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1
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Tufail M. PTEN-mediated resistance in cancer: From foundation to future therapies. Toxicol Rep 2025; 14:101987. [PMID: 40129883 PMCID: PMC11930710 DOI: 10.1016/j.toxrep.2025.101987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 03/01/2025] [Accepted: 03/02/2025] [Indexed: 03/26/2025] Open
Abstract
In cancer resistance, phosphatase and tensin homolog deleted (PTEN) has emerged as a prominent protagonist. PTEN exerts its influence by regulating crucial signaling pathways that govern cell proliferation, survival, and differentiation. This comprehensive review article investigates deeply into the complex realm of PTEN-mediated drug resistance mechanisms in cancers. Our journey begins by exploring PTEN's foundational role of PTEN, unveiling its significance as a molecular conductor that intricately coordinates vital cellular pathways. We thoroughly dissected the intricate milieu of PTEN alterations, including mutations, deletions, and epigenetic silencing, and elucidated their profound implications for fueling cancer growth and evading treatment. As we navigate the complex network of PTEN, we unravel the intricate interplay between PTEN and pivotal signaling pathways, such as PI3K/AKT, MAPK/ERK, and Wnt/β-catenin, further complicating the resistance landscape. This expedition, through these intricately intertwined signaling cascades, provides insight into the multifaceted mechanisms driving resistance, thereby revealing potential exploitable weaknesses. In our quest for therapeutic strategies, we need to explore innovative approaches to restore PTEN function, encompassing genetic therapies, pharmacological agents, and precision medicines tailored to PTEN status. The concept of combination therapy has emerged as a potent tool to overcome PTEN-associated resistance, offering promising synergistic interactions with standard treatments, targeted therapies, or immunotherapy. This review offers a comprehensive overview of PTEN-mediated drug resistance mechanisms in cancer and elucidates intricate interactions within this complex landscape. This underscores the central role of PTEN in drug resistance and provides valuable insights into promising strategies with the potential to reshape the future of cancer treatment.
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Öz H, Canacankatan N, Antmen ŞE, Aytan H, Tuncel F. 'Investigation of miRNAs That Affect the PI3K/AKT/mTOR Signaling Pathway in Endometrial Cancer'. Cell Biochem Biophys 2025:10.1007/s12013-025-01694-6. [PMID: 39982560 DOI: 10.1007/s12013-025-01694-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2025] [Indexed: 02/22/2025]
Abstract
Endometrial cancer is a prevalent type of cancer among women worldwide. The irregularity of the PI3K/AKT/mTOR signaling pathway plays a role in the pathogenesis of many cancer types. MicroRNAs are small noncoding RNAs that play crucial roles in the pathogenesis of different cancer types. MicroRNAs target many key components of the PI3K/AKT/mTOR pathway in human tumors. In this study the PI3K/AKT/mTOR pathway was affected in endometrial cancer, and the expression levels of miR-7, miR-17, miR-145, miR-155, miR-206, miR-221, miR-222 were determined. In addition, in silico analyses were examine the molecular interactions between miRNAs and target genes. Identifying dysregulated miRNA expression in endometrial cancer is important for developing miRNA-based therapeutic strategies. In our study, Grade 1 (n = 16), Grade 2 (n = 16), Grade 3 (n = 16), tissues diagnosed with endometrioid adeno carcinoma, control 1 (n = 16) secretory phase and control 2 (n = 16) proliferative phase healthy endometrial tissues without endometrial cancer were included. miRNA expression analysis was performed using the real-time PCR. In our study, the expression of miR-7-5p, miR-145-5p, and miR-206 decreased, whereas the expression of miR-17-5p, miR-221-3p, and miR-222-3p increased in endometrial cancer (p < 0,05). Statistically significant results were not obtained to for the expression levels of miR-21-5p and miR-155-5p. miR-7-5p targets PIK3CD, PIK3R3, PIK3CB and AKT3, miR-17-5p targets PIK3R1 and AKT3, miR-21-5p target PIK3R1, miR-145-5p target AKT3, miR-155-5p targets PIK3CA and PIK3R1, miR-206 target PIK3C2A, miR-221-3p and miR-222-3p target PIK3R1 as identified via in silico analysis. These results can shed light on the development of molecular-targeted therapy strategies. Treatment strategies can be developed by designing ASOs, LNAs, miRNA antagomirs, or miRNA sponges for upregulated miR-17-5p, miR-221-3p, and miR-222-3p, and miRNA mimics for downregulated miR-7-5p, miR-145-5p, and miR-206.
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Affiliation(s)
- Hasan Öz
- Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - Necmiye Canacankatan
- Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin, Turkey.
| | - Şerife Efsun Antmen
- Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - Hakan Aytan
- Department of Obstetrics and Gynecology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Ferah Tuncel
- Department of Pathology, Faculty of Medicine, Mersin University, Mersin, Turkey
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3
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Lu YY, Li Y, Chen ZL, Xiong XH, Wang QY, Dong HL, Zhu C, Cui JZ, Hu A, Wang L, Song N, Liu G, Chen HP. Genetic switch selectively kills hepatocellular carcinoma cell based on microRNA and tissue-specific promoter. Mol Cell Probes 2024; 77:101981. [PMID: 39197503 DOI: 10.1016/j.mcp.2024.101981] [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: 05/28/2024] [Revised: 08/26/2024] [Accepted: 08/26/2024] [Indexed: 09/01/2024]
Abstract
The clinical treatment of hepatocellular carcinoma (HCC) is still a heavy burden worldwide. Intracellular microRNAs (miRNAs) commonly express abnormally in cancers, thus they are potential therapeutic targets for cancer treatment. miR-21 is upregulated in HCC whereas miR-122 is enriched in normal hepatocyte but downregulated in HCC. In our study, we first generated a reporter genetic switch compromising of miR-21 and miR-122 sponges as sensor, green fluorescent protein (GFP) as reporter gene and L7Ae:K-turn as regulatory element. The reporter expression was turned up in miR-21 enriched environment while turned down in miR-122 enriched environment, indicating that the reporter switch is able to respond distinctly to different miRNA environment. Furthermore, an AAT promoter, which is hepatocyte-specific, is applied to increase the specificity to hepatocyte. A killing switch with AAT promoter and an apoptosis-inducing element, Bax, in addition to miR-21 and miR-122 significantly inhibited cell viability in Huh-7 by 70 % and in HepG2 by 60 %. By contrast, cell viability was not affected in five non-HCC cells. Thus, we provide a novel feasible strategy to improve the safety of miRNA-based therapeutic agent to cancer.
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Affiliation(s)
- Yuan-Yuan Lu
- Institutes of Physical Science and Information Technology, Anhui University, Hefei, 230000, China; Academy of Military Medical Sciences, Beijing, 100850, China
| | - Yi Li
- Academy of Military Medical Sciences, Beijing, 100850, China; Center for Disease Control and Prevention in Northern Theater Command of the People's Liberation Army, Shenyang, 110031, China
| | - Zhi-Li Chen
- Academy of Military Medical Sciences, Beijing, 100850, China
| | - Xiang-Hua Xiong
- Academy of Military Medical Sciences, Beijing, 100850, China
| | - Qing-Yang Wang
- Academy of Military Medical Sciences, Beijing, 100850, China
| | - Hao-Long Dong
- Academy of Military Medical Sciences, Beijing, 100850, China
| | - Chen Zhu
- Academy of Military Medical Sciences, Beijing, 100850, China
| | - Jia-Zhen Cui
- Academy of Military Medical Sciences, Beijing, 100850, China
| | - Ao Hu
- Institutes of Physical Science and Information Technology, Anhui University, Hefei, 230000, China; Academy of Military Medical Sciences, Beijing, 100850, China
| | - Lei Wang
- Department of Orthopedic Surgery, Senior Department of Orthopedics, The Fourth Medical Center of PLA General Hospital, Beijing, 100048, China.
| | - Na Song
- Department of Critical Care Medicine, People's Hospital of Laoling, Laoling, 253600, China
| | - Gang Liu
- Academy of Military Medical Sciences, Beijing, 100850, China.
| | - Hui-Peng Chen
- Academy of Military Medical Sciences, Beijing, 100850, China
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4
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Guo J, Jiang X, Lian J, Li H, Zhang F, Xie J, Deng J, Hou X, Du Z, Hao E. Evaluation of the effect of GSK-3β on liver cancer based on the PI3K/AKT pathway. Front Cell Dev Biol 2024; 12:1431423. [PMID: 39156976 PMCID: PMC11327086 DOI: 10.3389/fcell.2024.1431423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 07/22/2024] [Indexed: 08/20/2024] Open
Abstract
The PI3K/AKT/GSK-3β signaling pathway plays a pivotal role in numerous physiological and pathological processes, including cell proliferation, apoptosis, differentiation, and metabolic regulation. Aberrant activation of the PI3K/AKT pathway is intricately linked to development of tumor. GSK-3β, belonging to the serine/threonine protein kinase family, is crucial in the pathogenesis of liver cancer. As a key rate-limiting enzyme in the glucose metabolism pathway, GSK-3β significantly impacts the growth, proliferation, metastasis, and apoptosis of liver cancer cells. It is also implicated in chemotherapy resistance. Elevated expression of GSK-3β diminishes the sensitivity of liver cancer cells to chemotherapeutic agents, thereby playing a substantial role in the development of drug resistance. Consequently, targeting of GSK-3β, particularly within the PI3K/AKT signaling pathway, is regarded as a promising therapeutic strategy for liver cancer. The precise identification and subsequent modulation of this pathway represent a substantial potential for innovative clinical interventions in the management of liver cancer.
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Affiliation(s)
- Jiageng Guo
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
| | - Xinya Jiang
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Jing Lian
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
| | - Huaying Li
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
| | - Fan Zhang
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
| | - Jinling Xie
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
| | - Jiagang Deng
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
| | - Xiaotao Hou
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
| | - Zhengcai Du
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
| | - Erwei Hao
- Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Collaborative Innovation Center of Study on Functional Ingredients of Agricultural Residues, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of TCM Formulas Theory and Transformation for Damp Diseases, Guangxi University of Chinese Medicine, Nanning, China
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Maiyulan A, Matsumoto Y, Wang H, Murakami K, Toyozumi T, Otsuka R, Shiraishi T, Kinoshita K, Hu J, Iida S, Morishita H, Makiyama T, Nishioka Y, Kano M, Matsubara H. Hypoxia‑regulated exosomal miR‑185 inhibits esophageal squamous cell carcinoma progression and predicts prognosis. Oncol Lett 2024; 28:334. [PMID: 38827568 PMCID: PMC11140231 DOI: 10.3892/ol.2024.14467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 04/18/2024] [Indexed: 06/04/2024] Open
Abstract
Despite advances in treatment and diagnosis, the prognosis of patients with esophageal squamous cell carcinoma (ESCC) remains poor. MicroRNAs (miRNAs/miRs) are associated with prognosis in esophageal cancer, indicating that they may help guide treatment decisions. The aim of the present study was to explore exosomal miR-185 as a candidate prognostic biomarker and therapeutic target in ESCC, to investigate its biological function and clinical significance, and to ascertain the applicability of circulating exosomal miR-185 for the development of targeted drugs for ESCC treatment. A GeneChip miRNA array was used to compare exosomal miRNA expression in ESCC cell lines under hypoxia with those under normoxia. Exosomal miR-185 expression was then confirmed by reverse transcription-quantitative PCR. Patient background and prognosis were compared between high and low miR-185 expression groups. Functional analyses were performed to evaluate the antitumor effects of miR-185 in ESCC cells. Global Gene Set Enrichment Analysis of The Cancer Genome Atlas data was also performed, and differentially expressed exosomal miRNAs under hypoxia were identified compared to those under normoxia. Hypoxia markedly decreased the expression of exosomal miR-185 in KYSE-960 and T.Tn cell culture media. Overexpression of miR-185 suppressed the migration, invasion and colony-forming abilities of ESCC lines, and also suppressed cell cycle progression and promoted apoptosis after cisplatin treatment. Notably, high miR-185 expression was associated with signaling pathways related to cell death, DNA damage and p53. Furthermore, circulating exosomal miR-185 levels were associated with cN and cStage, and could predict progression-free survival and disease-specific survival of patients with ESCC after initial treatment. In conclusion, miR-185 holds potential as a prognostic biomarker and therapeutic target in ESCC.
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Affiliation(s)
- Abula Maiyulan
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Yasunori Matsumoto
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Huan Wang
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Kentaro Murakami
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Takeshi Toyozumi
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Ryota Otsuka
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tadashi Shiraishi
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Kazuya Kinoshita
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Jie Hu
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Shinichiro Iida
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hiroki Morishita
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tenshi Makiyama
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Yuri Nishioka
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Masayuki Kano
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
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6
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Murshed A, Alnoud MAH, Ahmad S, Khan SU, Alissa M, Alsuwat MA, Ahmed AE, Khan MU. Genetic Alchemy unveiled: MicroRNA-mediated gene therapy as the Artisan craft in the battlefront against hepatocellular carcinoma-a comprehensive chronicle of strategies and innovations. Front Genet 2024; 15:1356972. [PMID: 38915826 PMCID: PMC11194743 DOI: 10.3389/fgene.2024.1356972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 05/03/2024] [Indexed: 06/26/2024] Open
Abstract
Investigating therapeutic miRNAs is a rewarding endeavour for pharmaceutical companies. Since its discovery in 1993, our understanding of miRNA biology has advanced significantly. Numerous studies have emphasised the disruption of miRNA expression in various diseases, making them appealing candidates for innovative therapeutic approaches. Hepatocellular carcinoma (HCC) is a significant malignancy that poses a severe threat to human health, accounting for approximately 70%-85% of all malignant tumours. Currently, the efficacy of several HCC therapies is limited. Alterations in various biomacromolecules during HCC progression and their underlying mechanisms provide a basis for the investigation of novel and effective therapeutic approaches. MicroRNAs, also known as miRNAs, have been identified in the last 20 years and significantly impact gene expression and protein translation. This atypical expression pattern is strongly associated with the onset and progression of various malignancies. Gene therapy, a novel form of biological therapy, is a prominent research area. Therefore, miRNAs have been used in the investigation of tumour gene therapy. This review examines the mechanisms of action of miRNAs, explores the correlation between miRNAs and HCC, and investigates the use of miRNAs in HCC gene therapy.
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Affiliation(s)
- Abduh Murshed
- Department of Intensive Care Unit, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Mohammed A. H. Alnoud
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Saleem Ahmad
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | - Safir Ullah Khan
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Mohammed Alissa
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Meshari A. Alsuwat
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Ahmed Ezzat Ahmed
- Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia
- Prince Sultan Bin Abdelaziz for Environmental Research and Natural Resources Sustainability Center, King Khalid University, Abha, Saudi Arabia
| | - Munir Ullah Khan
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, International Research Center for XPolymers, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China
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7
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Wu L, Zhang Y, Ren J. Targeting non-coding RNAs and N 6-methyladenosine modification in hepatocellular carcinoma. Biochem Pharmacol 2024; 223:116153. [PMID: 38513741 DOI: 10.1016/j.bcp.2024.116153] [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: 02/09/2024] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 03/23/2024]
Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancers, accounts for a significant portion of cancer-related death globally. However, the molecular mechanisms driving the onset and progression of HCC are still not fully understood. Emerging evidence has indicated that non-protein-coding regions of genomes could give rise to transcripts, termed non-coding RNA (ncRNA), forming novel functional driving force for aberrant cellular activity. Over the past decades, overwhelming evidence has denoted involvement of a complex array of molecular function of ncRNAs at different stages of HCC tumorigenesis and progression. In this context, several pre-clinical studies have highlighted the potentials of ncRNAs as novel therapeutic modalities in the management of human HCC. Moreover, N6-methyladenosine (m6A) modification, the most prevalent form of internal mRNA modifications in mammalian cells, is essential for the governance of biological processes within cells. Dysregulation of m6A in ncRNAs has been implicated in human carcinogenesis, including HCC. In this review, we will discuss dysregulation of several hallmark ncRNAs (miRNAs, lncRNAs, and circRNAs) in HCC and address the latest advances for their involvement in the onset and progression of HCC. We also focus on dysregulation of m6A modification and various m6A regulators in the etiology of HCC. In the end, we discussed the contemporary preclinical and clinical application of ncRNA-based and m6A-targeted therapies in HCC.
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Affiliation(s)
- Lin Wu
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Yingmei Zhang
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Jun Ren
- Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, Shanghai 200032, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
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Li Y, Zhou P, Wang Z, Ren Y, Zhu X, Wang J, Yan H, Hua L, Gao F. Sea Anemone-like Nanomachine Based on DNA Strand Displacement Composed of Three Boolean Logic Gates: Diversified Input for Intracellular Multitarget Detection. Anal Chem 2024; 96:4120-4128. [PMID: 38412037 DOI: 10.1021/acs.analchem.3c05059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/29/2024]
Abstract
Efficient and accurate acquisition of cellular biomolecular information is crucial for exploring cell fate, achieving early diagnosis, and the effective treatment of various diseases. However, current DNA biosensors are mostly limited to single-target detection, with few complex logic circuits for comprehensive analysis of three or more targets. Herein, we designed a sea anemone-like DNA nanomachine based on DNA strand displacement composed of three logic gates (YES-AND-YES) and delivered into the cells using gold nano bipyramid carriers. The AND gate activation depends on the trigger chain released by upstream DNA strand displacement reactions, while the output signal relies on the downstream DNAzyme structure. Under the influence of diverse inputs (including enzymes, miRNA, and metal ions), the interconnected logic gates simultaneously perform logical analysis on multiple targets, generating a unique output signal in the YES/NO format. This sensor can successfully distinguish healthy cells from tumor cells and can be further used for the diagnosis of different tumor cells, providing a promising platform for accurate cell-type identification.
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Affiliation(s)
- Yuting Li
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Peng Zhou
- Department of Orthopedics, The Affiliated Huai'an Hospital of Xuzhou Medical University, The Second People's Hospital of Huai'an, Huai'an 223002, China
| | - Zhenxin Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Yiping Ren
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Xu Zhu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Jin Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Hanrong Yan
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Lei Hua
- Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China
| | - Fenglei Gao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
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Maji A, Paul A, Sarkar A, Nahar S, Bhowmik R, Samanta A, Nahata P, Ghosh B, Karmakar S, Kumar Maity T. Significance of TRAIL/Apo-2 ligand and its death receptors in apoptosis and necroptosis signalling: Implications for cancer-targeted therapeutics. Biochem Pharmacol 2024; 221:116041. [PMID: 38316367 DOI: 10.1016/j.bcp.2024.116041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 01/04/2024] [Accepted: 01/30/2024] [Indexed: 02/07/2024]
Abstract
The human immune defensesystem routinely expresses the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which is the most prevalent element for antitumor immunity. TRAIL associates with its death receptors (DRs), DR4 (TRAIL-R1), and DR5 (TRAIL-R2), in cancer cells to initiate the intracellular apoptosis cascade. Accordingly, numerous academic institutions and pharmaceutical companies havetried to exploreTRAIL's capacity to kill tumourcells by producing recombinant versions of it (rhTRAIL) or TRAIL receptor agonists (TRAs) [monoclonal antibody (mAb), synthetic and natural compounds, etc.] and molecules that sensitize TRAIL signalling pathway for therapeutic applications. Recently, several microRNAs (miRs) have been found to activate or inhibit death receptor signalling. Therefore, pharmacological regulation of these miRs may activate or resensitize the TRAIL DRs signal, and this is a novel approach for developing anticancer therapeutics. In this article, we will discuss TRAIL and its receptors and molecular pathways by which it induces various cell death events. We will unravel potential innovative applications of TRAIL-based therapeutics, and other investigated therapeutics targeting TRAIL-DRs and summarize the current preclinical pharmacological studies and clinical trials. Moreover, we will also emphasizea few situations where future efforts may be addressed to modulate the TRAIL signalling pathway.
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Affiliation(s)
- Avik Maji
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700 032, India.
| | - Abhik Paul
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700 032, India.
| | - Arnab Sarkar
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700 032, India; Bioequivalence Study Centre, Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata-700032, India.
| | - Sourin Nahar
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700 032, India.
| | - Rudranil Bhowmik
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700 032, India; Bioequivalence Study Centre, Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata-700032, India.
| | - Ajeya Samanta
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700 032, India.
| | - Pankaj Nahata
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700 032, India.
| | - Balaram Ghosh
- Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Hyderabad-500078, India.
| | - Sanmoy Karmakar
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700 032, India; Bioequivalence Study Centre, Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata-700032, India.
| | - Tapan Kumar Maity
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700 032, India.
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10
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Szczepanek J, Tretyn A. MicroRNA-Mediated Regulation of Histone-Modifying Enzymes in Cancer: Mechanisms and Therapeutic Implications. Biomolecules 2023; 13:1590. [PMID: 38002272 PMCID: PMC10669115 DOI: 10.3390/biom13111590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 10/22/2023] [Accepted: 10/26/2023] [Indexed: 11/26/2023] Open
Abstract
In the past decade, significant advances in molecular research have provided a deeper understanding of the intricate regulatory mechanisms involved in carcinogenesis. MicroRNAs, short non-coding RNA sequences, exert substantial influence on gene expression by repressing translation or inducing mRNA degradation. In the context of cancer, miRNA dysregulation is prevalent and closely associated with various stages of carcinogenesis, including initiation, progression, and metastasis. One crucial aspect of the cancer phenotype is the activity of histone-modifying enzymes that govern chromatin accessibility for transcription factors, thus impacting gene expression. Recent studies have revealed that miRNAs play a significant role in modulating these histone-modifying enzymes, leading to significant implications for genes related to proliferation, differentiation, and apoptosis in cancer cells. This article provides an overview of current research on the mechanisms by which miRNAs regulate the activity of histone-modifying enzymes in the context of cancer. Both direct and indirect mechanisms through which miRNAs influence enzyme expression are discussed. Additionally, potential therapeutic implications arising from miRNA manipulation to selectively impact histone-modifying enzyme activity are presented. The insights from this analysis hold significant therapeutic promise, suggesting the utility of miRNAs as tools for the precise regulation of chromatin-related processes and gene expression. A contemporary focus on molecular regulatory mechanisms opens therapeutic pathways that can effectively influence the control of tumor cell growth and dissemination.
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Affiliation(s)
- Joanna Szczepanek
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, ul. Wilenska 4, 87-100 Torun, Poland
| | - Andrzej Tretyn
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, ul. Lwowska 1, 87-100 Torun, Poland;
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11
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Bustamante-Marin X, Devlin KL, McDonell SB, Dave O, Merlino JL, Grindstaff EJ, Ho AN, Rezeli ET, Coleman MF, Hursting SD. Regulation of IGF1R by MicroRNA-15b Contributes to the Anticancer Effects of Calorie Restriction in a Murine C3-TAg Model of Triple-Negative Breast Cancer. Cancers (Basel) 2023; 15:4320. [PMID: 37686596 PMCID: PMC10486801 DOI: 10.3390/cancers15174320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/01/2023] [Accepted: 08/09/2023] [Indexed: 09/10/2023] Open
Abstract
Calorie restriction (CR) inhibits triple-negative breast cancer (TNBC) progression in several preclinical models in association with decreased insulin-like growth factor 1 (IGF1) signaling. To investigate the impact of CR on microRNAs (miRs) that target the IGF1/IGF1R pathway, we used the spontaneous murine model of TNBC, C3(1)/SV40 T-antigen (C3-TAg). In C3-TAg mice, CR reduced body weight, IGF1 levels, and TNBC progression. We evaluated the tumoral expression of 10 miRs. CR increased the expression of miR-199a-3p, miR-199a-5p, miR-486, and miR-15b. However, only miR-15b expression correlated with tumorigenicity in the M28, M6, and M6C C3-TAg cell lines of TNBC progression. Overexpressing miR-15b reduced the proliferation of mouse (M6) and human (MDA-MB-231) cell lines. Serum restriction alone or in combination with low levels of recombinant IGF1 significantly upregulated miR-15b expression and reduced Igf1r in M6 cells. These effects were reversed by the pharmacological inhibition of IGFR with BMS754807. In silico analysis using miR web tools predicted that miR-15b targets genes associated with IGF1/mTOR pathways and the cell cycle. Our findings suggest that CR in association with reduced IGF1 levels could upregulate miR-15b to downregulate Igf1r and contribute to the anticancer effects of CR. Thus, miR-15b may be a therapeutic target for mimicking the beneficial effects of CR against TNBC.
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Affiliation(s)
- Ximena Bustamante-Marin
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA
- Nutrition Research Institute, University of North Carolina, Chapel Hill, NC 28081, USA
| | - Kaylyn L. Devlin
- School of Medicine, Oregon Health and Science University, Portland, OR 97239, USA;
| | - Shannon B. McDonell
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Om Dave
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Jenna L. Merlino
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Emma J. Grindstaff
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Alyssa N. Ho
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA
- Nutrition Research Institute, University of North Carolina, Chapel Hill, NC 28081, USA
| | - Erika T. Rezeli
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Michael F. Coleman
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA
- Nutrition Research Institute, University of North Carolina, Chapel Hill, NC 28081, USA
| | - Stephen D. Hursting
- Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA
- Nutrition Research Institute, University of North Carolina, Chapel Hill, NC 28081, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
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12
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Bogaczyk A, Zawlik I, Zuzak T, Kluz M, Potocka N, Kluz T. The Role of miRNAs in the Development, Proliferation, and Progression of Endometrial Cancer. Int J Mol Sci 2023; 24:11489. [PMID: 37511248 PMCID: PMC10380838 DOI: 10.3390/ijms241411489] [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: 05/31/2023] [Revised: 06/30/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
Endometrial cancer is one of the most common cancers in developing and developed countries. Although the detection of this cancer is high at the early stages, there is still a lack of markers to monitor the disease, its recurrence, and metastasis. MiRNAs are in charge of the post-transcriptional regulation of genes responsible for the most important biological processes, which is why they are increasingly used as biomarkers in many types of cancer. Many studies have demonstrated the influence of miRNAs on the processes related to carcinogenesis. The characteristics of miRNA expression profiles in endometrial cancer will allow their use as diagnostic and prognostic biomarkers. This paper focuses on the discussion of selected miRNAs based on the literature and their role in the development of endometrial cancer.
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Affiliation(s)
- Anna Bogaczyk
- Department of Gynecology, Gynecology Oncology and Obstetrics, Fryderyk Chopin University Hospital, F.Szopena 2, 35-055 Rzeszow, Poland; (A.B.); (T.Z.); (T.K.)
| | - Izabela Zawlik
- Laboratory of Molecular Biology, Centre for Innovative Research in Medical and Natural Sciences, Medical College of Rzeszow University, Warzywna 1a, 35-959 Rzeszow, Poland;
- Institute of Medical Sciences, Medical College of Rzeszow University, Kopisto 2a, 35-959 Rzeszow, Poland
| | - Tomasz Zuzak
- Department of Gynecology, Gynecology Oncology and Obstetrics, Fryderyk Chopin University Hospital, F.Szopena 2, 35-055 Rzeszow, Poland; (A.B.); (T.Z.); (T.K.)
| | - Marta Kluz
- Department of Pathology, Fryderyk Chopin University Hospital, F.Szopena 2, 35-055 Rzeszow, Poland;
| | - Natalia Potocka
- Laboratory of Molecular Biology, Centre for Innovative Research in Medical and Natural Sciences, Medical College of Rzeszow University, Warzywna 1a, 35-959 Rzeszow, Poland;
| | - Tomasz Kluz
- Department of Gynecology, Gynecology Oncology and Obstetrics, Fryderyk Chopin University Hospital, F.Szopena 2, 35-055 Rzeszow, Poland; (A.B.); (T.Z.); (T.K.)
- Institute of Medical Sciences, Medical College of Rzeszow University, Kopisto 2a, 35-959 Rzeszow, Poland
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13
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Pei HZ, Peng Z, Zhuang X, Wang X, Lu B, Guo Y, Zhao Y, Zhang D, Xiao Y, Gao T, Yu L, He C, Wu S, Baek SH, Zhao ZJ, Xu X, Chen Y. miR-221/222 induce instability of p53 By downregulating deubiquitinase YOD1 in acute myeloid leukemia. Cell Death Discov 2023; 9:249. [PMID: 37454155 DOI: 10.1038/s41420-023-01537-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 06/20/2023] [Accepted: 06/28/2023] [Indexed: 07/18/2023] Open
Abstract
Acute myeloid leukemia (AML) is a hematological malignancy characterized by the impaired differentiation and uncontrolled proliferation of myeloid blasts. Tumor suppressor p53 is often downregulated in AML cells via ubiquitination-mediated degradation. While the role of E3 ligase MDM2 in p53 ubiquitination is well-accepted, little is known about the involvement of deubiquitinases (DUBs). Herein, we found that the expression of YOD1, among several DUBs, is substantially reduced in blood cells from AML patients. We identified that YOD1 deubiqutinated and stabilized p53 through interaction via N-terminus of p53 and OTU domain of YOD1. In addition, expression levels of YOD1 were suppressed by elevated miR-221/222 in AML cells through binding to the 3' untranslated region of YOD1, as verified by reporter gene assays. Treatment of cells with miR-221/222 mimics and inhibitors yielded the expected effects on YOD1 expressions, in agreement with the negative correlation observed between the expression levels of miR-221/222 and YOD1 in AML cells. Finally, overexpression of YOD1 stabilized p53, upregulated pro-apoptotic p53 downstream genes, and increased the sensitivity of AML cells to FLT3 inhibitors remarkably. Collectively, our study identified a pathway connecting miR-221/222, YOD1, and p53 in AML. Targeting miR-221/222 and stimulating YOD1 activity may improve the therapeutic effects of FLT3 inhibitors in patients with AML.
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Affiliation(s)
- Han Zhong Pei
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Zhiyong Peng
- Nanfang-Chunfu Children's Institute of Hematology, Taixin Hospital, Dongguan, Guangdong, China
| | - Xiaomei Zhuang
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Xiaobo Wang
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Bo Lu
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Yao Guo
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Yuming Zhao
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Dengyang Zhang
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Yunjun Xiao
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Tianshun Gao
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Liuting Yu
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Chunxiao He
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Shunjie Wu
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China
| | - Suk-Hwan Baek
- Department of Biochemistry & Molecular Biology, College of Medicine, Yeungnam University, 170 Hyeonchung-ro, Nam-gu, Daegu, 42415, South Korea.
| | - Zhizhuang Joe Zhao
- Department of Pathology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., BMSB 451, Oklahoma City, OK, 73104, USA.
| | - Xiaojun Xu
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.
| | - Yun Chen
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China.
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14
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Kempska J, Oliveira-Ferrer L, Grottke A, Qi M, Alawi M, Meyer F, Borgmann K, Hamester F, Eylmann K, Rossberg M, Smit DJ, Jücker M, Laakmann E, Witzel I, Schmalfeldt B, Müller V, Legler K. Impact of AKT1 on cell invasion and radiosensitivity in a triple negative breast cancer cell line developing brain metastasis. Front Oncol 2023; 13:1129682. [PMID: 37483521 PMCID: PMC10358765 DOI: 10.3389/fonc.2023.1129682] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 05/30/2023] [Indexed: 07/25/2023] Open
Abstract
Introduction The PI3K/AKT pathway is activated in 43-70% of breast cancer (BC)-patients and promotes the metastatic potential of BC cells by increasing cell proliferation, invasion and radioresistance. Therefore, AKT1-inhibition in combination with radiotherapy might be an effective treatment option for triple-negative breast cancer (TNBC)-patients with brain metastases. Methods The impact of AKT1-knockout (AKT1_KO) and AKT-inhibition using Ipatasertib on MDA-MB-231 BR cells was assessed using in vitro cell proliferation and migration assays. AKT1-knockout in MDA-MB-231BR cells was performed using CRISPR/Cas9. The effect of AKT1-knockout on radiosensitivity of MDA-MB-231BR cell lines was determined via colony formation assays after cell irradiation. To detect genomic variants in AKT1_KO MDA-MB-231BR cells, whole-genome sequencing (WGS) was performed. Results Pharmacological inhibition of AKT with the pan-AKT inhibitor Ipatasertib led to a significant reduction of cell viability but did not impact cell migration. Moreover, only MDA-MB-231BR cells were sensitized following Ipatasertib-treatment. Furthermore, specific AKT1-knockout in MDA-MB-231BR showed reduced cell viability in comparison to control cells, with significant effect in one of two analyzed clones. Unexpectedly, AKT1 knockout led to increased cell migration and clonogenic potential in both AKT1_KO clones. RNAseq-analysis revealed the deregulation of CTSO, CYBB, GPR68, CEBPA, ID1, ID4, METTL15, PBX1 and PTGFRN leading to the increased cell migration, higher clonogenic survival and decreased radiosensitivity as a consequence of the AKT1 knockout in MDA-MB-231BR. Discussion Collectively, our results demonstrate that Ipatasertib leads to radiosensitization and reduced cell proliferation of MDA-MB-231BR. AKT1-inhibition showed altered gene expression profile leading to modified cell migration, clonogenic survival and radioresistance in MDA-MB-231BR. We conclude, that AKT1-inhibition in combination with radiotherapy contribute to novel treatment strategies for breast cancer brain metastases.
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Affiliation(s)
- Joanna Kempska
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Astrid Grottke
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Minyue Qi
- Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Malik Alawi
- Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Felix Meyer
- Laboratory of Radiobiology & Experimental Radio Oncology, Department of Radiotherapy and Radiation Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kerstin Borgmann
- Laboratory of Radiobiology & Experimental Radio Oncology, Department of Radiotherapy and Radiation Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Fabienne Hamester
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kathrin Eylmann
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maila Rossberg
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Daniel J. Smit
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Manfred Jücker
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Elena Laakmann
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Isabell Witzel
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Barbara Schmalfeldt
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Volkmar Müller
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Karen Legler
- Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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15
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Stainthorp AK, Lin CC, Wang D, Medhi R, Ahmed Z, Suen KM, Miska EA, Whitehouse A, Ladbury JE. Regulation of microRNA expression by the adaptor protein GRB2. Sci Rep 2023; 13:9784. [PMID: 37328606 PMCID: PMC10276003 DOI: 10.1038/s41598-023-36996-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/14/2023] [Indexed: 06/18/2023] Open
Abstract
Protein interactions with the microRNA (miRNA)-mediated gene silencing protein Argonaute 2 (AGO2) control miRNA expression. miRNA biogenesis starts with the production of precursor transcripts and culminates with the loading of mature miRNA onto AGO2 by DICER1. Here we reveal an additional component to the regulatory mechanism for miRNA biogenesis involving the adaptor protein, growth factor receptor-bound protein 2 (GRB2). The N-terminal SH3 domain of GRB2 is recruited to the PAZ domain of AGO2 forming a ternary complex containing GRB2, AGO2 and DICER1. Using small-RNA sequencing we identified two groups of miRNAs which are regulated by the binding of GRB2. First, mature and precursor transcripts of mir-17~92 and mir-221 miRNAs are enhanced. Second, mature, but not precursor, let-7 family miRNAs are diminished suggesting that GRB2 directly affects loading of these miRNAs. Notably, the resulting loss of let-7 augments expression of oncogenic targets such as RAS. Thus, a new role for GRB2 is established with implications for cancer pathogenesis through regulation of miRNA biogenesis and oncogene expression.
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Affiliation(s)
- Amy K Stainthorp
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Chi-Chuan Lin
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Dapeng Wang
- LeedsOmics, University of Leeds, Leeds, LS2 9JT, UK
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK
- National Heart and Lung Institute, Imperial College London, London, SW3 6LY, UK
| | - Ragini Medhi
- Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK
| | - Zamal Ahmed
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Kin Man Suen
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - Eric A Miska
- Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK
| | - Adrian Whitehouse
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK
| | - John E Ladbury
- School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK.
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16
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Tepebaşı MY, Öztürk Ö. miR-21, miR-221, and miR-222 upregulation in lung cancer promotes metastasis by reducing oxidative stress and apoptosis. REVISTA DA ASSOCIACAO MEDICA BRASILEIRA (1992) 2023; 69:e20221688. [PMID: 37283359 DOI: 10.1590/1806-9282.20221688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 03/06/2023] [Indexed: 06/08/2023]
Abstract
OBJECTIVE The purpose of our research was to observe the effects of miR-21, miR-221, and miR-222, as well as their target genes on oxidative stress, lung cancer formation, and metastasis. METHODS Positron emission tomography/computed tomography, fiberoptic bronchoscopy, and/or endobronchial ultrasonography were performed on a total of 69 lung cancer patients to detect the presence or absence of metastasis, and the patients were classified based on the types of cancer. Total RNA and miRNA were isolated from the obtained biopsy samples. The quantitative analysis of hsa-miR-21-5p, hsa-miR-222-3p, and hsa-miR-221-3p and their target genes was performed by the RT-qPCR method. In determining oxidative stress, total antioxidant status and total oxidant status in tissue and total thiol and native thiol in blood were determined spectrophotometrically. OSI and disulfide were calculated. RESULTS We discovered that the metastasis group had higher levels of hsa-miR-21-5p, hsa-miR-221-3p, and hsa-miR-222-3p (p<0.05). While TIMP3, PTEN, and apoptotic genes decreased in metastasis, anti-apoptotic genes increased (p<0.05). In addition, while oxidative stress decreased in the metastasis group, no change was found in the serum (p>0.05). CONCLUSION Our findings show that upregulation of hsa-miR-21-5p, hsa-miR-221-3p, and hsa-miR-222-3p effectively contributes to both proliferation and invasion by influencing oxidative stress and mitochondrial apoptosis.
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Affiliation(s)
| | - Önder Öztürk
- University of Süleyman Demirel, Department of Chest Diseases - Isparta, Turkey
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17
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Shi M, Han W, Loudig O, Shah CD, Dobkin JB, Keller S, Sadoughi A, Zhu C, Siegel RE, Fernandez MK, DeLaRosa L, Patel D, Desai A, Siddiqui T, Gombar S, Suh Y, Wang T, Hosgood HD, Pradhan K, Ye K, Spivack SD. Initial development and testing of an exhaled microRNA detection strategy for lung cancer case-control discrimination. Sci Rep 2023; 13:6620. [PMID: 37095155 PMCID: PMC10126132 DOI: 10.1038/s41598-023-33698-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/18/2023] [Indexed: 04/26/2023] Open
Abstract
For detecting field carcinogenesis non-invasively, early technical development and case-control testing of exhaled breath condensate microRNAs was performed. In design, human lung tissue microRNA-seq discovery was reconciled with TCGA and published tumor-discriminant microRNAs, yielding a panel of 24 upregulated microRNAs. The airway origin of exhaled microRNAs was topographically "fingerprinted", using paired EBC, upper and lower airway donor sample sets. A clinic-based case-control study (166 NSCLC cases, 185 controls) was interrogated with the microRNA panel by qualitative RT-PCR. Data were analyzed by logistic regression (LR), and by random-forest (RF) models. Feasibility testing of exhaled microRNA detection, including optimized whole EBC extraction, and RT and qualitative PCR method evaluation, was performed. For sensitivity in this low template setting, intercalating dye-based URT-PCR was superior to fluorescent probe-based PCR (TaqMan). In application, adjusted logistic regression models identified exhaled miR-21, 33b, 212 as overall case-control discriminant. RF analysis of combined clinical + microRNA models showed modest added discrimination capacity (1.1-2.5%) beyond clinical models alone: all subjects 1.1% (p = 8.7e-04)); former smokers 2.5% (p = 3.6e-05); early stage 1.2% (p = 9.0e-03), yielding combined ROC AUC ranging from 0.74 to 0.83. We conclude that exhaled microRNAs are qualitatively measureable, reflect in part lower airway signatures; and when further refined/quantitated, can potentially help to improve lung cancer risk assessment.
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Affiliation(s)
- Miao Shi
- Pulmonary Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
| | - Weiguo Han
- Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA
| | | | - Chirag D Shah
- Pulmonary Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Jay B Dobkin
- Pulmonary Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | | | - Ali Sadoughi
- Pulmonary Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Changcheng Zhu
- Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Robert E Siegel
- Pulmonary Medicine, Icahn School of Medicine at Mount Sinai, James J. Peters Veterans Affairs Medical Center, New York, USA
| | | | - Lizett DeLaRosa
- Pulmonary Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | | | | | - Taha Siddiqui
- Pulmonary Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Saurabh Gombar
- Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Yousin Suh
- Reproductive Sciences (in Obstetrics and Gynecology), Columbia University, New York, USA
- Genetics and Development, Columbia University, New York, USA
| | - Tao Wang
- Biostatistics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - H Dean Hosgood
- Epidemiology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Kith Pradhan
- Biostatistics, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Kenny Ye
- Biostatistics, Albert Einstein College of Medicine, Bronx, NY, USA
- Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Simon D Spivack
- Pulmonary Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
- Genetics, Albert Einstein College of Medicine, Bronx, NY, USA
- Epidemiology, Albert Einstein College of Medicine, Bronx, NY, USA
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18
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Kim JY, Jung EJ, Kim JM, Son Y, Lee HS, Kwag SJ, Park JH, Cho JK, Kim HG, Park T, Jeong SH, Jeong CY, Ju YT. MiR‑221 and miR‑222 regulate cell cycle progression and affect chemosensitivity in breast cancer by targeting ANXA3. Exp Ther Med 2023; 25:127. [PMID: 36845963 PMCID: PMC9947582 DOI: 10.3892/etm.2023.11826] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 12/15/2022] [Indexed: 02/10/2023] Open
Abstract
Breast malignancy remains one of the most common causes of cancer-associated mortalities among women. MicroRNA (miR)-221 and miR-222 are homologous miRs and have a substantial impact on cancer progression. In the present study, the regulatory mechanisms of miR-221/222 and its target annexin A3 (ANXA3) in breast cancer cells were investigated. Breast tissue samples were collected to evaluate the expression patterns of miR-221/222 levels in breast cancer cell lines and cancer tissues according to clinical characteristics. The levels of miR-221/222 were increased or decreased in cancer cell lines compared with normal breast cell lines according to cell line subtype. Subsequently, the changes in the progression and invasion of breast cancer cells were investigated using cell proliferation, invasion assay, gap closure and colony formation assays. Western blotting of cell cycle proteins and flow cytometry were performed to evaluate the possible pathway of miR-221/222 and ANXA3 axis. Chemosensitivity tests were performed to explore the suitability of the miR-221/222 and ANXA3 axis as a therapeutic target in breast cancer. The expression levels of miR-221/222 were associated with aggressive characteristics of breast cancer subtypes. Cell transfection assay demonstrated the regulation of breast cancer proliferation and invasiveness by miR-221/222. MiR-221/222 directly targeted the 3'-untranslated region of ANXA3 and suppressed the expression of ANXA3 at the mRNA and protein levels. In addition, miR-221/222 negatively regulated cell proliferation and the cell cycle pathway in breast cancer cells by targeting ANXA3. In combination with adriamycin, downregulation of ANXA3 may sensitize adriamycin-induced cell death to induction of persistent G2/M and G0/G1 arrest. Decreased expression of ANXA3 through increased expression of miR-221/222 reduced breast cancer progression and increased the effectiveness of the chemotherapy drug. The present results indicated the miR-221/222 and ANXA3 axis to be a possible novel therapeutic target for the treatment of breast cancer.
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Affiliation(s)
- Ju-Yeon Kim
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Eun Jung Jung
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Changwon, Gyeongsang 51472, Republic of Korea
| | - Jae-Myung Kim
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Youngsim Son
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Han Shine Lee
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Changwon, Gyeongsang 51472, Republic of Korea
| | - Seung-Jin Kwag
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Ji-Ho Park
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Jin-Kyu Cho
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Han-Gil Kim
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Taejin Park
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Changwon, Gyeongsang 51472, Republic of Korea
| | - Sang-Ho Jeong
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Changwon, Gyeongsang 51472, Republic of Korea
| | - Chi-Young Jeong
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
| | - Young-Tae Ju
- Department of Surgery, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju, Gyeongsang 52727, Republic of Korea
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Yang M, Zhang Y, Li M, Liu X, Darvishi M. The various role of microRNAs in breast cancer angiogenesis, with a special focus on novel miRNA-based delivery strategies. Cancer Cell Int 2023; 23:24. [PMID: 36765409 PMCID: PMC9912632 DOI: 10.1186/s12935-022-02837-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/20/2022] [Indexed: 02/12/2023] Open
Abstract
After skin malignancy, breast cancer is the most widely recognized cancer detected in women in the United States. Breast cancer (BCa) can happen in all kinds of people, but it's much more common in women. One in four cases of cancer and one in six deaths due to cancer are related to breast cancer. Angiogenesis is an essential factor in the growth of tumors and metastases in various malignancies. An expanded level of angiogenesis is related to diminished endurance in BCa patients. This function assumes a fundamental part inside the human body, from the beginning phases of life to dangerous malignancy. Various factors, referred to as angiogenic factors, work to make a new capillary. Expanding proof demonstrates that angiogenesis is managed by microRNAs (miRNAs), which are small non-coding RNA with 19-25 nucleotides. MiRNA is a post-transcriptional regulator of gene expression that controls many critical biological processes. Endothelial miRNAs, referred to as angiomiRs, are probably concerned with tumor improvement and angiogenesis via regulation of pro-and anti-angiogenic factors. In this article, we reviewed therapeutic functions of miRNAs in BCa angiogenesis, several novel delivery carriers for miRNA-based therapeutics, as well as CRISPR/Cas9 as a targeted therapy in breast cancer.
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Affiliation(s)
- Min Yang
- College of Traditional Chinese Medicine, Jilin Agricultural Science and Technology University, Jilin, 132101 China
| | - Ying Zhang
- College of Traditional Chinese Medicine, Jilin Agricultural Science and Technology University, Jilin, 132101 China
| | - Min Li
- College of Traditional Chinese Medicine, Jilin Agricultural Science and Technology University, Jilin, 132101 China
| | - Xinglong Liu
- College of Traditional Chinese Medicine, Jilin Agricultural Science and Technology University, Jilin, 132101 China
| | - Mohammad Darvishi
- Infectious Diseases and Tropical Medicine Research Center (IDTMRC), Department of Aerospace and Subaquatic Medicine, AJA University of Medical Sciences, Tehran, Iran
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20
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miR-19-3p Targets PTEN to Regulate Cervical Cancer Cell Proliferation, Invasion, and Autophagy. Genet Res (Camb) 2023; 2023:4784500. [PMID: 36908850 PMCID: PMC10005872 DOI: 10.1155/2023/4784500] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 11/09/2022] [Accepted: 02/22/2023] [Indexed: 03/06/2023] Open
Abstract
Background Cervical cancer is the second most common cancer among women worldwide. Extensive studies have shown that microRNAs (miRNA/miR) can regulate the formation, progression, and metastasis of cancer. The purpose of this study was to investigate the effect of miR-19-3p on the proliferation, invasion, and autophagy of cervical cancer cells and to explore the underlying mechanism. Methods SiHa and HeLa cells were transfected with miR-19-3p mimic and inhibitor. miR-19-3p and PTEN expression were detected using real-time quantitative PCR and western blot, respectively. The binding between miR-19-3p and PTEN was predicted using Targetscan7.2 and verified by a dual-luciferase reporter gene assay. The effects of miR-19-3p on cell invasion and proliferation were evaluated by Transwell assays and MTT, respectively. The effect of miR-19-3p on autophagy was observed using fluorescence microscopy. Results The expression of miR-19-3p in cervical cancer tissues and SiHa and HeLa cells was significantly upregulated, whereas the expression of PTEN was significantly downregulated. PTEN was one of the direct targets of miR-19-3p. The miR-19-3p mimic significantly reduced the apoptosis rate and autophagy and promoted cell proliferation and invasion of the SiHa and HeLa cells. Conclusion In summary, miR-19b-3p can target PTEN to regulate the proliferation, invasion, and autophagy of cervical cancer cells. Our findings indicate the potential of miR-19-3p as a target for cervical cancer treatment in the future.
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Grandt CL, Brackmann LK, Poplawski A, Schwarz H, Marini F, Hankeln T, Galetzka D, Zahnreich S, Mirsch J, Spix C, Blettner M, Schmidberger H, Marron M. Identification of lncRNAs involved in response to ionizing radiation in fibroblasts of long-term survivors of childhood cancer and cancer-free controls. Front Oncol 2023; 13:1158176. [PMID: 37182169 PMCID: PMC10174438 DOI: 10.3389/fonc.2023.1158176] [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: 02/03/2023] [Accepted: 03/27/2023] [Indexed: 05/16/2023] Open
Abstract
Introduction Long non-coding ribonucleic acids (lncRNAs) are involved in the cellular damage response following exposure to ionizing radiation as applied in radiotherapy. However, the role of lncRNAs in radiation response concerning intrinsic susceptibility to late effects of radiation exposure has not been examined in general or in long-term survivors of childhood cancer with and without potentially radiotherapy-related second primary cancers, in particular. Methods Primary skin fibroblasts (n=52 each) of long-term childhood cancer survivors with a first primary cancer only (N1), at least one second primary neoplasm (N2+), as well as tumor-free controls (N0) from the KiKme case-control study were matched by sex, age, and additionally by year of diagnosis and entity of the first primary cancer. Fibroblasts were exposed to 0.05 and 2 Gray (Gy) X-rays. Differentially expressed lncRNAs were identified with and without interaction terms for donor group and dose. Weighted co-expression networks of lncRNA and mRNA were constructed using WGCNA. Resulting gene sets (modules) were correlated to the radiation doses and analyzed for biological function. Results After irradiation with 0.05Gy, few lncRNAs were differentially expressed (N0: AC004801.4; N1: PCCA-DT, AF129075.3, LINC00691, AL158206.1; N2+: LINC02315). In reaction to 2 Gy, the number of differentially expressed lncRNAs was higher (N0: 152, N1: 169, N2+: 146). After 2 Gy, AL109976.1 and AL158206.1 were prominently upregulated in all donor groups. The co-expression analysis identified two modules containing lncRNAs that were associated with 2 Gy (module1: 102 mRNAs and 4 lncRNAs: AL158206.1, AL109976.1, AC092171.5, TYMSOS, associated with p53-mediated reaction to DNA damage; module2: 390 mRNAs, 7 lncRNAs: AC004943.2, AC012073.1, AC026401.3, AC092718.4, MIR31HG, STXBP5-AS1, TMPO-AS1, associated with cell cycle regulation). Discussion For the first time, we identified the lncRNAs AL158206.1 and AL109976.1 as involved in the radiation response in primary fibroblasts by differential expression analysis. The co-expression analysis revealed a role of these lncRNAs in the DNA damage response and cell cycle regulation post-IR. These transcripts may be targets in cancer therapy against radiosensitivity, as well as provide grounds for the identification of at-risk patients for immediate adverse reactions in healthy tissues. With this work we deliver a broad basis and new leads for the examination of lncRNAs in the radiation response.
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Affiliation(s)
- Caine Lucas Grandt
- Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany
- Faculty of Human and Health Sciences, University of Bremen, Bremen, Germany
- *Correspondence: Caine Lucas Grandt,
| | - Lara Kim Brackmann
- Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany
| | - Alicia Poplawski
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Heike Schwarz
- Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany
| | - Federico Marini
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Thomas Hankeln
- Institute of Organismic and Molecular Evolution, Molecular Genetics and Genome Analysis, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Danuta Galetzka
- Department of Radiation Oncology and Radiation Therapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Sebastian Zahnreich
- Department of Radiation Oncology and Radiation Therapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Johanna Mirsch
- Radiation Biology and DNA Repair, Technical University of Darmstadt, Darmstadt, Germany
| | - Claudia Spix
- Division of Childhood Cancer Epidemiology, German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Maria Blettner
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Heinz Schmidberger
- Department of Radiation Oncology and Radiation Therapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Manuela Marron
- Leibniz Institute for Prevention Research and Epidemiology – BIPS, Bremen, Germany
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22
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Abdel Halim AS, Rudayni HA, Chaudhary AA, Ali MAM. MicroRNAs: Small molecules with big impacts in liver injury. J Cell Physiol 2023; 238:32-69. [PMID: 36317692 DOI: 10.1002/jcp.30908] [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: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
A type of small noncoding RNAs known as microRNAs (miRNAs) fine-tune gene expression posttranscriptionally by binding to certain messenger RNA targets. Numerous physiological processes in the liver, such as differentiation, proliferation, and apoptosis, are regulated by miRNAs. Additionally, there is growing evidence that miRNAs contribute to liver pathology. Extracellular vesicles like exosomes, which contain secreted miRNAs, may facilitate paracrine and endocrine communication between various tissues by changing the gene expression and function of distal cells. The use of stable miRNAs as noninvasive biomarkers was made possible by the discovery of these molecules in body fluids. Circulating miRNAs reflect the conditions of the liver that are abnormal and may serve as new biomarkers for the early detection, prognosis, and evaluation of liver pathological states. miRNAs are appealing therapeutic targets for a range of liver disease states because altered miRNA expression is associated with deregulation of the liver's metabolism, liver damage, liver fibrosis, and tumor formation. This review provides a comprehensive review and update on miRNAs biogenesis pathways and mechanisms of miRNA-mediated gene silencing. It also outlines how miRNAs affect hepatic cell proliferation, death, and regeneration as well as hepatic detoxification. Additionally, it highlights the diverse functions that miRNAs play in the onset and progression of various liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, fibrosis, hepatitis C virus infection, and hepatocellular carcinoma. Further, it summarizes the diverse liver-specific miRNAs, illustrating the potential merits and possible caveats of their utilization as noninvasive biomarkers and appealing therapeutic targets for liver illnesses.
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Affiliation(s)
- Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hassan Ahmed Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
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23
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Li L, Xun C, Yu CH. Role of microRNA-regulated cancer stem cells in recurrent hepatocellular carcinoma. World J Hepatol 2022; 14:1985-1996. [PMID: 36618329 PMCID: PMC9813843 DOI: 10.4254/wjh.v14.i12.1985] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/24/2022] [Accepted: 11/23/2022] [Indexed: 12/23/2022] Open
Abstract
Among the most common cancers, hepatocellular carcinoma (HCC) has a high rate of tumor recurrence, tumor dormancy, and drug resistance after initial successful chemotherapy or radiotherapy. A small subset of cancer cells, cancer stem cells (CSCs), exhibit stem cell characteristics and are present in various cancers, including HCC. The dysregulation of microRNAs (miRNAs) often accompanies the occurrence and development of HCC. miRNAs can influence tumorigenesis, progression, recurrence, and drug resistance by regulating CSCs properties, which supports their clinical utility in managing and treating HCC. This review summarizes the regulatory effects of miRNAs on CSCs in HCC with a special focus on their impact on HCC recurrence.
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Affiliation(s)
- Lei Li
- Department of Pathology, University of Otago, Dunedin 9016, New Zealand
| | - Chen Xun
- Department of Hepatobiliary Surgery, Zhuzhou Central Hospital, Zhuzhou 412000, Hunan Province, China
| | - Chun-Hong Yu
- School of Engineering Medicine, Beihang University, Beijing 100191, China
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24
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Mazzoni M, Todoerti K, Agnelli L, Minna E, Pagliardini S, Di Marco T, Borrello MG, Neri A, Greco A. Transcriptomic landscape of TIMP3 oncosuppressor activity in thyroid carcinoma. Cancer Cell Int 2022; 22:400. [PMID: 36503426 PMCID: PMC9743531 DOI: 10.1186/s12935-022-02811-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Papillary thyroid cancer (PTC) is the most frequent thyroid tumor. The tissue inhibitor of metalloproteinase-3 (TIMP3) gene encodes a matrix metalloproteinases inhibitor that exerts a tumor suppressor role in several tumor types. TIMP3 is frequently downregulated in PTC by promoter methylation. We have previously functionally demonstrated that TIMP3 exerts an oncosuppressor role in PTC: TIMP3 restoration in the PTC-derived NIM1 cell line affects in vitro migration, invasion and adhesive capability, while reduces tumor growth, angiogenesis and macrophage recruitment in vivo. To get a deeper insight on the mediators of TIMP3 oncosuppressor activity in thyroid tumors, here we focused on the TIMP3 related transcriptome. METHODS TCGA database was used for investigating the genes differentially expressed in PTC samples with low and high TIMP3 expression. Genome wide expression analysis of clones NIM1-T23 (expressing a high level of TIMP3 protein) and NIM1-EV (control empty vector) was performed. Gene sets and functional enrichment analysis with clusterProfiler were applied to identify the modulated biological processes and pathways. CIBERSORT was used to evaluate the distribution of different immunological cell types in TCGA-PTC tumor samples with different TIMP3 expression levels. Real time PCR was performed for the validation of selected genes. RESULTS Thyroid tumors with TIMP3-high expression showed a down-modulation of inflammation-related gene sets, along with a reduced protumoral hematopoietic cells fraction; an enrichment of cell adhesion functions was also identified. Similar results were obtained in the TIMP3-overexpessing NIM1 cells in vitro model, where a down-regulation of immune-related function gene sets, some of which also identified in tumor samples, was observed. Interestingly, through enrichment analysis, were also recognized terms related to cell adhesion, extracellular matrix organization, blood vessel maintenance and vascular process functions that have been found modulated in our previous in vitro and in vivo functional studies. CONCLUSIONS Our results highlight the correlation of TIMP3 expression levels with the regulation of inflammatory functions and the immune infiltration composition associated with different PTC prognosis, thus providing a broader view on the oncosuppressor role of TIMP3 in PTC.
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Affiliation(s)
- M. Mazzoni
- grid.417893.00000 0001 0807 2568Molecular Mechanisms Unit, Research Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - K. Todoerti
- grid.417893.00000 0001 0807 2568Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - L. Agnelli
- grid.417893.00000 0001 0807 2568Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - E. Minna
- grid.417893.00000 0001 0807 2568Molecular Mechanisms Unit, Research Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - S. Pagliardini
- grid.417893.00000 0001 0807 2568Molecular Mechanisms Unit, Research Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - T. Di Marco
- grid.417893.00000 0001 0807 2568Molecular Mechanisms Unit, Research Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - M. G. Borrello
- grid.417893.00000 0001 0807 2568Molecular Mechanisms Unit, Research Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
| | - A. Neri
- Scientific Directorate, Azienda USL-IRCCS Reggio Emilia, Reggio Emilia, Italy
| | - A. Greco
- grid.417893.00000 0001 0807 2568Molecular Mechanisms Unit, Research Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
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25
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Yuan Y, Fu D, Xu Y, Wang X, Deng X, Zhou S, Du F, Cui X, Deng Y, Tang Z. Pt(IV) Prodrug as a Potential Antitumor Agent with APE1 Inhibitory Activity. J Med Chem 2022; 65:15344-15357. [DOI: 10.1021/acs.jmedchem.2c01318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Yi Yuan
- Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Dingqiang Fu
- Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Yan Xu
- Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Xuyang Wang
- Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Xiongfei Deng
- Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Shan Zhou
- Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Feng Du
- Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Xin Cui
- Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
| | - Yun Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Zhuo Tang
- Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
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Fatima M, Sheikh A, Abourehab MAS, Kesharwani P. Advancements in Polymeric Nanocarriers to Mediate Targeted Therapy against Triple-Negative Breast Cancer. Pharmaceutics 2022; 14:2432. [PMID: 36365249 PMCID: PMC9695386 DOI: 10.3390/pharmaceutics14112432] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/06/2022] [Accepted: 11/08/2022] [Indexed: 11/12/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is a destructive disease with a poor prognosis, low survival rate and high rate of metastasis. It comprises 15% of total breast cancers and is marked by deficiency of three important receptor expressions, i.e., progesterone, estrogen, and human epidermal growth factor receptors. This absence of receptors is the foremost cause of current TNBC therapy failure, resulting in poor therapeutic response in patients. Polymeric nanoparticles are gaining much popularity for transporting chemotherapeutics, genes, and small-interfering RNAs. Due to their exclusive properties such as great stability, easy surface modification, stimuli-responsive and controlled drug release, ability to condense more than one therapeutic moiety inside, tumor-specific delivery of payload, enhanced permeation and retention effect, present them as ideal nanocarriers for increasing efficacy, bioavailability and reducing the toxicity of therapeutic agents. They can even be used as theragnostic agents for the diagnosis of TNBC along with its treatment. In this review, we discuss the limitations of already existing TNBC therapies and highlight the novel approach to designing and the functionalization of polymeric nanocarriers for the effective treatment of TNBC.
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Affiliation(s)
- Mahak Fatima
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Afsana Sheikh
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Mohammed A. S. Abourehab
- Department of Pharmaceutics, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
- Center for Transdisciplinary Research, Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Chennai 602105, India
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Kumar R, Mishra A, Gautam P, Feroz Z, Vijayaraghavalu S, Likos EM, Shukla GC, Kumar M. Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy. Cancers (Basel) 2022; 14:5268. [PMID: 36358687 PMCID: PMC9656396 DOI: 10.3390/cancers14215268] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/09/2022] [Accepted: 10/19/2022] [Indexed: 07/30/2023] Open
Abstract
Metabolic reprogramming enables cancer cells to proliferate and produce tumor biomass under a nutrient-deficient microenvironment and the stress of metabolic waste. A cancer cell adeptly undergoes a variety of adaptations in metabolic pathways and differential expression of metabolic enzyme genes. Metabolic adaptation is mainly determined by the physiological demands of the cancer cell of origin and the host tissue. Numerous metabolic regulators that assist cancer cell proliferation include uncontrolled anabolism/catabolism of glucose metabolism, fatty acids, amino acids metabolism, nucleotide metabolism, tumor suppressor genes, microRNAs, and many regulatory enzymes and genes. Using this paradigm, we review the current understanding of metabolic reprogramming in tumors and discuss the new strategies of cancer metabolomics that can be tapped into for cancer therapeutics.
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Affiliation(s)
- Rishabh Kumar
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, UP, India
| | - Anurag Mishra
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, UP, India
| | - Priyanka Gautam
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, UP, India
| | - Zainab Feroz
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, UP, India
| | | | - Eviania M. Likos
- Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA
| | - Girish C. Shukla
- Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA
| | - Munish Kumar
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, UP, India
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Yan H, Tang S, Tang S, Zhang J, Guo H, Qin C, Hu H, Zhong C, Yang L, Zhu Y, Zhou H. miRNAs in anti-cancer drug resistance of non-small cell lung cancer: Recent advances and future potential. Front Pharmacol 2022; 13:949566. [PMID: 36386184 PMCID: PMC9640411 DOI: 10.3389/fphar.2022.949566] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 09/12/2022] [Indexed: 12/12/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors worldwide. Clinical success is suboptimal owing to late diagnosis, limited treatment options, high recurrence rates, and the development of drug resistance. MicroRNAs (miRNAs), a range of small endogenous non-coding RNAs that are 22 nucleotides in length, have emerged as one of the most important players in cancer initiation and progression in recent decades. Current evidence has revealed the pivotal roles of miRNAs in regulating cell proliferation, migration, invasion, and metastasis in NSCLC. Recently, several studies have demonstrated that miRNAs are strongly associated with resistance to anti-cancer drugs, ranging from traditional chemotherapeutic and immunotherapy drugs to anti-vascular drugs, and even during radiotherapy. In this review, we briefly introduce the mechanism of miRNA dysregulation and resistance to anti-tumor therapy in NSCLC, and summarize the role of miRNAs in the malignant process of NSCLC. We then discuss studies of resistance-related miRNAs in chemotherapy, radiotherapy, targeted therapy, immunotherapy, and anti-vascular therapy in NSCLC. Finally, we will explore the application prospects of miRNA, an emerging small molecule, for future anti-tumor therapy. This review is the first to summarize the latest research progress on miRNAs in anti-cancer drug resistance based on drug classification, and to discuss their potential clinical applications.
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Affiliation(s)
- Hang Yan
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- Graduate School, Institute of Surgery, Zunyi Medical University, Zunyi, China
| | - Shengjie Tang
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
| | - Shoujun Tang
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
| | - Jun Zhang
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- Graduate School, Institute of Surgery, Zunyi Medical University, Zunyi, China
| | - Haiyang Guo
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- Graduate School, Institute of Surgery, Chengdu University of TCM, Chengdu, China
| | - Chao Qin
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- Graduate School, Institute of Surgery, Zunyi Medical University, Zunyi, China
| | - Haiyang Hu
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- Graduate School, Institute of Surgery, Zunyi Medical University, Zunyi, China
| | - Chuan Zhong
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
| | - Li Yang
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
| | - Yunhe Zhu
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- *Correspondence: Yunhe Zhu, ; Haining Zhou,
| | - Haining Zhou
- Department of Thoracic Surgery, Suining Central Hospital, An Affiliated Hospital of Chongqing Medical University, Suining, China
- Graduate School, Institute of Surgery, Zunyi Medical University, Zunyi, China
- Graduate School, Institute of Surgery, Chengdu University of TCM, Chengdu, China
- *Correspondence: Yunhe Zhu, ; Haining Zhou,
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Tsuchiya K, Yoshimura K, Iwashita Y, Inoue Y, Ohta T, Watanabe H, Yamada H, Kawase A, Tanahashi M, Ogawa H, Funai K, Shinmura K, Suda T, Sugimura H. m 6A demethylase ALKBH5 promotes tumor cell proliferation by destabilizing IGF2BPs target genes and worsens the prognosis of patients with non-small-cell lung cancer. Cancer Gene Ther 2022; 29:1355-1372. [PMID: 35318440 PMCID: PMC9576599 DOI: 10.1038/s41417-022-00451-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 01/03/2022] [Accepted: 02/24/2022] [Indexed: 12/14/2022]
Abstract
The modification of N6-methyladenosine (m6A) in RNA and its eraser ALKBH5, an m6A demethylase, play an important role across various steps of human carcinogenesis. However, the involvement of ALKBH5 in non-small-cell lung cancer (NSCLC) development remains to be completely elucidated. The current study revealed that the expression of ALKBH5 was increased in NSCLC and increased expression of ALKBH5 worsened the prognosis of patients with NSCLC. In vitro study revealed that ALKBH5 knockdown suppressed cell proliferation ability of PC9 and A549 cells and promoted G1 arrest and increased the number of apoptotic cells. Furthermore, ALKBH5 overexpression increased the cell proliferation ability of the immortalized cell lines. Microarray analysis and western blotting revealed that the expression of CDKN1A (p21) or TIMP3 was increased by ALKBH5 knockdown. These alterations were offset by a double knockdown of both ALKBH5 and one of the IGF2BPs. The decline of mRNAs was, at least partly, owing to the destabilization of these mRNAs by one of the IGF2BPs. In conclusions, the ALKBH5-IGF2BPs axis promotes cell proliferation and tumorigenicity, which in turn causes the unfavorable prognosis of NSCLC.
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Affiliation(s)
- Kazuo Tsuchiya
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Katsuhiro Yoshimura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yuji Iwashita
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yusuke Inoue
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tsutomu Ohta
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
- Department of Physical Therapy, Faculty of Health and Medical Sciences, Tokoha University, Hamamatsu, Japan
| | - Hirofumi Watanabe
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hidetaka Yamada
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Akikazu Kawase
- First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masayuki Tanahashi
- Division of Thoracic Surgery, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, Japan
| | - Hiroshi Ogawa
- Department of Pathology, Seirei Mikatahara General Hospital, Hamamatsu, Japan
| | - Kazuhito Funai
- First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kazuya Shinmura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takafumi Suda
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Haruhiko Sugimura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
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Woo SM, Kim S, Seo SU, Kim S, Park JW, Kim G, Choi YR, Hur K, Kwon TK. Inhibition of USP1 enhances anticancer drugs-induced cancer cell death through downregulation of survivin and miR-216a-5p-mediated upregulation of DR5. Cell Death Dis 2022; 13:821. [PMID: 36153316 PMCID: PMC9509337 DOI: 10.1038/s41419-022-05271-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 01/23/2023]
Abstract
Ubiquitin-specific protease 1 (USP1) is a deubiquitinase involved in DNA damage repair by modulating the ubiquitination of major regulators, such as PCNA and FANCD2. Because USP1 is highly expressed in many cancers, dysregulation of USP1 contributes to cancer therapy. However, the role of USP1 and the mechanisms underlying chemotherapy remain unclear. In this study, we found high USP1 expression in tumor tissues and that it correlated with poor prognosis in RCC. Mechanistically, USP1 enhanced survivin stabilization by removing ubiquitin. Pharmacological inhibitors (ML23 and pimozide) and siRNA targeting USP1 induced downregulation of survivin expression. In addition, ML323 upregulated DR5 expression by decreasing miR-216a-5p expression at the post-transcriptional level, and miR-216a-5p mimics suppressed the upregulation of DR5 by ML323. Inhibition of USP1 sensitized cancer cells. Overexpression of survivin or knockdown of DR5 markedly prevented the co-treatment with ML323 and TRAIL-induced apoptosis. These results of in vitro were proved in a mouse xenograft model, in which combined treatment significantly reduced tumor size and induced survivin downregulation and DR5 upregulation. Furthermore, USP1 and survivin protein expression showed a positive correlation, whereas miR-216a-5p and DR5 were inversely correlated in RCC tumor tissues. Taken together, our results suggest two target substrates of USP1 and demonstrate the involvement of survivin and DR5 in USP1-targeted chemotherapy.
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Affiliation(s)
- Seon Min Woo
- grid.412091.f0000 0001 0669 3109Department of Immunology, School of Medicine, Keimyung University, Daegu, 42601 South Korea
| | - Seok Kim
- grid.412091.f0000 0001 0669 3109Department of Immunology, School of Medicine, Keimyung University, Daegu, 42601 South Korea
| | - Seung Un Seo
- grid.412091.f0000 0001 0669 3109Department of Immunology, School of Medicine, Keimyung University, Daegu, 42601 South Korea
| | - Shin Kim
- grid.412091.f0000 0001 0669 3109Department of Immunology, School of Medicine, Keimyung University, Daegu, 42601 South Korea
| | - Jong-Wook Park
- grid.412091.f0000 0001 0669 3109Department of Immunology, School of Medicine, Keimyung University, Daegu, 42601 South Korea
| | - Gyeonghwa Kim
- grid.258803.40000 0001 0661 1556Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, 41944 South Korea
| | - Yu-Ra Choi
- grid.258803.40000 0001 0661 1556Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, 41944 South Korea
| | - Keun Hur
- grid.258803.40000 0001 0661 1556Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, 41944 South Korea
| | - Taeg Kyu Kwon
- grid.412091.f0000 0001 0669 3109Department of Immunology, School of Medicine, Keimyung University, Daegu, 42601 South Korea ,grid.412091.f0000 0001 0669 3109Center for Forensic Pharmaceutical Science, Keimyung University, Daegu, 42601 South Korea
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Polyphenols as Lung Cancer Chemopreventive Agents by Targeting microRNAs. Molecules 2022; 27:molecules27185903. [PMID: 36144639 PMCID: PMC9503430 DOI: 10.3390/molecules27185903] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/05/2022] [Accepted: 09/09/2022] [Indexed: 12/04/2022] Open
Abstract
Lung cancer is the second leading cause of cancer-related death worldwide. In recent decades, investigators have found that microRNAs, a group of non-coding RNAs, are abnormally expressed in lung cancer, and play important roles in the initiation and progression of lung cancer. These microRNAs have been used as biomarkers and potential therapeutic targets of lung cancer. Polyphenols are natural and bioactive chemicals that are synthesized by plants, and have promising anticancer effects against several kinds of cancer, including lung cancer. Recent studies identified that polyphenols exert their anticancer effects by regulating the expression levels of microRNAs in lung cancer. Targeting microRNAs using polyphenols may provide a novel strategy for the prevention and treatment of lung cancer. In this review, we reviewed the effects of polyphenols on oncogenic and tumor-suppressive microRNAs in lung cancer. We also reviewed and discussed the potential clinical application of polyphenol-regulated microRNAs in lung cancer treatment.
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Nguyen THN, Nguyen TTN, Nguyen TTM, Nguyen LHM, Huynh LH, Phan HN, Nguyen HT. Panels of circulating microRNAs as potential diagnostic biomarkers for breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat 2022; 196:1-15. [DOI: 10.1007/s10549-022-06728-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 08/26/2022] [Indexed: 11/02/2022]
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Multiomics Immune-Related lncRNA Analysis of Oral Squamous Cell Carcinoma and Its Correlation with Prognosis. DISEASE MARKERS 2022; 2022:6106503. [PMID: 36118668 PMCID: PMC9477588 DOI: 10.1155/2022/6106503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/21/2022] [Accepted: 08/19/2022] [Indexed: 11/17/2022]
Abstract
Objective To investigate the multiomics immune-related lncRNA analysis of oral squamous cell carcinoma and its correlation with prognosis. Methods Through the bioinformatics database, a total of 346 oral squamous cell carcinoma (OSCC) related samples were retrieved. Bioinformatics analysis screened out the difference lncRNAs in the sample tissue and normal tissue, combined with literature research to clarify the target. The biological functions of differentially expressed lncRNAs were predicted. The differential expression network of differentially expressed lncRNAs and mRNAs was established. The correlation analysis software was used to analyze the correlation between oral squamous cell carcinoma multiomics immune-related lncRNA and prognosis. Results 3054 lncRNAs in OSCC tissues are highly correlated with immune genes. 76 immune-related lncRNAs were different in tumor and adjacent tissues. Cancer Hallmark, Phenotype, and Subcellular Location analysis were completed. The results showed that lncRNAs can participate in tumor cell invasion, metastasis, proliferation, and apoptosis. Select the 15 most important lncRNAs above, draw Kaplan-Meier curve to complete the survival curve analysis, and complete the analysis and arrangement of the relevant data. LINC00460, CASC9, and HCG22 were screened for subsequent analysis. Complete the GO and KEGG enrichment analysis. LINC00460, CASC9, and macrophages M0 are positively correlated; CASC9 is negatively correlated with macrophages M1; LINC00460 is positively correlated with macrophages M1; HCG22 is associated with mast cells resting positive correlation; LINC00460 was negatively correlated with mast cell resting. CASC9 and HCG22 were significantly correlated with the age and stage of OSCC patients; 2 key lncRNA and 79 miRNAs were extracted from the database, to complete 86 pairs of interactions; the target mRNAs were predicted based on the above miRNAs. A total of 631 pairs of interactions were predicted (including 21 miRNAs and 562 mRNAs), and the regulatory mechanism of key gene ceRNA network was constructed. Conclusion The differential expression of multiple lncRNAs and mRNAs was screened, and the downregulated lncRNAs were more than the upregulated lncRNAs. The lncRNA LINC00460, CASC9, and HCG22 had a strong correlation with prognosis.
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Non-Coding RNAs in Hepatocellular Carcinoma. LIVERS 2022. [DOI: 10.3390/livers2030017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Liver cancer ranks as the fourth leading cause of cancer-related deaths. Despite extensive research efforts aiming to evaluate the biological mechanisms underlying hepatocellular carcinoma (HCC) development, little has been translated towards new diagnostic and treatment options for HCC patients. Historically, the focus has been centered on coding RNAs and their respective proteins. However, significant advances in sequencing and RNA detection technologies have shifted the research focus towards non-coding RNAs (ncRNA), as well as their impact on HCC development and progression. A number of studies reported complex post-transcriptional interactions between various ncRNA and coding RNA molecules. These interactions offer insights into the role of ncRNAs in both the known pathways leading to oncogenesis, such as dysregulation of p53, and lesser-known mechanisms, such as small nucleolar RNA methylation. Studies investigating these mechanisms have identified prevalent ncRNA changes in microRNAs, snoRNAs, and long non-coding RNAs that can both pre- and post-translationally regulate key factors in HCC progression. In this review, we present relevant publications describing ncRNAs to summarize the impact of different ncRNA species on liver cancer development and progression and to evaluate recent attempts at clinical translation.
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35
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Jain CK, Srivastava P, Pandey AK, Singh N, Kumar RS. miRNA therapeutics in precision oncology: a natural premium to nurture. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:511-532. [PMID: 36071981 PMCID: PMC9446160 DOI: 10.37349/etat.2022.00098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 06/02/2022] [Indexed: 11/22/2022] Open
Abstract
The dynamic spectrum of microRNA (miRNA) has grown significantly over the years with its identification and exploration in cancer therapeutics and is currently identified as an important resource for innovative strategies due to its functional behavior for gene regulation and modulation of complex biological networks. The progression of cancer is the consequence of uncontrolled, nonsynchronous procedural faults in the biological system. Diversified and variable cellular response of cancerous cells has always raised challenges in effective cancer therapy. miRNAs, a class of non-coding RNAs (ncRNAs), are the natural genetic gift, responsible to preserve the homeostasis of cell to nurture. The unprecedented significance of endogenous miRNAs has exhibited promising therapeutic potential in cancer therapeutics. Currently, miRNA mimic miR-34, and an antimiR aimed against miR-122 has entered the clinical trials for cancer treatments. This review, highlights the recent breakthroughs, challenges, clinical trials, and advanced delivery vehicles in the administration of miRNA therapies for precision oncology.
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Affiliation(s)
- Chakresh Kumar Jain
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida 201307, India
| | - Poornima Srivastava
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida 201307, India
| | - Amit Kumar Pandey
- Amity Institute of Biotechnology, Amity University Haryana, Panchgaon, Manesar, Haryana 122413, India
| | - Nisha Singh
- Department of Bioinformatics, Gujarat Biotechnology University, Gandhinagar, GIFT city 382355, India
| | - R Suresh Kumar
- Molecular Genetics Lab, Molecular Biology Group, National Institute of Cancer Prevention and Research (ICMR), Noida 201307, India
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Zhou Y, Liu F, Ma C, Cheng Q. Involvement of microRNAs and their potential diagnostic, therapeutic, and prognostic role in hepatocellular carcinoma. J Clin Lab Anal 2022; 36:e24673. [PMID: 36036748 PMCID: PMC9551129 DOI: 10.1002/jcla.24673] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 07/01/2022] [Accepted: 08/13/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) accounts for 85%-90% of primary liver cancer. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by targeting the 3'UTR of mRNA. Abnormal expression and regulation of miRNAs are involved in the occurrence and progression of HCC, and miRNAs can also play a role in the diagnosis and treatment of HCC as oncogenes or tumor suppressors. METHODS In the past decades, a large number of studies have shown that miRNAs play an essential regulatory role in HCC and have potential as biomarkers for HCC. We reviewed the literature to summarize these studies. RESULTS By reviewing the literature, we retrospected the roles of miRNAs in the development, diagnosis, treatment, and prognosis of HCC, and put forward prospects for the further research on miRNAs in the precision treatment of HCC. CONCLUSION MicroRNAs are important regulators and biomarkers in the occurrence, progression, outcome, and treatment of HCC, and can provide new targets and strategies for improving the therapeutic effect of HCC.
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Affiliation(s)
- Yilong Zhou
- Department of Surgery, Nantong Tumor Hospital, Tumor Hospital Affiliated to Nantong University, Nantong, China
| | - Fan Liu
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, China
| | - Chunyang Ma
- Department of Surgery, Nantong Tumor Hospital, Tumor Hospital Affiliated to Nantong University, Nantong, China
| | - Qiong Cheng
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
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Relationship Between the MicroRNAs and PI3K/AKT/mTOR Axis: Focus on Non-Small Cell Lung Cancer. Pathol Res Pract 2022; 239:154093. [DOI: 10.1016/j.prp.2022.154093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/19/2022] [Accepted: 08/23/2022] [Indexed: 11/21/2022]
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Zhou H, He Q, Li C, Alsharafi BLM, Deng L, Long Z, Gan Y. Focus on the tumor microenvironment: A seedbed for neuroendocrine prostate cancer. Front Cell Dev Biol 2022; 10:955669. [PMID: 35938167 PMCID: PMC9355504 DOI: 10.3389/fcell.2022.955669] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 07/01/2022] [Indexed: 11/13/2022] Open
Abstract
The tumor microenvironment (TME) is a microecology consisting of tumor and mesenchymal cells and extracellular matrices. The TME plays important regulatory roles in tumor proliferation, invasion, metastasis, and differentiation. Neuroendocrine differentiation (NED) is a mechanism by which castration resistance develops in advanced prostate cancer (PCa). NED is induced after androgen deprivation therapy and neuroendocrine prostate cancer (NEPC) is established finally. NEPC has poor prognosis and short overall survival and is a major cause of death in patients with PCa. Both the cellular and non-cellular components of the TME regulate and induce NEPC formation through various pathways. Insights into the roles of the TME in NEPC evolution, growth, and progression have increased over the past few years. These novel insights will help refine the NEPC formation model and lay the foundation for the discovery of new NEPC therapies targeting the TME.
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Affiliation(s)
- Hengfeng Zhou
- Andrology Center, Department of Urology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Qiangrong He
- Andrology Center, Department of Urology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Chao Li
- Andrology Center, Department of Urology, the Third Xiangya Hospital, Central South University, Changsha, China
| | | | - Liang Deng
- Andrology Center, Department of Urology, the Third Xiangya Hospital, Central South University, Changsha, China
| | - Zhi Long
- Andrology Center, Department of Urology, the Third Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Zhi Long, ; Yu Gan,
| | - Yu Gan
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Zhi Long, ; Yu Gan,
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39
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MiRNAs in Lung Cancer: Diagnostic, Prognostic, and Therapeutic Potential. Diagnostics (Basel) 2022; 12:diagnostics12071610. [PMID: 35885514 PMCID: PMC9322918 DOI: 10.3390/diagnostics12071610] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/13/2022] [Accepted: 04/17/2022] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is the dominant emerging factor in cancer-related mortality around the globe. Therapeutic interventions for lung cancer are not up to par, mainly due to reoccurrence/relapse, chemoresistance, and late diagnosis. People are currently interested in miRNAs, which are small double-stranded (20–24 ribonucleotides) structures that regulate molecular targets (tumor suppressors, oncogenes) involved in tumorigeneses such as cell proliferation, apoptosis, metastasis, and angiogenesis via post-transcriptional regulation of mRNA. Many studies suggest the emerging role of miRNAs in lung cancer diagnostics, prognostics, and therapeutics. Therefore, it is necessary to intensely explore the miRNOME expression of lung tumors and the development of anti-cancer strategies. The current review focuses on the therapeutic, diagnostic, and prognostic potential of numerous miRNAs in lung cancer.
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40
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Tan B, Xu X, Zhang Q, Yuan Z, Dong J. The tumor suppressive role of TIMP3 in the human osteosarcoma cells. J Orthop Sci 2022; 27:689-695. [PMID: 33814198 DOI: 10.1016/j.jos.2021.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 01/28/2021] [Accepted: 02/02/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Tissue inhibitor of metalloproteinase 3 (TIMP3) regulates a variety of cellular activities such as proliferation, viability, apoptosis, and motility. Functional loss of TIMP3 is reported in several human cancers. However, its role in osteosarcoma (OS) remains largely unclear. METHODS In this study, we explored the mechanism underlying the modulation of TIMP3 in the growth and aggressiveness of U2OS and 143B human OS cells at both cellular and molecular levels. RESULTS Our results show that overexpression of TIMP3 inhibits endogenous MMP activity and represses a series of oncogenic phenotypes of tumor cells independent of MMP inhibition, including reduced proliferation and survival, induced apoptosis, as well as improved sensitivity of tumor cells in response to cisplatin chemotherapy. TIMP3 overexpression also suppresses tumor cell invasion via its MMP inhibitory capacity. Importantly, TIMP3 modulates tumor cell oncogenesis via its induction of PTEN and subsequent inactivation of the PI3K/AKT pathway. CONCLUSION Our results suggest that TIMP3 is an oncosuppressor in human OS cells. Reactivation of TIMP3 function may be considered as a potential therapy for the treatment of this bone cancer.
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Affiliation(s)
- Bingyi Tan
- Department of Orthopaedics, Shangdong Provincial Hospital Affiliated to Shandong First Medical University, PR China
| | - Xiqiang Xu
- Department of Orthopaedics, Shangdong Provincial Hospital Affiliated to Shandong First Medical University, PR China
| | - Qingyu Zhang
- Department of Orthopaedics, Shangdong Provincial Hospital Affiliated to Shandong First Medical University, PR China
| | - Zenong Yuan
- Department of Orthopaedics, Shangdong Provincial Hospital Affiliated to Shandong First Medical University, PR China
| | - Jun Dong
- Department of Orthopaedics, Shangdong Provincial Hospital Affiliated to Shandong First Medical University, PR China.
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Adhikari S, Bhattacharya A, Adhikary S, Singh V, Gadad S, Roy S, Das C. The paradigm of drug resistance in cancer: an epigenetic perspective. Biosci Rep 2022; 42:BSR20211812. [PMID: 35438143 PMCID: PMC9069444 DOI: 10.1042/bsr20211812] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 03/24/2022] [Accepted: 03/24/2022] [Indexed: 12/12/2022] Open
Abstract
Innate and acquired resistance towards the conventional therapeutic regimen imposes a significant challenge for the successful management of cancer for decades. In patients with advanced carcinomas, acquisition of drug resistance often leads to tumor recurrence and poor prognosis after the first therapeutic cycle. In this context, cancer stem cells (CSCs) are considered as the prime drivers of therapy resistance in cancer due to their 'non-targetable' nature. Drug resistance in cancer is immensely influenced by different properties of CSCs such as epithelial-to-mesenchymal transition (EMT), a profound expression of drug efflux pump genes, detoxification genes, quiescence, and evasion of apoptosis, has been highlighted in this review article. The crucial epigenetic alterations that are intricately associated with regulating different mechanisms of drug resistance, have been discussed thoroughly. Additionally, special attention is drawn towards the epigenetic mechanisms behind the interaction between the cancer cells and their microenvironment which assists in tumor progression and therapy resistance. Finally, we have provided a cumulative overview of the alternative treatment strategies and epigenome-modifying therapies that show the potential of sensitizing the resistant cells towards the conventional treatment strategies. Thus, this review summarizes the epigenetic and molecular background behind therapy resistance, the prime hindrance of present day anti-cancer therapies, and provides an account of the novel complementary epi-drug-based therapeutic strategies to combat drug resistance.
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Affiliation(s)
- Swagata Adhikari
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
- Homi Bhaba National Institute, Mumbai 400094, India
| | - Apoorva Bhattacharya
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
| | - Santanu Adhikary
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India
| | - Vipin Singh
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
- Homi Bhaba National Institute, Mumbai 400094, India
| | - Shrikanth S. Gadad
- Department of Molecular and Translational Medicine, Center of Emphasis in Cancer, Texas Tech University Health Sciences Center El Paso, El Paso, TX, U.S.A
- Mays Cancer Center, UT Health San Antonio MD Anderson Cancer Center, San Antonio, TX 78229, U.S.A
| | - Siddhartha Roy
- Structural Biology and Bioinformatics Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, India
| | - Chandrima Das
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 700064, India
- Homi Bhaba National Institute, Mumbai 400094, India
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Golchert J, Staar D, Bennewitz J, Hartmann M, Hoffmann N, Ameling S, Völker U, Peters J, Wanka H. Overexpression of Renin-B Induces Warburg-like Effects That Are Associated with Increased AKT/mTOR Signaling. Cells 2022; 11:cells11091459. [PMID: 35563765 PMCID: PMC9103744 DOI: 10.3390/cells11091459] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/08/2022] [Accepted: 04/19/2022] [Indexed: 11/29/2022] Open
Abstract
The classical secretory renin-a is known to be involved in angiotensin generation, thereby regulating not only blood pressure, but also promoting oxidative stress as well as apoptotic and necrotic cell death. In contrast, another cytosolic renin isoform named renin-b has been described, exerting protective effects under ischemia-related conditions in H9c2 cardiomyoblasts. Using microarray-based transcriptome analyses, we aimed to identify the signaling pathways involved in mediating cardioprotection in H9c2 cells overexpressing renin-b. By transcriptome profiling, we identified increased gene expression of several genes encoding glycolytic enzymes and glucose transporters, while the transcript levels of TCA-cycle enzymes were decreased. Complementing data from metabolic analyses revealed enhanced glucose consumption and lactate accumulation due to renin-b overexpression. Renin-b overexpression further stimulated AKT/mTOR signaling, where numerous genes involved in this pathway showed altered transcript levels. For AKT, we also detected enhanced phosphorylation levels by means of Western blotting, suggesting an activation of this kinase. Moreover, analysis of the ROS levels identified an increase in ROS accumulation in renin-b-overexpressing cells. Altogether, our data demonstrate that renin-b overexpression induces the metabolic remodeling of H9c2 cells similar to that seen under oxygen deprivation. This metabolic phenotype exerting so-called aerobic glycolysis is also known as the Warburg effect.
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Affiliation(s)
- Janine Golchert
- Institute of Physiology, University Medicine Greifswald, 17475 Greifswald, Germany; (J.G.); (D.S.); (J.B.); (M.H.); (N.H.); (H.W.)
| | - Doreen Staar
- Institute of Physiology, University Medicine Greifswald, 17475 Greifswald, Germany; (J.G.); (D.S.); (J.B.); (M.H.); (N.H.); (H.W.)
| | - Jonathan Bennewitz
- Institute of Physiology, University Medicine Greifswald, 17475 Greifswald, Germany; (J.G.); (D.S.); (J.B.); (M.H.); (N.H.); (H.W.)
| | - Miriam Hartmann
- Institute of Physiology, University Medicine Greifswald, 17475 Greifswald, Germany; (J.G.); (D.S.); (J.B.); (M.H.); (N.H.); (H.W.)
| | - Nadin Hoffmann
- Institute of Physiology, University Medicine Greifswald, 17475 Greifswald, Germany; (J.G.); (D.S.); (J.B.); (M.H.); (N.H.); (H.W.)
| | - Sabine Ameling
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany; (S.A.); (U.V.)
- Partner Site Greifswald, DZHK (German Center for Cardiovascular Research), 17475 Greifswald, Germany
| | - Uwe Völker
- Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, 17475 Greifswald, Germany; (S.A.); (U.V.)
- Partner Site Greifswald, DZHK (German Center for Cardiovascular Research), 17475 Greifswald, Germany
| | - Jörg Peters
- Institute of Physiology, University Medicine Greifswald, 17475 Greifswald, Germany; (J.G.); (D.S.); (J.B.); (M.H.); (N.H.); (H.W.)
- Correspondence:
| | - Heike Wanka
- Institute of Physiology, University Medicine Greifswald, 17475 Greifswald, Germany; (J.G.); (D.S.); (J.B.); (M.H.); (N.H.); (H.W.)
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Abdel Wahab AHA, Hussein MM, Shouman SA, Fouad D, Kobaisi MH, El Habit O. Role of let7-g and miR-221 level as potential predictors for overall survival of hepatocellular carcinoma patients. Arab J Gastroenterol 2022; 23:151-158. [PMID: 35473687 DOI: 10.1016/j.ajg.2022.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 03/06/2022] [Accepted: 03/12/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND STUDY AIMS Hepatocellular carcinoma (HCC) is one of the most common cancer types worldwide. A hallmark of epithelial-mesenchymal transition is the loss of epithelial E-cadherin, which is considered an epithelial differentiation marker. MicroRNAs serve vital roles in various biological processes in the cell via post-transcriptional gene regulation. Therefore, the present study aimed to investigate the involvement of certain miRNAs in the progression of HCC. PATIENTS AND METHODS A reverse transcription-quantitative PCR assay was conducted to detect the expression levels of 20 EMT-related miRNAs in 36 fresh tissue biopsies from patients with primary HCC compared with healthy controls. Gene expression levels, as well as immunohistochemistry assays, were performed for E-cadherin, ZEB1 and ZEB2 proteins. The correlation between their expression levels and different clinicopathological factors was also assessed. RESULTS A significant decrease of E-Cadherin and an increase in ZEB1 expression levels were identified in HCC groups compared with controls, while no significant changes for ZEB2 were found. The absence of E-cadherin membranous protein was observed in ∼48% of the cases examined. Moreover, ZEB1 protein was absent in 46% of E-cadherin positive cases. Upregulation of miR-182, miR-221 and miR-222 expression levels, and downregulation of let-7g, miR-9, miR-16, miR29c, miR122, miR-145, miR-148a, miR-193b, miR-194 and miR-215 expression levels were identified. A positive correlation between let7-g with E-Cadherin expression was reported. No significant association was identified between each of E-cadherin, ZEB1, ZEB2 or miRNAs examined with different clinicopathological features of the patients. Furthermore, the low expression of let7-g and high expression of miR-221 were associated with poorer survival. CONCLUSION Collectively, the present data suggested that let7-g functions as a tumor suppressor in the development of HCC via regulating E-Cadherin. Furthermore, both let7-g and miR-221 may be potential biomarkers for the outcomes of HCC patients.
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Affiliation(s)
| | - Manal M Hussein
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt
| | - Samia A Shouman
- Department of Cancer Biology, National Cancer Institute, Cairo University, Egypt
| | - Dalia Fouad
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt
| | - Mohamed H Kobaisi
- Department of Pathology, National Institute of Urology and Nephrology, Cairo, Egypt
| | - Ola El Habit
- Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt
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Garofalo M, Jeon YJ, Nuovo GJ, Middleton J, Secchiero P, Joshi P, Alder H, Nazaryan N, Di Leva G, Romano G, Crawford M, Nana-Sinkam P, Croce CM. Correction: MiR-34a/c-Dependent PDGFR-α/β Downregulation Inhibits Tumorigenesis and Enhances TRAIL-Induced Apoptosis in Lung Cancer. PLoS One 2022; 17:e0267628. [PMID: 35443005 PMCID: PMC9020699 DOI: 10.1371/journal.pone.0267628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Xiao Y, Gu S, Yao W, Qin L, Luo J. Circ_0047921 acts as the sponge of miR-1287-5p to stimulate lung cancer progression by regulating proliferation, migration, invasion, and glycolysis of lung cancer cells. World J Surg Oncol 2022; 20:108. [PMID: 35365169 PMCID: PMC8976346 DOI: 10.1186/s12957-021-02466-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/05/2021] [Indexed: 12/24/2022] Open
Abstract
Background Lung cancer is a common respiratory system disease caused by multiple factors. Circular RNAs (circRNAs) play vital roles in tumorigenesis, including lung cancer. This study aimed to clarify the role and underlying molecular mechanisms of circ_0047921 in lung cancer. Methods Real-time quantitative polymerase chain reaction (RT-qPCR) was used to assess the expression levels of circ_0047921, La-related protein 1 (LARP1), and miR-1287-5p. Cell proliferation was analyzed by CCK-8 and EdU assays. Transwell assay was used to assess migration and invasion. Western blot assay was employed to quantify protein expression. Glycolysis ability of cell was determined by measuring glucose consumption and lactate production with matched kits. The relationship between miR-1287-5p and circ_0047921 or LARP1 was confirmed by dual-luciferase reporter assay. In addition, a xenograft model was established to clarify the functional role of circ_0047921 in vivo. Results Circ_0047921 was highly expressed in lung cancer tissues and cells. Circ_0047921 downregulation repressed proliferation, migration, invasion, epithelial-mesenchymal transition (EMT) and glycolysis in lung cancer cells. Circ_0047921 targeted miR-1287-5p to deplete miR-1287-5p expression. The effects caused by circ_0047921 downregulation were reversed by miR-1287-5p inhibition. In addition, LARP1 was a target of miR-1287-5p, and circ_0047921 could directly interact with miR-1287-5p to increase the expression of LARP1. The effects caused by circ_0047921 downregulation were also reversed by LARP1 overexpression. Circ_0047921 silencing impeded the growth of tumor in vivo. Conclusion Circ_0047921 was overexpressed in lung cancer, and circ_0047921 targeted miR-1287-5p to modulate LARP1 expression, thereby facilitating the development of lung cancer. Trial registration The present study was approved by the ethical review committee of The First People’s Hospital of Chenzhou, Southern Medical University with reference no. 20210106. 1. Circ_0047921 was upregulated in lung cancer tissues and cells. 2. Circ_0047921/miR-1287-5p/LARP1 axis played a key role in proliferation, migration, invasion, EMT and glycolysis of lung cancer cells. 3. Circ_0047921 regulated LARP1 by sponging miR-1287-5p in lung cancer.
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Affiliation(s)
- Yuehua Xiao
- The First General Surgery Department of Carcinoma, The First People's Hospital of Chenzhou, Southern Medical University, Chenzhou, Hunan, China
| | - Shequn Gu
- The First Department of Medical Oncology, The First People's Hospital of Chenzhou, Southern Medical University, Chenzhou, Hunan, China.
| | - Wenxiu Yao
- Department of Thoracic Oncology, The Cancer Hospital of Sichuan Province, Chengdu, Sichuan, China
| | - Ling Qin
- The First Department of Medical Oncology, The First People's Hospital of Chenzhou, Southern Medical University, Chenzhou, Hunan, China
| | - Jihui Luo
- The Second General Surgery Department of Carcinoma, The First People's Hospital of Chenzhou, Southern Medical University, Chenzhou, 423000, Hunan, China
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Tulinsky L, Dzian A, Matakova T, Ihnat P. Overexpression of the miR-143/145 and reduced expression of the let-7 and miR-126 for early lung cancer diagnosis. J Appl Biomed 2022; 20:1-6. [PMID: 35302725 DOI: 10.32725/jab.2022.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 02/21/2022] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Lung cancer is the leading cause of cancer-related deaths worldwide. For this reason, huge efforts are being invested in discovering suitable blood biomarkers that would allow early diagnosis and treatment. One of the possible promising candidates for this role are microRNA molecules (miRNAs). The aim of the study was to identify individual blood miRNAs that could be used as potential biomarkers for early diagnosis of lung cancer. METHODS This prospective study analyzed blood samples of 60 patients with early-stage lung cancer, and blood samples of 60 healthy individuals. All study patients with lung cancer had undergone radical pulmonary resection at the University Hospital Ostrava within the study period (2015-2017). Definitive diagnosis of lung cancer was confirmed by histopathology examination of the resected pulmonary specimen. We investigated relative expressions in selected 13 blood miRNAs; the examined miRNAs were miR-126, miR-155, miR-221, miR-21, miR-143, miR-145, miR-133a, let-7a, miR-146a, miR-31, miR-182, let-7g and miR-19b. RESULTS The outcome of this study showed that the levels of the majority of the tested circulating miRNA in lung cancer patients are significantly altered. The most significant serum miRNA biomarkers for the early detection of lung cancer are as follows: miR-143, let-7g, miR-126, let-7a, and miR-145 (miR-143 and miR-145 have oncogene functions, while miR-126, let-7g and let-7a have suppressor functions). CONCLUSIONS We have demonstrated the excellent diagnostic value of several miRNAs (miR-126, miR-143, miR-145, let-7a and let7g). These have an estimated sensitivity and specificity of 75-85% and 0.90-0.93 AUC. However, these individual miRNA biomarkers require further validation in larger prospective cohorts.
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Affiliation(s)
- Lubomir Tulinsky
- University Hospital Ostrava, Department of Surgery, Ostrava, Czech Republic
| | - Anton Dzian
- Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Department of Thoracic Surgery, Martin, Slovak Republic
| | - Tatiana Matakova
- Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Biomedical Center Martin, Martin, Slovak Republic
| | - Peter Ihnat
- University Hospital Ostrava, Department of Surgery, Ostrava, Czech Republic
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Di Martino MT, Arbitrio M, Caracciolo D, Cordua A, Cuomo O, Grillone K, Riillo C, Caridà G, Scionti F, Labanca C, Romeo C, Siciliano MA, D'Apolito M, Napoli C, Montesano M, Farenza V, Uppolo V, Tafuni M, Falcone F, D'Aquino G, Calandruccio ND, Luciano F, Pensabene L, Tagliaferri P, Tassone P. miR-221/222 as biomarkers and targets for therapeutic intervention on cancer and other diseases: A systematic review. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:1191-1224. [PMID: 35282417 PMCID: PMC8891816 DOI: 10.1016/j.omtn.2022.02.005] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Among deregulated microRNAs (miRs) in human malignancies, miR-221 has been widely investigated for its oncogenic role and as a promising biomarker. Moreover, recent evidence suggests miR-221 as a fine-tuner of chronic liver injury and inflammation-related events. Available information also supports the potential of miR-221 silencing as promising therapeutic intervention. In this systematic review, we selected papers from the principal databases (PubMed, MedLine, Medscape, ASCO, ESMO) between January 2012 and December 2020, using the keywords "miR-221" and the specific keywords related to the most important hematologic and solid malignancies, and some non-malignant diseases, to define and characterize deregulated miR-221 as a valuable therapeutic target in the modern vision of molecular medicine. We found a major role of miR-221 in this view.
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Affiliation(s)
| | - Mariamena Arbitrio
- Institute for Research and Biomedical Innovation (IRIB), Italian National Council (CNR), Catanzaro, Italy
| | - Daniele Caracciolo
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Alessia Cordua
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Onofrio Cuomo
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Katia Grillone
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Caterina Riillo
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Giulio Caridà
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Francesca Scionti
- Institute for Research and Biomedical Innovation (IRIB), Italian National Council (CNR), Messina, Italy
| | - Caterina Labanca
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Caterina Romeo
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Maria Anna Siciliano
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Maria D'Apolito
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Cristina Napoli
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Martina Montesano
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Valentina Farenza
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Valentina Uppolo
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Michele Tafuni
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Federica Falcone
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Giuseppe D'Aquino
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | | | - Francesco Luciano
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
| | - Licia Pensabene
- Department of Surgical and Medical Sciences, Magna Græcia University, Catanzaro, Italy
| | | | - Pierfrancesco Tassone
- Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy
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Tissue Inhibitor of Metalloproteases 3 (TIMP-3): In Vivo Analysis Underpins Its Role as a Master Regulator of Ectodomain Shedding. MEMBRANES 2022; 12:membranes12020211. [PMID: 35207132 PMCID: PMC8878240 DOI: 10.3390/membranes12020211] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/29/2022] [Accepted: 02/03/2022] [Indexed: 01/06/2023]
Abstract
The proteolytical cleavage of transmembrane proteins with subsequent release of their extracellular domain, so-called ectodomain shedding, is a post-translational modification that plays an essential role in several biological processes, such as cell communication, adhesion and migration. Metalloproteases are major proteases in ectodomain shedding, especially the disintegrin metalloproteases (ADAMs) and the membrane-type matrix metalloproteases (MT-MMPs), which are considered to be canonical sheddases for their membrane-anchored topology and for the large number of proteins that they can release. The unique ability of TIMP-3 to inhibit different families of metalloproteases, including the canonical sheddases (ADAMs and MT-MMPs), renders it a master regulator of ectodomain shedding. This review provides an overview of the different functions of TIMP-3 in health and disease, with a major focus on the functional consequences in vivo related to its ability to control ectodomain shedding. Furthermore, herein we describe a collection of mass spectrometry-based approaches that have been used in recent years to identify new functions of sheddases and TIMP-3. These methods may be used in the future to elucidate the pathological mechanisms triggered by the Sorsby’s fundus dystrophy variants of TIMP-3 or to identify proteins released by less well characterized TIMP-3 target sheddases whose substrate repertoire is still limited, thus providing novel insights into the physiological and pathological functions of the inhibitor.
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Xue D, Han J, Liang Z, Jia L, Liu Y, Tuo H, Peng Y. Current Perspectives on the Unique Roles of Exosomes in Drug Resistance of Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:99-112. [PMID: 35211428 PMCID: PMC8863332 DOI: 10.2147/jhc.s351038] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 01/29/2022] [Indexed: 12/14/2022] Open
Abstract
As a common malignant tumor worldwide, the prognosis of hepatocellular carcinoma (HCC) remains unsatisfactory, even though treatment methods have improved. Despite the developments in traditional chemotherapy and emerging targeted immunotherapy, the problem of recurrence and metastasis of HCC and adverse effects on survival and prognosis are still serious. Drug resistance is a daunting challenge that impedes HCC treatment. Exosomes, a class of extracellular vesicles ranging in size from 30 to 100 nm, have been the focus of recent studies. Exosomes can activate various signaling pathways and regulate the tumor microenvironment with their cargo, which includes functional lipids, proteins, and nucleic acids. Thus, they change the phenotype of recipient cells via exosome-mediated communication. Exosomes secreted by tumors or stromal cells can also transfer drug-resistant traits to other tumor cells. However, their effects on drug resistance in HCC are not completely understood. In this review, we summarize and discuss the underlying relationship between exosomes and drug resistance in HCC. In addition, we also show that exosomes may act as candidate biomarkers for predicting and monitoring drug responses and as potential targets or vectors to reverse the drug resistance of HCC.
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Affiliation(s)
- Dongdong Xue
- Department of Hepatobiliary Surgery, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Jingzhao Han
- Department of Hepatobiliary Surgery, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Ze Liang
- Department of Hepatobiliary Surgery, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Lin Jia
- Department of Hepatobiliary Surgery, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Yifan Liu
- Department of Hepatobiliary Surgery, Hebei General Hospital, Shijiazhuang, People’s Republic of China
- Department of Graduate School, Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Hongfang Tuo
- Department of Hepatobiliary Surgery, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Yanhui Peng
- Department of Hepatobiliary Surgery, Hebei General Hospital, Shijiazhuang, People’s Republic of China
- Correspondence: Yanhui Peng, Department of Hepatobiliary Surgery, Hebei General Hospital, No. 348 Heping West Road, Xinhua District, Shijiazhuang, 050051, Hebei Province, People’s Republic of China, Tel/Fax +86-311-859 8321, Email
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