composing epithelial tissue lose requirements for physical contact with neighboring cells and acquire mesenchymal characteristics consisting of increased migratory and invasive behaviors. EMT is a fundamental process that is required for initial and later events during embryogenesis. Cancer stem cells (CSCs) possess multipotency sufficient for their differentiation into bulk tumor cells and also have the capacity to undergo EMT. When CSCs initiate EMT programs the resulting cancerous mesenchymal cells become invasive and this migratory behavior also poises them for metastatic activity. Long noncoding RNAs (lncRNAs) are functional RNA molecules that do not encode proteins, yet regulate the expression of protein-coding genes through recruitment or sequestration of gene-regulatory proteins and microRNAs. lncRNA exhibit tissue-specific patterns of gene expression during development and specific sets of lncRNAs are also involved in various cancer types. This review considers the interplay between lncRNAs and the biogenesis of CSCs. We also review function of lncRNAs in EMT in CSCs. In addition, we discuss the utility of lncRNAs as biomarkers of cancer progression, and their potential use as therapeutic targets for treatment of cancer.
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Affiliation(s)
- Evan M McCabe
- Department of Molecular and Cell Biology, University of Connecticut, USA
| | - Theodore P Rasmussen
- Department of Molecular and Cell Biology, University of Connecticut, USA; Department of Pharmaceutical Sciences, University of Connecticut, USA; University of Connecticut Stem Cell Institute, University of Connecticut, USA.
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Huang X, Chen Q, Luo W, Pakvasa M, Zhang Y, Zheng L, Li S, Yang Z, Zeng H, Liang F, Zhang F, Hu DA, Qin KH, Wang EJ, Qin DS, Reid RR, He TC, Athiviraham A, El Dafrawy M, Zhang H. SATB2: A versatile transcriptional regulator of craniofacial and skeleton development, neurogenesis and tumorigenesis, and its applications in regenerative medicine. Genes Dis 2020; 9:95-107. [PMID: 35005110 PMCID: PMC8720659 DOI: 10.1016/j.gendis.2020.10.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/30/2020] [Accepted: 10/06/2020] [Indexed: 02/07/2023] Open
Abstract
SATB2 (special AT-rich sequence-binding protein 2) is a member of the special AT-rich binding protein family. As a transcription regulator, SATB2 mainly integrates higher-order chromatin organization. SATB2 expression appears to be tissue- and stage-specific, and is governed by several cellular signaling molecules and mediators. Expressed in branchial arches and osteoblast-lineage cells, SATB2 plays a significant role in craniofacial pattern and skeleton development. In addition to regulating osteogenic differentiation, SATB2 also displays versatile functions in neural development and cancer progression. As an osteoinductive factor, SATB2 holds great promise in improving bone regeneration toward bone defect repair. In this review, we have summarized our current understanding of the physiological and pathological functions of SATB2 in craniofacial and skeleton development, neurogenesis, tumorigenesis and regenerative medicine.
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Affiliation(s)
- Xia Huang
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, PR China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, PR China
| | - Qiuman Chen
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, PR China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, PR China
| | - Wenping Luo
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, PR China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, PR China.,Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Mikhail Pakvasa
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA.,The Pritzker School of Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA.,Department of Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yuxin Zhang
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, PR China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, PR China
| | - Liwen Zheng
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, PR China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, PR China
| | - Shuang Li
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, PR China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, PR China
| | - Zhuohui Yang
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, PR China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, PR China
| | - Huan Zeng
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, PR China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, PR China
| | - Fang Liang
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, PR China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, PR China
| | - Fugui Zhang
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, PR China.,Chongqing Key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, PR China.,Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Daniel A Hu
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Kevin H Qin
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Eric J Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - David S Qin
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Russell R Reid
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA.,Department of Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA.,Department of Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Aravind Athiviraham
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Mostafa El Dafrawy
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hongmei Zhang
- Stomatological Hospital of Chongqing Medical University, Chongqing 401147, PR China.,Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA.,Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, PR China
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Vermani L, Kumar R, Kannan RR, Deka MK, Talukdar A, Kumar NS. Expression pattern of ALDH1, E-cadherin, Vimentin and Twist in early and late onset sporadic colorectal cancer. Biomark Med 2020; 14:1371-1382. [PMID: 33064013 DOI: 10.2217/bmm-2020-0206] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 07/30/2020] [Indexed: 12/21/2022] Open
Abstract
Aim: To evaluate the expression pattern of ALDH1 (aldehyde dehydrogenase 1), E-cadherin, Vimentin and Twist in early and late onset sporadic colorectal cancer (CRC) and to study association of their expression with the occurrence of CRC at a young age. Materials & methods: Immunohistochemistry of ALDH1, E-cadherin, Vimentin and Twist was performed on 103 pretreated CRC biopsy samples. Results: ALDH1 expression was found to have strong correlation with early onset CRC (p < 0.0001). Conclusion: High ALDH1 expression correlates with the early onset of CRC. ALDH1 over-expression correlates with poor overall survival in colon cancer.
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Affiliation(s)
- Litika Vermani
- Mizoram University, Biotechnology, Aizawl, Mizoram 796004, India
| | - Rajeev Kumar
- Cachar Cancer Hospital & Research Centre, Research Silchar, 788015, India
| | | | - Monoj K Deka
- Silchar Medical College & Hospital, 788015, India
| | - Anuradha Talukdar
- Cachar Cancer Hospital & Research Centre, Research Silchar, 788015, India
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Chung HH, Lee CT, Hu JM, Chou YC, Lin YW, Shih YL. NKX6.1 Represses Tumorigenesis, Metastasis, and Chemoresistance in Colorectal Cancer. Int J Mol Sci 2020; 21:ijms21145106. [PMID: 32707737 PMCID: PMC7404324 DOI: 10.3390/ijms21145106] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 07/14/2020] [Accepted: 07/16/2020] [Indexed: 12/28/2022] Open
Abstract
Accumulating evidence suggests that NKX6.1 (NK homeobox 1) plays a role in various types of cancer. In our previous studies, we identified NKX6.1 hypermethylation as a promising marker and demonstrated that the NKX6.1 gene functions as a metastasis suppressor through the epigenetic regulation of the epithelial-to-mesenchymal transition (EMT) in cervical cancer. More recently, we have demonstrated that NKX6.1 methylation is related to the chemotherapy response in colorectal cancer (CRC). Nevertheless, the biological function of NKX6.1 in the tumorigenesis of CRC remains unclear. In this study, we showed that NKX6.1 suppresses tumorigenic and metastatic ability both in vitro and in vivo. NKX6.1 represses cell invasion partly through the modulation of EMT. The overexpression of NKX6.1 enhances chemosensitivity in CRC cells. To further explore how NKX6.1 exerts its tumor-suppressive function, we used RNA sequencing technology for comprehensive analysis. The results showed that differentially expressed genes (DEGs) were mainly related to cell migration, response to drug, transcription factor activity, and growth factor activity, suggesting that these DEGs are involved in the function of NKX6.1 suppressing cancer invasion and metastasis. Our results demonstrated that NKX6.1 functions as a tumor suppressor partly by repressing EMT and enhancing chemosensitivity in CRC, making it a potential therapeutic target.
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Affiliation(s)
- Hsin-Hua Chung
- Graduate Institute of Medical Sciences, National Defense Medical Center, No.161, Sec.6, Minquan East Rd., Neihu District, Taipei 11490, Taiwan; (H.-H.C.); (J.-M.H.); (Y.-W.L.)
| | - Chun-Te Lee
- Division of Urological Surgery, Department of Surgery, Tri-Service General Hospital Songshan Branch, No.131, Jiankang Rd., Songshan District, Taipei 10581, Taiwan;
| | - Je-Ming Hu
- Graduate Institute of Medical Sciences, National Defense Medical Center, No.161, Sec.6, Minquan East Rd., Neihu District, Taipei 11490, Taiwan; (H.-H.C.); (J.-M.H.); (Y.-W.L.)
- Division of Colorectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, No.325, Sec.2, Chenggong Rd., Neihu District, Taipei 11490, Taiwan
| | - Yu-Ching Chou
- School of Public Health, National Defense Medical Center, No.161, Sec.6, Minquan East Rd., Neihu District, Taipei 11490, Taiwan;
| | - Ya-Wen Lin
- Graduate Institute of Medical Sciences, National Defense Medical Center, No.161, Sec.6, Minquan East Rd., Neihu District, Taipei 11490, Taiwan; (H.-H.C.); (J.-M.H.); (Y.-W.L.)
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, No.161, Sec.6, Minquan East Rd., Neihu District, Taipei 11490, Taiwan
- Graduate Institute of Life Sciences, National Defense Medical Center, No.161, Sec.6, Minquan East Rd., Neihu District, Taipei 11490, Taiwan
| | - Yu-Lueng Shih
- Graduate Institute of Medical Sciences, National Defense Medical Center, No.161, Sec.6, Minquan East Rd., Neihu District, Taipei 11490, Taiwan; (H.-H.C.); (J.-M.H.); (Y.-W.L.)
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Chenggong Rd., Neihu District, Taipei 11490, Taiwan
- Correspondence: ; Tel./Fax: +886-2-87917654
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The SNAIL1 promoter contains G-quadruplex structures regulating its gene expression and DNA replication. Exp Cell Res 2020; 394:112158. [PMID: 32610184 DOI: 10.1016/j.yexcr.2020.112158] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 06/23/2020] [Accepted: 06/24/2020] [Indexed: 01/17/2023]
Abstract
SNAIL1 is a key regulator of epithelial-mesenchymal transition (EMT) and its expression is associated with tumor progression and poor clinical prognosis of cancer patients. Compared to the studies of SNAIL1 stability and its transcriptional regulation, very limited knowledge is available regarding effective approaches to directly target SNAIL1. In this study, we revealed the potential regulation of SNAIL1 gene expression by G-quadruplex structures in its promoter. We first revealed that the negative strand of the SNAIL1 promoter contained a multi-G-tract region with high potential of forming G-quadruplex structures. In circular dichroism studies, the oligonucleotide based on this region showed characteristic molar ellipticity at specific wavelengths of G-quadruplex structures. We also utilized native polyacrylamide gel electrophoresis, gel-shift assays, immunofluorescent staining, dimethyl sulfate footprinting and chromatin immunoprecipitation studies to verify the G-quadruplex structures formed by the oligonucleotide. In reporter assays, disruption of G-quadruplex potential increased SNAIL1 promoter-mediated transcription, suggesting that G-quadruplexes played a negative role in SNAIL1 expression. In a DNA synthesis study, we detected G-quadruplex-mediated retardation in the SNAIL1 promoter replication. Consistently, we discovered that the G-quadruplex region of the SNAIL1 promoter is highly enriched for mutations, implicating the clinical relevance of G-quadruplexes to the altered SNAIL1 expression in cancer cells.
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Kim Y, Ghil S. Regulators of G-protein signaling, RGS2 and RGS4, inhibit protease-activated receptor 4-mediated signaling by forming a complex with the receptor and Gα in live cells. Cell Commun Signal 2020; 18:86. [PMID: 32517689 PMCID: PMC7285472 DOI: 10.1186/s12964-020-00552-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 03/11/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Protease-activated receptor 4 (PAR4) is a seven transmembrane G-protein coupled receptor (GPCR) activated by endogenous proteases, such as thrombin. PAR4 is involved in various pathophysiologies including cancer, inflammation, pain, and thrombosis. Although regulators of G-protein signaling (RGS) are known to modulate GPCR/Gα-mediated pathways, their specific effects on PAR4 are not fully understood at present. We previously reported that RGS proteins attenuate PAR1- and PAR2-mediated signaling through interactions with these receptors in conjunction with distinct Gα subunits. METHODS We employed a bioluminescence resonance energy transfer technique and confocal microscopy to examine potential interactions among PAR4, RGS, and Gα subunits. The inhibitory effects of RGS proteins on PAR4-mediated downstream signaling and cancer progression were additionally investigated by using several assays including ERK phosphorylation, calcium mobilization, RhoA activity, cancer cell proliferation, and related gene expression. RESULTS In live cells, RGS2 interacts with PAR4 in the presence of Gαq while RGS4 binding to PAR4 occurs in the presence of Gαq and Gα12/13. Co-expression of PAR4 and Gαq induced a shift in the subcellular localization of RGS2 and RGS4 from the cytoplasm to plasma membrane. Combined PAR4 and Gα12/13 expression additionally promoted translocation of RGS4 from the cytoplasm to the membrane. Both RGS2 and RGS4 abolished PAR4-activated ERK phosphorylation, calcium mobilization and RhoA activity, as well as PAR4-mediated colon cancer cell proliferation and related gene expression. CONCLUSIONS RGS2 and RGS4 forms ternary complex with PAR4 in Gα-dependent manner and inhibits its downstream signaling. Our findings support a novel physiological function of RGS2 and RGS4 as inhibitors of PAR4-mediated signaling through selective PAR4/RGS/Gα coupling. Video Abstract.
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Affiliation(s)
- Yukeyoung Kim
- Department of Life Science, Kyonggi University, Suwon, 16227, South Korea
| | - Sungho Ghil
- Department of Life Science, Kyonggi University, Suwon, 16227, South Korea.
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Ribatti D, Tamma R, Annese T. Epithelial-Mesenchymal Transition in Cancer: A Historical Overview. Transl Oncol 2020; 13:100773. [PMID: 32334405 PMCID: PMC7182759 DOI: 10.1016/j.tranon.2020.100773] [Citation(s) in RCA: 554] [Impact Index Per Article: 110.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/26/2020] [Accepted: 04/01/2020] [Indexed: 12/12/2022] Open
Abstract
Epithelial-mesenchymal transitions (EMTs), the acquisition of mesenchymal features from epithelial cells, occur during some biological processes and are classified into three types: the first type occurs during embryonic development, the second type is associated with adult tissue regeneration, and the third type occurs in cancer progression. EMT occurring during embryonic development in gastrulation, renal development, and the origin and fate of the neural crest is a highly regulated process, while EMT occurring during tumor progression is highly deregulated. EMT allows the solid tumors to become more malignant, increasing their invasiveness and metastatic activity. Secondary tumors frequently maintain the typical histologic characteristics of the primary tumor. These histologic features connecting the secondary metastatic tumors to the primary is due to a process called mesenchymal-epithelial transition (MET). MET has been demonstrated in different mesenchymal tumors and is the expression of the reversibility of EMT. EMT modulation could constitute an approach to avoid metastasis. Some of the targeted small molecules utilized as antiproliferative agents have revealed to inhibit EMT initiation or maintenance because EMT is regulated through signaling pathways for which these molecules have been designed.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.
| | - Roberto Tamma
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
| | - Tiziana Annese
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy
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