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Fang Y, Tan C, Zheng Z, Yang J, Tang J, Guo R, Silli EK, Chen Z, Chen J, Ge R, Liu Y, Wen X, Liang J, Zhu Y, Jin Y, Li Q, Wang Y. The function of microRNA related to cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Biochem Pharmacol 2025; 236:116849. [PMID: 40056941 DOI: 10.1016/j.bcp.2025.116849] [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: 11/11/2024] [Revised: 02/13/2025] [Accepted: 03/03/2025] [Indexed: 03/17/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignant tumor characterized by a poor prognosis. A prominent feature of PDAC is the rich and dense stroma present in the tumor microenvironment (TME), which significantly hinders drug penetration. Cancer-associated fibroblasts (CAFs), activated fibroblasts originating from various cell sources, including pancreatic stellate cells (PSCs) and mesenchymal stem cells (MSCs), play a critical role in PDAC progression and TME formation. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules that are frequently involved in tumorigenesis and progression, exhibiting either oncolytic or oncogenic activity. Increasing evidence suggests that aberrant expression of miRNAs can mediate interactions between cancer cells and CAFs, thereby providing novel therapeutic targets for PDAC treatment. In this review, we will focus on the potential roles of miRNAs that target CAFs or CAFs-derived exosomes in PDAC progression, highlighting the feasibility of therapeutic strategies aimed at restoring aberrantly expressed miRNAs associated with CAFs, offering new pathways for the clinical management of PDAC.
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Affiliation(s)
- Yaohui Fang
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Chunlu Tan
- Department of Pancreatic Surgery and General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Zhenjiang Zheng
- Department of Pancreatic Surgery and General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jianchen Yang
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
| | - Jiali Tang
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Ruizhe Guo
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Epiphane K Silli
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Zhe Chen
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Jia Chen
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Ruyu Ge
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yuquan Liu
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Xiuqi Wen
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Jingdan Liang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yunfei Zhu
- School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yutong Jin
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Qian Li
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Ying Wang
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
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Saadh MJ, Jasim NY, Ahmed MH, Ballal S, Kumar A, Atteri S, Vashishth R, Rizaev J, Alhili A, Jawad MJ, Yazdi F, Salajegheh A, Akhavan-Sigari R. Critical roles of miR-21 in promotions angiogenesis: friend or foe? Clin Exp Med 2025; 25:66. [PMID: 39998742 PMCID: PMC11861128 DOI: 10.1007/s10238-025-01600-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 02/11/2025] [Indexed: 02/27/2025]
Abstract
MiRNAs are small RNA strands that are managed following transcription and are of substantial importance in blood vessel formation. It is essential to oversee the growth, differentiation, death, movement and construction of tubes by angiogenesis-affiliated cells. If miRNAs are not correctly regulated in regard to angiogenesis, it can deteriorate the health and lead to various illnesses, which include cancer, cardiovascular disorder, critical limb ischemia, Crohn's disease, ocular diseases, diabetic microvascular complications, and more. Consequently, it is vital to understand the crucial part that miRNAs play in the development of blood vessels, so we can develop reliable treatment plans for vascular diseases. This write-up will assess the critical role of miR-21/exosomal miR-21 in managing angiogenesis associated with bone growth, wound recovery, and other pathological conditions like tumor growth, ocular illnesses, diabetes, and other diseases connected to formation of blood vessels. Previous investigations have demonstrated that miR-21 is present at higher amounts in certain cancerous cells, and it influences a multitude of genes that moderate the increased creation of blood vessels. Furthermore, studies demonstrated that exosomal miR-21 has the capacity to interact with endothelial cells to foster tumor angiogenesis. For that reason, this review explains the critical importance of miR-21/exosomal miR-21 in managing both healthy and diseased states of angiogenesis.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | - Nisreen Yasir Jasim
- College of Nursing, National University of Science and Technology, Nasiriyah, Dhi Qar, Iraq
| | | | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Abhishek Kumar
- School of Pharmacy-Adarsh Vijendra Institute of Pharmaceutical Sciences, Shobhit University, Gangoh, Uttar Pradesh, 247341, India
- Department of Pharmacy, Arka Jain University, Jamshedpur, Jharkhand, 831001, India
| | - Shikha Atteri
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjheri, Mohali, Punjab, 140307, India
| | - Raghav Vashishth
- Department of Surgery, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Jasur Rizaev
- Department of Public Health and Healthcare Management, Rector, Samarkand State Medical University, 18, Amir Temur Street, Samarkand, Uzbekistan
| | - Ahmed Alhili
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | | | - Farzaneh Yazdi
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
| | | | - Reza Akhavan-Sigari
- Dr. Schneiderhan GmbH and ISAR Klinikum, Munich, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw, Management University Warsaw, Warsaw, Poland
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Huang X, Chen W, Wang Y, Shytikov D, Wang Y, Zhu W, Chen R, He Y, Yang Y, Guo W. Canonical and noncanonical NOTCH signaling in the nongenetic resistance of cancer: distinct and concerted control. Front Med 2025; 19:23-52. [PMID: 39745621 DOI: 10.1007/s11684-024-1107-1] [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: 04/19/2024] [Accepted: 09/18/2024] [Indexed: 02/27/2025]
Abstract
Therapeutic resistance in cancer is responsible for numerous cancer deaths in clinical practice. While target mutations are well recognized as the basis of genetic resistance to targeted therapy, nontarget mutation resistance (or nongenetic resistance) remains poorly characterized. Despite its complex and unintegrated mechanisms in the literature, nongenetic resistance is considered from our perspective to be a collective response of innate or acquired resistant subpopulations in heterogeneous tumors to therapy. These subpopulations, e.g., cancer stem-like cells, cancer cells with epithelial-to-mesenchymal transition, and drug-tolerant persisters, are protected by their resistance traits at cellular and molecular levels. This review summarizes recent advances in the research on resistant populations and their resistance traits. NOTCH signaling, as a central regulator of nongenetic resistance, is discussed with a special focus on its canonical maintenance of resistant cancer cells and noncanonical regulation of their resistance traits. This novel view of canonical and noncanonical NOTCH signaling pathways is translated into our proposal of reshaping therapeutic strategies targeting NOTCH signaling in resistant cancer cells. We hope that this review will lead researchers to study the canonical and noncanonical arms of NOTCH signaling as an integrated resistant mechanism, thus promoting the development of innovative therapeutic strategies.
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Affiliation(s)
- Xianzhe Huang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Wenwei Chen
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yanyan Wang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Dmytro Shytikov
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yanwen Wang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Wangyi Zhu
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Ruyi Chen
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yuwei He
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Yanjia Yang
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China
| | - Wei Guo
- Zhejiang University-University of Edinburgh Institute, School of Medicine, Zhejiang University, Jiaxing, 314400, China.
- First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
- Biomedical and Health Translational Research Center of Zhejiang Province, Jiaxing, 314400, China.
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Deng Q, Gao Y, Wang Y, Mao J, Yan Y, Yang Z, Cong Y, Yang Y, Wan S. LSD1 inhibition by tranylcypromine hydrochloride reduces alkali burn-induced corneal neovascularization and ferroptosis by suppressing HIF-1α pathway. Front Pharmacol 2024; 15:1411513. [PMID: 39130627 PMCID: PMC11316257 DOI: 10.3389/fphar.2024.1411513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 07/09/2024] [Indexed: 08/13/2024] Open
Abstract
Background Corneal neovascularization (CNV) is a sight-threatening condition that necessitates epigenetic control. The role of lysine-specific demethylase 1 (LSD1) in CNV remains unclear, despite its established significance in tumor angiogenesis regulation. Methods An alkali burn-induced CNV mouse model was used in vivo. The effects of LSD1 inhibitor tranylcypromine hydrochloride (TCP) were examined through slit lamp, histological staining, and immunofluorescence. The expression of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were assessed in corneal tissues. Oxidative stress and ferrous ion expression during CNV were determined using 4-HNE, GPX4, and FerroOrange staining. In vitro, a hypoxia-reoxygenation (H/R) model was established using human umbilical vein endothelial cells (HUVECs) to study LSD1 or hypoxia-inducible factor (HIF-1α) knockdown and lentiviral overexpression of HIF-1α. The effects on HUVECs migration, invasion, and angiogenesis were evaluated through cell scratching assay, transwell migration assay and tube formation assay. The role of ferroptosis was investigated using ROS staining, FerroOrange staining, and key ferroptosis proteins. Further, The JAK2/STAT3 pathway's involvement in CNV regulation was explored through in vivo experiments with subconjunctival injection of AG490. Results The results showed a substantial correlation between corneal damage and LSD1 levels. In addition, HIF-1α expression was also elevated after alkali burns, and subconjunctival injection of TCP reduced corneal inflammation and neovascularization. Corneal alkali burns increased ROS levels and reduced antioxidative stress indicators, accompanied by elevated ferrous ion levels, which were reversed by TCP injection. In vitro, TCP or siRNAs inhibited H/R-induced ferroptosis and angiogenesis in HUVECs by affecting specific protein expressions and MDA, SOD, and GSH levels. HIF-1α levels, associated with ROS production, ferroptosis, and angiogenesis, increased during H/R, but were reversed by TCP or siRNA administration. HIF-1α overexpression counteracted the effects of LSD1 inhibition. Additionally, AG490 injection effectively reduced HIF-1α and VEGFA expression in the CNV model. Discussion These findings suggest that LSD1 inhibition via the HIF-1α-driven pathway prevents angiogenesis, oxidative stress, and ferroptosis in corneal alkali burn-induced CNV, highlighting LSD1 as a potential therapeutic target.
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Affiliation(s)
| | | | | | | | | | | | | | - Yanning Yang
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Shanshan Wan
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Zhang Q, Dunbar KB, Odze RD, Agoston AT, Wang X, Su T, Nguyen AD, Zhang X, Spechler SJ, Souza RF. Hypoxia-inducible factor-1α mediates reflux-induced epithelial-mesenchymal plasticity in Barrett's oesophagus patients. Gut 2024; 73:1269-1279. [PMID: 38641363 PMCID: PMC11239289 DOI: 10.1136/gutjnl-2023-331467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 04/06/2024] [Indexed: 04/21/2024]
Abstract
INTRODUCTION Epithelial-mesenchymal plasticity (EMP), the process through which epithelial cells acquire mesenchymal features, is needed for wound repair but also might contribute to cancer initiation. Earlier, in vitro studies showed that Barrett's cells exposed to acidic bile salt solutions (ABS) develop EMP. Now, we have (1) induced reflux oesophagitis in Barrett's oesophagus (BO) patients by stopping proton pump inhibitors (PPIs), (2) assessed their biopsies for EMP and (3) explored molecular pathways underlying reflux-induced EMP in BO cells and spheroids. METHODS 15 BO patients had endoscopy with biopsies of Barrett's metaplasia while on PPIs, and 1 and 2 weeks after stopping PPIs; RNA-seq data were assessed for enrichments in hypoxia-inducible factors (HIFs), angiogenesis and EMP pathways. In BO biopsies, cell lines and spheroids, EMP features (motility) and markers (vascular endothelial growth factor (VEGF), ZEB1, miR-200a&b) were evaluated by morphology, migration assays, immunostaining and qPCR; HIF-1α was knocked down with siRNA or shRNA. RESULTS At 1 and/or 2 weeks off PPIs, BO biopsies exhibited EMP features and markers, with significant enrichment for HIF-1α, angiogenesis and EMP pathways. In BO cells, ABS induced HIF-1α activation, which decreased miR-200a&b while increasing VEGF, ZEB1 and motility; HIF-1α knockdown blocked these effects. After ABS treatment, BO spheroids exhibited migratory protrusions showing nuclear HIF-1α, increased VEGF and decreased miR-200a&b. CONCLUSIONS In BO patients, reflux oesophagitis induces EMP changes associated with increased HIF-1α signalling in Barrett's metaplasia. In Barrett's cells, ABS trigger EMP via HIF-1α signalling. Thus, HIF-1α appears to play a key role in mediating reflux-induced EMP that might contribute to cancer in BO. TRIAL REGISTRATION NUMBER NCT02579460.
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Affiliation(s)
- Qiuyang Zhang
- Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA
- Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA
| | - Kerry B Dunbar
- Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Internal Medicine, VA North Texas Health Care System, Dallas, Texas, USA
| | - Robert D Odze
- Department of Pathology, Tufts Medical Center, Boston, Massachusetts, USA
- Robert D Odze Pathology, LLC, Boston, Massachusetts, USA
| | - Agoston T Agoston
- Department of Pathology, Brigham and Womens Hospital, Boston, Massachusetts, USA
| | - Xuan Wang
- Biostatistics Core, Baylor Scott & White Research Insitute, Dallas, Texas, USA
| | - Tianhong Su
- Department of Oncology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, Guangdong, China
| | - Anh D Nguyen
- Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA
- Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA
| | - Xi Zhang
- Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA
- Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA
| | - Stuart Jon Spechler
- Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA
- Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA
| | - Rhonda F Souza
- Department of Medicine, Baylor University Medical Center, Dallas, Texas, USA
- Center for Esophageal Research, Baylor Scott & White Research Institute, Dallas, Texas, USA
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Valencia-Cervantes J, Sierra-Vargas MP. Regulation of Cancer-Associated miRNAs Expression under Hypoxic Conditions. Anal Cell Pathol (Amst) 2024; 2024:5523283. [PMID: 38766303 PMCID: PMC11101257 DOI: 10.1155/2024/5523283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 04/17/2024] [Accepted: 04/27/2024] [Indexed: 05/22/2024] Open
Abstract
Solid tumors frequently experience hypoxia or low O2 levels. In these conditions, hypoxia-inducible factor 1 alpha (HIF-1α) is activated and acts as a transcription factor that regulates cancer cell adaptation to O2 and nutrient deprivation. HIF-1α controls gene expression associated with various signaling pathways that promote cancer cell proliferation and survival. MicroRNAs (miRNAs) are 22-nucleotide noncoding RNAs that play a role in various biological processes essential for cancer progression. This review presents an overview of how hypoxia regulates the expression of multiple miRNAs in the progression of cancer cells.
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Affiliation(s)
- Jesús Valencia-Cervantes
- Departamento de Investigación en Toxicología y Medicina Ambiental, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico
- Estancias Posdoctorales por México 2022 (1), Consejo Nacional de Humanidades, Ciencias y Tecnologías CONAHCYT, Mexico City 03940, Mexico
| | - Martha Patricia Sierra-Vargas
- Departamento de Investigación en Toxicología y Medicina Ambiental, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico
- Subdirección de Investigación Clínica, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico
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Lamichhane A, Tavana H. Three-Dimensional Tumor Models to Study Cancer Stemness-Mediated Drug Resistance. Cell Mol Bioeng 2024; 17:107-119. [PMID: 38737455 PMCID: PMC11082110 DOI: 10.1007/s12195-024-00798-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 02/01/2024] [Indexed: 05/14/2024] Open
Abstract
Solid tumors often contain genetically different populations of cancer cells, stromal cells, various structural and soluble proteins, and other soluble signaling molecules. The American Cancer society estimated 1,958,310 new cancer cases and 609,820 cancer deaths in the United States in 2023. A major barrier against successful treatment of cancer patients is drug resistance. Gain of stem cell-like states by cancer cells under drug pressure or due to interactions with the tumor microenvironment is a major mechanism that renders therapies ineffective. Identifying approaches to target cancer stem cells is expected to improve treatment outcomes for patients. Most of our understanding of drug resistance and the role of cancer stemness is from monolayer cell cultures. Recent advances in cell culture technologies have enabled developing sophisticated three-dimensional tumor models that facilitate mechanistic studies of cancer drug resistance. This review summarizes the role of cancer stemness in drug resistance and highlights the various tumor models that are used to discover the underlying mechanisms and test potentially novel therapeutics.
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Affiliation(s)
- Astha Lamichhane
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325 USA
| | - Hossein Tavana
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325 USA
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Sarker DB, Xue Y, Mahmud F, Jocelyn JA, Sang QXA. Interconversion of Cancer Cells and Induced Pluripotent Stem Cells. Cells 2024; 13:125. [PMID: 38247819 PMCID: PMC10814385 DOI: 10.3390/cells13020125] [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: 12/19/2023] [Revised: 01/07/2024] [Accepted: 01/08/2024] [Indexed: 01/23/2024] Open
Abstract
Cancer cells, especially cancer stem cells (CSCs), share many molecular features with induced pluripotent stem cells (iPSCs) that enable the derivation of induced pluripotent cancer cells by reprogramming malignant cells. Conversely, normal iPSCs can be converted into cancer stem-like cells with the help of tumor microenvironment components and genetic manipulation. These CSC models can be utilized in oncogenic initiation and progression studies, understanding drug resistance, and developing novel therapeutic strategies. This review summarizes the role of pluripotency factors in the stemness, tumorigenicity, and therapeutic resistance of cancer cells. Different methods to obtain iPSC-derived CSC models are described with an emphasis on exposure-based approaches. Culture in cancer cell-conditioned media or cocultures with cancer cells can convert normal iPSCs into cancer stem-like cells, aiding the examination of processes of oncogenesis. We further explored the potential of reprogramming cancer cells into cancer-iPSCs for mechanistic studies and cancer dependencies. The contributions of genetic, epigenetic, and tumor microenvironment factors can be evaluated using these models. Overall, integrating iPSC technology into cancer stem cell research holds significant promise for advancing our knowledge of cancer biology and accelerating the development of innovative and tailored therapeutic interventions.
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Affiliation(s)
- Drishty B. Sarker
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
| | - Yu Xue
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
| | - Faiza Mahmud
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
| | - Jonathan A. Jocelyn
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
| | - Qing-Xiang Amy Sang
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
- Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306-4380, USA
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Sharma R, Malviya R. Cancer Stem Cells in Carcinogenesis and Potential Role in Pancreatic Cancer. Curr Stem Cell Res Ther 2024; 19:1185-1194. [PMID: 37711007 DOI: 10.2174/1574888x19666230914103420] [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: 04/11/2023] [Revised: 07/14/2023] [Accepted: 08/11/2023] [Indexed: 09/16/2023]
Abstract
A poor prognosis is associated with pancreatic cancer because of resistance during treatment and early distant metastases. The discovery of cancer stem cells has opened up novel avenues for research into the biology and treatment of cancer. Many investigations have pointed out the role of these types of stem cells in the oncogenesis and progression of hematologic and solid malignancies, specifically. Due to the existence of cancer stem cells in the proliferation and preservation of pancreatic tumors, such malignancies could be difficult to eradicate using conventional treatment techniques like chemotherapy and radiotherapy. It is hypothesized that pancreatic malignancies originate from a limited population of aberrant cancer stem cells to promote carcinogenesis, tumour metastasis, and therapeutic resistance. This review examines the role of pancreatic cancer stem cells in this disease and their significance in carcinogenesis, as well as the signals which modulate them, and also examines the ongoing clinical studies that are now being conducted with pancreatic stem cells.
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Affiliation(s)
- Rishav Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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10
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Rezakhani L, Salmani S, Eliyasi Dashtaki M, Ghasemi S. Resveratrol: Targeting Cancer Stem Cells and ncRNAs to Overcome Cancer Drug Resistance. Curr Mol Med 2024; 24:951-961. [PMID: 37592772 DOI: 10.2174/1566524023666230817102114] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 06/07/2023] [Accepted: 06/09/2023] [Indexed: 08/19/2023]
Abstract
A major challenge in treating cancer is the development of drug resistance, which can result in treatment failure and tumor recurrence. Targeting cancer stem cells (CSCs) and non-coding RNAs (ncRNAs) with a polyphenolic substance called resveratrol has the ability to combat this problem by lowering cancer resistance to drugs and opening up new therapeutic options. Resveratrol alters the expression of genes related to self-renewal, modulating important signaling pathways involved in cancer initiation and CSC control. Additionally, resveratrol affects non-coding RNAs (ncRNAs), including Micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs which are essential for stemness, drug resistance, and other cancer-related activities. Numerous studies have shown that resveratrol has the potential to be an effective anticancer drug when used in combination therapy, but issues with absorption and pharmacokinetics still need to be resolved before it can be used in clinical applications. Reducing chemotherapy resistance by better understanding the intricate mechanisms by which resveratrol affects cancer cells and CSCs, as well as its impact on ncRNA expression, could eventually contribute to more effective cancer treatments. To completely understand these pathways and optimize the utilization of resveratrol in combination treatments, additional study is necessary.
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Affiliation(s)
- Leila Rezakhani
- Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sima Salmani
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Masoumeh Eliyasi Dashtaki
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Sorayya Ghasemi
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
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Lasorsa F, Rutigliano M, Milella M, Ferro M, Pandolfo SD, Crocetto F, Autorino R, Battaglia M, Ditonno P, Lucarelli G. Cancer Stem Cells in Renal Cell Carcinoma: Origins and Biomarkers. Int J Mol Sci 2023; 24:13179. [PMID: 37685983 PMCID: PMC10487877 DOI: 10.3390/ijms241713179] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/14/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
The term "cancer stem cell" (CSC) refers to a cancer cell with the following features: clonogenic ability, the expression of stem cell markers, differentiation into cells of different lineages, growth in nonadhesive spheroids, and the in vivo ability to generate serially transplantable tumors that reflect the heterogeneity of primary cancers (tumorigenicity). According to this model, CSCs may arise from normal stem cells, progenitor cells, and/or differentiated cells because of striking genetic/epigenetic mutations or from the fusion of tissue-specific stem cells with circulating bone marrow stem cells (BMSCs). CSCs use signaling pathways similar to those controlling cell fate during early embryogenesis (Notch, Wnt, Hedgehog, bone morphogenetic proteins (BMPs), fibroblast growth factors, leukemia inhibitory factor, and transforming growth factor-β). Recent studies identified a subpopulation of CD133+/CD24+ cells from ccRCC specimens that displayed self-renewal ability and clonogenic multipotency. The development of agents targeting CSC signaling-specific pathways and not only surface proteins may ultimately become of utmost importance for patients with RCC.
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Affiliation(s)
- Francesco Lasorsa
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Monica Rutigliano
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Martina Milella
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Matteo Ferro
- Division of Urology, European Institute of Oncology, IRCCS, 71013 Milan, Italy
| | - Savio Domenico Pandolfo
- Department of Neurosciences and Reproductive Sciences and Odontostomatology, University of Naples “Federico II”, 80131 Naples, Italy
| | - Felice Crocetto
- Department of Neurosciences and Reproductive Sciences and Odontostomatology, University of Naples “Federico II”, 80131 Naples, Italy
| | - Riccardo Autorino
- Department of Urology, Rush University Medical Center, Chicago, IL 60612, USA
| | - Michele Battaglia
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Pasquale Ditonno
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Giuseppe Lucarelli
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
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12
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Maharati A, Samsami Y, Latifi H, Tolue Ghasaban F, Moghbeli M. Role of the long non-coding RNAs in regulation of Gemcitabine response in tumor cells. Cancer Cell Int 2023; 23:168. [PMID: 37580768 PMCID: PMC10426205 DOI: 10.1186/s12935-023-03004-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 07/26/2023] [Indexed: 08/16/2023] Open
Abstract
Chemotherapy is widely used as one of the first line therapeutic methods in cancer patients. However, chemotherapeutic resistance is one of the most common problems in cancer patients, which leads to the therapeutic failure and tumor relapse. Considering the side effects of chemotherapy drugs in normal tissues, it is required to investigate the molecular mechanisms involved in drug resistance to improve the therapeutic strategies in cancer patients. Long non-coding RNAs (lncRNAs) have pivotal roles in regulation of cellular processes associated with drug resistance. LncRNAs deregulations have been frequently reported in a wide range of chemo-resistant tumors. Gemcitabine (GEM) as a nucleoside analog has a wide therapeutic application in different cancers. However, GEM resistance is considered as a therapeutic challenge. Considering the role of lncRNAs in the occurrence of GEM resistance, in the present review we discussed the molecular mechanisms of lncRNAs in regulation of GEM response among cancer patients. It has been reported that lncRNAs have mainly an oncogenic role as the inducers of GEM resistance through direct or indirect regulation of transcription factors, autophagy, polycomb complex, and signaling pathways such as PI3K/AKT, MAPK, WNT, JAK/STAT, and TGF-β. This review paves the way to present the lncRNAs as non-invasive markers to predict GEM response in cancer patients. Therefore, lncRNAs can be introduced as the efficient markers to reduce the possible chemotherapeutic side effects in GEM resistant cancer patients and define a suitable therapeutic strategy among these patients.
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Affiliation(s)
- Amirhosein Maharati
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Yalda Samsami
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanieh Latifi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Faezeh Tolue Ghasaban
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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13
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Anu RI, Shiu KK, Khan KH. The immunomodulatory role of IDO1-Kynurenine-NAD + pathway in switching cold tumor microenvironment in PDAC. Front Oncol 2023; 13:1142838. [PMID: 37456260 PMCID: PMC10348419 DOI: 10.3389/fonc.2023.1142838] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 06/01/2023] [Indexed: 07/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common exocrine tumor of the pancreas characterized by late diagnosis, adverse overall 5-year survival, a higher propensity for metastatic disease, and lack of efficacy of systemic therapy options. These adverse outcomes can be partly attributed to complex tumor microenvironment (TME). Over the past decade, immunotherapy has revolutionized the management of certain cancers; thus far, the immunologically 'non-inflamed' tumor microenvironment in PDACs has proven to be challenging. Indolamine 2,3-dioxygenase 1 (IDO1) is the rate-limiting enzyme in the catabolic pathway of L-Tryptophan, an essential amino acid, that gives rise to the immunosuppressive metabolite Kynurenine. IDO1, Indolamine 2,3-dioxygenase 2 (IDO2), and Tryptophan 2,3-dioxygenase (TDO) are the key enzymes in the tryptophan catabolic pathway but we focus on the role of the predominant enzyme form IDO1 in this review. Nicotinamide phosphoribosyl transferase (iNAMPT) regulates the intracellular concentration of NAD and is upregulated in the tumor. In light of the potential role of IDO1 as a driver of hostile TME in PDAC and NAD+ as a key coenzyme in anti-tumor immune response, this review urges focus on extensive research and initiation of clinical trials using IDO1 and NAMPT inhibitors in pancreatic cancer in the future.
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Affiliation(s)
- R. I. Anu
- Department of Cancer Biology and Therapeutics, Precision Oncology and Multi-Omics Clinic, Genetic Counseling Clinic, Department of Clinical Biochemistry, MVR Cancer Centre and Research Institute, Calicut, Kerala, India
| | - Kai-Keen Shiu
- Gastrointestinal Oncology Service, University College London Hospitals National Health Services (NHS) Foundation Trust, London, United Kingdom
- Universtiy College London (UCL) Cancer Institute, University College London Hospitals National Health Services (NHS) Foundation Trust, London, United Kingdom
| | - Khurum Hayat Khan
- Gastrointestinal Oncology Service, University College London Hospitals National Health Services (NHS) Foundation Trust, London, United Kingdom
- Universtiy College London (UCL) Cancer Institute, University College London Hospitals National Health Services (NHS) Foundation Trust, London, United Kingdom
- Whittington Health, National Health Services (NHS), London, United Kingdom
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14
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Dytrych P, Kejík Z, Hajduch J, Kaplánek R, Veselá K, Kučnirová K, Skaličková M, Venhauerová A, Hoskovec D, Martásek P, Jakubek M. Therapeutic potential and limitations of curcumin as antimetastatic agent. Biomed Pharmacother 2023; 163:114758. [PMID: 37141738 DOI: 10.1016/j.biopha.2023.114758] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/06/2023] Open
Abstract
Treatment of metastatic cancer is one of the biggest challenges in anticancer therapy. Curcumin is interesting nature polyphenolic compound with unique biological and medicinal effects, including repression of metastases. High impact studies imply that curcumin can modulate the immune system, independently target various metastatic signalling pathways, and repress migration and invasiveness of cancer cells. This review discusses the potential of curcumin as an antimetastatic agent and describes potential mechanisms of its antimetastatic activity. In addition, possible strategies (curcumin formulation, optimization of the method of administration and modification of its structure motif) to overcome its limitation such as low solubility and bioactivity are also presented. These strategies are discussed in the context of clinical trials and relevant biological studies.
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Affiliation(s)
- Petr Dytrych
- 1st Department of Surgery-Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 2, 121 08 Prague, Czech Republic
| | - Zdeněk Kejík
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Jan Hajduch
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic
| | - Robert Kaplánek
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic
| | - Kateřina Veselá
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Kateřina Kučnirová
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Markéta Skaličková
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - Anna Venhauerová
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic
| | - David Hoskovec
- 1st Department of Surgery-Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 2, 121 08 Prague, Czech Republic
| | - Pavel Martásek
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic.
| | - Milan Jakubek
- BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455/2, 128 08 Prague, Czech Republic.
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15
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Rezazadeh-Gavgani E, Oladghaffari M, Bahramian S, Majidazar R, Dolati S. MicroRNA-21: A critical underestimated molecule in diabetic retinopathy. Gene 2023; 859:147212. [PMID: 36690226 DOI: 10.1016/j.gene.2023.147212] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 12/11/2022] [Accepted: 01/16/2023] [Indexed: 01/22/2023]
Abstract
Diabetes mellitus (DM) has grown in attention in recent years as a result of its debilitating complications and chronic disabilities. Diabetic retinopathy (DR) is a chronic microvascular complication of DM and is considered as the primary reason for blindness in adults. Early diagnosis of diabetes complications along with targeted therapy options are critical in avoiding morbidity and mortality associated with complications of diabetes. miR-21 is an important and widely studied non-coding-RNA (ncRNA) with considerable roles in various pathologic conditions including diabetic complications. miR-21 is one of the most elevated miRNAs in response to hyperglycemia and its role in angiogenesis is a major culprit of a wide range of disorders including DR. The main role of miR-21 in DR pathophysiology is believed to be through regulating angiogenesis in retina. This article aims to outline miR-21 biogenesis and distribution in human body along with discussions about its role in DR pathogenesis and its biomarker value in order to facilitate understanding of the new characteristics of miR-21 in DR management.
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Affiliation(s)
| | - Mobina Oladghaffari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Shirin Bahramian
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Reza Majidazar
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Sanam Dolati
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
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16
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Bhattacharyya S, Ghosh H, Covarrubias-Zambrano O, Jain K, Swamy KV, Kasi A, Hamza A, Anant S, VanSaun M, Weir SJ, Bossmann SH, Padhye SB, Dandawate P. Anticancer Activity of Novel Difluorinated Curcumin Analog and Its Inclusion Complex with 2-Hydroxypropyl-β-Cyclodextrin against Pancreatic Cancer. Int J Mol Sci 2023; 24:ijms24076336. [PMID: 37047307 PMCID: PMC10093935 DOI: 10.3390/ijms24076336] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/14/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the primary reason for cancer-related deaths in the US. Genetic mutations, drug resistance, the involvement of multiple signaling pathways, cancer stem cells (CSCs), and desmoplastic stroma, which hinders drug penetrance, contribute to poor chemotherapeutic efficacy. Hence, there is a need to identify novel drugs with improved delivery to improve treatment outcomes. Curcumin is one such compound that can inhibit multiple signaling pathways and CSCs. However, curcumin’s clinical applicability for treating PDAC is limited because of its poor solubility in water and metabolic instability. Hence, we developed a difluorinated curcumin (CDF) analog that accumulates selectively in the pancreas and inhibits PDAC growth in vitro and in vivo. In the present work, we developed its 2-hydroxy-propyl-β-cyclodextrin (HCD) inclusion complex to increase its water solubility and hydrolytic stability. The CDFHCD inclusion complex was characterized by spectroscopic, thermal, and microscopic techniques. The inclusion complex exhibited increased aqueous solubility, hydrolytic stability, and antiproliferative activity compared to parent CDF. Moreover, CDF and CDFHCD inhibited colony and spheroid formation, and induced cell cycle and apoptosis in PDAC cell lines. Hence, CDFHCD self-assembly is an efficient approach to increase water solubility and anticancer therapeutic efficacy, which now warrants advancement towards a clinical proof of concept in PDAC patients.
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Affiliation(s)
- Sangita Bhattacharyya
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Hindole Ghosh
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | | | - Krishan Jain
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - K. Venkateswara Swamy
- MIT School of Bioengineering, Sciences & Research, MIT Art, Design and Technology University, Pune 412201, India
| | - Anup Kasi
- Division of Medical Oncology, University of Kansas, Kansas City, KS 66160, USA
| | - Ameer Hamza
- Pathology and Laboratory Medicine, University of Kansas, Kansas City, KS 66160, USA
| | - Shrikant Anant
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Michael VanSaun
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Scott J. Weir
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
- Division of Medical Oncology, University of Kansas, Kansas City, KS 66160, USA
- Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Stefan H. Bossmann
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
| | - Subhash B. Padhye
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
- Interdisciplinary Science & Technology Research Academy (ISTRA), Azam Campus, University of Pune, Pune 411001, India
| | - Prasad Dandawate
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS 66103, USA
- Correspondence: ; Tel.: +1-913-945-6336
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17
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Funamizu N, Honjo M, Tamura K, Sakamoto K, Ogawa K, Takada Y. microRNAs Associated with Gemcitabine Resistance via EMT, TME, and Drug Metabolism in Pancreatic Cancer. Cancers (Basel) 2023; 15:1230. [PMID: 36831572 PMCID: PMC9953943 DOI: 10.3390/cancers15041230] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Despite extensive research, pancreatic cancer remains a lethal disease with an extremely poor prognosis. The difficulty in early detection and chemoresistance to therapeutic agents are major clinical concerns. To improve prognosis, novel biomarkers, and therapeutic strategies for chemoresistance are urgently needed. microRNAs (miRNAs) play important roles in the development, progression, and metastasis of several cancers. During the last few decades, the association between pancreatic cancer and miRNAs has been extensively elucidated, with several miRNAs found to be correlated with patient prognosis. Moreover, recent evidence has revealed that miRNAs are intimately involved in gemcitabine sensitivity and resistance through epithelial-to-mesenchymal transition, the tumor microenvironment, and drug metabolism. Gemcitabine is the gold standard drug for pancreatic cancer treatment, but gemcitabine resistance develops easily after chemotherapy initiation. Therefore, in this review, we summarize the gemcitabine resistance mechanisms associated with aberrantly expressed miRNAs in pancreatic cancer, especially focusing on the mechanisms associated with epithelial-to-mesenchymal transition, the tumor microenvironment, and metabolism. This novel evidence of gemcitabine resistance will drive further research to elucidate the mechanisms of chemoresistance and improve patient outcomes.
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Affiliation(s)
- Naotake Funamizu
- Department of Hepatobiliary Pancreatic and Transplantation Surgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
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18
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Mandys V, Popov A, Gürlich R, Havránek J, Pfeiferová L, Kolář M, Vránová J, Smetana K, Lacina L, Szabo P. Expression of Selected miRNAs in Normal and Cancer-Associated Fibroblasts and in BxPc3 and MIA PaCa-2 Cell Lines of Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2023; 24:ijms24043617. [PMID: 36835029 PMCID: PMC9961675 DOI: 10.3390/ijms24043617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/07/2023] [Accepted: 02/07/2023] [Indexed: 02/15/2023] Open
Abstract
Therapy for pancreatic ductal adenocarcinoma remains challenging, and the chances of a complete cure are very limited. As in other types of cancer, the expression and role of miRNAs in controlling the biological properties of this type of tumor have been extensively studied. A better insight into miRNA biology seems critical to refining diagnostics and improving their therapeutic potential. In this study, we focused on the expression of miR-21, -96, -196a, -210, and -217 in normal fibroblasts, cancer-associated fibroblasts prepared from a ductal adenocarcinoma of the pancreas, and pancreatic carcinoma cell lines. We compared these data with miRNAs in homogenates of paraffin-embedded sections from normal pancreatic tissues. In cancer-associated fibroblasts and cancer cell lines, miRNAs differed significantly from the normal tissue. In detail, miR-21 and -210 were significantly upregulated, while miR-217 was downregulated. Similar transcription profiles were earlier reported in cancer-associated fibroblasts exposed to hypoxia. However, the cells in our study were cultured under normoxic conditions. We also noted a relation to IL-6 production. In conclusion, cultured cancer-associated fibroblasts and carcinoma cells reflect miR-21 and -210 expression similarly to the cancer tissue samples harvested from the patients.
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Affiliation(s)
- Václav Mandys
- Department of Pathology, Third Faculty of Medicine, Charles University and University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic
| | - Alexey Popov
- Department of Pathology, Third Faculty of Medicine, Charles University and University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic
| | - Robert Gürlich
- Department of Surgery, Third Faculty of Medicine, Charles University and University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic
| | - Jan Havránek
- Institute of Molecular Genetics, Czech Academy of Sciences, 100 00 Prague, Czech Republic
- Laboratory of Informatics and Chemistry, University of Chemistry and Technology, 166 28 Prague, Czech Republic
| | - Lucie Pfeiferová
- Institute of Molecular Genetics, Czech Academy of Sciences, 100 00 Prague, Czech Republic
- Laboratory of Informatics and Chemistry, University of Chemistry and Technology, 166 28 Prague, Czech Republic
| | - Michal Kolář
- Institute of Molecular Genetics, Czech Academy of Sciences, 100 00 Prague, Czech Republic
- Laboratory of Informatics and Chemistry, University of Chemistry and Technology, 166 28 Prague, Czech Republic
| | - Jana Vránová
- Department of Medical Biophysics and Medical Informatics, Third Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic
| | - Karel Smetana
- First Faculty of Medicine, BIOCEV, Charles University, 252 50 Vestec, Czech Republic
- First Faculty of Medicine, Institute of Anatomy, Charles University, 128 00 Prague, Czech Republic
| | - Lukáš Lacina
- First Faculty of Medicine, BIOCEV, Charles University, 252 50 Vestec, Czech Republic
- First Faculty of Medicine, Institute of Anatomy, Charles University, 128 00 Prague, Czech Republic
- Department Dermatovenereology, First Faculty of Medicine, Charles University and General University Hospital, 128 08 Prague, Czech Republic
| | - Pavol Szabo
- First Faculty of Medicine, BIOCEV, Charles University, 252 50 Vestec, Czech Republic
- First Faculty of Medicine, Institute of Anatomy, Charles University, 128 00 Prague, Czech Republic
- Correspondence:
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19
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Hashemi M, Mirdamadi MSA, Talebi Y, Khaniabad N, Banaei G, Daneii P, Gholami S, Ghorbani A, Tavakolpournegari A, Farsani ZM, Zarrabi A, Nabavi N, Zandieh MA, Rashidi M, Taheriazam A, Entezari M, Khan H. Pre-clinical and clinical importance of miR-21 in human cancers: Tumorigenesis, therapy response, delivery approaches and targeting agents. Pharmacol Res 2023; 187:106568. [PMID: 36423787 DOI: 10.1016/j.phrs.2022.106568] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/18/2022] [Accepted: 11/19/2022] [Indexed: 11/23/2022]
Abstract
The field of non-coding RNA (ncRNA) has made significant progress in understanding the pathogenesis of diseases and has broadened our knowledge towards their targeting, especially in cancer therapy. ncRNAs are a large family of RNAs with microRNAs (miRNAs) being one kind of endogenous RNA which lack encoded proteins. By now, miRNAs have been well-coined in pathogenesis and development of cancer. The current review focuses on the role of miR-21 in cancers and its association with tumor progression. miR-21 has both oncogenic and onco-suppressor functions and most of the experiments are in agreement with the tumor-promoting function of this miRNA. miR-21 primarily decreases PTEN expression to induce PI3K/Akt signaling in cancer progression. Overexpression of miR-21 inhibits apoptosis and is vital for inducing pro-survival autophagy. miR-21 is vital for metabolic reprogramming and can induce glycolysis to enhance tumor progression. miR-21 stimulates EMT mechanisms and increases expression of MMP-2 and MMP-9 thereby elevating tumor metastasis. miR-21 is a target of anti-cancer agents such as curcumin and curcumol and its down-regulation impairs tumor progression. Upregulation of miR-21 results in cancer resistance to chemotherapy and radiotherapy. Increasing evidence has revealed the role of miR-21 as a biomarker as it is present in both the serum and exosomes making them beneficial biomarkers for non-invasive diagnosis of cancer.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Motahare Sadat Ayat Mirdamadi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Biology, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Yasmin Talebi
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Biology, Islamic Azad University Central Tehran Branch, Tehran, Iran
| | - Nasrin Khaniabad
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Gooya Banaei
- Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona, Spain
| | - Pouria Daneii
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Sadaf Gholami
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Amin Ghorbani
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Alireza Tavakolpournegari
- Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona, Spain
| | - Zoheir Mohammadian Farsani
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Industrial and Environmental Biotechnology, National Institute for Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkey
| | - Noushin Nabavi
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H3Z6, Canada
| | - Mohammad Arad Zandieh
- Department of Food Hygiene and Quality Control, Division of epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran.
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, 23200, Pakistan.
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20
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Pouliquen DL, Boissard A, Henry C, Coqueret O, Guette C. Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies. Front Pharmacol 2022; 13:934534. [PMID: 35873564 PMCID: PMC9304619 DOI: 10.3389/fphar.2022.934534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 06/15/2022] [Indexed: 11/21/2022] Open
Abstract
Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host’s immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.
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Affiliation(s)
- Daniel L. Pouliquen
- Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
- *Correspondence: Daniel L. Pouliquen,
| | - Alice Boissard
- ICO, Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
| | - Cécile Henry
- ICO, Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
| | - Olivier Coqueret
- Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
| | - Catherine Guette
- ICO, Inserm, CNRS, Nantes Université, CRCI2NA, Université d’Angers, Angers, France
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21
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Hashem S, Ali TA, Akhtar S, Nisar S, Sageena G, Ali S, Al-Mannai S, Therachiyil L, Mir R, Elfaki I, Mir MM, Jamal F, Masoodi T, Uddin S, Singh M, Haris M, Macha M, Bhat AA. Targeting cancer signaling pathways by natural products: Exploring promising anti-cancer agents. Biomed Pharmacother 2022; 150:113054. [PMID: 35658225 DOI: 10.1016/j.biopha.2022.113054] [Citation(s) in RCA: 145] [Impact Index Per Article: 48.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/24/2022] [Accepted: 04/26/2022] [Indexed: 11/29/2022] Open
Abstract
Cancer is one of the leading causes of death and significantly burdens the healthcare system. Due to its prevalence, there is undoubtedly an unmet need to discover novel anticancer drugs. The use of natural products as anticancer agents is an acceptable therapeutic approach due to accessibility, applicability, and reduced cytotoxicity. Natural products have been an incomparable source of anticancer drugs in the modern era of drug discovery. Along with their derivatives and analogs, natural products play a major role in cancer treatment by modulating the cancer microenvironment and different signaling pathways. These compounds are effective against several signaling pathways, mainly cell death pathways (apoptosis and autophagy) and embryonic developmental pathways (Notch pathway, Wnt pathway, and Hedgehog pathway). The historical record of natural products is strong, but there is a need to investigate the current role of natural products in the discovery and development of cancer drugs and determine the possibility of natural products being an important source of future therapeutic agents. Many target-specific anticancer drugs failed to provide successful results, which accounts for a need to investigate natural products with multi-target characteristics to achieve better outcomes. The potential of natural products to be promising novel compounds for cancer treatment makes them an important area of research. This review explores the significance of natural products in inhibiting the various signaling pathways that serve as drivers of carcinogenesis and thus pave the way for developing and discovering anticancer drugs.
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Affiliation(s)
- Sheema Hashem
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar
| | - Tayyiba Akbar Ali
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar
| | - Sabah Akhtar
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar
| | | | - Shahid Ali
- International Potato Center (CIP), Shillong, Meghalaya, India
| | - Sharefa Al-Mannai
- Division of Translational Medicine, Research Branch, Sidra Medicine, Doha 26999, Qatar
| | - Lubna Therachiyil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Department of Pharmaceutical Sciences, College of Pharmacy, Qatar University, Doha, Qatar
| | - Rashid Mir
- Prince Fahd Bin Sultan Research chair, Department Of Medical Lab Technology, FAMS, University of Tabuk,Saudi Arabia
| | - Imadeldin Elfaki
- Department of Biochemistry, University of Tabuk, Tabuk, Saudi Arabia
| | - Mohammad Muzaffar Mir
- Department of Basic Medical Sciences, College of Medicine, University of Bisha, Saudi Arabia
| | - Farrukh Jamal
- Dr. Rammanohar Lohia Avadh University, Ayodhya, India
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Mayank Singh
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha 2713, Qatar; Center for Advanced Metabolic Imaging in Precision Medicine, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
| | - Muzafar Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Kashmir, India.
| | - Ajaz A Bhat
- Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar.
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22
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Huang Q, Zhang Y, Zheng Y, Yang H, Yang Y, Mo Y, Li L, Zhang H. Molecular Mechanism of Curcumin and Its Analogs as Multifunctional Compounds against Pancreatic Cancer. Nutr Cancer 2022; 74:3096-3108. [PMID: 35583289 DOI: 10.1080/01635581.2022.2071451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 03/30/2022] [Accepted: 04/25/2022] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer (PC) is one of the most common malignant tumors with a poor prognosis and high mortality. Surgical resection is the most effective treatment for PC; however, only a minority of patients have resectable tumors. Chemotherapy is the primary treatment for PC. Curcumin is a natural chemical substance obtained from plants with a wide range of pharmacological activities. Research evidence suggests that curcumin can influence PC development through multiple molecular mechanisms. The synthesis of novel curcumin analogs and preparation of curcumin nano-formulations are effective strategies to overcome the low bioavailability of curcumin in the treatment of PC. This review aims to summarize the mechanisms of action of curcumin in preclinical and clinical studies on PC and research progress in enhancing its bioavailability.
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Affiliation(s)
- Qun Huang
- Department of Ophthalmology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ya Zhang
- Endocrinology Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanlin Zheng
- Department of Ophthalmology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hongjing Yang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yang Yang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ya Mo
- Department of Ophthalmology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Liuying Li
- Department of Integrated Chinese and Western Medicine, The First People's Hospital of Zigong City, Zigong, China
| | - Hong Zhang
- Emergency Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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23
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Florentin J, O'Neil SP, Ohayon LL, Uddin A, Vasamsetti SB, Arunkumar A, Ghosh S, Boatz JC, Sui J, Kliment CR, Chan SY, Dutta P. VEGF Receptor 1 Promotes Hypoxia-Induced Hematopoietic Progenitor Proliferation and Differentiation. Front Immunol 2022; 13:882484. [PMID: 35634304 PMCID: PMC9133347 DOI: 10.3389/fimmu.2022.882484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 04/19/2022] [Indexed: 11/13/2022] Open
Abstract
Although it is well known that hypoxia incites unleashed cellular inflammation, the mechanisms of exaggerated cellular inflammation in hypoxic conditions are not known. We observed augmented proliferation of hematopoietic stem and progenitor cells (HSPC), precursors of inflammatory leukocytes, in mice under hypoxia. Consistently, a transcriptomic analysis of human HSPC exposed to hypoxic conditions revealed elevated expression of genes involved in progenitor proliferation and differentiation. Additionally, bone marrow cells in mice expressed high amount of vascular endothelial growth factor (VEGF), and HSPC elevated VEGF receptor 1 (VEGFr1) and its target genes in hypoxic conditions. In line with this, VEGFr1 blockade in vivo and in vitro decreased HSPC proliferation and attenuated inflammation. In silico and ChIP experiments demonstrated that HIF-1α binds to the promoter region of VEGFR1. Correspondingly, HIF1a silencing decreased VEGFr1 expression in HSPC and diminished their proliferation. These results indicate that VEGF signaling in HSPC is an important mediator of their proliferation and differentiation in hypoxia-induced inflammation and represents a potential therapeutic target to prevent aberrant inflammation in hypoxia-associated diseases.
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Affiliation(s)
- Jonathan Florentin
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Scott P O'Neil
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Lee L Ohayon
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Afaz Uddin
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Sathish Babu Vasamsetti
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Anagha Arunkumar
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Samit Ghosh
- Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA, United States
| | - Jennifer C Boatz
- Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA, United States
| | - Justin Sui
- Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA, United States
| | - Corrine R Kliment
- Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA, United States
| | - Stephen Y Chan
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Partha Dutta
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
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24
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Rezayatmand H, Razmkhah M, Razeghian-Jahromi I. Drug resistance in cancer therapy: the Pandora's Box of cancer stem cells. Stem Cell Res Ther 2022; 13:181. [PMID: 35505363 PMCID: PMC9066908 DOI: 10.1186/s13287-022-02856-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 04/14/2022] [Indexed: 12/18/2022] Open
Abstract
Drug resistance is the main culprit of failure in cancer therapy that may lead to cancer relapse. This resistance mostly originates from rare, but impactful presence of cancer stem cells (CSCs). Ability to self-renewal and differentiation into heterogeneous cancer cells, and harboring morphologically and phenotypically distinct cells are prominent features of CSCs. Also, CSCs substantially contribute to metastatic dissemination. They possess several mechanisms that help them to survive even after exposure to chemotherapy drugs. Although chemotherapy is able to destroy the bulk of tumor cells, CSCs are left almost intact, and make tumor entity resistant to treatment. Eradication of a tumor mass needs complete removal of tumor cells as well as CSCs. Therefore, it is important to elucidate key features underlying drug resistance raised by CSCs in order to apply effective treatment strategies. However, the challenging point that threatens safety and specificity of chemotherapy is the common characteristics between CSCs and normal peers such as signaling pathways and markers. In the present study, we tried to present a comprehensive appraisal on CSCs, mechanisms of their drug resistance, and recent therapeutic methods targeting this type of noxious cells.
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Affiliation(s)
| | - Mahboobeh Razmkhah
- Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Iman Razeghian-Jahromi
- Cardiovascular Research Center, Shiraz University of Medical Sciences, 3rd Floor, Mohammad Rasoolallah Research Tower, Namazi Hospital, Shiraz, Iran.
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25
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Huldani H, Jasim SA, Sergeenva KN, Bokov DO, Abdelbasset WK, Turakulov R, Al-Gazally ME, Ahmadzadeh B, Jawhar ZH, Siahmansouri H. Mechanisms of cancer stem cells drug resistance and the pivotal role of HMGA2. Pathol Res Pract 2022; 234:153906. [PMID: 35468338 DOI: 10.1016/j.prp.2022.153906] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/02/2022] [Accepted: 04/15/2022] [Indexed: 11/24/2022]
Abstract
Nowadays, the focus of researchers is on perceiving the heterogeneity observed in a tumor. The researchers studied the role of a specific subset of cancer cells with high resistance to traditional treatments, recurrence, and unregulated metastasis. This small population of tumor cells that have stem-cell-like specifications was named Cancer Stem Cells (CSCs). The unique features that distinguish this type of cancer cell are self-renewing, generating clones of the tumor, plasticity, recurrence, and resistance to therapies. There are various mechanisms that contribute to the drug resistance of CSCs, such as CSCs markers, Epithelial mesenchymal transition, hypoxia, other cells, inflammation, and signaling pathways. Recent investigations have revealed the primary role of HMGA2 in the development and invasion of cancer cells. Importantly, HMGA2 also plays a key role in resistance to treatment through their function in the drug resistance mechanisms of CSCs and challenge it. Therefore, a deep understanding of this issue can provide a clearer perspective for researchers in the face of this problem.
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Affiliation(s)
- Huldani Huldani
- Department of Physiology, Lambung Mangkurat University, Banjarmasin, South Borneo, Indonesia
| | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, Al-Maarif University College, Al-Anbar-Ramadi, Iraq
| | - Klunko Nataliya Sergeenva
- Department of post-graduate and doctoral programs, Russian New University, Building 5, Radio Street, Moscow City, Russian Federation
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., Bldg. 2, Moscow 119991, Russian Federation
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia; Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Rustam Turakulov
- Department of Internal diseases, Tashkent Medical Academy, Tashkent, Uzbekistan
| | | | - Behnam Ahmadzadeh
- Doctoral School of the University of Szczecin, Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland
| | - Zanko Hassan Jawhar
- Department of Medical Laboratory Science, College of Health Science, Lebanese French University, Kurdistan Region, Iraq
| | - Homayoon Siahmansouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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26
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Abstract
Hypoxia is defined as a cellular stress condition caused by a decrease in oxygen below physiologically normal levels. Cells in the core of a rapidly growing solid tumor are faced with the challenge of inadequate supply of oxygen through the blood, owing to improper vasculature inside the tumor. This hypoxic microenvironment inside the tumor initiates a gene expression program that alters numerous signaling pathways, allowing the cancer cell to eventually evade adverse conditions and attain a more aggressive phenotype. A multitude of studies covering diverse aspects of gene regulation has tried to uncover the mechanisms involved in hypoxia-induced tumorigenesis. The role of epigenetics in executing widespread and dynamic changes in gene expression under hypoxia has been gaining an increasing amount of support in recent years. This chapter discusses, in detail, various epigenetic mechanisms driving the cellular response to hypoxia in cancer.
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Affiliation(s)
- Deepak Pant
- Epigenetics and RNA Processing Lab (ERPL), Indian Institute of Science Education and Research Bhopal, Bhopal, India
| | - Srinivas Abhishek Mutnuru
- Epigenetics and RNA Processing Lab (ERPL), Indian Institute of Science Education and Research Bhopal, Bhopal, India
| | - Sanjeev Shukla
- Epigenetics and RNA Processing Lab (ERPL), Indian Institute of Science Education and Research Bhopal, Bhopal, India.
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27
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Kumar A, Hegde M, Parama D, Kunnumakkara AB. Curcumin: The Golden Nutraceutical on the Road to Cancer Prevention and Therapeutics. A Clinical Perspective. Crit Rev Oncog 2022; 27:33-63. [PMID: 37183937 DOI: 10.1615/critrevoncog.2023045587] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
Cancer is considered as the major public health scourge of the 21st century. Although remarkable strides were made for developing targeted therapeutics, these therapies suffer from lack of efficacy, high cost, and debilitating side effects. Therefore, the search for safe, highly efficacious, and affordable therapies is paramount for establishing a treatment regimen for this deadly disease. Curcumin, a known natural, bioactive, polyphenol compound from the spice turmeric (Curcuma longa), has been well documented for its wide range of pharmacological and biological activities. A plethora of literature indicates its potency as an anti-inflammatory and anti-cancer agent. Curcumin exhibits anti-neoplastic attributes via regulating a wide array of biological cascades involved in mutagenesis, proliferation, apoptosis, oncogene expression, tumorigenesis, and metastasis. Curcumin has shown a wide range of pleiotropic anti-proliferative effect in multiple cancers and is a known inhibitor of varied oncogenic elements, including nuclear factor kappa B (NF-κB), c-myc, cyclin D1, Bcl-2, VEGF, COX-2, NOS, tumor necrosis factor alpha (TNF-α), interleukins, and MMP-9. Further, curcumin targets different growth factor receptors and cell adhesion molecules involved in tumor growth and progression, making it a most promising nutraceutical for cancer therapy. To date, curcumin-based therapeutics have completed more than 50 clinical trials for cancer. Although creative experimentation is still elucidating the immense potential of curcumin, systematic validation by proper randomized clinical trials warrant its transition from lab to bedside. Therefore, this review summarizes the outcome of diverse clinical trials of curcumin in various cancer types.
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Affiliation(s)
- Aviral Kumar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam-781039, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam-781039, India
| | - Dey Parama
- Cancer Biology Laboratory, DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati, Assam-781039, India
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam-781039, India
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28
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Davoodvandi A, Farshadi M, Zare N, Akhlagh SA, Alipour Nosrani E, Mahjoubin-Tehran M, Kangari P, Sharafi SM, Khan H, Aschner M, Baniebrahimi G, Mirzaei H. Antimetastatic Effects of Curcumin in Oral and Gastrointestinal Cancers. Front Pharmacol 2021; 12:668567. [PMID: 34456716 PMCID: PMC8386020 DOI: 10.3389/fphar.2021.668567] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 07/05/2021] [Indexed: 12/17/2022] Open
Abstract
Gastrointestinal (GI) cancers are known as frequently occurred solid malignant tumors that can cause the high rate mortality in the world. Metastasis is a significant destructive feature of tumoral cells, which directly correlates with decreased prognosis and survival. Curcumin, which is found in turmeric, has been identified as a potent therapeutic natural bioactive compound (Curcuma longa). It has been traditionally applied for centuries to treat different diseases, and it has shown efficacy for its anticancer properties. Numerous studies have revealed that curcumin inhibits migration and metastasis of GI cancer cells by modulating various genes and proteins, i.e., growth factors, inflammatory cytokines and their receptors, different types of enzymes, caspases, cell adhesion molecules, and cell cycle proteins. Herein, we summarized the antimetastatic effects of curcumin in GI cancers, including pancreatic cancer, gastric cancer, colorectal cancer, oral cancer, and esophageal cancer.
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Affiliation(s)
- Amirhossein Davoodvandi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | | | - Noushid Zare
- Faculty of Pharmacy, International Campus, Tehran University of Medical Science, Tehran, Iran
| | | | - Esmail Alipour Nosrani
- Department of Nutrition, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parisa Kangari
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyedeh Maryam Sharafi
- Environment Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Ghazaleh Baniebrahimi
- Department of Pediatric Dentistry, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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29
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Estaras M, Gonzalez A. Modulation of cell physiology under hypoxia in pancreatic cancer. World J Gastroenterol 2021; 27:4582-4602. [PMID: 34366624 PMCID: PMC8326256 DOI: 10.3748/wjg.v27.i28.4582] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/28/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
In solid tumors, the development of vasculature is, to some extent, slower than the proliferation of the different types of cells that form the tissue, both cancer and stroma cells. As a consequence, the oxygen availability is compromised and the tissue evolves toward a condition of hypoxia. The presence of hypoxia is variable depending on where the cells are localized, being less extreme at the periphery of the tumor and more severe in areas located deep within the tumor mass. Surprisingly, the cells do not die. Intracellular pathways that are critical for cell fate such as endoplasmic reticulum stress, apoptosis, autophagy, and others are all involved in cellular responses to the low oxygen availability and are orchestrated by hypoxia-inducible factor. Oxidative stress and inflammation are critical conditions that develop under hypoxia. Together with changes in cellular bioenergetics, all contribute to cell survival. Moreover, cell-to-cell interaction is established within the tumor such that cancer cells and the microenvironment maintain a bidirectional communication. Additionally, the release of extracellular vesicles, or exosomes, represents short and long loops that can convey important information regarding invasion and metastasis. As a result, the tumor grows and its malignancy increases. Currently, one of the most lethal tumors is pancreatic cancer. This paper reviews the most recent advances in the knowledge of how cells grow in a pancreatic tumor by adapting to hypoxia. Unmasking the physiological processes that help the tumor increase its size and their regulation will be of major relevance for the treatment of this deadly tumor.
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Affiliation(s)
- Matias Estaras
- Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, Caceres 10003, Spain
| | - Antonio Gonzalez
- Department of Physiology, Cell Biology and Communication Research Group, University of Extremadura, Caceres 10003, Spain
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30
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Ventura M, Bernards N, De Souza R, Fricke IB, Hendriks BS, Fitzgerald JB, Lee H, Klinz SG, Zheng J. Longitudinal PET Imaging to Monitor Treatment Efficacy by Liposomal Irinotecan in Orthotopic Patient-Derived Pancreatic Tumor Models of High and Low Hypoxia. Mol Imaging Biol 2021; 22:653-664. [PMID: 31482415 PMCID: PMC7782415 DOI: 10.1007/s11307-019-01374-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Purpose Hypoxia is linked to aggressiveness, resistance to therapy, and poor prognosis of pancreatic tumors. Liposomal irinotecan (nal-IRI, ONIVYDE®) has shown potential in reducing hypoxia in the HT29 colorectal cancer model, and here, we investigate its therapeutic activity and ability to modulate hypoxia in patient-derived orthotopic tumor models of pancreatic cancer. Procedures Mice were randomized into nal-IRI treated and untreated controls. Magnetic resonance imaging was used for monitoring treatment efficacy, positron emission tomography (PET) imaging with F-18-labelled fluoroazomycinarabinoside ([18F]FAZA) for tumor hypoxia quantification, and F-18-labelled fluorothymidine ([18F]FLT) for tumor cell proliferation. Results The highly hypoxic OCIP51 tumors showed significant response following nal-IRI treatment compared with the less hypoxic OCIP19 tumors. [18F]FAZA-PET detected significant hypoxia reduction in treated OCIP51 tumors, 8 days before significant changes in tumor volume. OCIP19 tumors also responded to therapy, although tumor volume control was not accompanied by any reduction in [18F]FAZA uptake. In both models, no differences were observable in [18F]FLT uptake in treated tumors compared with control mice. Conclusions Hypoxia modulation may play a role in nal-IRI’s mechanism of action. Nal-IRI demonstrated greater anti-tumor activity in the more aggressive and hypoxic tumor model. Furthermore, hypoxia imaging provided early prediction of treatment response. Electronic supplementary material The online version of this article (10.1007/s11307-019-01374-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Manuela Ventura
- TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada
| | - Nicholas Bernards
- TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada
| | - Raquel De Souza
- TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada
| | - Inga B Fricke
- TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada
| | | | | | - Helen Lee
- Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA
| | - Stephan G Klinz
- Merrimack Pharmaceuticals, Inc., Cambridge, MA, USA
- Ipsen Bioscience, Cambridge, MA, USA
| | - Jinzi Zheng
- TECHNA Institute for the Advancement of Technology for Health, University Health Network, Toronto, Ontario, Canada.
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.
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31
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Shakeri A, Ghanbari M, Tasbandi A, Sahebkar A. Regulation of microRNA-21 expression by natural products in cancer. Phytother Res 2021; 35:3732-3746. [PMID: 33724576 DOI: 10.1002/ptr.7069] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 02/09/2021] [Accepted: 02/22/2021] [Indexed: 12/19/2022]
Abstract
Natural products have been of much interest in research studies owing to their wide pharmacological applications, chemical diversity, low side effects, and multitarget activities. Examples of these compounds include matrine, sulforaphane, silibinin, curcumin, berberin, resveratrol, and quercetin. Some of the present anticancer drugs, such as taxol, vincristine, vinblastine, and doxorubicin are also derived from natural products. The anti-carcinogenic effects of these products are partly mediated through modulation of microRNA-21 (miR-21) expression. To date, numerous downstream targets of miR-21 have been recognized, which include phosphatase and tensin homolog (PTEN), ras homolog gene family member B (RHOB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), programmed cell death 4 (PDCD4), signal transducer and activator of transcription (STAT)-3, and nuclear factor kappa B (NF-κB) pathways. These signaling pathways, their regulation by oncomiR-21 in cancer, and the modulating impact of natural products are the main focus of this review.
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Affiliation(s)
- Abolfazl Shakeri
- Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Ghanbari
- Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.,Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Aida Tasbandi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Li H, Zhou L, Zhou J, Li Q, Ji Q. Underlying mechanisms and drug intervention strategies for the tumour microenvironment. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:97. [PMID: 33722297 PMCID: PMC7962349 DOI: 10.1186/s13046-021-01893-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 02/24/2021] [Indexed: 02/08/2023]
Abstract
Cancer occurs in a complex tissue environment, and its progression depends largely on the tumour microenvironment (TME). The TME has a highly complex and comprehensive system accompanied by dynamic changes and special biological characteristics, such as hypoxia, nutrient deficiency, inflammation, immunosuppression and cytokine production. In addition, a large number of cancer-associated biomolecules and signalling pathways are involved in the above bioprocesses. This paper reviews our understanding of the TME and describes its biological and molecular characterization in different stages of cancer development. Furthermore, we discuss in detail the intervention strategies for the critical points of the TME, including chemotherapy, targeted therapy, immunotherapy, natural products from traditional Chinese medicine, combined drug therapy, etc., providing a scientific basis for cancer therapy from the perspective of key molecular targets in the TME.
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Affiliation(s)
- Haoze Li
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lihong Zhou
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jing Zhou
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qi Li
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. .,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Qing Ji
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. .,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC.
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Emami Nejad A, Najafgholian S, Rostami A, Sistani A, Shojaeifar S, Esparvarinha M, Nedaeinia R, Haghjooy Javanmard S, Taherian M, Ahmadlou M, Salehi R, Sadeghi B, Manian M. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int 2021; 21:62. [PMID: 33472628 PMCID: PMC7816485 DOI: 10.1186/s12935-020-01719-5] [Citation(s) in RCA: 367] [Impact Index Per Article: 91.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 12/11/2020] [Accepted: 12/16/2020] [Indexed: 12/13/2022] Open
Abstract
Hypoxia is a common feature of solid tumors, and develops because of the rapid growth of the tumor that outstrips the oxygen supply, and impaired blood flow due to the formation of abnormal blood vessels supplying the tumor. It has been reported that tumor hypoxia can: activate angiogenesis, thereby enhancing invasiveness and risk of metastasis; increase survival of tumor, as well as suppress anti-tumor immunity and hamper the therapeutic response. Hypoxia mediates these effects by several potential mechanisms: altering gene expression, the activation of oncogenes, inactivation of suppressor genes, reducing genomic stability and clonal selection. We have reviewed the effects of hypoxia on tumor biology and the possible strategiesto manage the hypoxic tumor microenvironment (TME), highlighting the potential use of cancer stem cells in tumor treatment.
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Affiliation(s)
- Asieh Emami Nejad
- Department of Biology, Payame Noor University (PNU), P.O.Box 19395-3697, Tehran, Iran
| | - Simin Najafgholian
- Department of Emergency Medicine, School of Medicine , Arak University of Medical Sciences, Arak, Iran
| | - Alireza Rostami
- Department of Surgery, School of Medicine Amiralmomenin Hospital, Arak University of Medical Sciences, Arak, Iran
| | - Alireza Sistani
- Department of Emergency Medicine, School of Medicine Valiasr Hospital, Arak University of Medical Sciences, Arak, Iran
| | - Samaneh Shojaeifar
- Department of Midwifery, Faculty of Nursing and Midwifery , Arak University of Medical Sciences , Arak, Iran
| | - Mojgan Esparvarinha
- Department of Immunology, School of Medicine , Tabriz University of Medical Sciences , Tabriz, Iran
| | - Reza Nedaeinia
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease , Isfahan University of Medical Sciences , Isfahan, Iran
| | - Shaghayegh Haghjooy Javanmard
- Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences , Isfahan, Iran
| | - Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mojtaba Ahmadlou
- Sciences Medical of University Arak, Hospital Amiralmomenin, Center Development Research Clinical, Arak, Iran
| | - Rasoul Salehi
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease , Isfahan University of Medical Sciences , Isfahan, Iran.,Department of Genetics and Molecular Biology, School of Medicine , Isfahan University of Medical Sciences , Isfahan, Iran
| | - Bahman Sadeghi
- Department of Health and Community Medicine, School of Medicine, Arak University of Medical Sciences, Arak, 3848176341, Iran.
| | - Mostafa Manian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. .,Department of Medical Laboratory Science, Faculty of Medical Science Kermanshah Branch, Islamic Azad University, Imam Khomeini Campus, Farhikhtegan Bld., Shahid J'afari St., Kermanshah, 3848176341, Iran.
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35
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Emerging roles for the IL-6 family of cytokines in pancreatic cancer. Clin Sci (Lond) 2020; 134:2091-2115. [PMID: 32808663 PMCID: PMC7434989 DOI: 10.1042/cs20191211] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 07/29/2020] [Accepted: 08/07/2020] [Indexed: 12/13/2022]
Abstract
Pancreatic cancer has one of the poorest prognoses of all malignancies, with little improvement in clinical outcome over the past 40 years. Pancreatic ductal adenocarcinoma is responsible for the vast majority of pancreatic cancer cases, and is characterised by the presence of a dense stroma that impacts therapeutic efficacy and drives pro-tumorigenic programs. More specifically, the inflammatory nature of the tumour microenvironment is thought to underlie the loss of anti-tumour immunity and development of resistance to current treatments. Inflammatory pathways are largely mediated by the expression of, and signalling through, cytokines, chemokines, and other cellular messengers. In recent years, there has been much attention focused on dual targeting of cancer cells and the tumour microenvironment. Here we review our current understanding of the role of IL-6, and the broader IL-6 cytokine family, in pancreatic cancer, including their contribution to pancreatic inflammation and various roles in pancreatic cancer pathogenesis. We also summarise potential opportunities for therapeutic targeting of these pathways as an avenue towards combating poor patient outcomes.
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36
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Lin L, Wang Q, Xu F, Luo X, Xu J, Yan L, Li Q, Hao H. BML-111, the lipoxin A 4 agonist, modulates VEGF or CoCl 2-induced migration, angiogenesis and permeability in tumor-derived endothelial cells. Immunol Lett 2020; 230:27-35. [PMID: 33347917 DOI: 10.1016/j.imlet.2020.12.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/14/2020] [Accepted: 12/15/2020] [Indexed: 01/14/2023]
Abstract
Tumor angiogenesis plays a vital role in carcinogenesis, cancer progression, and metastasis. Lipoxin A4 (LXA4) is an endogenously-produced family of effective anti-inflammatory with a potent inhibitory effect on angiogenesis. However, BML-111, a LXA4 agonist, its governing tumor-derived endothelial cells (Td-EC) mechanisms remain unknown. In the present study, we utilized VEGF or CoCl2 to mimic tumor microenvironment in vitro to study the effect of BML-111 on angiogenesis and permeability of Td-EC, and preliminarily explore its specific mechanism. Data suggested that BML-111 inhibited viability, migration and angiogenesis in VEGF or CoCl2-treated Td-EC by modulating MMP2/9-TIMP1, and decreasing the production of HIF-1α and COX-2 level. In addition, we observed that BML-111 inhibited Td-EC permeability induced by VEGF or CoCl2, through the stabilization of VE-cadherin/β-catenin-dependent adherens junctions and TRPC1 pathway. Nevertheless, these effects could be blocked by BOC-2 which was the specific inhibitor of FPR2/ALX (the receptor of LXA4).These results suggest that BML-111 may have inhibitory effects on VEGF or CoCl2-induced migration, angiogenesis and permeability in tumor-derived endothelial cells.
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Affiliation(s)
- Lan Lin
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Qingyu Wang
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Fen Xu
- Department of General Medicine, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Xuliang Luo
- Department of Breast Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Jing Xu
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Liping Yan
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Qing Li
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Hua Hao
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, PR China.
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37
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Liu J, Niu Q, Hu Y, Ran S, Li S. The Mechanism of Trivalent Inorganic Arsenic on HIF-1α: a Systematic Review and Meta-analysis. Biol Trace Elem Res 2020; 198:449-463. [PMID: 32124230 DOI: 10.1007/s12011-020-02087-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 02/21/2020] [Indexed: 12/11/2022]
Abstract
The purpose of our study was to investigate the role of hypoxia-inducible factor-1α (HIF-1α) in arsenic-induced carcinogenesis. We included 39 articles for meta-analysis. The results showed that low-dose exposure to arsenic (≤ 10 μmol/L) could promote the expression of phosphatidylinositol 3-kinase (PI3K) and phosphorylation-protein kinase B (p-AKT). High-dose arsenic exposure (> 10 μmol/L) promoted the expression of PI3K, HIF-1α, vascular endothelial growth factor (VEGF), and p38MAPK (P38). Acute arsenic exposure (< 24 h) promoted the expression of PI3K, HIF-1α, and VEGF. Chronic arsenic exposure (≥ 24 h) promoted the expression of PI3K, p-AKT, and P38. Moreover, for normal tissue-derived cells, arsenic could induce the increased expression of PI3K, p-AKT, HIF-1α, and VEGF. For tumor tissue-derived cells, arsenic could induce the expression of PI3K, p-AKT, and P38. We found that arsenic exposure could activate the PI3K/AKT pathway, further induce the high expression of HIF-1α, and then upregulate the levels of miRNA-21 and VEGF, promote the expression of proliferating cell nuclear antigen (PCNA), and ultimately lead to malignant cell proliferation. Our findings indicated that arsenic could increase the expression of HIF-1α by activating the PI3K/AKT pathway and eventually induce malignant cell proliferation.
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Affiliation(s)
- Jiaqing Liu
- Department of Public Health, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China
| | - Qiang Niu
- Department of Public Health, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China
| | - Yunhua Hu
- Department of Public Health, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China
| | - Shanshan Ran
- Department of Public Health, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China
| | - Shugang Li
- Department of Public Health, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China.
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Warrier S, Patil M, Bhansali S, Varier L, Sethi G. Designing precision medicine panels for drug refractory cancers targeting cancer stemness traits. Biochim Biophys Acta Rev Cancer 2020; 1875:188475. [PMID: 33188876 DOI: 10.1016/j.bbcan.2020.188475] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 11/05/2020] [Accepted: 11/06/2020] [Indexed: 02/06/2023]
Abstract
Cancer is one amongst the major causes of death today and cancer biology is one of the most well researched fields in medicine. The driving force behind cancer is considered to be a minor subpopulation of cells, the cancer stem cells (CSCs). Similar to other stem cells, these cells are self-renewing and proliferating but CSCs are also difficult to target by chemo- or radio-therapies. Cancer stem cells are known to be present in most of the cancer subgroups such as carcinoma, sarcoma, myeloma, leukemia, lymphomas and mixed cancer types. There is a wide gamut of factors attributed to the stemness of cancers, ranging from dysregulated signaling pathways, and activation of enzymes aiding immune evasion, to conducive tumor microenvironment, to name a few. The defining outcome of the increased presence of CSCs is tumor metastasis and relapse. Predictive medicine approach based on the plethora of CSC markers would be a move towards precision medicine to specifically identify CSC-rich tumors. In this review, we discuss the cancer subtypes and the role of different CSC specific markers in these varying subtypes. We also categorize the CSC markers based their defining trait contributing to stemness. This review thus provides a comprehensive approach to catalogue a predictive set of markers to identify the resistant and refractory cancer stem cell population within different tumor subtypes, so as to facilitate better prognosis and targeted therapeutic strategies.
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Affiliation(s)
- Sudha Warrier
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560 065, India; Cuor Stem Cellutions Pvt Ltd, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560 065, India.
| | - Manasi Patil
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560 065, India
| | - Sanyukta Bhansali
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore 560 065, India
| | | | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117 600, Singapore
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Trošelj KG, Samaržija I, Tomljanović M, Kujundžić RN, Đaković N, Mojzeš A. Implementing Curcumin in Translational Oncology Research. Molecules 2020; 25:E5240. [PMID: 33182817 PMCID: PMC7698148 DOI: 10.3390/molecules25225240] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 10/29/2020] [Accepted: 11/04/2020] [Indexed: 12/11/2022] Open
Abstract
Most data published on curcumin and curcumin-based formulations are very promising. In cancer research, the majority of data has been obtained in vitro. Less frequently, researchers used experimental animals. The results of several clinical studies are conclusive, and these studies have established a good foundation for further research focusing on implementing curcumin in clinical oncology. However, the issues regarding timely data reporting and lack of disclosure of the exact curcumin formulations used in these studies should not be neglected. This article is a snapshot of the current status of publicly available data on curcumin clinical trials and a detailed presentation of results obtained so far with some curcumin formulations. Phenomena related to the observed effects of curcumin shown in clinical trials are presented, and its modifying effect on gut microbiota and metabolic reprogramming is discussed. Based on available data, there is a strong indication that curcumin and its metabolites present molecules that do not necessarily need to be abundant in order to act locally and benefit systemically. Future clinical studies should be designed in a way that will take that fact into consideration.
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Affiliation(s)
- Koraljka Gall Trošelj
- Laboratory for Epigenomics, Ruđer Bošković Institute, Division of Molecular Medicine, 10000 Zagreb, Croatia; (I.S.); (M.T.); (R.N.K.); (A.M.)
| | - Ivana Samaržija
- Laboratory for Epigenomics, Ruđer Bošković Institute, Division of Molecular Medicine, 10000 Zagreb, Croatia; (I.S.); (M.T.); (R.N.K.); (A.M.)
| | - Marko Tomljanović
- Laboratory for Epigenomics, Ruđer Bošković Institute, Division of Molecular Medicine, 10000 Zagreb, Croatia; (I.S.); (M.T.); (R.N.K.); (A.M.)
| | - Renata Novak Kujundžić
- Laboratory for Epigenomics, Ruđer Bošković Institute, Division of Molecular Medicine, 10000 Zagreb, Croatia; (I.S.); (M.T.); (R.N.K.); (A.M.)
| | - Nikola Đaković
- Institute for Clinical Medical Research and Education, University Hospital Centre Sisters of Charity, 10000 Zagreb, Croatia;
- Department of Clinical Oncology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Anamarija Mojzeš
- Laboratory for Epigenomics, Ruđer Bošković Institute, Division of Molecular Medicine, 10000 Zagreb, Croatia; (I.S.); (M.T.); (R.N.K.); (A.M.)
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40
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Dzobo K, Ganz C, Thomford NE, Senthebane DA. Cancer Stem Cell Markers in Relation to Patient Survival Outcomes: Lessons for Integrative Diagnostics and Next-Generation Anticancer Drug Development. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2020; 25:81-92. [PMID: 33170084 DOI: 10.1089/omi.2020.0185] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Solid tumors display a complex biology that requires a multipronged treatment strategy. Most anticancer interventions, including chemotherapy, are currently unable to prevent treatment resistance and relapse. In general, therapeutics target cancer cells and overlook the tumor microenvironment (TME) and the presence of cancer stem cells (CSCs) with self-renewal and tumorigenic abilities. CSCs have been postulated to play key roles in tumor initiation, progression, therapy resistance, and metastasis. Hence, CSC markers have been suggested as diagnostics to forecast cancer prognosis as well as molecular targets for new-generation cancer treatments, especially in resistant disease. We report here original findings on expression and prognostic significance of CSC markers in several cancers. We examined and compared the transcriptional expression of CSC markers (ABCB1, ABCG2, ALDH1A1, CD24, CD44, CD90, CD133, CXCR4, EPCAM, ICAM1, and NES) in tumor tissues versus the adjacent normal tissues using publicly available databases, The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis. We found that CSC transcriptional markers were, to a large extent, expressed in higher abundance in solid tumors such as colon, lung, pancreatic, and esophageal cancers. On the other hand, no CSC marker in our analysis was expressed in the same pattern in all cancers, while individual CSC marker expression, alone, was not significantly associated with overall patient survival. Innovation in next-generation cancer therapeutics and diagnostics ought to combine CSC markers as well as integrative diagnostics that pool knowledge from CSCs and other TME components and cancer cells.
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Affiliation(s)
- Kevin Dzobo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa.,Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Chelene Ganz
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa.,Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Nicholas Ekow Thomford
- Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.,Department of Medical Biochemistry, School of Medical Sciences, College of Health Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Dimakatso Alice Senthebane
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa.,Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
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Ashrafizadeh M, Zarrabi A, Hashemipour M, Vosough M, Najafi M, Shahinozzaman M, Hushmandi K, Khan H, Mirzaei H. Sensing the scent of death: Modulation of microRNAs by Curcumin in gastrointestinal cancers. Pharmacol Res 2020; 160:105199. [DOI: 10.1016/j.phrs.2020.105199] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 09/06/2020] [Accepted: 09/07/2020] [Indexed: 02/06/2023]
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Najafzadeh B, Asadzadeh Z, Motafakker Azad R, Mokhtarzadeh A, Baghbanzadeh A, Alemohammad H, Abdoli Shadbad M, Vasefifar P, Najafi S, Baradaran B. The oncogenic potential of NANOG: An important cancer induction mediator. J Cell Physiol 2020; 236:2443-2458. [PMID: 32960465 DOI: 10.1002/jcp.30063] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/02/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022]
Abstract
Cancer stem cells (CSCs) are a unique population in the tumor, but they only comprise 2%-5% of the tumor bulk. Although CSCs share several features with embryonic stem cells, CSCs can give rise to the tumor cells. CSCs overexpress embryonic transcription factor NANOG, which is downregulated in differentiated tissues. This transcription factor confers CSC's stemness, unlimited self-renewal, metastasis, invasiveness, angiogenesis, and drug-resistance with the assistance of WNT, OCT4, SOX2, Hedgehog, BMI-1, and other complexes. NANOG facilitates CSCs development via multiple pathways, like angiogenesis and lessening E-cadherin expression levels, which paves the road for metastasis. Moreover, NANOG represses apoptosis and leads to drug-resistance. This review aims to highlight the pivotal role of NANOG and the pertained pathways in CSCs. Also, this current study intends to demonstrate that targeting NANOG can dimmish the CSCs, sensitize the tumor to chemotherapy, and eradicate the cancer cells.
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Affiliation(s)
- Basira Najafzadeh
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hajar Alemohammad
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | - Parisa Vasefifar
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Fukukura Y, Kumagae Y, Higashi R, Hakamada H, Nagano H, Hidaka S, Kamimura K, Maemura K, Arima S, Yoshiura T. Visual enhancement pattern during the delayed phase of enhanced CT as an independent prognostic factor in stage IV pancreatic ductal adenocarcinoma. Pancreatology 2020; 20:1155-1163. [PMID: 32800574 DOI: 10.1016/j.pan.2020.07.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 07/08/2020] [Accepted: 07/12/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) has substantial heterogeneity in biophysical features and in outcomes of patients. Identifying reliable pretreatment imaging biomarkers for PDAC with distant metastases (stage IV) is a key imperative. Our objective was to determine whether visual tumor enhancement pattern on enhanced computed tomography (CT) can be used as a prognostic factor in stage IV PDAC treated with chemotherapy. METHODS This is a retrospective cohort study of 133 patients with stage IV PDAC who underwent multiphasic enhanced CT before systemic chemotherapy. The enhancement pattern of PDAC was qualitatively categorized as hypoattenuation, isoattenuation, or hyperattenuation on each of the pancreatic, portal venous, and delayed phases. The effects of clinical prognostic factors and the visual tumor enhancement pattern on progression-free survival (PFS) and overall survival (OS) were assessed in univariate and multivariate analyses using Cox proportional hazards models. RESULTS On univariate analysis, the number of metastatic organs and the visual tumor enhancement pattern during the delayed phase were significantly associated with PFS (p = 0.003 and < 0.001, respectively) and OS (p = 0.005 and < 0.001, respectively). Multivariate analysis identified the number of metastatic organs (PFS, p = 0.021; OS, p = 0.041) and visual tumor enhancement pattern during the delayed phase (PFS, p < 0.001; OS, p < 0.001) as independent predictors of PFS and OS. CONCLUSION Visual enhancement pattern of PDAC on delayed phase enhanced CT appears to be associated with outcomes and could be a useful prognostic factor in stage IV PDAC, despite the need to add the delayed phase to CT protocol for pancreatic disease.
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Affiliation(s)
- Yoshihiko Fukukura
- Departments of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
| | - Yuichi Kumagae
- Departments of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Ryutaro Higashi
- Departments of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Hiroto Hakamada
- Departments of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Hiroaki Nagano
- Departments of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Seiya Hidaka
- Departments of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kiyohisa Kamimura
- Departments of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kosei Maemura
- Departments of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Shiho Arima
- Departments of Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Takashi Yoshiura
- Departments of Radiology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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Zhou X, Jiao D, Dou M, Zhang W, Lv L, Chen J, Li L, Wang L, Han X. Curcumin inhibits the growth of triple-negative breast cancer cells by silencing EZH2 and restoring DLC1 expression. J Cell Mol Med 2020; 24:10648-10662. [PMID: 32725802 PMCID: PMC7521266 DOI: 10.1111/jcmm.15683] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 05/28/2020] [Accepted: 07/09/2020] [Indexed: 12/24/2022] Open
Abstract
Enhancer of zeste homolog 2 (EZH2), an oncogene, is a commonly up‐regulated epigenetic factor in human cancer. Hepatocellular carcinoma deletion gene 1 (DLC1) is an antioncogene that is either expressed at low levels or not expressed in many malignant tumours. Curcumin is a promising anticancer drug that has antitumour effects in many tumours, but its mechanism of action is unclear. Our research demonstrated that EZH2 was up‐regulated in breast cancer (BC) tissues and cells, whereas DLC1 was down‐regulated, and the expression of EZH2 and DLC1 was negatively correlated in BC. By analysing the characteristics of clinical cases, we found that positive expression of EZH2 and negative expression of DLC1 may be predictors of poor prognosis in patients with triple‐negative breast cancer (TNBC). Moreover, knockdown of EZH2 expression restored the expression of DLC1 and inhibited the migration, invasion and proliferation, promoted the apoptosis, and blocked the cell cycle of MDA‐MB‐231 cells. Furthermore, we found that curcumin restored the expression of DLC1 by inhibiting EZH2; it also inhibited the migration, invasion and proliferation of MDA‐MB‐231 cells, promoted their apoptosis and blocked the cell cycle. Finally, xenograft tumour models were used to demonstrate that curcumin restored DLC1 expression by inhibiting EZH2 and also inhibited the growth and promoted the apoptosis of TNBC cells. In conclusion, our results suggest that curcumin can inhibit the migration, invasion and proliferation, promote the apoptosis, block the cycle of TNBC cells and restore the expression of DLC1 by inhibiting the expression of EZH2.
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Affiliation(s)
- Xueliang Zhou
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Dechao Jiao
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mengmeng Dou
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Weijie Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Liying Lv
- Department of Oncology, The Central Hospital of Kaifeng, Kaifeng, China
| | - Jianjian Chen
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lifeng Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Liuxing Wang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Wan SS, Pan YM, Yang WJ, Rao ZQ, Yang YN. Inhibition of EZH2 alleviates angiogenesis in a model of corneal neovascularization by blocking FoxO3a-mediated oxidative stress. FASEB J 2020; 34:10168-10181. [PMID: 32562311 DOI: 10.1096/fj.201902814rrr] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 05/13/2020] [Accepted: 05/15/2020] [Indexed: 11/11/2022]
Abstract
Enhancer of zeste homolog 2 (EZH2), a well-known methyltransferase, mediates histone H3 lysine 27 trimethylation (H3K27me3) and plays a vital role in ophthalmological disease. However, its role in corneal neovascularization (CoNV) remains unclear. In vitro and in vivo models were assessed in hypoxia-stimulated angiogenesis and in a mouse model of alkali burn-induced CoNV. Human umbilical vein endothelial cells (HUVECs) were cultured under hypoxic conditions and different reoxygenation times to identify the molecular mechanisms involved in this process. In this study, we found that EZH2 was positively related to corneal alkali burn-induced injury. Inhibition of EZH2 with 3-Deazaneplanocin A (DZNeP) alleviated corneal injury, including oxidative stress and neovascularization in vivo. Similarly, inhibition of EZH2 with either DZNeP or small interfering RNA (siRNA) exerted an inhibitory effect on hypoxia/reoxygenation (H/R)-induced oxidative stress and angiogenesis in HUVECs. Moreover, our study revealed that ablation of reactive oxygen species (ROS) with N-acetyl-cysteine suppressed angiogenesis in HUVECs exposed to H/R stimulation. Furthermore, Forkhead-box protein O3a (FoxO3a), which was positively associated with ROS production and angiogenesis, was elevated during H/R. This effect could be reversed through the suppression of the transcription activity of EZH2 with DZNeP or siRNA. In addition, the PI3K/Akt pathway, which is the upstream of FoxO3a, was activated in both DZNeP-treated mice and EZH2-inhibited HUVECs. Collectively, our results demonstrated that the inhibition of EZH2 alleviated corneal angiogenesis by inhibiting FoxO3a-dependent ROS production through the PI3K/Akt signaling pathway. These findings indicate that EZH2 may be a valuable therapeutic target for CoNV.
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Affiliation(s)
- Shan-Shan Wan
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yu-Miao Pan
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wan-Ju Yang
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhuo-Qun Rao
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yan-Ning Yang
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, China
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Chen Y, Chang G, Chen X, Li Y, Li H, Cheng D, Tang Y, Sang H. IL-6-miR-210 Suppresses Regulatory T Cell Function and Promotes Atrial Fibrosis by Targeting Foxp3. Mol Cells 2020; 43:438-447. [PMID: 32345003 PMCID: PMC7264473 DOI: 10.14348/molcells.2019.2275] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/07/2018] [Accepted: 10/01/2018] [Indexed: 02/08/2023] Open
Abstract
The aim of this study was to explore the role of IL-6-miR-210 in the regulation of Tregs function and atrial fibrosis in atrial fibrillation (AF). The levels of interleukin (IL)-6 and IL-10 in AF patients were detected by using ELISA. Proportions of Treg cells were detected by fluorescence activated cell sorting analysis in AF patients. The expression of Foxp3, α-SMA, collagen I and collagen III were determined by western blot. The atrial mechanocytes were authenticated by vimentin immunostaining. The expression of miR-210 was performed by quantitative real-time polymerase chain reaction (qRT-PCR). TargetScan was used to predict potential targets of miR-210. The cardiomyocyte transverse sections in AF model group were observed by H&E staining. The myocardial filaments were observed by masson staining. The level of IL-6 was highly increased while the level of IL-10 (Tregs) was significantly decreased in AF patients as compared to normal control subjects, and IL-6 suppressed Tregs function and promoted the expression of α-SMA, collagen I and collagen III. Furthermore, miR-210 regulated Tregs function by targeting Foxp3, and IL-6 promoted expression of miR-210 via regulating hypoxia inducible factor-1α (HIF-1α). IL-6-miR-210 suppresses regulatory T cell function and promotes atrial fibrosis by targeting Foxp3.
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Affiliation(s)
- YingWei Chen
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
| | - GuoDong Chang
- Department of Cardiology, The First People’s Hospital of Shangqiu, Shangqiu 476100, China
| | - XiaoJie Chen
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
| | - YunPeng Li
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
| | - HaiYu Li
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
| | - Dong Cheng
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
| | - Yi Tang
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
| | - HaiQiang Sang
- Department of Cardiology, The First Affiliated Hospital of Zheng Zhou University, Zhengzhou 450052, China
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Abstract
During nearly 100 years of research on cancer cachexia (CC), science has been reciting the same mantra: it is a multifactorial syndrome. The aim of this paper is to show that the symptoms are many, but they have a single cause: anoxia. CC is a complex and devastating condition that affects a high proportion of advanced cancer patients. Unfortunately, it cannot be reversed by traditional nutritional support and it generally reduces survival time. It is characterized by significant weight loss, mainly from fat deposits and skeletal muscles. The occurrence of cachexia in cancer patients is usually a late phenomenon. The conundrum is why do similar patients with similar tumors, develop cachexia and others do not? Even if cachexia is mainly a metabolic dysfunction, there are other issues involved such as the activation of inflammatory responses and crosstalk between different cell types. The exact mechanism leading to a wasting syndrome is not known, however there are some factors that are surely involved, such as anorexia with lower calorie intake, increased glycolytic flux, gluconeogenesis, increased lipolysis and severe tumor hypoxia. Based on this incomplete knowledge we put together a scheme explaining the molecular mechanisms behind cancer cachexia, and surprisingly, there is one cause that explains all of its characteristics: anoxia. With this different view of CC we propose a treatment based on the physiopathology that leads from anoxia to the symptoms of CC. The fundamentals of this hypothesis are based on the idea that CC is the result of anoxia causing intracellular lactic acidosis. This is a dangerous situation for cell survival which can be solved by activating energy consuming gluconeogenesis. The process is conducted by the hypoxia inducible factor-1α. This hypothesis was built by putting together pieces of evidence produced by authors working on related topics.
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G9a Suppression Alleviates Corneal Neovascularization through Blocking Nox4-Mediated Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6983268. [PMID: 32256958 PMCID: PMC7093909 DOI: 10.1155/2020/6983268] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 02/16/2020] [Accepted: 02/22/2020] [Indexed: 01/18/2023]
Abstract
Background G9a, a well-known methyltransferase, plays a vital role in biological processes. However, its role in corneal neovascularization (CoNV) remains unclear. Methods. In vitro and in vivo models were assessed in hypoxia-stimulated angiogenesis and in a mouse model of alkali burn-induced CoNV. Human umbilical vein endothelial cells (HUVECs) were cultured under hypoxic conditions and different reoxygenation times to identify the molecular mechanisms involved in this process. Results In this study, we found that G9a was positively related to corneal alkali burn-induced injury. Inhibition of G9a with BIX 01294 (BIX) alleviated corneal injury, including oxidative stress and neovascularization in vivo models were assessed in hypoxia-stimulated angiogenesis and in a mouse model of alkali burn-induced CoNV. Human umbilical vein endothelial cells (HUVECs) were cultured under hypoxic conditions and different reoxygenation times to identify the molecular mechanisms involved in this process.
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49
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Peng X, Gao H, Xu R, Wang H, Mei J, Liu C. The interplay between HIF-1α and noncoding RNAs in cancer. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:27. [PMID: 32014012 PMCID: PMC6998277 DOI: 10.1186/s13046-020-1535-y] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 01/27/2020] [Indexed: 12/19/2022]
Abstract
Hypoxia is a classic characteristic of the tumor microenvironment with a significant impact on cancer progression and therapeutic response. Hypoxia-inducible factor-1 alpha (HIF-1α), the most important transcriptional regulator in the response to hypoxia, has been demonstrated to significantly modulate hypoxic gene expression and signaling transduction networks. In past few decades, growing numbers of studies have revealed the importance of noncoding RNAs (ncRNAs) in hypoxic tumor regions. These hypoxia-responsive ncRNAs (HRNs) play pivotal roles in regulating hypoxic gene expression at the transcriptional, posttranscriptional, translational and posttranslational levels. In addition, as a significant gene expression regulator, ncRNAs exhibit promising roles in regulating HIF-1α expression at multiple levels. In this review, we briefly elucidate the reciprocal regulation between HIF-1α and ncRNAs, as well as their effect on cancer cell behaviors. We also try to summarize the complex feedback loop existing between these two components. Moreover, we evaluated the biomarker potential of HRNs for the diagnosis and prognosis of cancer, as well as the potential clinical utility of shared regulatory mechanisms between HIF-1α and ncRNAs in cancer treatment, providing novel insights into tumorigenicity, which may lead to innovative clinical applications.
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Affiliation(s)
- Xiafeng Peng
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, China.,The First Clinical Medicine School, Nanjing Medical University, Nanjing, 211166, China
| | - Han Gao
- Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, China
| | - Rui Xu
- School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China
| | - Huiyu Wang
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, China
| | - Jie Mei
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, China.
| | - Chaoying Liu
- Department of Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, 299 Qingyang Road, Wuxi, 214023, China.
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Zhang Y, Yuan F, Liu L, Chen Z, Ma X, Lin Z, Zou J. The Role of the miR-21/SPRY2 Axis in Modulating Proangiogenic Factors, Epithelial Phenotypes, and Wound Healing in Corneal Epithelial Cells. Invest Ophthalmol Vis Sci 2020; 60:3854-3862. [PMID: 31529118 PMCID: PMC6881141 DOI: 10.1167/iovs.19-27013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Purpose Subconjunctival injection of antagomir-21 attenuates the progression of corneal neovascularization. We examined the underlying mechanism by investigating the regulation of microRNA (miR)-21 expression and the involvement of miR-21 in the homeostasis of corneal epithelial cells. Methods Corneal epithelial cells were cultured with TGF-β1 and/or under hypoxia conditions. miR-21 expression was measured by quantitative PCR. The direct targets of miR-21 were validated by the 3'-UTR luciferase reporter assay. Alterations of proangiogenic signaling and the epithelial-mesenchymal transition (EMT) phenotype after miR-21/Sprouty2 (SPRY2) knockdown were examined by Western blotting. The effect of conditioned medium on angiogenesis was assessed using the tube formation assay. Wound healing was evaluated by the migration and scratch assays. Results TGF-β1 or hypoxia upregulated miR-21, and miR-21 silencing abolished TGF-β1/hypoxia-induced hypoxia inducible factor (HIF)-1α and VEGF expression. miR-21 inhibited SPRY2 by directly targeting its 3'-UTR. Simultaneous silencing of miR-21 and SPRY2 significantly upregulated p-ERK, HIF-1α, and VEGF and promoted angiogenesis. Induction of miR-21 or inhibition of SPRY2 reduced the levels of cytokeratin (CK)-3 and CK-12 and promoted EMT. Transwell and wound healing assays indicated that miR-21 promoted cell migration. Conclusions TGF-β1 or hypoxia induced miR-21 and inhibited SPRY2, thereby enhancing proangiogenic signaling, suppressing the epithelial phenotype, and promoting wound healing in corneal epithelial cells.
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Affiliation(s)
- Yun Zhang
- Department of Ophthalmology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China.,Institute of Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Fukang Yuan
- Department of Vascular Surgery, XuZhou Central Hospital, Xuzhou, China
| | - Lin Liu
- Department of Ophthalmology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Zufeng Chen
- Department of Ophthalmology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Xiaoyun Ma
- Department of Ophthalmology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
| | - Zhen Lin
- Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana, United States
| | - Jun Zou
- Department of Ophthalmology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
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