|
1
|
Zhang J, Guan X, Zhong X. Immunosenescence in digestive system cancers: Mechanisms, research advances, and therapeutic strategies. Semin Cancer Biol 2024; 106-107:234-250. [PMID: 39510149 DOI: 10.1016/j.semcancer.2024.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/21/2024] [Accepted: 10/30/2024] [Indexed: 11/15/2024]
Abstract
Increasing lifespans and external environmental factors have contributed to the increase of age-related diseases, particularly cancer. A decrease in immune surveillance and clearance of cancer cells is the result of immunosenescence, which involves the remodeling of immune organs, the changes and functional decline of immune cell subsets, in association with systemic low-grade chronic inflammation. Stem cells aging in bone marrow and thymic involution are the most important causes of immunosenescence. Senescent cancer cells promote the differentiation, recruitment, and functional upregulation of immune-suppressive cell subsets e.g. regulatory T cells (Tregs), myeloid-derived suppressor cell (MDSC), tumor-associated macrophages (TAMS) through senescence-associated secretory phenotype (SASP) further exacerbating the immunosuppressive microenvironment. For digestive system cancers, age-related damage to the intestinal mucosal barrier, the aging of gut-associated lymphoid tissue (GALT), exposure to xenobiotic stimuli throughout life, and dysbiosis make the local immune microenvironment more vulnerable. This article systematically reviews the research progress of immunosenescence and immune microenvironment in digestive system cancers, as well as the exploration of related therapy strategies, hoping to point out new directions for research in the digestive system cancers.
Collapse
Affiliation(s)
- Junyan Zhang
- Department of Surgical Oncology and General Surgery, First Affiliated Hospital, China Medical University, Shenyang, China
| | - Xiaojiao Guan
- Department of Pathology, Shengjing Hospital, China Medical University, Shenyang, China.
| | - Xinwen Zhong
- Department of Thoracic Surgery, First Affiliated Hospital, China Medical University, Shenyang, China.
| |
Collapse
|
|
2
|
Pasculli E, Gadaleta RM, Arconzo M, Cariello M, Moschetta A. The Role of Exogenous microRNAs on Human Health: The Plant-Human Trans-Kingdom Hypothesis. Nutrients 2024; 16:3658. [PMID: 39519491 PMCID: PMC11547593 DOI: 10.3390/nu16213658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 10/25/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
MicroRNAs (miRNAs) are small, endogenous, single-stranded RNAs that act on gene silencing at the post-transcriptional level by binding to a target messenger RNA (mRNA), leading to its degradation or inhibiting translation into functional proteins. The key role of miRNAs in development, proliferation, differentiation andapoptosis has been deeply investigated, revealing that deregulation in their expression is critical in various diseases, such as metabolic disorders and cancer. Since these small molecules initially evolved as a mechanism of protection against viruses and transposable elements, the fascinating hypothesis that they can move between organisms both of the same or different species has been postulated. Trans-kingdom is the term used to define the migration that occurs between species. This mechanism has been well analyzed between plants and their pests, in order to boost defense and increase pathogenicity, respectively. Intriguingly, in the last decades, the plant-human trans-kingdom migration via food intake hypothesis arose. In particular, various studies highlighted the ability of exogenous miRNAs, abundant in the mainly consumed plant-derived food, to enter the human body affecting gene expression. Notably, plant miRNAs can resist the strict conditions of the gastrointestinal tract through a methylation step that occurs during miRNA maturation, conferring high stability to these small molecules. Recent studies observed the anti-tumoral, immune modulator and anti-inflammatory abilities of trans-kingdom interaction between plant and human. Here, we depict the existing knowledge and discuss the fascinating plant-human trans-kingdom interaction, highlighting first the eventual role of plant miRNAs from foods on our somatic gene identity card and then the potential impact of using plant miRNAs as novel therapeutic avenues.
Collapse
Affiliation(s)
- Emanuela Pasculli
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (E.P.); (R.M.G.); (M.A.)
| | - Raffaella Maria Gadaleta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (E.P.); (R.M.G.); (M.A.)
- INBB National Institute for Biostructure and Biosystems, Viale delle Medaglie d’Oro 305, 00136 Rome, Italy
| | - Maria Arconzo
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (E.P.); (R.M.G.); (M.A.)
| | - Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (E.P.); (R.M.G.); (M.A.)
- INBB National Institute for Biostructure and Biosystems, Viale delle Medaglie d’Oro 305, 00136 Rome, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (E.P.); (R.M.G.); (M.A.)
- INBB National Institute for Biostructure and Biosystems, Viale delle Medaglie d’Oro 305, 00136 Rome, Italy
| |
Collapse
|
|
3
|
Tang J, Li S, Zhou Z, Wang Y, Ni D, Zhou S. MiR-3680-3p is a novel biomarker for the diagnosis and prognosis of liver cancer and is involved in regulating the progression of liver cancer. IUBMB Life 2024; 76:820-831. [PMID: 38822621 DOI: 10.1002/iub.2856] [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: 03/17/2024] [Accepted: 04/27/2024] [Indexed: 06/03/2024]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that can actively participate in post-transcriptional regulation of genes. A number of studies have shown that miRNAs can serve as important regulators of cancer cell growth, differentiation, and apoptosis. They can also act as markers for the diagnosis and prognosis of certain cancers. To explore the potential prognosis-related miRNAs in liver cancer patients, to provide theoretical basis for early diagnosis and prognosis of liver cancer, as well as to provide a new direction for the targeted therapy of liver cancer. The miRNA expression profiles of liver cancer patients in the the Cancer Genome Atlas database were comprehensively analyzed and various prognostic-related miRNAs of liver cancer were screened out. The data was further subjected to survival analysis, prognostic analysis, gene ontology and kyoto encyclopedia of genes and genomes enrichment analysis, microenvironment analysis, and drug sensitivity analysis by R Language version 4.2.0. Finally, the screened miRNAs were further validated by different experiments. Thus, miNRAs involved in liver cancer diagnosis and prognosis were identified. MiRNA-3680-3p was found to be significantly different in 10 different cancers, including liver cancer, and was significantly associated with the microenvironment, survival, and prognosis of liver cancer patients. In addition, drug sensitivity analysis revealed that miRNA-3680-3p can provide a useful reference for drug selection in targeted therapy for liver cancer. MiRNA-3680-3p can serve as a biomarker for the diagnosis and prognosis of liver cancer patients and down-regulation of miRNA-3680-3p could significantly inhibit both the proliferation and migration of liver cancer cells.
Collapse
Affiliation(s)
- Jie Tang
- General Surgery, Shenzhen Yantian District People's Hospital, Shenzhen, Guangdong, China
- Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, China
| | - Song Li
- Department of Hepatobilary Pancreatic Gastrointestinal Surgery, JinHua People's Hospital, Jinhua, China
| | - Zixiao Zhou
- Xiangya Medical College, Central South University, Changsha, China
| | - Yongqiang Wang
- General Surgery, Shenzhen Yantian District People's Hospital, Shenzhen, Guangdong, China
| | - DeSheng Ni
- Department of Hepatobilary Pancreatic Gastrointestinal Surgery, JinHua People's Hospital, Jinhua, China
| | - Shaobo Zhou
- General Surgery, Shenzhen Yantian District People's Hospital, Shenzhen, Guangdong, China
| |
Collapse
|
|
4
|
Atsavapranee E, Haley RM, Billingsley MM, Chan A, Ruan B, Figueroa-Espada CG, Gong N, Mukalel AJ, Bryan PN, Mitchell MJ. Ionizable lipid nanoparticles for RAS protease delivery to inhibit cancer cell proliferation. J Control Release 2024; 370:614-625. [PMID: 38729436 PMCID: PMC11210981 DOI: 10.1016/j.jconrel.2024.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 05/03/2024] [Accepted: 05/07/2024] [Indexed: 05/12/2024]
Abstract
Mutations in RAS, a family of proteins found in all human cells, drive a third of cancers, including many pancreatic, colorectal, and lung cancers. However, there is a lack of clinical therapies that can effectively prevent RAS from causing tumor growth. Recently, a protease was engineered that specifically degrades active RAS, offering a promising new tool for treating these cancers. However, like many other intracellularly acting protein-based therapies, this protease requires a delivery vector to reach its site of action within the cell. In this study, we explored the incorporation of cationic lipids into ionizable lipid nanoparticles (LNPs) to develop a RAS protease delivery platform capable of inhibiting cancer cell proliferation in vitro and in vivo. A library of 13 LNPs encapsulating RAS protease was designed, and each formulation was evaluated for in vitro delivery efficiency and toxicity. A subset of four top-performing LNP formulations was identified and further evaluated for their impact on cancer cell proliferation in human colorectal cancer cells with mutated KRAS in vitro and in vivo, as well as their in vivo biodistribution and toxicity. In vivo, both the concentration of cationic lipid and type of cargo influenced LNP and cargo distribution. All lead candidate LNPs showed RAS protease functionality in vitro, and the top-performing formulation achieved effective intracellular RAS protease delivery in vivo, decreasing cancer cell proliferation in an in vivo xenograft model and significantly reducing tumor growth and size. Overall, this work demonstrates the use of LNPs as an effective delivery platform for RAS proteases, which could potentially be utilized for cancer therapies.
Collapse
Affiliation(s)
- Ella Atsavapranee
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Rebecca M Haley
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | - Alexander Chan
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Biao Ruan
- Potomac Affinity Proteins, LLC, North Potomac, MD 20878, USA
| | | | - Ningqiang Gong
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Alvin J Mukalel
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Philip N Bryan
- Potomac Affinity Proteins, LLC, North Potomac, MD 20878, USA; Institute for Bioscience and Biotechnology Research, University of Maryland, Rockville, MD 20850, USA
| | - Michael J Mitchell
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Penn Institute for RNA Innovation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
| |
Collapse
|
|
5
|
Gao W, Zhou J, Morshedi M. MicroRNA-34 and gastrointestinal cancers: a player with big functions. Cancer Cell Int 2024; 24:163. [PMID: 38725047 PMCID: PMC11084024 DOI: 10.1186/s12935-024-03338-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 04/18/2024] [Indexed: 05/12/2024] Open
Abstract
It is commonly assumed that gastrointestinal cancer is the most common form of cancer across the globe and is the leading contributor to cancer-related death. The intricate mechanisms underlying the growth of GI cancers have been identified. It is worth mentioning that both non-coding RNAs (ncRNAs) and certain types of RNA, such as circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), can have considerable impact on the development of gastrointestinal (GI) cancers. As a tumour suppressor, in the group of short non-coding regulatory RNAs is miR-34a. miR-34a silences multiple proto-oncogenes at the post-transcriptional stage by targeting them, which inhibits all physiologically relevant cell proliferation pathways. However, it has been discovered that deregulation of miR-34a plays important roles in the growth of tumors and the development of cancer, including invasion, metastasis, and the tumor-associated epithelial-mesenchymal transition (EMT). Further understanding of miR-34a's molecular pathways in cancer is also necessary for the development of precise diagnoses and effective treatments. We outlined the most recent research on miR-34a functions in GI cancers in this review. Additionally, we emphasize the significance of exosomal miR-34 in gastrointestinal cancers.
Collapse
Affiliation(s)
- Wei Gao
- Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, The First Hospital, China Medical University, Shenyang, 110001, China
| | - Jianping Zhou
- Department of Gastrointestinal and Hernia and Abdominal Wall Surgery, The First Hospital, China Medical University, Shenyang, 110001, China.
| | - Mohammadamin Morshedi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| |
Collapse
|
|
6
|
Kzar Al-Shukri HH, Abdul-Jabbar Ali S, Al-Akkam KA, Hjazi A, Rasulova I, Mustafa YF, Al-Saidi DN, Alasheqi MQ, Alawadi A, Alsaalamy A. The role of exo-miRNA in diagnosis and treatment of cancers, focusing on effective miRNAs in colorectal cancer. Cell Biol Int 2024; 48:280-289. [PMID: 38225535 DOI: 10.1002/cbin.12122] [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: 09/24/2023] [Revised: 11/26/2023] [Accepted: 12/27/2023] [Indexed: 01/17/2024]
Abstract
Small extracellular (EV) particles known as exosomes are released by a variety of cell types, including immune system cells, stem cells, and tumor cells. They are regarded as a subgroup of EVs and have a diameter that ranges from 30 to 150 nm. Proteins, lipids, nucleic acids (including RNA and DNA), and different bioactive compounds are among the wide range of biomolecules that make up the cargo of exosomes. Exosomes are crucial for intercellular communication because they let cells share information and signaling chemicals. They are involved in various physiological and pathological processes, including immune responses, tissue regeneration, cancer progression, and neurodegenerative diseases. In conclusion, it is essential to continue research into exosome-based cancer medicines to advance understanding, improve treatment plans, create personalized tactics, ensure safety, and speed up clinical translation.
Collapse
Affiliation(s)
- Hamzah H Kzar Al-Shukri
- Department of Biochemistry, College of Veterinary Medicine, Al-Qasim Green University, Babylon, Iraq
| | | | | | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Irodakhon Rasulova
- School of Humanities, Natural & Social Sciences, New Uzbekistan University, Uzbekistan
- Department of Public Health, Samarkand State Medical University, Samarkand, Uzbekistan
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq
| | - Dahlia N Al-Saidi
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | | | - Ahmed Alawadi
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- College of Technical Engineering, The Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- College of Technical Engineering, The Islamic University of Babylon, Babylon, Iraq
| | - Ali Alsaalamy
- College of Technical Engineering, Imam Ja'afar Al-Sadiq University, Kirkuk, Iraq
| |
Collapse
|
|
7
|
Dogbey DM, Torres VES, Fajemisin E, Mpondo L, Ngwenya T, Akinrinmade OA, Perriman AW, Barth S. Technological advances in the use of viral and non-viral vectors for delivering genetic and non-genetic cargos for cancer therapy. Drug Deliv Transl Res 2023; 13:2719-2738. [PMID: 37301780 PMCID: PMC10257536 DOI: 10.1007/s13346-023-01362-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2023] [Indexed: 06/12/2023]
Abstract
The burden of cancer is increasing globally. Several challenges facing its mainstream treatment approaches have formed the basis for the development of targeted delivery systems to carry and distribute anti-cancer payloads to their defined targets. This site-specific delivery of drug molecules and gene payloads to selectively target druggable biomarkers aimed at inducing cell death while sparing normal cells is the principal goal for cancer therapy. An important advantage of a delivery vector either viral or non-viral is the cumulative ability to penetrate the haphazardly arranged and immunosuppressive tumour microenvironment of solid tumours and or withstand antibody-mediated immune response. Biotechnological approaches incorporating rational protein engineering for the development of targeted delivery systems which may serve as vehicles for packaging and distribution of anti-cancer agents to selectively target and kill cancer cells are highly desired. Over the years, these chemically and genetically modified delivery systems have aimed at distribution and selective accumulation of drug molecules at receptor sites resulting in constant maintenance of high drug bioavailability for effective anti-tumour activity. In this review, we highlighted the state-of-the art viral and non-viral drug and gene delivery systems and those under developments focusing on cancer therapy.
Collapse
Affiliation(s)
- Dennis Makafui Dogbey
- South African Research Chair in Cancer Biotechnology, Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa
| | | | - Emmanuel Fajemisin
- South African Research Chair in Cancer Biotechnology, Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa
| | - Liyabona Mpondo
- South African Research Chair in Cancer Biotechnology, Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa
| | - Takunda Ngwenya
- South African Research Chair in Cancer Biotechnology, Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa
| | - Olusiji Alex Akinrinmade
- South African Research Chair in Cancer Biotechnology, Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa
| | - Adam W Perriman
- School of Cellular and Molecular Medicine, University of Bristol, BS8 1TD, Bristol, UK
| | - Stefan Barth
- South African Research Chair in Cancer Biotechnology, Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
- Medical Biotechnology and Immunotherapy Research Unit, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
| |
Collapse
|
|
8
|
Viegas C, Patrício AB, Prata J, Fonseca L, Macedo AS, Duarte SOD, Fonte P. Advances in Pancreatic Cancer Treatment by Nano-Based Drug Delivery Systems. Pharmaceutics 2023; 15:2363. [PMID: 37765331 PMCID: PMC10536303 DOI: 10.3390/pharmaceutics15092363] [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: 07/09/2023] [Revised: 09/12/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Pancreatic cancer represents one of the most lethal cancer types worldwide, with a 5-year survival rate of less than 5%. Due to the inability to diagnose it promptly and the lack of efficacy of existing treatments, research and development of innovative therapies and new diagnostics are crucial to increase the survival rate and decrease mortality. Nanomedicine has been gaining importance as an innovative approach for drug delivery and diagnosis, opening new horizons through the implementation of smart nanocarrier systems, which can deliver drugs to the specific tissue or organ at an optimal concentration, enhancing treatment efficacy and reducing systemic toxicity. Varied materials such as lipids, polymers, and inorganic materials have been used to obtain nanoparticles and develop innovative drug delivery systems for pancreatic cancer treatment. In this review, it is discussed the main scientific advances in pancreatic cancer treatment by nano-based drug delivery systems. The advantages and disadvantages of such delivery systems in pancreatic cancer treatment are also addressed. More importantly, the different types of nanocarriers and therapeutic strategies developed so far are scrutinized.
Collapse
Affiliation(s)
- Cláudia Viegas
- Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Gambelas Campus, 8005-139 Faro, Portugal;
- Center for Marine Sciences (CCMar), University of Algarve, Gambelas Campus, 8005-139 Faro, Portugal
- iBB—Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal; (A.B.P.); (S.O.D.D.)
- Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Ana B. Patrício
- iBB—Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal; (A.B.P.); (S.O.D.D.)
- Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - João Prata
- iBB—Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal; (A.B.P.); (S.O.D.D.)
- Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Leonor Fonseca
- iBB—Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal; (A.B.P.); (S.O.D.D.)
- Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Ana S. Macedo
- iBB—Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal; (A.B.P.); (S.O.D.D.)
- Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
- LAQV, REQUIMTE, Applied Chemistry Lab—Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
| | - Sofia O. D. Duarte
- iBB—Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal; (A.B.P.); (S.O.D.D.)
- Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Pedro Fonte
- Center for Marine Sciences (CCMar), University of Algarve, Gambelas Campus, 8005-139 Faro, Portugal
- iBB—Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal; (A.B.P.); (S.O.D.D.)
- Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
- Department of Chemistry and Pharmacy, Faculty of Sciences and Technology, University of Algarve, Gambelas Campus, 8005-139 Faro, Portugal
| |
Collapse
|
|
9
|
Vahabi M, Dehni B, Antomás I, Giovannetti E, Peters GJ. Targeting miRNA and using miRNA as potential therapeutic options to bypass resistance in pancreatic ductal adenocarcinoma. Cancer Metastasis Rev 2023; 42:725-740. [PMID: 37490255 PMCID: PMC10584721 DOI: 10.1007/s10555-023-10127-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 07/12/2023] [Indexed: 07/26/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with poor prognosis due to early metastasis, low diagnostic rates at early stages, and resistance to current therapeutic regimens. Despite numerous studies and clinical trials, the mortality rate for PDAC has shown limited improvement. Therefore, there is a pressing need to attain. a more comprehensive molecular characterization to identify biomarkers enabling early detection and evaluation of treatment response. MicroRNA (miRNAs) are critical regulators of gene expression on the post-transcriptional level, and seem particularly interesting as biomarkers due to their relative stability, and the ability to detect them in fixed tissue specimens and biofluids. Deregulation of miRNAs is common and affects several hallmarks of cancer and contribute to the oncogenesis and metastasis of PDAC. Unique combinations of upregulated oncogenic miRNAs (oncomiRs) and downregulated tumor suppressor miRNAs (TsmiRs), promote metastasis, characterize the tumor and interfere with chemosensitivity of PDAC cells. Here, we review several oncomiRs and TsmiRs involved in chemoresistance to gemcitabine and FOLFIRINOX in PDAC and highlighted successful/effective miRNA-based therapy approaches in vivo. Integrating miRNAs in PDAC treatment represents a promising therapeutic avenue that can be used as guidance for personalized medicine for PDAC patients.
Collapse
Affiliation(s)
- Mahrou Vahabi
- Department of Medical Oncology, Amsterdam UMC, location VUMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Bilal Dehni
- Department of Medical Oncology, Amsterdam UMC, location VUMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Inés Antomás
- Department of Medical Oncology, Amsterdam UMC, location VUMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Elisa Giovannetti
- Department of Medical Oncology, Amsterdam UMC, location VUMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana per La Scienza, Pisa, Italy
| | - Godefridus J Peters
- Department of Medical Oncology, Amsterdam UMC, location VUMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands.
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland.
| |
Collapse
|
|
10
|
Li F, Han Y, Chen R, Jiang Y, Chen C, Wang X, Zhou J, Xu Q, Jiang S, Zhang S, Yu K, Zhang S. MicroRNA-143 acts as a tumor suppressor through Musashi-2/DLL1/Notch1 and Musashi-2/Snail1/MMPs axes in acute myeloid leukemia. J Transl Med 2023; 21:309. [PMID: 37149661 PMCID: PMC10164318 DOI: 10.1186/s12967-023-04106-6] [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: 09/30/2022] [Accepted: 04/05/2023] [Indexed: 05/08/2023] Open
Abstract
BACKGROUND The previous studies have revealed that abnormal RNA-binding protein Musashi-2 (MSI2) expression is associated with cancer progression through post-transcriptional mechanisms, however mechanistic details of this regulation in acute myeloid leukemia (AML) still remain unclear. Our study aimed to explore the relationship between microRNA-143 (miR-143) and MSI2 and to clarify their clinical significance, biological function and mechanism. METHODS Abnormal expression of miR-143 and MSI2 were evaluated in bone marrow samples from AML patients by quantitative real time-PCR. Effects of miR-143 on regulating MSI2 expression were investigated using luciferase reporter assay. Functional roles of MSI2 and miR-143 on AML cell proliferation and migration were determined by CCK-8 assay, colony formation, and transwell assays in vitro and in mouse subcutaneous xenograft and orthotopic transplantation models in vivo. RNA immunoprecipitation, RNA stability measurement and Western blotting were performed to assess the effects of MSI2 on AML. RESULTS We found that MSI2 was significantly overexpressed in AML and exerted its role of promoting AML cell growth by targeting DLL1 and thereby activating Notch signaling pathway. Moreover, we found that MSI2 bound to Snail1 transcript and inhibited its degradation, which in turn upregulated the expression of matrix metalloproteinases. We also found that MSI2 targeting miR-143 is downregulated in AML. In the AML xenograft mouse model, overexpression of MSI2 recapitulated its leukemia-promoting effects, and overexpression of miR-143 partially attenuated tumor growth and prevented metastasis. Notably, low expression of miR-143, and high expression of MSI2 were associated with poor prognosis in AML patients. CONCLUSIONS Our data demonstrate that MSI2 exerts its malignant properties via DLL1/Notch1 cascade and the Snail1/MMPs axes in AML, and upregulation of miR-143 may be a potential therapeutic approach for AML.
Collapse
Affiliation(s)
- Fanfan Li
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China
- Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Wenzhou Key Laboratory of Hematology, Wenzhou, 325015, Zhejiang, China
| | - Yixiang Han
- Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Wenzhou Key Laboratory of Hematology, Wenzhou, 325015, Zhejiang, China
- Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Rongrong Chen
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China
- Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Wenzhou Key Laboratory of Hematology, Wenzhou, 325015, Zhejiang, China
| | - Yinyan Jiang
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China
- Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Wenzhou Key Laboratory of Hematology, Wenzhou, 325015, Zhejiang, China
| | - Cheng Chen
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China
- Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Wenzhou Key Laboratory of Hematology, Wenzhou, 325015, Zhejiang, China
| | - Xiaofang Wang
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China
- Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Wenzhou Key Laboratory of Hematology, Wenzhou, 325015, Zhejiang, China
| | - Jifan Zhou
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China
- Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Wenzhou Key Laboratory of Hematology, Wenzhou, 325015, Zhejiang, China
| | - Qingqing Xu
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Songfu Jiang
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China
- Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Wenzhou Key Laboratory of Hematology, Wenzhou, 325015, Zhejiang, China
| | - Si Zhang
- Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Kang Yu
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China.
- Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China.
- Wenzhou Key Laboratory of Hematology, Wenzhou, 325015, Zhejiang, China.
| | - Shenghui Zhang
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, Zhejiang, China.
- Institute of Hematology, Wenzhou Medical University, Wenzhou, Zhejiang, China.
- Wenzhou Key Laboratory of Hematology, Wenzhou, 325015, Zhejiang, China.
- Laboratory Animal Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| |
Collapse
|
|
11
|
Bašić D, Ignjatović I, Janković Veličković L, Veljković A. Molecular Characterization of Microrna Interference and Aristolochic Acid Intoxication Found in Upper Tract Urothelial Carcinoma in Patients with Balkan Endemic Nephropathy: A Systematic Review of the Current Literature. Balkan J Med Genet 2023; 25:105-111. [PMID: 37265966 PMCID: PMC10230835 DOI: 10.2478/bjmg-2022-0027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023] Open
Abstract
The term "aristolochic acid nephropathy" (AAN) is used to include any form of toxic interstitial nephropathy that is caused either by ingestion of plants containing aristolochic acids (AA) or by the environmental contaminants in food such as in Balkan endemic nephropathy (BEN). Aristolochic acid (AA) intoxication is strongly associated with the development of upper tract urothelial carcinoma (UTUC); however, the underlying molecular mechanism remains to be defined. MicroRNAs (miRNA) regulate several biological processes, including cell proliferation, differentiation, and metabolism, acting as oncogenes or tumor suppressors. A unique miRNA expression profile suggested that miRNAs could function as regulators in UTUC developmental processes. This review aimed to summarize data available in the literature about underlying molecular mechanisms leading to the expression of miRNAs in AA-UTUC patients with BEN. Strong correlation in AA-UTUC has a distinctive gene alteration pattern, AL-DNA adducts, and a unique tumor protein (TP53) mutational spectrum AAG to TAG (A: T→T: A) transversion in codon 139 (Lys → Stop) of exon 5 activates the p53 tumor suppressor protein. Further, p53 protein is responsible not only for the expression of miRNAs but also acts as a target molecule for miRNAs and plays a crucial function in the AA-UTUC pathogenicity through activation of cyclin-dependent kinase (CyclinD1) and cyclin protein kinase 6(CDK6) to support cell cycle arrest. This study, proposed a molecular mechanism that represented a possible unique relationship between AA intoxication, miRNAs expression, and the progression of UTUC in patients with BEN.
Collapse
Affiliation(s)
- D Bašić
- Urology Clinic, University Clinical Center Niš, Faculty of Medicine, University of Niš, Niš, Serbia
| | - I Ignjatović
- Urology Clinic, University Clinical Center Niš, Faculty of Medicine, University of Niš, Niš, Serbia
| | - Lj Janković Veličković
- Center for Pathology, University Clinical Center Niš, Faculty of Medicine, University of Niš, Niš, Serbia
| | - A Veljković
- Department of Biochemistry, Faculty of Medicine, University of Niš, Niš, Serbia
| |
Collapse
|
|
12
|
Mozammel N, Amini M, Baradaran B, Mahdavi SZB, Hosseini SS, Mokhtarzadeh A. The function of miR-145 in colorectal cancer progression; an updated review on related signaling pathways. Pathol Res Pract 2023; 242:154290. [PMID: 36621158 DOI: 10.1016/j.prp.2022.154290] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 12/23/2022] [Accepted: 12/25/2022] [Indexed: 12/28/2022]
Abstract
MicroRNAs (miRNA) are a broad class of small, highly conserved non-coding RNAs that largely influence gene expression after transcription through binding to various target mRNAs. miRNAs are frequently dysregulated in a wide array of human cancers, possessing great value as diagnostic and therapeutic targets. miR-145, as promising tumor suppressor miRNA, also exhibits deregulated expression levels in human malignancies and participates in various processes, including cell proliferation, apoptosis, migration and differentiation. In particular, miR-145 has been shown to be downregulated in colorectal cancer (CRC), which in turn leads to cell growth, invasion, metastasis and drug resistance. Furthermore, miR-145 is involved in the regulation of multiple tumor specific signaling pathways, such as KRAS and P53 signaling by targeting various genes through colorectal tumorigenesis. Therefore, considering its diagnostic and therapeutic potential, it was aimed to present the recent finding focusing on miR-145 functions to better understand its involvement in CRC incidence and progression through interplay with various signaling pathways. This study is based on articles indexed in PubMed and Google scholar until 2021.
Collapse
Affiliation(s)
- Nazila Mozammel
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
13
|
Huang T, Tian Q, He Z, Xiao H, Yuan C, Lin Z, Yuan J, Yao M. Transcriptome analysis of PBMCs isolated from piglets treated with a miR-124 sponge construct identified miR124/IQGAP2/Rho GTPase as a target pathway support Salmonella Typhimurium infection. Mol Genet Genomics 2023; 298:213-227. [PMID: 36380106 DOI: 10.1007/s00438-022-01976-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 11/03/2022] [Indexed: 11/16/2022]
Abstract
miR-124 is a significantly up-regulated miRNA in peripheral blood collected from piglets infected with Salmonella Typhimurium, suggesting that it may play an important role in Salmonella pathogenesis. This study focused on the transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) isolated from miR-124 sponge and Salmonella Typhimurium-treated piglets, and trying to investigate the function of miR-124 in Salmonella infection. The transcriptome profiling analysis revealed that 2778 genes in miR-124 sponge + Salmonella Typhimurium treatment versus control, 2271 genes in Salmonella Typhimurium treatment versus control, and 1301 genes in miR-124 sponge + Salmonella Typhimurium versus Salmonella Typhimurium treatment, were differentially expressed, respectively (FDR < 0.05 and fold change > 2.0). Pathway analysis indicated that the MAPK signaling pathway, Ribosome pathway, and T-cell receptor signaling pathway were the most significantly enriched pathway in differentially expressed genes between miR-124 sponge + Salmonella Typhimurium and Salmonella Typhimurium along treatment (FDR < 0.05). Reporter assays and electrophoretic mobility shift assays showed that miR-124 is a crucial regulatory factor that targets IQ motif containing GTPase-activating protein 2 (IQGAP2). Cell culture experiment indicated that miR-124 attenuated the Salmonella Typhimurium-mediated activation of CDC42 and RAC1 (P < 0.05). Cultured PBMCs treated with miR-124 and IQGAP2-siRNA had higher intracellular Salmonella count than control samples, particularly 12 h post-infection (P < 0.05). Immunofluorescence analysis revealed that miR-124 treatment reduced the percentage of LAMP-1-positive phagosomes. The miR-124 could be an important regulator for IQGAP2/Rho GTPase pathway in Salmonella Typhimurium-infected PBMCs, and this pathway could be a target for Salmonella that support its infection in PBMCs in piglets.
Collapse
Affiliation(s)
- Tinghua Huang
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China
| | - Qi Tian
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China
| | - Zhen He
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China
| | - Hong Xiao
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China
| | - Chen Yuan
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China
| | - Zezhao Lin
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China
| | - Jing Yuan
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China.
| | - Min Yao
- College of Animal Science, Yangtze University, Jingzhou, 434025, Hubei, China.
| |
Collapse
|
|
14
|
Deng S, Wang M, Wang C, Zeng Y, Qin X, Tan Y, Liang B, Cao Y. p53 downregulates PD-L1 expression via miR-34a to inhibit the growth of triple-negative breast cancer cells: a potential clinical immunotherapeutic target. Mol Biol Rep 2023; 50:577-587. [PMID: 36352176 DOI: 10.1007/s11033-022-08047-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 10/19/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND Compared with other breast cancer subtypes, triple-negative breast cancer (TNBC) has poorer responses to therapy and lower overall survival rates. The use of an inhibitor of immune checkpoint programmed cell death ligand 1 (PD-L1) is a promising treatment strategy and is approved for malignant tumors, especially for TNBC. p53 regulates various biological processes, but the association between p53 and immune evasion remains unknown. miR-34a is a known tumor suppressor and p53-regulated miRNA that is downregulated in several cancers; however, it has not been reported in TNBC. Herein, we aimed to explore the regulatory signaling axis among p53, miR-34a and PD-L1 in TNBC cells in vivo and in tissue and to improve our understanding of immunotherapy for TNBC. METHODS AND RESULTS p53-EGFP, p53-siRNA and miR-34a mimics were transfected into TNBC cell lines, and the interaction between miR-34a and PD-L1 was analyzed via dual-luciferase reporter assays. We found that p53 could inhibit the expression of PD-L1 via miR-34a and that miR-34a could inhibit both cell activity and migration and promoted apoptosis and cytotoxicity in TNBC. Furthermore, miR-34a agomir was injected into MDA-MB-231 tumors of nude mice. The results showed that miR-34a could inhibit tumor growth and downregulate the expression of PD-L1 in vivo. A total of 133 TNBC tissue samples were analyzed by immunochemistry; the proportion of positive expression of PD-L1 was 57.14% (76/133), and the proportion of samples with negative expression of PD-L1 was 42.86% (57/133). CONCLUSION Our research may provide a novel potential target for TNBC.
Collapse
Affiliation(s)
- Siyu Deng
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong Distinct, Chongqing, 400016, P.R. China
| | - Mengna Wang
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong Distinct, Chongqing, 400016, P.R. China
| | - Chenglong Wang
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong Distinct, Chongqing, 400016, P.R. China
- Department of Pathology, Chongqing Traditional Chinese Medicine Hospital, No. 6 Panxi Seventh Branch Road, Jiangbei District, Chongqing, 400021, P. R. China
| | - Yan Zeng
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong Distinct, Chongqing, 400016, P.R. China
| | - Xue Qin
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong Distinct, Chongqing, 400016, P.R. China
| | - Yiwen Tan
- Department of Pathology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, P.R. China
| | - Bing Liang
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong Distinct, Chongqing, 400016, P.R. China.
| | - Youde Cao
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong Distinct, Chongqing, 400016, P.R. China.
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, 1 Yixueyuan Road, Yuzhong Distinct, Chongqing, 400016, P.R. China.
| |
Collapse
|
|
15
|
Palihaderu PADS, Mendis BILM, Premarathne JMKJK, Dias WKRR, Yeap SK, Ho WY, Dissanayake AS, Rajapakse IH, Karunanayake P, Senarath U, Satharasinghe DA. Therapeutic Potential of miRNAs for Type 2 Diabetes Mellitus: An Overview. Epigenet Insights 2022; 15:25168657221130041. [PMID: 36262691 PMCID: PMC9575458 DOI: 10.1177/25168657221130041] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 09/14/2022] [Indexed: 11/05/2022] Open
Abstract
MicroRNA(miRNA)s have been identified as an emerging class for therapeutic
interventions mainly due to their extracellularly stable presence in humans and
animals and their potential for horizontal transmission and action. However,
treating Type 2 diabetes mellitus using this technology has yet been in a
nascent state. MiRNAs play a significant role in the pathogenesis of Type 2
diabetes mellitus establishing the potential for utilizing miRNA-based
therapeutic interventions to treat the disease. Recently, the administration of
miRNA mimics or antimiRs in-vivo has resulted in positive modulation of glucose
and lipid metabolism. Further, several cell culture-based interventions have
suggested beta cell regeneration potential in miRNAs. Nevertheless, few such
miRNA-based therapeutic approaches have reached the clinical phase. Therefore,
future research contributions would identify the possibility of miRNA
therapeutics for tackling T2DM. This article briefly reported recent
developments on miRNA-based therapeutics for treating Type 2 Diabetes mellitus,
associated implications, gaps, and recommendations for future studies.
Collapse
Affiliation(s)
- PADS Palihaderu
- Department of Basic Veterinary
Sciences, Faculty of Veterinary Medicine and Animal Science, University of
Peradeniya, Peradeniya, Sri Lanka
| | - BILM Mendis
- Department of Basic Veterinary
Sciences, Faculty of Veterinary Medicine and Animal Science, University of
Peradeniya, Peradeniya, Sri Lanka
| | - JMKJK Premarathne
- Department of Livestock and Avian
Sciences, Faculty of Livestock, Fisheries, and Nutrition, Wayamba University of Sri
Lanka, Makandura, Gonawila (NWP), Sri Lanka
| | - WKRR Dias
- Department of North Indian Music,
Faculty of Music, University of the Visual and Performing Arts, Colombo, Sri
Lanka
| | - Swee Keong Yeap
- China-ASEAN College of Marine Sciences,
Xiamen University Malaysia Campus, Jalan Sunsuria, Bandar Sunsuria, Sepang,
Selangor, Malaysia
| | - Wan Yong Ho
- Division of Biomedical Sciences,
Faculty of Medicine and Health Sciences, University of Nottingham (Malaysia Campus),
Semenyih, Malaysia
| | - AS Dissanayake
- Department of Clinical Medicine,
Faculty of Medicine, University of Ruhuna, Galle, Sri Lanka
| | - IH Rajapakse
- Department of Psychiatry, Faculty of
Medicine, University of Ruhuna, Galle, Sri Lanka
| | - P Karunanayake
- Department of Clinical Medicine,
Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - U Senarath
- Department of Community Medicine,
Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
| | - DA Satharasinghe
- Department of Basic Veterinary
Sciences, Faculty of Veterinary Medicine and Animal Science, University of
Peradeniya, Peradeniya, Sri Lanka,DA Satharasinghe, Department of Basic
Veterinary Sciences, Faculty of Veterinary Medicine and Animal Science,
University of Peradeniya, Peradeniya, 20400, Sri Lanka.
| |
Collapse
|
|
16
|
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.
Collapse
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
| |
Collapse
|
|
17
|
Transforming Growth Factor-Beta Signaling in Cancer-Induced Cachexia: From Molecular Pathways to the Clinics. Cells 2022; 11:cells11172671. [PMID: 36078078 PMCID: PMC9454487 DOI: 10.3390/cells11172671] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/23/2022] [Accepted: 08/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cachexia is a metabolic syndrome consisting of massive loss of muscle mass and function that has a severe impact on the quality of life and survival of cancer patients. Up to 20% of lung cancer patients and up to 80% of pancreatic cancer patients are diagnosed with cachexia, leading to death in 20% of them. The main drivers of cachexia are cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), macrophage inhibitory cytokine 1 (MIC-1/GDF15) and transforming growth factor-beta (TGF-β). Besides its double-edged role as a tumor suppressor and activator, TGF-β causes muscle loss through myostatin-based signaling, involved in the reduction in protein synthesis and enhanced protein degradation. Additionally, TGF-β induces inhibin and activin, causing weight loss and muscle depletion, while MIC-1/GDF15, a member of the TGF-β superfamily, leads to anorexia and so, indirectly, to muscle wasting, acting on the hypothalamus center. Against this background, the blockade of TGF-β is tested as a potential mechanism to revert cachexia, and antibodies against TGF-β reduced weight and muscle loss in murine models of pancreatic cancer. This article reviews the role of the TGF-β pathway and to a minor extent of other molecules including microRNA in cancer onset and progression with a special focus on their involvement in cachexia, to enlighten whether TGF-β and such other players could be potential targets for therapy.
Collapse
|
|
18
|
Kabiraj L, Kundu A. Potential role of microRNAs in pancreatic cancer manifestation: a review. J Egypt Natl Canc Inst 2022; 34:26. [PMID: 35718815 DOI: 10.1186/s43046-022-00127-2] [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: 02/02/2022] [Accepted: 05/15/2022] [Indexed: 11/10/2022] Open
Abstract
Cancer cells are different from normal cells in regard to phenotypic and functional expression. Cancer is the outcome of aberrant gene expression affecting various cellular signaling pathways. MicroRNAs (MiRs) are small, non-coding RNAs regulating the expression of various protein-coding genes post-transcriptionally and are known to play critical roles in the complicated cellular pathways leading to cell growth, proliferation, development, and apoptosis. MiRs are involved in various cancer-related pathways and function both as tumor suppressor and cancer-causing genes. There is a need for significant biomarkers, and better prognostication of response to a particular treatment and liquid biopsy could be useful to appraise such potential biomarkers. This review has focused on the involvement of anomalous expression of miRs in human pancreatic cancer and the investigation of miR-based biomarkers for disease diagnosis and better therapeutic selection.
Collapse
Affiliation(s)
- Lisa Kabiraj
- Department of Microbiology, Techno India University, EM-4, Sector-V, Salt Lake City, Kolkata, 700091, India
| | - Atreyee Kundu
- Department of Microbiology, Techno India University, EM-4, Sector-V, Salt Lake City, Kolkata, 700091, India.
| |
Collapse
|
|
19
|
Papaefthymiou A, Doukatas A, Galanopoulos M. Pancreatic cancer and oligonucleotide therapy: Exploring novel therapeutic options and targeting chemoresistance. Clin Res Hepatol Gastroenterol 2022; 46:101911. [PMID: 35346893 DOI: 10.1016/j.clinre.2022.101911] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/15/2022] [Accepted: 03/18/2022] [Indexed: 02/04/2023]
Abstract
Pancreatic cancer (PC) represents a malignancy with increased mortality rate, as less than 10% of patients survive for 5 years after diagnosis. Current evolution in basic sciences has revealed promising results by decrypting genetic loci vulnerable to mutations, as potential targets of novel treatment choices. In this regard, the "Oligonucleotide therapeutics", based on synthetic nucleotides, modify the function and expression of their targets. Antisense oligonucleotides (ASOs), small interfering RNA (siRNA), microRNAs (miRNAs), aptamers, CpG oligodeoxynucleotides and decoys comprise the main representatives of this emerging technology, by regulating oncogenes' expression, restoring DNA repairment mechanisms, sensitizing cancer cells in chemotherapy, and inhibiting PC progress. A plethora of genetic treatment molecules and respective targets have been described and are currently studied, thus providing a broad range of probable pharmaceutical options. This narrative review illuminates the main parameters of genetic treatment molecules for PC and underlines their deficiencies, to clarify the upcoming future and trigger further investigation in PC management.
Collapse
Affiliation(s)
- Apostolis Papaefthymiou
- Department of Gastroenterology, University Hospital of Larissa, Larissa, 41110, Thessaly, Greece.
| | - Aris Doukatas
- Department of Pharmacy, National and Kapodistrian University of Athens, Attiki, Greece
| | - Michail Galanopoulos
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom
| |
Collapse
|
|
20
|
Popov A, Mandys V. Senescence-Associated miRNAs and Their Role in Pancreatic Cancer. Pathol Oncol Res 2022; 28:1610156. [PMID: 35570840 PMCID: PMC9098800 DOI: 10.3389/pore.2022.1610156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 04/12/2022] [Indexed: 01/17/2023]
Abstract
Replicative senescence is irreversible cell proliferation arrest for somatic cells which can be circumvented in cancers. Cellular senescence is a process, which may play two opposite roles. On the one hand, this is a natural protection of somatic cells against unlimited proliferation and malignant transformation. On the other hand, cellular secretion caused by senescence can stimulate inflammation and proliferation of adjacent cells that may promote malignancy. The main genes controlling the senescence pathways are also well known as tumor suppressors. Almost 140 genes regulate both cellular senescence and cancer pathways. About two thirds of these genes (64%) are regulated by microRNAs. Senescence-associated miRNAs can stimulate cancer progression or act as tumor suppressors. Here we review the role playing by senescence-associated miRNAs in development, diagnostics and treatment of pancreatic cancer.
Collapse
Affiliation(s)
- Alexey Popov
- Department of Pathology, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czechia
| | | |
Collapse
|
|
21
|
Salamat J, Abbott KL, Flannery PC, Ledbetter EL, Pondugula SR. Interplay between the Cannabinoid System and microRNAs in Cancer. ACS OMEGA 2022; 7:9995-10000. [PMID: 35382335 PMCID: PMC8973111 DOI: 10.1021/acsomega.2c00635] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/02/2022] [Indexed: 05/29/2023]
Abstract
Cancer patients often use cannabinoids for alleviating symptoms induced by cancer pathogenesis and cancer treatment. This use of cannabinoids can have unexpected effects in cancer patients depending on the cancer type, resulting in either beneficial (e.g., anticancer) or adverse (e.g., oncogenic) effects. While cannabinoids can enhance the growth and progression of some cancers, they can also suppress the growth and progression of other cancers. However, the underlying mechanisms of such differential effects are poorly understood. miRNAs have been shown to be involved in driving the hallmarks of cancer, affecting cancer growth and progression as well as cancer therapy response. Although the understanding of the effects of cannabinoids and miRNAs as they relate to cancer continues to improve, the interplay between cannabinoid system and miRNAs in cancer pathogenesis and cancer treatment response is poorly understood. Investigation of such interactions between the cannabinoid system and miRNAs could provide novel insights into the underlying mechanisms of the differential effects of cannabinoids in cancer and can help predict and improve the prognosis of cancer patients.
Collapse
Affiliation(s)
- Julia
M. Salamat
- Department
of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, Alabama 36849, United States
| | - Kodye L. Abbott
- Salk
Institute for Biological Studies, La Jolla, California 92037, United States
| | - Patrick C. Flannery
- Rocky
Vista University College of Osteopathic Medicine, Parker, Colorado 80134, United States
| | - Elizabeth L. Ledbetter
- Department
of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, Alabama 36849, United States
| | - Satyanarayana R. Pondugula
- Department
of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, Alabama 36849, United States
| |
Collapse
|
|
22
|
Szczepanek J, Skorupa M, Tretyn A. MicroRNA as a Potential Therapeutic Molecule in Cancer. Cells 2022; 11:1008. [PMID: 35326459 PMCID: PMC8947269 DOI: 10.3390/cells11061008] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/11/2022] [Accepted: 03/16/2022] [Indexed: 12/11/2022] Open
Abstract
Small noncoding RNAs, as post-translational regulators of many target genes, are not only markers of neoplastic disease initiation and progression, but also markers of response to anticancer therapy. Hundreds of miRNAs have been identified as biomarkers of drug resistance, and many have demonstrated the potential to sensitize cancer cells to therapy. Their properties of modulating the response of cells to therapy have made them a promising target for overcoming drug resistance. Several methods have been developed for the delivery of miRNAs to cancer cells, including introducing synthetic miRNA mimics, DNA plasmids containing miRNAs, and small molecules that epigenetically alter endogenous miRNA expression. The results of studies in animal models and preclinical studies for solid cancers and hematological malignancies have confirmed the effectiveness of treatment protocols using microRNA. Nevertheless, the use of miRNAs in anticancer therapy is not without limitations, including the development of a stable nanoconstruct, delivery method choices, and biodistribution. The aim of this review was to summarize the role of miRNAs in cancer treatment and to present new therapeutic concepts for these molecules. Supporting anticancer therapy with microRNA molecules has been verified in numerous clinical trials, which shows great potential in the treatment of cancer.
Collapse
Affiliation(s)
- Joanna Szczepanek
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Ul. Wilenska 4, 87-100 Torun, Poland;
| | - Monika Skorupa
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Ul. Wilenska 4, 87-100 Torun, Poland;
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100 Torun, Poland;
| | - Andrzej Tretyn
- Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Ul. Lwowska 1, 87-100 Torun, Poland;
| |
Collapse
|
|
23
|
Gupta P, Neupane YR, Parvez S, Kohli K. Recent advances in targeted nanotherapeutic approaches for breast cancer management. Nanomedicine (Lond) 2021; 16:2605-2631. [PMID: 34854336 DOI: 10.2217/nnm-2021-0281] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most commonly occurring tumor disease worldwide. Breast cancer is currently managed by conventional chemotherapy, which is inadequate in curbing this heterogeneous disease and results in off-site toxic effects, suggesting effective treatment approaches with better therapeutic profiles are needed. This review, therefore, focuses on the recent advancements in delivering therapeutics to the target site using passive and/or active targeted nanodrug-delivery systems to ameliorate endolysosomal escape. In addition, recent strategies in targeting breast cancer stem cells are discussed. The role of naturally cell-secreted nanovesicles (exosomes) in the management of triple-negative breast cancer is also discussed.
Collapse
Affiliation(s)
- Priya Gupta
- Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India
| | - Yub Raj Neupane
- Department of Pharmacy, National University of Singapore, Singapore, 117559
| | - Suhel Parvez
- Department of Toxicology, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi, 110062, India
| | - Kanchan Kohli
- Department of Pharmaceutics, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India.,Lloyd Institute of Management & Technology (Pharm.), Plot No. 11, Knowledge Park-II, Greater Noida, 201308, Uttar Pradesh, India
| |
Collapse
|
|
24
|
Liu QL, Zhang Z, Wei X, Zhou ZG. Noncoding RNAs in tumor metastasis: molecular and clinical perspectives. Cell Mol Life Sci 2021; 78:6823-6850. [PMID: 34499209 PMCID: PMC11073083 DOI: 10.1007/s00018-021-03929-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 08/12/2021] [Accepted: 08/26/2021] [Indexed: 02/08/2023]
Abstract
Metastasis is the main culprit of cancer-associated mortality and involves a complex and multistage process termed the metastatic cascade, which requires tumor cells to detach from the primary site, intravasate, disseminate in the circulation, extravasate, adapt to the foreign microenvironment, and form organ-specific colonization. Each of these processes has been already studied extensively for molecular mechanisms focused mainly on protein-coding genes. Recently, increasing evidence is pointing towards RNAs without coding potential for proteins, referred to as non-coding RNAs, as regulators in shaping cellular activity. Since those first reports, the detection and characterization of non-coding RNA have explosively thrived and greatly enriched the understanding of the molecular regulatory networks in metastasis. Moreover, a comprehensive description of ncRNA dysregulation will provide new insights into novel tools for the early detection and treatment of metastatic cancer. In this review, we focus on discussion of the emerging role of ncRNAs in governing cancer metastasis and describe step by step how ncRNAs impinge on cancer metastasis. In particular, we highlight the diagnostic and therapeutic applications of ncRNAs in metastatic cancer.
Collapse
Affiliation(s)
- Qiu-Luo Liu
- Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Zhe Zhang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China.
| | - Zong-Guang Zhou
- Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
| |
Collapse
|
|
25
|
Gupta A, Andresen JL, Manan RS, Langer R. Nucleic acid delivery for therapeutic applications. Adv Drug Deliv Rev 2021; 178:113834. [PMID: 34492233 DOI: 10.1016/j.addr.2021.113834] [Citation(s) in RCA: 159] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/25/2021] [Accepted: 06/11/2021] [Indexed: 02/07/2023]
Abstract
Recent medical advances have exploited the ability to address a given disease at the underlying level of transcription and translation. These treatment paradigms utilize nucleic acids - including short interfering RNA (siRNA), microRNA (miRNA), antisense oligonucleotides (ASO), and messenger RNA (mRNA) - to achieve a desired outcome ranging from gene knockdown to induced expression of a selected target protein. Towards this end, numerous strategies for encapsulation or stabilization of various nucleic acid structures have been developed in order to achieve intracellular delivery. In this review, we discuss several therapeutic applications of nucleic acids directed towards specific diseases and tissues of interest, in particular highlighting recent technologies which have reached late-stage clinical trials and received FDA approval.
Collapse
Affiliation(s)
- Akash Gupta
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
| | - Jason L Andresen
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Rajith S Manan
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Robert Langer
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
| |
Collapse
|
|
26
|
Host miRNA and immune cell interactions: relevance in nano-therapeutics for human health. Immunol Res 2021; 70:1-18. [PMID: 34716546 DOI: 10.1007/s12026-021-09247-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022]
Abstract
Around 2200 miRNA (microRNA) genes were found in the human genome. miRNAs are arranged in clusters within the genome and share the same transcriptional regulatory units. It has been revealed that approximately 50% of miRNAs elucidated in the genome are transcribed from non-protein-coding genes, and the leftover miRNAs are present in the introns of coding sequences. We are now approaching a stage in which miRNA diagnostics and therapies can be established confidently, and several commercial efforts are underway to carry these innovations from the bench to the clinic. MiRNAs control many of the significant cellular activities such as production, differentiation, growth, and metabolism. Particularly in the immune system, miRNAs have emerged as a crucial biological component during diseased state and homeostasis. miRNAs have been found to regulate inflammatory responses and autoimmune disorders. Moreover, each miRNA targets multiple genes simultaneously, making miRNAs promising tools as diagnostic biomarkers and as remedial targets. Still, one of the major obstacles in miRNA-based approaches is the achievement of specific and efficient systemic delivery of miRNAs. To overcome these challenges, nanoformulations have been synthesized to protect miRNAs from degradation and enhance cellular uptake. The current review deals with the miRNA-mediated regulation of the recruitment and activation of immune cells, especially in the tumor microenvironment, viral infection, inflammation, and autoimmunity. The nano-based miRNA delivery modes are also discussed here, especially in the context of immune modulation.
Collapse
|
|
27
|
Baltan S, Sandau US, Brunet S, Bastian C, Tripathi A, Nguyen H, Liu H, Saugstad JA, Zarnegarnia Y, Dutta R. Identification of miRNAs That Mediate Protective Functions of Anti-Cancer Drugs During White Matter Ischemic Injury. ASN Neuro 2021; 13:17590914211042220. [PMID: 34619990 PMCID: PMC8642107 DOI: 10.1177/17590914211042220] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
We have previously shown that two anti-cancer drugs, CX-4945 and MS-275, protect and preserve white matter (WM) architecture and improve functional recovery in a model of WM ischemic injury. While both compounds promote recovery, CX-4945 is a selective Casein kinase 2 (CK2) inhibitor and MS-275 is a selective Class I histone deacetylase (HDAC) inhibitor. Alterations in microRNAs (miRNAs) mediate some of the protective actions of these drugs. In this study, we aimed to (1) identify miRNAs expressed in mouse optic nerves (MONs); (2) determine which miRNAs are regulated by oxygen glucose deprivation (OGD); and (3) determine the effects of CX-4945 and MS-275 treatment on miRNA expression. RNA isolated from MONs from control and OGD-treated animals with and without CX-4945 or MS-275 treatment were quantified using NanoString nCounter® miRNA expression profiling. Comparative analysis of experimental groups revealed that 12 miRNAs were expressed at high levels in MONs. OGD upregulated five miRNAs (miR-1959, miR-501-3p, miR-146b, miR-201, and miR-335-3p) and downregulated two miRNAs (miR-1937a and miR-1937b) compared to controls. OGD with CX-4945 upregulated miR-1937a and miR-1937b, and downregulated miR-501-3p, miR-200a, miR-1959, and miR-654-3p compared to OGD alone. OGD with MS-275 upregulated miR-2134, miR-2141, miR-2133, miR-34b-5p, miR-153, miR-487b, miR-376b, and downregulated miR-717, miR-190, miR-27a, miR-1959, miR-200a, miR-501-3p, and miR-200c compared to OGD alone. Interestingly, miR-501-3p and miR-1959 were the only miRNAs upregulated by OGD, and downregulated by OGD plus CX-4945 and MS-275. Therefore, we suggest that protective functions of CX-4945 or MS-275 against WM injury maybe mediated, in part, through miRNA expression.
Collapse
Affiliation(s)
- Selva Baltan
- Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239, USA
- Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
- Selva Baltan, Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Mackenzie Hall 2140A, L459, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239, USA.
| | - Ursula S. Sandau
- Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239, USA
| | - Sylvain Brunet
- Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Chinthasagar Bastian
- Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Ajai Tripathi
- Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| | - Hung Nguyen
- Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239, USA
| | - Helen Liu
- Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239, USA
| | - Julie A. Saugstad
- Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239, USA
| | - Yalda Zarnegarnia
- Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239, USA
| | - Ranjan Dutta
- Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
| |
Collapse
|
|
28
|
RNAi-Based Approaches for Pancreatic Cancer Therapy. Pharmaceutics 2021; 13:pharmaceutics13101638. [PMID: 34683931 PMCID: PMC8541396 DOI: 10.3390/pharmaceutics13101638] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/23/2021] [Accepted: 09/27/2021] [Indexed: 01/17/2023] Open
Abstract
Pancreatic cancer is one of the most lethal forms of cancer, predicted to be the second leading cause of cancer-associated death by 2025. Despite intensive research for effective treatment strategies and novel anticancer drugs over the past decade, the overall patient survival rate remains low. RNA interference (RNAi) is capable of interfering with expression of specific genes and has emerged as a promising approach for pancreatic cancer because genetic aberrations and dysregulated signaling are the drivers for tumor formation and the stromal barrier to conventional therapy. Despite its therapeutic potential, RNA-based drugs have remaining hurdles such as poor tumor delivery and susceptibility to serum degradation, which could be overcome with the incorporation of nanocarriers for clinical applications. Here we summarize the use of small interfering RNA (siRNA) and microRNA (miRNA) in pancreatic cancer therapy in preclinical reports with approaches for targeting either the tumor or tumor microenvironment (TME) using various types of nanocarriers. In these studies, inhibition of oncogene expression and induction of a tumor suppressive response in cancer cells and surrounding immune cells in TME exhibited a strong anticancer effect in pancreatic cancer models. The review discusses the remaining challenges and prospective strategies suggesting the potential of RNAi-based therapeutics for pancreatic cancer.
Collapse
|
|
29
|
Pei Y, Parks JS, Kang HW. Quercetin alleviates high-fat diet-induced inflammation in brown adipose tissue. J Funct Foods 2021. [DOI: 10.1016/j.jff.2021.104614] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
|
|
30
|
Role of non-coding RNAs in tumor progression and metastasis in pancreatic cancer. Cancer Metastasis Rev 2021; 40:761-776. [PMID: 34591242 PMCID: PMC8556175 DOI: 10.1007/s10555-021-09995-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/13/2021] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with an overall 5-year survival rate of less than 10%. The 1-year survival rate of patients with locally advanced or metastatic disease is abysmal. The aggressive nature of cancer cells, hypovascularization, extensive desmoplastic stroma, and immunosuppressive tumor microenvironment (TME) endows PDAC tumors with multiple mechanisms of drug resistance. With no obvious genetic mutation(s) driving tumor progression or metastatic transition, the challenges for understanding the biological mechanism(s) of these processes are paramount. A better understanding of the molecular and cellular mechanisms of these processes could lead to new diagnostic tools for patient management and new targets for therapeutic intervention. microRNAs (miRNAs) are an evolutionarily conserved gene class of short non-coding regulatory RNAs. miRNAs are an extensive regulatory layer that controls gene expression at the posttranscriptional level. This review focuses on preclinical models that functionally dissect miRNA activity in tumor progression or metastatic processes in PDAC. Collectively, these studies suggest an influence of miRNAs and RNA-RNA networks in the processes of epithelial to mesenchymal cell transition and cancer cell stemness. At a cell-type level, some miRNAs mainly influence cancer cell–intrinsic processes and pathways, whereas other miRNAs predominantly act in distinct cellular compartments of the TME to regulate fibroblast and immune cell functions and/or influence other cell types’ function via cell-to-cell communications by transfer of extracellular vesicles. At a molecular level, the influence of miRNA-mediated regulation often converges in core signaling pathways, including TGF-β, JAK/STAT, PI3K/AKT, and NF-κB.
Collapse
|
|
31
|
Smolarz B, Durczyński A, Romanowicz H, Hogendorf P. The Role of microRNA in Pancreatic Cancer. Biomedicines 2021; 9:biomedicines9101322. [PMID: 34680441 PMCID: PMC8533140 DOI: 10.3390/biomedicines9101322] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are small ribonucleic acid molecules that play a key role in regulating gene expression. The increasing number of studies undertaken on the functioning of microRNAs in the tumor formation clearly indicates their important potential in oncological therapy. Pancreatic cancer is one of the deadliest cancers. The expression of miRNAs released into the bloodstream appears to be a good indicator of progression and evaluation of the aggressiveness of pancreatic cancer, as indicated by studies. The work reviewed the latest literature on the importance of miRNAs for pancreatic cancer development.
Collapse
Affiliation(s)
- Beata Smolarz
- Laboratory of Cancer Genetics, Department of Pathology, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland;
- Correspondence: ; Tel.: +48-42-271-1290
| | - Adam Durczyński
- Department of General and Transplant Surgery, N. Barlicki Memorial Clinical Hospital, Medical University of Lodz, 90-153 Lodz, Poland; (A.D.); (P.H.)
| | - Hanna Romanowicz
- Laboratory of Cancer Genetics, Department of Pathology, Polish Mother’s Memorial Hospital Research Institute, 93-338 Lodz, Poland;
| | - Piotr Hogendorf
- Department of General and Transplant Surgery, N. Barlicki Memorial Clinical Hospital, Medical University of Lodz, 90-153 Lodz, Poland; (A.D.); (P.H.)
| |
Collapse
|
|
32
|
The Role of miRNA in the Pathophysiology of Neuroendocrine Tumors. Int J Mol Sci 2021; 22:ijms22168569. [PMID: 34445276 PMCID: PMC8395312 DOI: 10.3390/ijms22168569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/16/2021] [Accepted: 08/06/2021] [Indexed: 12/14/2022] Open
Abstract
Neuroendocrine tumors (NETs) represent a tumor group that is both rare and heterogeneous. Prognosis is largely determined by the tumor grading and the site of the primary tumor and metastases. Despite intensive research efforts, only modest advances in diagnostic and therapeutic approaches have been achieved in recent years. For patients with non-respectable tumor stages, prognosis is poor. In this context, the development of novel diagnostic tools for early detection of NETs and prediction of tumor response to therapy as well as estimation of the overall prognosis would greatly improve the clinical management of NETs. However, identification of novel diagnostic molecules is hampered by an inadequate understanding of the pathophysiology of neuroendocrine malignancies. It has recently been demonstrated that microRNA (miRNA), a family of small RNA molecules with an established role in the pathophysiology of quite different cancer entities, may also play a role as a biomarker. Here, we summarize the available knowledge on the role of miRNAs in the development of NET and highlight their potential use as serum-based biomarkers in the context of this disease. We discuss important challenges currently preventing their use in clinical routine and give an outlook on future directions of miRNA research in NET.
Collapse
|
|
33
|
Song S, Johnson KS, Lujan H, Pradhan SH, Sayes CM, Taube JH. Nanoliposomal Delivery of MicroRNA-203 Suppresses Migration of Triple-Negative Breast Cancer through Distinct Target Suppression. Noncoding RNA 2021; 7:45. [PMID: 34449670 PMCID: PMC8395754 DOI: 10.3390/ncrna7030045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/14/2021] [Accepted: 07/21/2021] [Indexed: 02/07/2023] Open
Abstract
Triple-negative breast cancers affect thousands of women in the United States and disproportionately drive mortality from breast cancer. MicroRNAs are small, non-coding RNAs that negatively regulate gene expression post-transcriptionally by inhibiting target mRNA translation or by promoting mRNA degradation. We have identified that miRNA-203, silenced by epithelial-mesenchymal transition (EMT), is a tumor suppressor and can promote differentiation of breast cancer stem cells. In this study, we tested the ability of liposomal delivery of miR-203 to reverse aspects of breast cancer pathogenesis using breast cancer and EMT cell lines. We show that translationally relevant methods for increasing miR-203 abundance within a target tissue affects cellular properties associated with cancer progression. While stable miR-203 expression suppresses LASP1 and survivin, nanoliposomal delivery suppresses BMI1, indicating that suppression of distinct mRNA target profiles can lead to loss of cancer cell migration.
Collapse
Affiliation(s)
- Shuxuan Song
- Department of Biology, Baylor University, Waco, TX 76706, USA; (S.S.); (K.S.J.)
| | - Kelsey S. Johnson
- Department of Biology, Baylor University, Waco, TX 76706, USA; (S.S.); (K.S.J.)
| | - Henry Lujan
- Department of Environmental Science, Baylor University, Waco, TX 76706, USA; (H.L.); (S.H.P.); (C.M.S.)
| | - Sahar H. Pradhan
- Department of Environmental Science, Baylor University, Waco, TX 76706, USA; (H.L.); (S.H.P.); (C.M.S.)
| | - Christie M. Sayes
- Department of Environmental Science, Baylor University, Waco, TX 76706, USA; (H.L.); (S.H.P.); (C.M.S.)
| | - Joseph H. Taube
- Department of Biology, Baylor University, Waco, TX 76706, USA; (S.S.); (K.S.J.)
| |
Collapse
|
|
34
|
Mortoglou M, Tabin ZK, Arisan ED, Kocher HM, Uysal-Onganer P. Non-coding RNAs in pancreatic ductal adenocarcinoma: New approaches for better diagnosis and therapy. Transl Oncol 2021; 14:101090. [PMID: 33831655 PMCID: PMC8042452 DOI: 10.1016/j.tranon.2021.101090] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/14/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a 5-year survival rate less than 8%, which has remained unchanged over the last 50 years. Early detection is particularly difficult due to the lack of disease-specific symptoms and a reliable biomarker. Multimodality treatment including chemotherapy, radiotherapy (used sparingly) and surgery has become the standard of care for patients with PDAC. Carbohydrate antigen 19-9 (CA 19-9) is the most common diagnostic biomarker; however, it is not specific enough especially for asymptomatic patients. Non-coding RNAs are often deregulated in human malignancies and shown to be involved in cancer-related mechanisms such as cell growth, differentiation, and cell death. Several micro, long non-coding and circular RNAs have been reported to date which are involved in PDAC. Aim of this review is to discuss the roles and functions of non-coding RNAs in diagnosis and treatments of PDAC.
Collapse
Affiliation(s)
- Maria Mortoglou
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
| | - Zoey Kathleen Tabin
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
| | - E Damla Arisan
- Institution of Biotechnology, Gebze Technical University, Gebze, Turkey.
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute-a CRUK Centre of Excellence, Queen Mary University London, London EC1M 6BQ, UK.
| | - Pinar Uysal-Onganer
- Cancer Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK.
| |
Collapse
|
|
35
|
Di Y, Jiang Y, Shen X, Liu J, Gao Y, Cai H, Sun X, Ning D, Liu B, Lei J, Jin S. Downregulation of miR-135b-5p Suppresses Progression of Esophageal Cancer and Contributes to the Effect of Cisplatin. Front Oncol 2021; 11:679348. [PMID: 34277424 PMCID: PMC8281352 DOI: 10.3389/fonc.2021.679348] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/03/2021] [Indexed: 01/02/2023] Open
Abstract
Esophageal cancer (EC) is one of the commonest human cancers, which accompany high morbidity. MicroRNAs (miRNAs) play a pivotal role in various cancers, including EC. Our research aimed to reveal the function and mechanism of miR-135b-5p. Our research identified that miR-135b-5p was elevated in EC samples from TCGA database. Correspondingly real-time PCR assay also showed the miR-135b-5p is also higher expressed in Eca109, EC9706, KYSE150 cells than normal esophageal epithelial cells (Het-1A). CCK8, Edu, wound healing, Transwell assay, and western blot demonstrated miR-135b-5p inhibition suppresses proliferation, invasion, migration and promoted the apoptosis in Eca109 and EC9706 cells. Moreover, the miR-135b-5p inhibition also inhibited xenograft lump growth. We then predicted the complementary gene of miR-135b-5p using miRTarBase, TargetScan, and DIANA-microT. TXNIP was estimated as a complementary gene for miR-135b-5p. Luciferase report assay verified the direct binding site for miR-135b-5p and TXNIP. Real-time PCR and western blot assays showed that the inhibition of miR-135b-5p remarkably enhanced the levels of TXNIP in Eca109 and EC9706 cells. Furthermore, cisplatin (cis-diamminedichloroplatinum II, DDP) decreased miR-135b-5p expression and increased TXNIP expression. Enhanced expression of miR-135b-5p attenuated the inhibitory ability of cisplatin (cis-diamminedichloroplatinum II, DDP) in Eca109 cells, accompanied by TXNIP downregulation. In conclusion, the downregulation of miR-135b-5p suppresses the progression of EC through targeting TXNIP. MiR-135b-5p/TXNIP pathway contributes to the anti-tumor effect of DDP. These findings may provide new insight into the treatment of EC.
Collapse
Affiliation(s)
- Yuzhu Di
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yanan Jiang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Xiuyun Shen
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China
| | - Jing Liu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yang Gao
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Huimin Cai
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaoli Sun
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dandan Ning
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bing Liu
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China
| | - Jiaji Lei
- Department of Thoracic Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shizhu Jin
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| |
Collapse
|
|
36
|
Li S, Wei X, He J, Cao Q, Du D, Zhan X, Zeng Y, Yuan S, Sun L. The comprehensive landscape of miR-34a in cancer research. Cancer Metastasis Rev 2021; 40:925-948. [PMID: 33959850 DOI: 10.1007/s10555-021-09973-3] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 04/29/2021] [Indexed: 12/12/2022]
Abstract
MicroRNA-34 (miR-34) plays central roles in human diseases, especially cancers. Inactivation of miR-34 is detected in cancer cell lines and tumor tissues versus normal controls, implying its potential tumor-suppressive effect. Clinically, miR-34 has been identified as promising prognostic indicators for various cancers. In fact, members of the miR-34 family, especially miR-34a, have been convincingly proved to affect almost the whole cancer progression process. Here, a total of 512 (miR-34a, 10/21), 85 (miR-34b, 10/16), and 114 (miR-34c, 10/14) putative targets of miR-34a/b/c are predicted by at least ten miRNA databases, respectively. These targets are further analyzed in gene ontology (GO), KEGG pathway, and the Reactome pathway dataset. The results suggest their involvement in the regulation of signal transduction, macromolecule metabolism, and protein modification. Also, the targets are implicated in critical signaling pathways, such as MAPK, Notch, Wnt, PI3K/AKT, p53, and Ras, as well as apoptosis, cell cycle, and EMT-related pathways. Moreover, the upstream regulators of miR-34a, mainly including transcription factors (TFs), lncRNAs, and DNA methylation, will be summarized. Meanwhile, the potential TF upstream of miR-34a/b/c will be predicted by PROMO, JASPAR, Animal TFDB 3.0, and GeneCard databases. Notably, miR-34a is an attractive target for certain cancers. In fact, miR-34a-based systemic delivery combined with chemotherapy or radiotherapy can more effectively control tumor progression. Collectively, this review will provide a panorama for miR-34a in cancer research.
Collapse
Affiliation(s)
- Sijing Li
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
| | - Xiaohui Wei
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Jinyong He
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
- China Cell-Gene Therapy Translational Medicine Research Center, Biotherapy Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China
- School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China
| | - Quanquan Cao
- MARBEC, Université Montpellier, UM-CNRS-IRD-IFREMER, cc 092, Place E. Bataillon, 34095, Montpellier Cedex 05, France
| | - Danyu Du
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
| | - Xiaoman Zhan
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
| | - Yuqi Zeng
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China
| | - Shengtao Yuan
- Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.
| | - Li Sun
- New Drug Screening Center, China Pharmaceutical University, Nanjing, 210009, China.
| |
Collapse
|
|
37
|
Kumar S, Ashraf MU, Kumar A, Bae YS. Therapeutic Potential of microRNA Against Th2-associated Immune Disorders. Curr Top Med Chem 2021; 21:753-766. [PMID: 33655864 DOI: 10.2174/1568026621666210303150235] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 11/17/2020] [Accepted: 11/28/2020] [Indexed: 11/22/2022]
Abstract
MicroRNAs (miRNAs) are short ~18-22 nucleotide, single-stranded, non-coding RNA molecules playing a crucial role in regulating diverse biological processes and are frequently dysregulated during disease pathogenesis. Thus, targeting miRNA could be a potential candidate for therapeutic invention. This systemic review aims to summarize our current understanding regarding the role of miRNAs associated with Th2-mediated immune disorders and strategies for therapeutic drug development and current clinical trials.
Collapse
Affiliation(s)
- Sunil Kumar
- Department of Biological Sciences, Science Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan University, Jangan-gu, Suwon, Gyeonggi-do 16419, South Korea
| | - Muhammad Umer Ashraf
- Department of Biological Sciences, Science Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan University, Jangan-gu, Suwon, Gyeonggi-do 16419, South Korea
| | - Anil Kumar
- Amity Institute of Biotechnology, Amity University Haryana, Amity Education Valley, Gurugram-122413, India
| | - Yong-Soo Bae
- Department of Biological Sciences, Science Research Center (SRC) for Immune Research on Non-lymphoid Organ (CIRNO), Sungkyunkwan University, Jangan-gu, Suwon, Gyeonggi-do 16419, South Korea
| |
Collapse
|
|
38
|
Chakraborty C, Sharma AR, Sharma G, Lee SS. Therapeutic advances of miRNAs: A preclinical and clinical update. J Adv Res 2021; 28:127-138. [PMID: 33364050 PMCID: PMC7753224 DOI: 10.1016/j.jare.2020.08.012] [Citation(s) in RCA: 264] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 06/10/2020] [Accepted: 08/17/2020] [Indexed: 12/15/2022] Open
Abstract
miRNAs, a class of small endogenous RNAs, are one of the essential biopharmaceuticals which are in commercial spans as next-generation medicine in recent times. A snapshot of the current scenario regarding the miRNAs as biopharmaceuticals have been discussed. In this work, biopharmaceutical companies working with miRNAs and the current status of preclinical/clinical trials about miRNA therapeutics have been reviewed. Finally, recent updates on the absorption, distribution, metabolism, and excretion (ADME), as well as a delivery system of miRNAs, have been illustrated.
Collapse
Affiliation(s)
- Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Barasat-Barrackpore Rd, Kolkata, West Bengal 700126, India
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, Gangwon-Do 24252, Republic of Korea
| | - Ashish Ranjan Sharma
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, Gangwon-Do 24252, Republic of Korea
| | - Garima Sharma
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Sang-Soo Lee
- Institute for Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, Gangwon-Do 24252, Republic of Korea
| |
Collapse
|
|
39
|
Translational control of enzyme scavenger expression with toxin-induced micro RNA switches. Sci Rep 2021; 11:2462. [PMID: 33510250 PMCID: PMC7844233 DOI: 10.1038/s41598-021-81679-6] [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: 09/03/2020] [Accepted: 01/08/2021] [Indexed: 12/19/2022] Open
Abstract
Biological computation requires in vivo control of molecular behavior to progress development of autonomous devices. miRNA switches represent excellent, easily engineerable synthetic biology tools to achieve user-defined gene regulation. Here we present the construction of a synthetic network to implement detoxification functionality. We employed a modular design strategy by engineering toxin-induced control of an enzyme scavenger. Our miRNA switch results show moderate synthetic expression control over a biologically active detoxification enzyme molecule, using an established design protocol. However, following a new design approach, we demonstrated an evolutionarily designed miRNA switch to more effectively activate enzyme activity than synthetically designed versions, allowing markedly improved extrinsic user-defined control with a toxin as inducer. Our straightforward new design approach is simple to implement and uses easily accessible web-based databases and prediction tools. The ability to exert control of toxicity demonstrates potential for modular detoxification systems that provide a pathway to new therapeutic and biocomputing applications.
Collapse
|
|
40
|
Saini V, Dawar R, Suneja S, Gangopadhyay S, Kaur C. Can microRNA become next-generation tools in molecular diagnostics and therapeutics? A systematic review. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2021. [DOI: 10.1186/s43042-020-00125-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Abstract
Background
MicroRNAs (miRNAs) represent a novel class of single-stranded RNA molecules of 18–22 nucleotides that serve as powerful tools in the regulation of gene expression. They are important regulatory molecules in several biological processes.
Main body
Alteration in the expression profiles of miRNAs have been found in several diseases. It is anticipated that miRNA expression profiling can become a novel diagnostic tool in the future.
Hence, this review evaluates the implications of miRNAs in various diseases and the recent advances in miRNA expression level detection and their target identification. A systematic approach to review existing literature available on databases such as Medline, PubMed, and EMBASE was conducted to have a better understanding of mechanisms mediating miRNA-dependent gene regulation and their role as diagnostic markers and therapeutic agents.
Conclusion
A clear understanding of the complex multilevel regulation of miRNA expression is a prerequisite to explicate the origin of a wide variety of diseases. It is understandable that miRNAs offer potential targets both in diagnostics and therapeutics of a multitude of diseases. The inclusion of specific miRNA expression profiles as biomarkers may lead to crucial advancements in facilitating disease diagnosis and classification, monitoring its prognosis, and treatment. However, standardization of methods has a pivotal role in the success of extensive use of miRNA expression profiling in routine clinical settings.
Collapse
|
|
41
|
Toden S, Zumwalt TJ, Goel A. Non-coding RNAs and potential therapeutic targeting in cancer. Biochim Biophys Acta Rev Cancer 2021; 1875:188491. [PMID: 33316377 PMCID: PMC7856203 DOI: 10.1016/j.bbcan.2020.188491] [Citation(s) in RCA: 162] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 12/02/2020] [Accepted: 12/02/2020] [Indexed: 12/11/2022]
Abstract
Recent advances have begun to clarify the physiological and pathological roles of non-coding RNAs (ncRNAs) in various diseases, including cancer. Among these, microRNAs (miRNAs) have been the most studied and have emerged as key players that are involved in the regulation of important growth regulatory pathways in cancer pathogenesis. The ability of a single ncRNA to modulate the expression of multiple downstream gene targets and associated pathways, have provided a rationale to pursue them for therapeutic drug development in cancer. In this context, early data from pre-clinical studies have demonstrated that synthetic miRNA-based therapeutic molecules, along with various protective coating approaches, has allowed for their efficient delivery and anti-tumor activity. In fact, some of the miRNA-based cancer therapeutic strategies have shown promising results even in early-phase human clinical trials. While the enthusiasm for ncRNA-based cancer therapeutics continue to evolve, the field is still in the midst of unraveling a more precise understanding of the molecular mechanisms and specific downstream therapeutic targets of other lesser studied ncRNAs such as the long-non-coding RNAs, transfer RNAs, circular RNAs, small nucleolar RNAs, and piwi-interacting RNAs. This review article provides the current state of knowledge and the evolving principles for ncRNA-based therapeutic approaches in cancer, and specifically highlights the importance of data to date and the approaches that are being developed to overcome the challenges associated with their delivery and mitigating the off-target effects in human cancers.
Collapse
Affiliation(s)
- Shusuke Toden
- Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
| | - Timothy J Zumwalt
- Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
| | - Ajay Goel
- Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA; Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
| |
Collapse
|
|
42
|
Potter ML, Hill WD, Isales CM, Hamrick MW, Fulzele S. MicroRNAs are critical regulators of senescence and aging in mesenchymal stem cells. Bone 2021; 142:115679. [PMID: 33022453 PMCID: PMC7901145 DOI: 10.1016/j.bone.2020.115679] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 07/16/2020] [Accepted: 07/28/2020] [Indexed: 01/10/2023]
Abstract
MicroRNAs (miRNAs) have recently come under scrutiny for their role in various age-related diseases. Similarly, cellular senescence has been linked to disease and aging. MicroRNAs and senescence likely play an intertwined role in driving these pathologic states. In this review, we present the connection between these two drivers of age-related disease concerning mesenchymal stem cells (MSCs). First, we summarize key miRNAs that are differentially expressed in MSCs and other musculoskeletal lineage cells during senescence and aging. Additionally, we also reviewed miRNAs that are regulated via traditional senescence-associated secretory phenotype (SASP) cytokines in MSC. Lastly, we summarize miRNAs that have been found to target components of the cell cycle arrest pathways inherently activated in senescence. This review attempts to highlight potential miRNA targets for regenerative medicine applications in age-related musculoskeletal disease.
Collapse
Affiliation(s)
- Matthew L Potter
- Department of Orthopedics, Augusta University, Augusta, GA, United States of America
| | - William D Hill
- Medical University of South Carolina, Charleston, SC 29403, United States of America; Ralph H Johnson Veterans Affairs Medical Center, Charleston, SC, 29403, United States of America
| | - Carlos M Isales
- Department of Orthopedics, Augusta University, Augusta, GA, United States of America; Department of Medicine, Augusta University, Augusta, GA, United States of America; Institute of Healthy Aging, Augusta University, Augusta, GA, United States of America
| | - Mark W Hamrick
- Department of Orthopedics, Augusta University, Augusta, GA, United States of America; Institute of Healthy Aging, Augusta University, Augusta, GA, United States of America; Department of Cell Biology and Anatomy, Augusta University, Augusta, GA, United States of America
| | - Sadanand Fulzele
- Department of Orthopedics, Augusta University, Augusta, GA, United States of America; Department of Medicine, Augusta University, Augusta, GA, United States of America; Institute of Healthy Aging, Augusta University, Augusta, GA, United States of America; Department of Cell Biology and Anatomy, Augusta University, Augusta, GA, United States of America.
| |
Collapse
|
|
43
|
Zhang S, Gong Y, Li C, Yang W, Li L. Beyond regulations at DNA levels: A review of epigenetic therapeutics targeting cancer stem cells. Cell Prolif 2020; 54:e12963. [PMID: 33314500 PMCID: PMC7848960 DOI: 10.1111/cpr.12963] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 11/10/2020] [Accepted: 11/12/2020] [Indexed: 02/05/2023] Open
Abstract
In the past few years, the paramount role of cancer stem cells (CSCs), in terms of cancer initiation, proliferation, metastasis, invasion and chemoresistance, has been revealed by accumulating studies. However, this level of cellular plasticity cannot be entirely explained by genetic mutations. Research on epigenetic modifications as a complementary explanation for the properties of CSCs has been increasing over the past several years. Notably, therapeutic strategies are currently being developed in an effort to reverse aberrant epigenetic alterations using specific chemical inhibitors. In this review, we summarize the current understanding of CSCs and their role in cancer progression, and provide an overview of epigenetic alterations seen in CSCs. Importantly, we focus on primary cancer therapies that target the epigenetic modification of CSCs by the use of specific chemical inhibitors, such as histone deacetylase (HDAC) inhibitors, DNA methyltransferase (DNMT) inhibitors and microRNA‐based (miRNA‐based) therapeutics.
Collapse
Affiliation(s)
- Shunhao Zhang
- State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Disease, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Sichuan Province, Chengdu, China
| | - Yanji Gong
- State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Disease, Department of Temporomandibular Joint, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan Province, China.,State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Disease, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan Province, China
| | - Chunjie Li
- State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Disease, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan Province, China
| | - Wenbin Yang
- State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Disease, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Sichuan Province, Chengdu, China
| | - Longjiang Li
- State Key Laboratory of Oral Disease, National Clinical Research Center for Oral Disease, Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan Province, China
| |
Collapse
|
|
44
|
Kimna C, Lieleg O. Molecular micromanagement: DNA nanotechnology establishes spatio-temporal control for precision medicine. BIOPHYSICS REVIEWS 2020; 1:011305. [PMID: 38505628 PMCID: PMC10903406 DOI: 10.1063/5.0033378] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 12/08/2020] [Indexed: 03/21/2024]
Abstract
Current advances in DNA nanotechnology pinpoint exciting perspectives for the design of customized, patient-specific treatments. This advance is made possible by the exceptionally high precision and specificity that are typical for DNA base pairing on the one hand and our growing ability to harness those features in synthetic, DNA-based constructs on the other hand. Modern medicine may soon benefit from recent developments in this field, especially regarding the targeted delivery of drugs and the rational interference of synthetic DNA strands with cellular oligonucleotides. In this Review, we summarize selected examples from the area of DNA nanotechnology, where the development of precisely controlled, advanced functional mechanisms was achieved. To demonstrate the high versatility of these rationally designed structures, we categorize the dynamic DNA-based materials suggested for precision medicine according to four fundamental tasks: "hold & release," "heal," "detect & measure," as well as "guide & direct." In all the biomedical applications we highlight, DNA strands not only constitute structural building blocks but allow for creating stimuli-responsive objects, serve as an active cargo, or act as molecular control/guidance tools. Moreover, we discuss several issues that need to be considered when DNA-based structures are designed for applications in the field of precision medicine. Even though the majority of DNA-based objects have not been used in clinical settings yet, recent progress regarding the stability, specificity, and control over the dynamic behavior of synthetic DNA structures has advanced greatly. Thus, medical applications of those nanoscopic objects should be feasible in the near future.
Collapse
|
|
45
|
Yu AM, Choi YH, Tu MJ. RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges. Pharmacol Rev 2020; 72:862-898. [PMID: 32929000 PMCID: PMC7495341 DOI: 10.1124/pr.120.019554] [Citation(s) in RCA: 226] [Impact Index Per Article: 45.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.
Collapse
MESH Headings
- Aptamers, Nucleotide/pharmacology
- Aptamers, Nucleotide/therapeutic use
- Betacoronavirus
- COVID-19
- Chemistry Techniques, Analytical/methods
- Chemistry Techniques, Analytical/standards
- Clustered Regularly Interspaced Short Palindromic Repeats
- Coronavirus Infections/drug therapy
- Drug Delivery Systems/methods
- Drug Development/organization & administration
- Drug Discovery
- Humans
- MicroRNAs/pharmacology
- MicroRNAs/therapeutic use
- Oligonucleotides, Antisense/pharmacology
- Oligonucleotides, Antisense/therapeutic use
- Pandemics
- Pneumonia, Viral/drug therapy
- RNA/adverse effects
- RNA/drug effects
- RNA/pharmacology
- RNA, Antisense/pharmacology
- RNA, Antisense/therapeutic use
- RNA, Messenger/drug effects
- RNA, Messenger/pharmacology
- RNA, Ribosomal/drug effects
- RNA, Ribosomal/pharmacology
- RNA, Small Interfering/pharmacology
- RNA, Small Interfering/therapeutic use
- RNA, Viral/drug effects
- Ribonucleases/metabolism
- Riboswitch/drug effects
- SARS-CoV-2
Collapse
Affiliation(s)
- Ai-Ming Yu
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, California (A.-M.Y., Y.H.C., M.-J.T.) and College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyonggi-do, Republic of Korea (Y.H.C.)
| | - Young Hee Choi
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, California (A.-M.Y., Y.H.C., M.-J.T.) and College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyonggi-do, Republic of Korea (Y.H.C.)
| | - Mei-Juan Tu
- Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, California (A.-M.Y., Y.H.C., M.-J.T.) and College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyonggi-do, Republic of Korea (Y.H.C.)
| |
Collapse
|
|
46
|
Vares G, Ahire V, Sunada S, Ho Kim E, Sai S, Chevalier F, Romeo PH, Yamamoto T, Nakajima T, Saintigny Y. A multimodal treatment of carbon ions irradiation, miRNA-34 and mTOR inhibitor specifically control high-grade chondrosarcoma cancer stem cells. Radiother Oncol 2020; 150:253-261. [PMID: 32717360 DOI: 10.1016/j.radonc.2020.07.034] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 07/20/2020] [Accepted: 07/20/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND PURPOSE High-grade chondrosarcomas are chemo- and radio-resistant cartilage-forming tumors of bone that often relapse and metastase. Thus, new therapeutic strategies are urgently needed. MATERIAL AND METHODS Chondrosarcoma cells (CH-2879) were exposed to carbon-ion irradiation, combined with miR-34 mimic and/or rapamycin administration. The effects of treatment on cancer stem cells, stemness-associated phenotype, radioresistance and tumor-initiating properties were evaluated. RESULTS We show that high-grade chondrosarcoma cells contain a population of radioresistant cancer stem cells that can be targeted by a combination of carbon-ion therapy, miR-34 mimic administration and/or rapamycin treatment that triggers FOXO3 and miR-34 over-expression. mTOR inhibition by rapamycin triggered FOXO3 and miR-34, leading to KLF4 repression. CONCLUSION Our results show that particle therapy combined with molecular treatments effectively controls cancer stem cells and may overcome treatment resistance of high-grade chondrosarcoma.
Collapse
Affiliation(s)
- Guillaume Vares
- Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University (OIST), Japan.
| | - Vidhula Ahire
- Research Laboratory and Open Facility for Radiation Biology with Accelerated Ions (LARIA), CEA/DRF/IBFJ/IRCM, Caen, France; Centre de Recherche sur les Ions, les Matériaux et la Photonique (CIMAP), Normandie Univ/ENSICAEN/UNICAEN/CEA/CNRS, Caen, France
| | - Shigeaki Sunada
- Department of Radiation Effects Research, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan; Department of Molecular Genetics, Tokyo Medical and Dental University (TMDU), Japan
| | - Eun Ho Kim
- Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, South Korea
| | - Sei Sai
- Department of Charged Particle Therapy Research, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan
| | - François Chevalier
- Research Laboratory and Open Facility for Radiation Biology with Accelerated Ions (LARIA), CEA/DRF/IBFJ/IRCM, Caen, France; Centre de Recherche sur les Ions, les Matériaux et la Photonique (CIMAP), Normandie Univ/ENSICAEN/UNICAEN/CEA/CNRS, Caen, France
| | - Paul-Henri Romeo
- Research Laboratory on Repair and Transcription in Hematopoietic Stem Cells (LRTS), François Jacob Institute of Biology, CEA/DRF/IBFJ/IRCM, Fontenay-aux-Roses, France
| | - Tadashi Yamamoto
- Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University (OIST), Japan
| | - Tetsuo Nakajima
- Department of Radiation Effects Research, National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan
| | - Yannick Saintigny
- Research Laboratory and Open Facility for Radiation Biology with Accelerated Ions (LARIA), CEA/DRF/IBFJ/IRCM, Caen, France; Centre de Recherche sur les Ions, les Matériaux et la Photonique (CIMAP), Normandie Univ/ENSICAEN/UNICAEN/CEA/CNRS, Caen, France.
| |
Collapse
|
|
47
|
Xue VW, Wong SCC, Song G, Cho WCS. Promising RNA-based cancer gene therapy using extracellular vesicles for drug delivery. Expert Opin Biol Ther 2020; 20:767-777. [PMID: 32125904 DOI: 10.1080/14712598.2020.1738377] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 03/02/2020] [Indexed: 12/21/2022]
Abstract
INTRODUCTION RNA-based cancer gene therapy shows potential in cancer treatment. However, the safe and efficient transfer of therapeutic RNA to target cells has always been a challenge. The ideal drug delivery system should be effective with low immunogenicity and toxicity. Besides, a high specificity of drug delivery is necessary to improve efficacy and avoid the side effects associated with tumor heterogeneity. As endogenous RNA vehicles, extracellular vesicles (EVs) have shown their advantages and potential as drug delivery systems in gene therapy. AREAS COVERED We summarize the performance of EVs as a drug delivery system in RNA-based cancer gene therapy and discuss the advantages, limitations, and potentials of this translational medicine. In addition, we compare the characteristics and differences of current drug delivery systems and expound the principles of selecting a drug delivery system suitable for cancer gene therapy. EXPERT OPINION EVs are highly biocompatible membrane structures with low cytotoxicity which provide a new choice for drug delivery in RNA-based cancer gene therapy. The specificity of engineered EVs and artificial EV-mimetics can be improved through peptide or polymer decoration. However, apart from therapeutic RNA, EVs naturally carry many molecules. This may lead to unpredictable effects and thus should be applied with caution.
Collapse
Affiliation(s)
- Vivian Weiwen Xue
- Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong , Kowloon, Hong Kong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
| | - Sze Chuen Cesar Wong
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University , Kowloon, Hong Kong
| | - Guoqi Song
- Department of Hematology, Affiliated Hospital of Nantong University , Nantong, China
| | | |
Collapse
|
|
48
|
miR-331-3p Inhibits Inflammatory Response after Intracerebral Hemorrhage by Directly Targeting NLRP6. BIOMED RESEARCH INTERNATIONAL 2020; 2020:6182464. [PMID: 32596340 PMCID: PMC7298275 DOI: 10.1155/2020/6182464] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 05/18/2020] [Indexed: 01/02/2023]
Abstract
Background The mechanism of inflammatory reaction after intracerebral hemorrhage remains unclear, which to some extent restrains the therapeutic development of hemorrhagic stroke. The present study attempts to verify whether NLRP6 plays an important role in inflammatory reaction after intracerebral hemorrhage and identify the critical microRNA during the process. Methods Suitable simulated cerebral hemorrhage environments were established in vitro and in vivo. BV2 cells were treated with hemin to induce cell damage. Collagenase was used to establish a model of mouse cerebral hemorrhage. The relationship among NLRP6, miR-331-3p, and the corresponding inflammatory expression was closely observed during this process. Techniques, such as western blot, real-time quantitative PCR, immunofluorescence, and immunocytochemistry, were used to detect the expression of relative genes and molecules in the in vitro and in vivo models. Results Downregulated miR-331-3p increased the expression of NLRP6 and alleviated the expression of TNF-α and IL-6. The neurological function recovery of mice was promoted after intracerebral hemorrhage. Conclusion miR-331-3p regulated the inflammatory response after cerebral hemorrhage by negatively regulating the expression of NLRP6.
Collapse
|
|
49
|
Barzaman K, Karami J, Zarei Z, Hosseinzadeh A, Kazemi MH, Moradi-Kalbolandi S, Safari E, Farahmand L. Breast cancer: Biology, biomarkers, and treatments. Int Immunopharmacol 2020; 84:106535. [PMID: 32361569 DOI: 10.1016/j.intimp.2020.106535] [Citation(s) in RCA: 403] [Impact Index Per Article: 80.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 04/20/2020] [Accepted: 04/20/2020] [Indexed: 02/07/2023]
Abstract
During the past recent years, various therapies emerged in the era of breast cancer. Breast cancer is a heterogeneous disease in which genetic and environmental factors are involved. Breast cancer stem cells (BCSCs) are the main player in the aggressiveness of different tumors and also, these cells are the main challenge in cancer treatment. Moreover, the major obstacle to achieve an effective treatment is resistance to therapies. There are various types of treatment for breast cancer (BC) patients. Therefore, in this review, we present the current treatments, novel approaches such as antibody-drug conjugation systems (ADCs), nanoparticles (albumin-, metal-, lipid-, polymer-, micelle-based nanoparticles), and BCSCs-based therapies. Furthermore, prognostic and predictive biomarkers will be discussed also biomarkers that have been applied by some tests such as Oncotype DX, Mamm αPrint, and uPA/PAI-1 are regarded as suitable prognostic and predictive factors in breast cancer.
Collapse
Affiliation(s)
- Khadijeh Barzaman
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Jafar Karami
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Zeinab Zarei
- Department of Biomaterials and Tissue Engineering, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Aysooda Hosseinzadeh
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Mohammad Hossein Kazemi
- Student Research Committee, Department of Immunology, School of Medicine, Iran University of Medical Science, Tehran, Iran; ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Shima Moradi-Kalbolandi
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Elahe Safari
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran.
| | - Leila Farahmand
- Recombinant Proteins Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran.
| |
Collapse
|
|
50
|
Kong J, Wang W. A Systemic Review on the Regulatory Roles of miR-34a in Gastrointestinal Cancer. Onco Targets Ther 2020; 13:2855-2872. [PMID: 32308419 PMCID: PMC7138617 DOI: 10.2147/ott.s234549] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 12/22/2019] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of endogenous non-coding single-stranded small-molecule RNAs that regulate gene expression by repressing target messenger RNA (mRNA) translation or degrading mRNA. miR-34a is one of the most important miRNAs participating in various physiological and pathological processes. miR-34a is abnormally expressed in a variety of tumors. The roles of miR-34a in gastrointestinal cancer (GIC) draw lots of attention. Numerous studies have demonstrated that dysregulated miR-34a is closely related to the proliferation, differentiation, migration, and invasion of tumor cells, as well as the diagnosis, prognosis, treatment, and chemo-resistance of tumors. Thus, we systematically reviewed the abnormal expression and regulatory roles of miR-34a in GICs including esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), pancreatic cancer (PC), and gallbladder cancer (GBC). It may provide a profile of versatile roles of miR-34a in GICs.
Collapse
Affiliation(s)
- Jiehong Kong
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China
| | - Weipeng Wang
- Center for Drug Metabolism and Pharmacokinetics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China
| |
Collapse
|