|
1
|
Foutadakis S, Soureas K, Roupakia E, Besta S, Avgeris M, Kolettas E. Identification of Oncogene-Induced Senescence-Associated MicroRNAs. Methods Mol Biol 2025; 2906:189-213. [PMID: 40082357 DOI: 10.1007/978-1-0716-4426-3_11] [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] [Indexed: 03/16/2025]
Abstract
Cellular senescence, a state of permanent cell cycle arrest, recapitulates the aging process at the cellular level. It can be triggered by intrinsic or extrinsic factors including telomere shortening (replicative senescence) and in response to various types of stresses such as oncogenic stress (oncogene-induced senescence, OIS). Senescence has been detected in vitro and in premalignant lesions in mice and humans expressing mutant oncogenes. MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression at the posttranscriptional level, and have been involved in both replicative senescence and OIS. Several methods have been used to identify miRNAs and compare their expression in normal versus oncogene-induced senescent cells, as well as to analyze their role and their targets in senescence. Here, we describe several methods that can be employed to identify miRNAs in cells undergoing OIS, including miRNA-sequencing, RT-qPCR-based detection and quantification of miRNAs and Nanostring miRNA analysis (nCounter miRNA Expression Assay). Moreover, we perform a meta-analysis of studies employing the above methodologies, pinpoint miRNAs with consistent expression changes across senescence models, and predict their target genes and the pathways in which they partake.
Collapse
Affiliation(s)
- Spyros Foutadakis
- Center of Basic Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece
- Hellenic Institute for the Study of Sepsis, Athens, Greece
| | - Konstantinos Soureas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
- Laboratory of Clinical Biochemistry-Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, 'P. & A. Kyriakou' Children's Hospital, Athens, Greece
| | - Eugenia Roupakia
- Laboratory of Biology, School of Medicine, Faculty of Health Sciences, and Institute of Biosciences, Centre for Research and Innovation, University of Ioannina, Ioannina, Greece
- Molecular Cancer Biology & Senescence Group, Biomedical Research Institute, Foundation for Research and Technology, Ioannina, Greece
| | - Simoni Besta
- Laboratory of Biology, School of Medicine, Faculty of Health Sciences, and Institute of Biosciences, Centre for Research and Innovation, University of Ioannina, Ioannina, Greece
- Molecular Cancer Biology & Senescence Group, Biomedical Research Institute, Foundation for Research and Technology, Ioannina, Greece
- International Oncology Institute, The first affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Margaritis Avgeris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece
- Laboratory of Clinical Biochemistry-Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, 'P. & A. Kyriakou' Children's Hospital, Athens, Greece
| | - Evangelos Kolettas
- Laboratory of Biology, School of Medicine, Faculty of Health Sciences, and Institute of Biosciences, Centre for Research and Innovation, University of Ioannina, Ioannina, Greece.
- Molecular Cancer Biology & Senescence Group, Biomedical Research Institute, Foundation for Research and Technology, Ioannina, Greece.
| |
Collapse
|
|
2
|
Shankar N, Nath U. Advantage looping: Gene regulatory circuits between microRNAs and their target transcription factors in plants. PLANT PHYSIOLOGY 2024; 196:2304-2319. [PMID: 39230893 DOI: 10.1093/plphys/kiae462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 08/14/2024] [Accepted: 08/14/2024] [Indexed: 09/05/2024]
Abstract
The 20 to 24 nucleotide microRNAs (miRNAs) and their target transcription factors (TF) have emerged as key regulators of diverse processes in plants, including organ development and environmental resilience. In several instances, the mature miRNAs degrade the TF-encoding transcripts, while their protein products in turn bind to the promoters of the respective miRNA-encoding genes and regulate their expression, thus forming feedback loops (FBLs) or feedforward loops (FFLs). Computational analysis suggested that such miRNA-TF loops are recurrent motifs in gene regulatory networks (GRNs) in plants as well as animals. In recent years, modeling and experimental studies have suggested that plant miRNA-TF loops in GRNs play critical roles in driving organ development and abiotic stress responses. Here, we discuss the miRNA-TF FBLs and FFLs that have been identified and studied in plants over the past decade. We then provide some insights into the possible roles of such motifs within GRNs. Lastly, we provide perspectives on future directions for dissecting the functions of miRNA-centric GRNs in plants.
Collapse
Affiliation(s)
- Naveen Shankar
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India
| | - Utpal Nath
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru 560012, India
| |
Collapse
|
|
3
|
Ladurner M, Lindner AK, Rehder P, Tulchiner G. The influence of sex hormones on renal cell carcinoma. Ther Adv Med Oncol 2024; 16:17588359241269664. [PMID: 39175990 PMCID: PMC11339752 DOI: 10.1177/17588359241269664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 06/25/2024] [Indexed: 08/24/2024] Open
Abstract
Kidney cancer is a common malignancy that constitutes around 5% of all cancer cases. Males are twice as likely to acquire renal cell carcinoma (RCC) compared to females and experience a higher rate of mortality. These disparities indicate that sex hormone (SH)-dependent pathways may have an impact on the aetiology and pathophysiology of RCC. Examination of SH involvement in conventional signalling pathways, as well as genetics and genomics, especially the involvement of ribonucleic acid, reveal further insights into sex-related differences. An understanding of SHs and their influence on kidney cancer is essential to offer patients individualized medicine that would better meet their needs in terms of prevention, diagnosis and treatment. This review presents the understanding of sex-related differences in the clinical manifestation of kidney cancer patients and the underlying biological processes.
Collapse
Affiliation(s)
- Michael Ladurner
- Department of Urology, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Peter Rehder
- Department of Urology, Medical University of Innsbruck, Innsbruck, Austria
| | - Gennadi Tulchiner
- Department of Urology, Medical University of Innsbruck, Anichstrasse 35, Innsbruck 6020, Austria
| |
Collapse
|
|
4
|
Przybyszewski O, Mik M, Nowicki M, Kusiński M, Mikołajczyk-Solińska M, Śliwińska A. Using microRNAs Networks to Understand Pancreatic Cancer-A Literature Review. Biomedicines 2024; 12:1713. [PMID: 39200178 PMCID: PMC11351910 DOI: 10.3390/biomedicines12081713] [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: 05/30/2024] [Revised: 07/26/2024] [Accepted: 07/28/2024] [Indexed: 09/02/2024] Open
Abstract
Pancreatic cancer is a severe disease, challenging to diagnose and treat, and thereby characterized by a poor prognosis and a high mortality rate. Pancreatic ductal adenocarcinoma (PDAC) represents approximately 90% of pancreatic cancer cases, while other cases include neuroendocrine carcinoma. Despite the growing knowledge of the pathophysiology of this cancer, the mortality rate caused by it has not been effectively reduced. Recently, microRNAs have aroused great interest among scientists and clinicians, as they are negative regulators of gene expression, which participate in many processes, including those related to the development of pancreatic cancer. The aim of this review is to show how microRNAs (miRNAs) affect key signaling pathways and related cellular processes in pancreatic cancer development, progression, diagnosis and treatment. We included the results of in vitro studies, animal model of pancreatic cancer and those performed on blood, saliva and tumor tissue isolated from patients suffering from PDAC. Our investigation identified numerous dysregulated miRNAs involved in KRAS, JAK/STAT, PI3/AKT, Wnt/β-catenin and TGF-β signaling pathways participating in cell cycle control, proliferation, differentiation, apoptosis and metastasis. Moreover, some miRNAs (miRNA-23a, miRNA-24, miRNA-29c, miRNA-216a) seem to be engaged in a crosstalk between signaling pathways. Evidence concerning the utility of microRNAs in the diagnosis and therapy of this cancer is poor. Therefore, despite growing knowledge of the involvement of miRNAs in several processes associated with pancreatic cancer, we are beginning to recognize and understand their role and usefulness in clinical practice.
Collapse
Affiliation(s)
- Oskar Przybyszewski
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland
| | - Michał Mik
- Department of General and Colorectal Surgery, Medical University of Lodz, 113 Stefana Żeromskiego St., 90-549 Lodz, Poland; (M.M.); (M.N.)
| | - Michał Nowicki
- Department of General and Colorectal Surgery, Medical University of Lodz, 113 Stefana Żeromskiego St., 90-549 Lodz, Poland; (M.M.); (M.N.)
| | - Michał Kusiński
- Department of Endocrinological, General and Oncological Surgery, Medical University of Lodz, 62 Pabianicka St., 93-513 Lodz, Poland;
| | - Melania Mikołajczyk-Solińska
- Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland;
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska St., 92-213 Lodz, Poland
| |
Collapse
|
|
5
|
ELfieky MMM, Abd El Rahman M, Fayed AM, Haleem Al-Qaim Z, Khalid Aldhalmi A, Ae Badr E, Abdel Aziz A, Ibrahim GMA. Relapse and Survival in Bladder Cancer Patients Undergoing microRNA-129 and microRNA-145 Assays. Asian Pac J Cancer Prev 2024; 25:2113-2121. [PMID: 38918674 PMCID: PMC11382840 DOI: 10.31557/apjcp.2024.25.6.2113] [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: 02/01/2024] [Indexed: 06/27/2024] Open
Abstract
OBJECTIVE The lack of indicators to measure tumor's invasive biological behavior is an important issue. The aim of this study was to examine the effect of miRNAs 129 and 145 on tumor progression as well as patient survival. METHOD Seventy five breast cancer (BC) patients and 75 controls were included in this research. Two miRNA expressions were estimated using real-time PCR. Biomarkers for BC detection was tested using ROC curves and AUC. RESULT miR-129 and miR-145 expressions were significant. miR-129 and miR-145 classifiers (AUC = 0.943 and 0.748, respectively) help diagnose BC. Unlike miR-145, miR-129 did not affect the Kaplan-Meier survival curve analysis for progression-free survival at the end of the trial. The development of transitional cell carcinoma disease was found to have a strong correlation with miR-145 in both univariate and multivariate Cox regression analyses. Additionally, infiltrating + invasive urothelial carcinoma was also found to be correlated with miR-145. Conversely, elevated miR-129 expression in BC patients did not lead to an increase in cancer-specific recurrence or mortality, as observed in both univariate and multivariate Cox regression studies. CONCLUSION The miRNA signature can help detect survival-associated miRNAs and develop BC miRNA therapeutics.
Collapse
Affiliation(s)
- Mostafa M M ELfieky
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Egypt
| | - Mohamed Abd El Rahman
- College of Pharmacy, Al-Mustaqbal University, Babylon, 51001, Iraq
- Clinical Pharmacy Department, Badr University Hospital, Faculty of Medicine, Helwan University, Egypt
| | - Aysam M Fayed
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Egypt
- Medical Laboratory Techniques Department, College of Health and Medical Technique, Al-Mustaqbal University, Babylon,51001, Iraq
| | | | | | - Eman Ae Badr
- Medical Biochemistry and Molecular Biology, Faculty of Medicine, Menoufia University, Egypt
| | - Amal Abdel Aziz
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Egypt
| | - Gehan M A Ibrahim
- Molecular Biology Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Egypt
| |
Collapse
|
|
6
|
Usha Satheesan S, Chowdhury S, Kolthur-Seetharam U. Metabolic and circadian inputs encode anticipatory biogenesis of hepatic fed microRNAs. Life Sci Alliance 2024; 7:e202302180. [PMID: 38408795 PMCID: PMC10897495 DOI: 10.26508/lsa.202302180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 02/13/2024] [Accepted: 02/13/2024] [Indexed: 02/28/2024] Open
Abstract
Starvation and refeeding are mostly unanticipated in the wild in terms of duration, frequency, and nutritional value of the refed state. Notwithstanding this, organisms mount efficient and reproducible responses to restore metabolic homeostasis. Hence, it is intuitive to invoke expectant molecular mechanisms that build anticipatory responses to enable physiological toggling during fed-fast cycles. In this regard, we report anticipatory biogenesis of oscillatory hepatic microRNAs that peak during a fed state and inhibit starvation-responsive genes. Our results clearly demonstrate that the levels of primary and precursor microRNA transcripts increase during a fasting state, in anticipation of a fed response. We delineate the importance of both metabolic and circadian cues in orchestrating hepatic fed microRNA homeostasis in a physiological setting. Besides illustrating metabo-endocrine control, our findings provide a mechanistic basis for the overarching influence of starvation on anticipatory biogenesis. Importantly, by using pharmacological agents that are widely used in clinics, we point out the high potential of interventions to restore homeostasis of hepatic microRNAs, whose deregulated expression is otherwise well established to cause metabolic diseases.
Collapse
Affiliation(s)
- Sandra Usha Satheesan
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Shreyam Chowdhury
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
| | - Ullas Kolthur-Seetharam
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
- Tata Institute of Fundamental Research- Hyderabad (TIFR-H), Hyderabad, India
| |
Collapse
|
|
7
|
Mattoo S, Gupta A, Chauhan M, Agrawal A, Pore SK. Prospects and challenges of noncoding-RNA-mediated inhibition of heat shock protein 90 for cancer therapy. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2024; 1867:195006. [PMID: 38218528 DOI: 10.1016/j.bbagrm.2024.195006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 01/06/2024] [Accepted: 01/08/2024] [Indexed: 01/15/2024]
Abstract
Heat Shock Protein 90 (HSP90) is a potential drug target for cancer therapy as it is often dysregulated in several cancers, including lung, breast, pancreatic, and prostate cancers. In cancer, HSP90 fails to maintain the structural and functional integrity of its several client proteins which are involved in the hallmarks of cancer such as cell proliferation, invasion, migration, angiogenesis, and apoptosis. Several small molecule inhibitors of HSP90 have been shown to exhibit anticancer effects in vitro and in vivo animal models. However, a few of them are currently under clinical studies. The status and potential limitations of these inhibitors are discussed here. Studies demonstrate that several noncoding RNAs (ncRNAs) such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) regulate HSP90 and its client proteins to modulate cellular processes to exhibit oncogenic or tumor suppressing properties. Over the last decade, miRNAs and lncRNAs have drawn significant interest from the scientific community as therapeutic agents or targets for clinical applications. Here, we discuss the detailed mechanistic regulation of HSP90 and its client proteins by ncRNAs. Moreover, we highlight the significance of these ncRNAs as potential therapeutic agents/targets, and the challenges associated with ncRNA-based therapies. This article aims to provide a holistic view on HSP90-regulating ncRNAs for the development of novel therapeutic strategies to combat cancer.
Collapse
Affiliation(s)
- Shria Mattoo
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University Uttar Pradesh, Noida 201311, India
| | - Abha Gupta
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University Uttar Pradesh, Noida 201311, India
| | - Manvee Chauhan
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University Uttar Pradesh, Noida 201311, India
| | - Akshi Agrawal
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida 201311, India
| | - Subrata Kumar Pore
- Amity Institute of Molecular Medicine & Stem Cell Research, Amity University Uttar Pradesh, Noida 201311, India.
| |
Collapse
|
|
8
|
Pal A, Ojha A, Ju J. Functional and Potential Therapeutic Implication of MicroRNAs in Pancreatic Cancer. Int J Mol Sci 2023; 24:17523. [PMID: 38139352 PMCID: PMC10744132 DOI: 10.3390/ijms242417523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/01/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
The alarmingly low five-year survival rate for pancreatic cancer presents a global health challenge, contributing to about 7% of all cancer-related deaths. Late-stage diagnosis and high heterogeneity are the biggest hurdles in treating pancreatic cancer. Thus, there is a pressing need to discover novel biomarkers that could help in early detection as well as improve therapeutic strategies. MicroRNAs (miRNAs), a class of short non-coding RNA, have emerged as promising candidates with regard to both diagnostics and therapeutics. Dysregulated miRNAs play pivotal roles in accelerating tumor growth and metastasis, orchestrating tumor microenvironment, and conferring chemoresistance in pancreatic cancer. The differential expression profiles of miRNAs in pancreatic cancer could be utilized to explore novel therapeutic strategies. In this review, we also covered studies on recent advancements in various miRNA-based therapeutics such as restoring miRNAs with a tumor-suppressive function, suppressing miRNA with an oncogenic function, and combination with chemotherapeutic drugs. Despite several challenges in terms of specificity and targeted delivery, miRNA-based therapies hold the potential to revolutionize the treatment of pancreatic cancer by simultaneously targeting multiple signaling pathways.
Collapse
Affiliation(s)
- Amartya Pal
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; (A.P.); (A.O.)
- Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Anushka Ojha
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; (A.P.); (A.O.)
- Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Jingfang Ju
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; (A.P.); (A.O.)
- The Northport Veteran’s Administration Medical Center, Northport, NY 11768, USA
| |
Collapse
|
|
9
|
Lavacchi D, Polvani S, Taddei A, Scolari F, Messerini L, Caliman E, Moraldi L, Guidolin A, Grazi GL, Galli A, Pillozzi S, Antonuzzo L. KRAS-related miR-143 expression is associated with lymph node involvement and correlates with outcome in pancreatic adenocarcinoma patients. Front Oncol 2023; 13:1295936. [PMID: 38130990 PMCID: PMC10735715 DOI: 10.3389/fonc.2023.1295936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 11/21/2023] [Indexed: 12/23/2023] Open
Abstract
Introduction Pancreatic adenocarcinoma (PC) is one of the most lethal malignancies; even after resection the patients' 5-year disease-free survival (DFS) is lower than 26%. The genetic mutational landscape of PC is dominated by activating KRAS mutations, that have been reported in approximately 90% of cases; however, beyond KRAS - direct mutations, several KRAS-targeting miRNAs appear to be downregulated, strengthening the already activated RAS signaling. In addition, the interplay between miRNAs and RAS includes poorly investigated downstream miRNAs. The aim of this study was to determine the prognostic value of some of these candidate KRAS-related miRNAs. Patients and methods Between 2015 and 2022, 44 patients with pathologically confirmed PC, who received surgery and were enrolled by the Clinical Oncology Unit, Careggi University Hospital, Florence (Italy). PC Total RNA was extracted from FFPE sections, retro-transcribed and the resulting cDNA was then used for qPCR analysis. A panel of KRAS-related miRNA (miR-155, miR-206 and miR-143) was analyzed. Results In this observational study patients sex distribution was unequal with 34.1% being male and 65.9% female. The most frequent tumor localization was the head of the pancreas (65.9%) and the pathological stages were pT1-2 (45.5%), pT3 (54.5%), pN0 (22.7%), pN+ (77.3%). Adjuvant therapy was administered to 63.6% of patients; disease recurrence was observed in 69% of cases. Twenty-three patients, whose RNA was of adequate quality, were used in the mRNAs expression studies. When comparing the miRNA expression between PC and a pool of healthy tissues, miR-155 was overexpressed and miR-206 downregulated in PC, while miR-143 expression was unchanged. However, when categorized in low- and high- miR-143 expressing PC (according to the median value), high miR-143 was associated with nodal involvement (pN+) (p=0.029), who in turn was linked with shorter DFS (p=0.009) and overall survival (OS) (p=0.021) compared to pN0. A trend toward inferior DFS was observed for higher expression of miR-206 (p=0.095) and miR-143 (p=0.092). Finally, responders to a first-line treatment for advanced disease had miR-155 overexpressed (p=0.048). Conclusions miRNAs are involved in PC tumorigenesis and metastatic spread. In light of miR-143 association with lymphatic spread and poor prognosis, a comprehensive analysis of miRNA interplay with KRAS deserves further investigation.
Collapse
Affiliation(s)
- Daniele Lavacchi
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Simone Polvani
- Department of Clinical and Experimental Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Antonio Taddei
- HPB Surgery Unit, Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Federico Scolari
- Department of Health Sciences, University of Florence, Florence, Italy
| | - Luca Messerini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Enrico Caliman
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Luca Moraldi
- HPB Surgery Unit, Careggi University Hospital, Florence, Italy
| | - Alessia Guidolin
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Gian Luca Grazi
- HPB Surgery Unit, Careggi University Hospital, Florence, Italy
| | - Andrea Galli
- Department of Clinical and Experimental Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Serena Pillozzi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Lorenzo Antonuzzo
- Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| |
Collapse
|
|
10
|
Izdebska WM, Daniluk J, Niklinski J. Microbiome and MicroRNA or Long Non-Coding RNA-Two Modern Approaches to Understanding Pancreatic Ductal Adenocarcinoma. J Clin Med 2023; 12:5643. [PMID: 37685710 PMCID: PMC10488817 DOI: 10.3390/jcm12175643] [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: 07/21/2023] [Revised: 08/18/2023] [Accepted: 08/19/2023] [Indexed: 09/10/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of humans' most common and fatal neoplasms. Nowadays, a number of PDAC studies are being conducted in two different fields: non-coding RNA (especially microRNA and long non-coding RNA) and microbiota. It has been recently discovered that not only does miRNA affect particular bacteria in the gut microbiome that can promote carcinogenesis in the pancreas, but the microbiome also has a visible impact on the miRNA. This suggests that it is possible to use the combined impact of the microbiome and noncoding RNA to suppress the development of PDAC. Nevertheless, insufficient research has focused on bounding both approaches to the diagnosis, treatment, and prevention of pancreatic ductal adenocarcinoma. In this article, we summarize the recent literature on the molecular basis of carcinogenesis in the pancreas, the two-sided impact of particular types of non-coding RNA and the pancreatic cancer microbiome, and possible medical implications of the discovered phenomenon.
Collapse
Affiliation(s)
- Wiktoria Maria Izdebska
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Jaroslaw Daniluk
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, 15-089 Bialystok, Poland
| | - Jacek Niklinski
- Department of Clinical Molecular Biology, Medical University of Bialystok, 15-089 Bialystok, Poland
| |
Collapse
|
|
11
|
Xiong B, Huang Q, Zheng H, Lin S, Xu J. Recent advances microRNAs and metabolic reprogramming in colorectal cancer research. Front Oncol 2023; 13:1165862. [PMID: 37576895 PMCID: PMC10415904 DOI: 10.3389/fonc.2023.1165862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 06/07/2023] [Indexed: 08/15/2023] Open
Abstract
Colorectal cancer (CRC) is a cancer with the highest incidence and mortality. Alteration of gene expression is the main pathophysiological mechanism of CRC, which results in disturbed signaling pathways and cellular metabolic processes. MicroRNAs are involved in almost all pathophysiological processes and are correlative with colorectal cancer metabolism, proliferation, and chemotherapy resistance. Metabolic reprogramming, an important feature of cancer, is strongly correlative with the development and prognosis of cancers, including colorectal cancer. MicroRNAs can target enzymes involved in metabolic processes, thus playing a regulatory role in tumor metabolism. The disorder of the signaling pathway is another characteristic of tumor, which induces the occurrence and proliferation of tumors, and is closely correlative with the prognosis and chemotherapy resistance of tumor patients. MicroRNAs can target the components of the signaling pathways to regulate their transduction. Understanding the function of microRNAs in the occurrence and proliferation of CRC provides novel insights into the optimal treatment strategies, prognosis, and development of diagnosis in CRC. This article reviews the relationship between CRC and microRNA expression and hopes to provide new options for the diagnosis and treatment of CRC.
Collapse
Affiliation(s)
- Bin Xiong
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Qiaoyi Huang
- Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Huida Zheng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Shu Lin
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
- Group of Neuroendocrinology, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Jianhua Xu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| |
Collapse
|
|
12
|
Khamis T, Diab AAAA, Zahra MH, El-Dahmy SE, Abd Al-Hameed BA, Abdelkhalek A, Said MA, Abdellatif H, Fericean LM, Banatean-Dunea I, Arisha AH, Attia MS. The Antiproliferative Activity of Adiantum pedatum Extract and/or Piceatannol in Phenylhydrazine-Induced Colon Cancer in Male Albino Rats: The miR-145 Expression of the PI-3K/ Akt/ p53 and Oct4/ Sox2/ Nanog Pathways. Molecules 2023; 28:5543. [PMID: 37513415 PMCID: PMC10383735 DOI: 10.3390/molecules28145543] [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: 06/04/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Colon cancer is one of the most common types of cancer worldwide, and its incidence is increasing. Despite advances in medical science, the treatment of colon cancer still poses a significant challenge. This study aimed to investigate the potential protective effects of Adiantum pedatum (AP) extract and/or piceatannol on colon cancer induced via phenylhydrazine (PHZ) in terms of the antioxidant and apoptotic pathways and histopathologic changes in the colons of male albino rats. The rats were randomly divided into eight groups: control, AP extract, piceatannol (P), PHZ, PHZ and AP treatments, PHZ and P treatments, PHZ and both AP and P, and PHZ and prophylaxis with both AP and P. The results demonstrated that PHZ induced oxidative damage, apoptosis, and histopathological changes compared to the control group. However, the administration of AP or P or AP + P as therapy or prophylaxis significantly ameliorated these changes and upregulated the colonic mir-145 and mRNA expression of P53 and PDCD-4 while downregulating the colonic mRNA expression of PI3K, AKT, c-Myc, CK-20, SOX-2, OCT-4, and NanoG compared to the PHZ group. These findings suggest that the candidate drugs may exert their anti-cancer effects through multiple mechanisms, including antioxidant and apoptotic activities.
Collapse
Affiliation(s)
- Tarek Khamis
- Department of Pharmacology and Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | | | - Mansour H Zahra
- Zoology Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
| | - Samih Ebrahim El-Dahmy
- Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | | | - Adel Abdelkhalek
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr City 11829, Egypt
| | - Mahmoud A Said
- Zagazig University Hospital, Zagazig University, Zagazig 44511, Egypt
| | - Hussein Abdellatif
- Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman
- Anatomy and Embryology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Liana Mihaela Fericean
- Department of Biology, Faculty of Agriculture, University of Life Sciences, King Mihai I" from Timisoara [ULST], Aradului St. 119, 300645 Timisoara, Romania
| | - Ioan Banatean-Dunea
- Department of Biology, Faculty of Agriculture, University of Life Sciences, King Mihai I" from Timisoara [ULST], Aradului St. 119, 300645 Timisoara, Romania
| | - Ahmed Hamed Arisha
- Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo, Badr City 11829, Egypt
- Department of Physiology, Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Mai S Attia
- Zoology Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
| |
Collapse
|
|
13
|
Martínez-Hernández R, Marazuela M. MicroRNAs in autoimmune thyroid diseases and their role as biomarkers. Best Pract Res Clin Endocrinol Metab 2023; 37:101741. [PMID: 36801129 DOI: 10.1016/j.beem.2023.101741] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level. They are emerging as potential biomarkers and as therapeutic targets for several diseases including autoimmune thyroid diseases (AITD). They control a wide range of biological phenomena, including immune activation, apoptosis, differentiation and development, proliferation and metabolism. This function makes miRNAs attractive as disease biomarker candidates or even as therapeutic agents. Because of their stability and reproducibility circulating miRNAs have been an interesting area of research in many diseases, and studies describing their role in the immune response and in autoimmune diseases have progressively developed. The mechanisms underlying AITD remain elusive. AITD pathogenesis is characterized by a multifactorial interplay based on the synergy between susceptibility genes and environmental stimulation, together with epigenetic modulation. Understanding the regulatory role of miRNAs could lead to identify potential susceptibility pathways, diagnostic biomarkers and therapeutic targets for this disease. Herein we update our present knowledge on the role of microRNAs in AITD and discuss on their importance as possible diagnostic and prognostic biomarkers in the most prevalent AITDs: Hashimoto's thyroiditis (HT), Graves' disease (GD) and Graves' Ophthalmopathy (GO). This review provides an overview of the state of the art in the pathological roles of microRNAs as well as in possible novel miRNA-based therapeutic approaches in AITD.
Collapse
Affiliation(s)
- Rebeca Martínez-Hernández
- Department of Endocrinology, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, C/ Diego de León 62, 28006 Madrid, Spain; Faculty of Medicine, Universidad San Pablo CEU, CEU Universities, Urbanizacion Monteprincipe, Alcorcon, Madrid, Spain.
| | - Mónica Marazuela
- Department of Endocrinology, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, C/ Diego de León 62, 28006 Madrid, Spain.
| |
Collapse
|
|
14
|
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
|
|
15
|
Li H, Jiang Y, Hu J, Xu J, Chen L, Zhang G, Zhao J, Zong S, Guo Z, Li X, Zhao X, Jing Z. The U2AF65/circNCAPG/RREB1 feedback loop promotes malignant phenotypes of glioma stem cells through activating the TGF-β pathway. Cell Death Dis 2023; 14:23. [PMID: 36635261 PMCID: PMC9837049 DOI: 10.1038/s41419-023-05556-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 12/23/2022] [Accepted: 01/04/2023] [Indexed: 01/14/2023]
Abstract
Glioma is the most aggressive and common malignant neoplasms in human brain tumors. Numerous studies have showed that glioma stem cells (GSCs)drive the malignant progression of gliomas. Recent studies have revealed that circRNAs can maintain stemness and promote malignant progression of glioma stem cells. We used bioinformatics analysis to identify circRNAs and potential RNA-binding proteins (RBPs) in glioma. qRT-PCR, western blotting, RNA FISH, RNA pull-down, RNA immunoprecipitation assay, ChIP, immunohistochemistry, and immunofluorescence methods were used to quantified the expression of circNCAPG, U2AF65, RREB1 and TGF-β1, and the underlying mechanisms between them. MTS, EDU, neurosphere formation, limiting dilution neurosphere formation and transwell assays examined the proliferation and invasive capability of GSCs, respectively. We identified a novel circRNA named circNCAPG was overexpressed and indicated the poor prognosis in glioma patients. Upregulating circNCAPG promoted the malignant progression of GSCs. RNA binding protein U2AF65 could stabilize circNCAPG by direct binding. Mechanically, circNCAPG interacted with and stabilized RREB1, as well as stimulated RREB1 nuclear translocation to activate TGF-β1 signaling pathway. Furthermore, RREB1 transcriptionally upregulated U2AF65 expression to improve the stability of circNCAPG in GSCs, which established a feedback loop involving U2AF65, circNCAPG and RREB1. Since circRNA is more stable than mRNA and can execute its function continuously, targeting circNCAPG in glioma may be a novel promising therapeutic.
Collapse
Affiliation(s)
- Hao Li
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, China
| | - Yang Jiang
- Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Jinpeng Hu
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, China
| | - Jinkun Xu
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, China
| | - Lian Chen
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, China
| | - Guoqing Zhang
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, China
| | - Junshuang Zhao
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, China
| | - Shengliang Zong
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, China
| | - Zhengting Guo
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, China
| | - Xinqiao Li
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, China
| | - Xiang Zhao
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, China
| | - Zhitao Jing
- Department of Neurosurgery, The First Hospital of China Medical University, No. 155 North Nanjing Street, Shenyang, 110001, China.
| |
Collapse
|
|
16
|
Sers C, Schäfer R. Silencing effects of mutant RAS signalling on transcriptomes. Adv Biol Regul 2023; 87:100936. [PMID: 36513579 DOI: 10.1016/j.jbior.2022.100936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 11/23/2022] [Indexed: 11/30/2022]
Abstract
Mutated genes of the RAS family encoding small GTP-binding proteins drive numerous cancers, including pancreatic, colon and lung tumors. Besides the numerous effects of mutant RAS gene expression on aberrant proliferation, transformed phenotypes, metabolism, and therapy resistance, the most striking consequences of chronic RAS activation are changes of the genetic program. By performing systematic gene expression studies in cellular models that allow comparisons of pre-neoplastic with RAS-transformed cells, we and others have estimated that 7 percent or more of all transcripts are altered in conjunction with the expression of the oncogene. In this context, the number of up-regulated transcripts approximates that of down-regulated transcripts. While up-regulated transcription factors such as MYC, FOSL1, and HMGA2 have been identified and characterized as RAS-responsive drivers of the altered transcriptome, the suppressed factors have been less well studied as potential regulators of the genetic program and transformed phenotype in the breadth of their occurrence. We therefore have collected information on downregulated RAS-responsive factors and discuss their potential role as tumor suppressors that are likely to antagonize active cancer drivers. To better understand the active mechanisms that entail anti-RAS function and those that lead to loss of tumor suppressor activity, we focus on the tumor suppressor HREV107 (alias PLAAT3 [Phospholipase A and acyltransferase 3], PLA2G16 [Phospholipase A2, group XVI] and HRASLS3 [HRAS-like suppressor 3]). Inactivating HREV107 mutations in tumors are extremely rare, hence epigenetic causes modulated by the RAS pathway are likely to lead to down-regulation and loss of function.
Collapse
Affiliation(s)
- Christine Sers
- Laboratory of Molecular Tumor Pathology and systems Biology, Institute of Pathology, Charité Universitätstmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany; German Cancer Consortium, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany
| | - Reinhold Schäfer
- Comprehensive Cancer Center, Charité Universitätsmedizin Berlin, Charitéplatz 1, D-10117, Berlin, Germany; German Cancer Consortium, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany.
| |
Collapse
|
|
17
|
Varvil MS, Bailey T, Dhawan D, Knapp DW, Ramos-Vara JA, dos Santos AP. The miRNome of canine invasive urothelial carcinoma. Front Vet Sci 2022; 9:945638. [PMID: 36072391 PMCID: PMC9443663 DOI: 10.3389/fvets.2022.945638] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022] Open
Abstract
Urothelial carcinoma (UC) comprises up to 2% of all naturally occurring neoplasia in dogs and can be challenging to diagnose. MicroRNAs (miRNAs) have been reported to be dysregulated in numerous diseases, including neoplasia. MiRNA expression has been evaluated in human UC, but there is limited information regarding the miRNA transcriptome of UC in dogs. Our study aimed to evaluate differential miRNA expression in bladder tissue collected from normal canine urothelium and canine invasive UC (iUC) to elucidate the dysregulated pathways in canine UC. Next-Generation RNA sequencing (RNA-Seq) was performed for dogs with UC (n = 29) and normal canine urothelium (n = 4). Raw RNA data were subjected to normalization, and pairwise comparison was performed using EdgeR with Benjamini-Hochberg FDR multiple testing correction (p < 0.05; >2-fold change) comparing tissue samples of normal urothelium to canine iUC samples. Principal component analysis and hierarchical cluster analysis were performed. MiRNA of FFPE tissue samples of separate iUC (n = 5) and normal urothelium (n = 5) were used to evaluate five miRNAs using RT-qPCR. Pathway analysis was performed utilizing miRWalk, STRING database, and Metascape utilizing KEGG pathways and GO terms databases. Twenty-eight miRNAs were differentially expressed (DE) by RNA-Seq. RT-qPCR confirmed that four miRNAs are significantly downregulated in UC compared to healthy urothelial samples (miR-105a, miR-143, miR-181a, and miR-214). Principal component analysis and hierarchical cluster analysis showed separation between miRNAs in iUC and the control group. The DE miRNAs are most often associated with gene silencing by miRNA, miRNAs in cancer, and miRNAs involved in DNA damage responses. Proteins involved include HRAS, KRAS, ARAF, RAF1, MAPK1, MAP2K1, MAPK3, FGFR3, EGFR, HBEGF, RASSF1, E2F2, E2F3, ERBB2, SRC, MMP1, and UP3KA. The differential expression of miRNAs in canine iUC compared to normal canine urothelial tissue indicates that these markers should be further evaluated for their potential role as diagnostic and therapeutic targets.
Collapse
Affiliation(s)
- Mara S. Varvil
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
| | - Taylor Bailey
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
| | - Deepika Dhawan
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
| | - Deborah W. Knapp
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
- Center for Cancer Research, Purdue University Center for Cancer Research, West Lafayette, IN, United States
| | - José A. Ramos-Vara
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
- Center for Cancer Research, Purdue University Center for Cancer Research, West Lafayette, IN, United States
| | - Andrea P. dos Santos
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
| |
Collapse
|
|
18
|
Rahnama N, Jahangir M, Alesaeid S, Kahrizi MS, Adili A, Mohammed RN, Aslaminabad R, Akbari M, Özgönül AM. Association between microRNAs and chemoresistance in pancreatic cancer: Current knowledge, new insights, and forthcoming perspectives. Pathol Res Pract 2022; 236:153982. [PMID: 35779293 DOI: 10.1016/j.prp.2022.153982] [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: 04/10/2022] [Revised: 05/27/2022] [Accepted: 06/11/2022] [Indexed: 11/25/2022]
Abstract
Pancreatic duct adenocarcinoma, commonly known as pancreatic cancer (PC), is a cancer-related cause of death due to delayed diagnosis, metastasis, and drug resistance. Patients with PC suffer from incorrect responses to chemotherapy due to inherent and acquired chemical resistance. Numerous studies have shown the mechanism of the effect of chemoresistance on PC, such as genetic and epigenetic changes or the elucidation of signaling pathways. In this regard, microRNAs (miRNAs) have been identified as essential modulators of gene expression in various cellular functions, including chemoresistance. Thus, identifying the underlying link between microRNAs and PC chemoresistance helps determine the exact pathogenesis of PC. This study aims to classify miRNAs and signaling pathways related to PC chemoresistance, suggesting new therapeutic approaches to overcome PC chemoresistance.
Collapse
Affiliation(s)
- Negin Rahnama
- Department of Internal Medicine and Health Services, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Samira Alesaeid
- Department of Internal Medicine and Rheumatology, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ali Adili
- Senior Adult Oncology Department, Moffitt Cancer Center, University of South Florida, FL, USA; Department of Oncology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rebar N Mohammed
- Medical Laboratory Analysis Department, College of Health Sciences, Cihan University of Sulaimaniya, Kurdistan Region, Iraq; College of Veterinary Medicine, University of Sulaimani, Sulaimaniyah, Iraq
| | - Ramin Aslaminabad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Akbari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Ali Mert Özgönül
- Department of Biochemistry, Faculty of Medicine, Ege University, Bornova, Izmir, Turkey.
| |
Collapse
|
|
19
|
Reggiardo RE, Maroli SV, Halasz H, Ozen M, Hrabeta-Robinson E, Behera A, Peddu V, Carrillo D, LaMontagne E, Whitehead L, Kim E, Malik S, Fernandes J, Marinov G, Collisson E, Brooks A, Demirci U, Kim DH. Mutant KRAS regulates transposable element RNA and innate immunity via KRAB zinc-finger genes. Cell Rep 2022; 40:111104. [PMID: 35858545 PMCID: PMC9374308 DOI: 10.1016/j.celrep.2022.111104] [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: 11/08/2020] [Revised: 04/04/2022] [Accepted: 06/27/2022] [Indexed: 12/22/2022] Open
Abstract
RAS genes are the most frequently mutated oncogenes in cancer, yet the effects of oncogenic RAS signaling on the noncoding transcriptome remain unclear. We analyzed the transcriptomes of human airway and bronchial epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We find that oncogenic KRAS signaling upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements (TEs). These TE RNAs exhibit differential expression, are preferentially released in extracellular vesicles, and are regulated by KRAB zinc-finger (KZNF) genes, which are broadly downregulated in mutant KRAS cells and lung adenocarcinomas in vivo. Moreover, mutant KRAS induces an intrinsic IFN-stimulated gene (ISG) signature that is often seen across many different cancers. Our results indicate that mutant KRAS remodels the repetitive noncoding transcriptome, demonstrating the broad scope of intracellular and extracellular RNAs regulated by this oncogenic signaling pathway. Many human cancers are driven by mutant KRAS, but its effects on noncoding RNA are unclear. Reggiardo et al. show that mutant KRAS regulates this RNA landscape by silencing KRAB zinc-finger genes that normally repress transposable element noncoding RNAs, which are preferentially released from mutant KRAS cells in extracellular vesicles.
Collapse
Affiliation(s)
- Roman E Reggiardo
- Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Sreelakshmi Velandi Maroli
- Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Haley Halasz
- Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Mehmet Ozen
- Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94305, USA
| | - Eva Hrabeta-Robinson
- Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Amit Behera
- Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Vikas Peddu
- Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - David Carrillo
- Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Erin LaMontagne
- Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Lila Whitehead
- Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Eejung Kim
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Shivani Malik
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Jason Fernandes
- Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Georgi Marinov
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Eric Collisson
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Angela Brooks
- Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Center for Molecular Biology of RNA, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
| | - Utkan Demirci
- Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94305, USA
| | - Daniel H Kim
- Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Canary Center at Stanford for Cancer Early Detection, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94305, USA; Institute for the Biology of Stem Cells, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA; Center for Molecular Biology of RNA, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
| |
Collapse
|
|
20
|
Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression. Cells 2022; 11:cells11142155. [PMID: 35883598 PMCID: PMC9318640 DOI: 10.3390/cells11142155] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 01/27/2023] Open
Abstract
Approximately 90% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is the fourth leading cause of cancer death world-wide. Therapies for PDAC are largely ineffective due to the dense desmoplastic tumor microenvironment which prevents chemotherapeutic drugs and small molecule inhibitors from exerting effective anti-cancer effects. In this review, we will discuss the roles of TP53 and miRs on the PDAC tumor microenvironment and how loss of the normal functions of TP53 promote tumor progression. The TP53 gene is mutated in approximately 50% of pancreatic cancers. Often, these TP53 mutations are point mutations which confer additional functions for the TP53 proteins. These are called gain of function (GOF) mutations (mut). Another class of TP53 mutations are deletions which result in loss of the TP53 protein; these are referred to TP53-null mutations. We have organized this review into various components/properties of the PDAC microenvironment and how they may be altered in the presence of mutant TP53 and loss of certain miR expression.
Collapse
|
|
21
|
Piperigkou Z, Tzaferi K, Makrokanis G, Cheli K, Karamanos NK. The microRNA-cell surface proteoglycan axis in cancer progression. Am J Physiol Cell Physiol 2022; 322:C825-C832. [PMID: 35294845 DOI: 10.1152/ajpcell.00041.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Proteoglycans consist one of the major extracellular matrix class of biomolecules that demonstrate nodal roles in cancer progression. Μodern diagnostic and therapeutic approaches include proteoglycan detection and pharmacological targeting in various cancers. Proteoglycans orchestrate critical signaling pathways for cancer development and progression through dynamic interactions with matrix components. It is well established that the epigenetic signatures of cancer cells play critical role in guiding their functional properties and metastatic potential. Secreted microRNAs (miRNAs) reside in a complex network with matrix proteoglycans, thus affecting cell-cell and cell-matrix communication. This mini-review aims to highlight current knowledge on the proteoglycan-mediated signaling cascades that regulate miRNA biogenesis in cancer. Moreover, the miRNA-mediated proteoglycan regulation during cancer progression and mechanistic aspects on the way that proteoglycans affect miRNA expression are presented. Recent advances on the role of cell surface proteoglycans in exosome biogenesis and miRNA packaging and expression are also discussed.
Collapse
Affiliation(s)
- Zoi Piperigkou
- Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece.,Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras, Greece
| | - Kyriaki Tzaferi
- Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - George Makrokanis
- Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Konsatntina Cheli
- Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece
| | - Nikos K Karamanos
- Biochemical Analysis and Matrix Pathobiology Research Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras, Greece.,Foundation for Research and Technology-Hellas (FORTH)/Institute of Chemical Engineering Sciences (ICE-HT), Patras, Greece
| |
Collapse
|
|
22
|
Epigenetic Regulation: A Link between Inflammation and Carcinogenesis. Cancers (Basel) 2022; 14:cancers14051221. [PMID: 35267528 PMCID: PMC8908969 DOI: 10.3390/cancers14051221] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/17/2022] [Accepted: 02/24/2022] [Indexed: 12/19/2022] Open
Abstract
Simple Summary Epigenetics encompasses all the modifications that occur within cells that are independent of gene mutations. The environment is the main influencer of these alterations. It is well known that a proinflammatory environment can promote and sustain the carcinogenic process and that this environment induces epigenetic alterations. In this review, we will report how a proinflammatory microenvironment that encircles the tumor core can be responsible for the induction of epigenetic drift. Abstract Epigenetics encompasses a group of dynamic, reversible, and heritable modifications that occur within cells that are independent of gene mutations. These alterations are highly influenced by the environment, from the environment that surrounds the human being to the internal microenvironments located within tissues and cells. The ways that pigenetic modifications promote the initiation of the tumorigenic process have been widely demonstrated. Similarly, it is well known that carcinogenesis is supported and prompted by a strong proinflammatory environment. In this review, we introduce our report of a proinflammatory microenvironment that encircles the tumor core but can be responsible for the induction of epigenetic drift. At the same time, cancer cells can alter their epigenetic profile to generate a positive loop in the promotion of the inflammatory process. Therefore, an in-depth understanding of the epigenetic networks between the tumor microenvironment and cancer cells might highlight new targetable mechanisms that could prevent tumor progression.
Collapse
|
|
23
|
Liang C, Huang M, Li T, Li L, Sussman H, Dai Y, Siemann DW, Xie M, Tang X. Towards an integrative understanding of cancer mechanobiology: calcium, YAP, and microRNA under biophysical forces. SOFT MATTER 2022; 18:1112-1148. [PMID: 35089300 DOI: 10.1039/d1sm01618k] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
An increasing number of studies have demonstrated the significant roles of the interplay between microenvironmental mechanics in tissues and biochemical-genetic activities in resident tumor cells at different stages of tumor progression. Mediated by molecular mechano-sensors or -transducers, biomechanical cues in tissue microenvironments are transmitted into the tumor cells and regulate biochemical responses and gene expression through mechanotransduction processes. However, the molecular interplay between the mechanotransduction processes and intracellular biochemical signaling pathways remains elusive. This paper reviews the recent advances in understanding the crosstalk between biomechanical cues and three critical biochemical effectors during tumor progression: calcium ions (Ca2+), yes-associated protein (YAP), and microRNAs (miRNAs). We address the molecular mechanisms underpinning the interplay between the mechanotransduction pathways and each of the three effectors. Furthermore, we discuss the functional interactions among the three effectors in the context of soft matter and mechanobiology. We conclude by proposing future directions on studying the tumor mechanobiology that can employ Ca2+, YAP, and miRNAs as novel strategies for cancer mechanotheraputics. This framework has the potential to bring insights into the development of novel next-generation cancer therapies to suppress and treat tumors.
Collapse
Affiliation(s)
- Chenyu Liang
- Department of Mechanical & Aerospace Engineering, Herbert Wertheim College of Engineering (HWCOE), Gainesville, FL, 32611, USA.
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
| | - Miao Huang
- Department of Mechanical & Aerospace Engineering, Herbert Wertheim College of Engineering (HWCOE), Gainesville, FL, 32611, USA.
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
| | - Tianqi Li
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
- Department of Biochemistry and Molecular Biology, College of Medicine (COM), Gainesville, FL, 32611, USA.
| | - Lu Li
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
- Department of Biochemistry and Molecular Biology, College of Medicine (COM), Gainesville, FL, 32611, USA.
| | - Hayley Sussman
- Department of Radiation Oncology, COM, Gainesville, FL, 32611, USA
| | - Yao Dai
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
- UF Genetics Institute (UFGI), University of Florida (UF), Gainesville, FL, 32611, USA
| | - Dietmar W Siemann
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
- UF Genetics Institute (UFGI), University of Florida (UF), Gainesville, FL, 32611, USA
| | - Mingyi Xie
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
- Department of Biochemistry and Molecular Biology, College of Medicine (COM), Gainesville, FL, 32611, USA.
- Department of Biomedical Engineering, College of Engineering (COE), University of Delaware (UD), Newark, DE, 19716, USA
| | - Xin Tang
- Department of Mechanical & Aerospace Engineering, Herbert Wertheim College of Engineering (HWCOE), Gainesville, FL, 32611, USA.
- UF Health Cancer Center (UFHCC), Gainesville, FL, 32611, USA
| |
Collapse
|
|
24
|
Shui B, La Rocca G, Ventura A, Haigis KM. Interplay between K-RAS and miRNAs. Trends Cancer 2022; 8:384-396. [PMID: 35093302 PMCID: PMC9035052 DOI: 10.1016/j.trecan.2022.01.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/25/2021] [Accepted: 01/03/2022] [Indexed: 02/06/2023]
Abstract
K-RAS is frequently mutated in cancers, and its overactivation can lead to oncogene-induced senescence (OIS), a barrier to cellular transformation. Feedback onto K-RAS limits its signaling to avoid senescence while achieving the appropriate level of activation that promotes proliferation and survival. Such regulation could be mediated by miRNAs, as aberrant RAS signaling and miRNA activity coexist in several cancers, with miRNAs acting both up- and downstream of K-RAS. Several miRNAs both regulate and are regulated by K-RAS, suggesting a noncoding RNA-based feedback mechanism. Functional interactions between K-RAS and the miRNA machinery have also begun to unfold. This review comprehensively surveys the state of knowledge connecting K-RAS to miRNA function and proposes a model for the regulation of K-RAS signaling by noncoding RNAs.
Collapse
|
|
25
|
Chen X, Luo J, Liu J, Chen T, Sun J, Zhang Y, Xi Q. Exploration of the Effect on Genome-Wide DNA Methylation by miR-143 Knock-Out in Mice Liver. Int J Mol Sci 2021; 22:13075. [PMID: 34884879 PMCID: PMC8658369 DOI: 10.3390/ijms222313075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/30/2021] [Accepted: 12/01/2021] [Indexed: 12/12/2022] Open
Abstract
MiR-143 play an important role in hepatocellular carcinoma and liver fibrosis via inhibiting hepatoma cell proliferation. DNA methyltransferase 3 alpha (DNMT3a), as a target of miR-143, regulates the development of primary organic solid tumors through DNA methylation mechanisms. However, the effect of miR-143 on DNA methylation profiles in liver is unclear. In this study, we used Whole-Genome Bisulfite Sequencing (WGBS) to detect the differentially methylated regions (DMRs), and investigated DMR-related genes and their enriched pathways by miR-143. We found that methylated cytosines increased 0.19% in the miR-143 knock-out (KO) liver fed with high-fat diet (HFD), compared with the wild type (WT). Furthermore, compared with the WT group, the CG methylation patterns of the KO group showed lower CG methylation levels in CG islands (CGIs), promoters and hypermethylation in CGI shores, 5'UTRs, exons, introns, 3'UTRs, and repeat regions. A total of 984 DMRs were identified between the WT and KO groups consisting of 559 hypermethylation and 425 hypomethylation DMRs. Furthermore, DMR-related genes were enriched in metabolism pathways such as carbon metabolism (serine hydroxymethyltransferase 2 (Shmt2), acyl-Coenzyme A dehydrogenase medium chain (Acadm)), arginine and proline metabolism (spermine synthase (Sms), proline dehydrogenase (Prodh2)) and purine metabolism (phosphoribosyl pyrophosphate synthetase 2 (Prps2)). In summary, we are the first to report the change in whole-genome methylation levels by miR-143-null through WGBS in mice liver, and provide an experimental basis for clinical diagnosis and treatment in liver diseases, indicating that miR-143 may be a potential therapeutic target and biomarker for liver damage-associated diseases and hepatocellular carcinoma.
Collapse
Affiliation(s)
| | | | | | | | | | - Yongliang Zhang
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou 510642, China; (X.C.); (J.L.); (J.L.); (T.C.); (J.S.)
| | - Qianyun Xi
- Guangdong Provincial Key Laboratory of Animal Nutrition Control, National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, No. 483 Wushan Road, Guangzhou 510642, China; (X.C.); (J.L.); (J.L.); (T.C.); (J.S.)
| |
Collapse
|
|
26
|
Arghiani N, Shah K. Modulating microRNAs in cancer: Next-generation therapies. Cancer Biol Med 2021; 19:j.issn.2095-3941.2021.0294. [PMID: 34846108 PMCID: PMC8958885 DOI: 10.20892/j.issn.2095-3941.2021.0294] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 07/27/2021] [Indexed: 11/16/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of endogenously expressed non-coding regulators of the genome with an ability to mediate a variety of biological and pathological processes. There is growing evidence demonstrating frequent dysregulation of microRNAs in cancer cells, which is associated with tumor initiation, development, migration, invasion, resisting cell death, and drug resistance. Studies have shown that modulation of these small RNAs is a novel and promising therapeutic tool in the treatment of a variety of diseases, especially cancer, due to their broad influence on multiple cellular processes. However, suboptimal delivery of the appropriate miRNA to the cancer sites, quick degradation by nucleases in the blood circulation, and off target effects have limited their research and clinical applications. Therefore, there is a pressing need to improve the therapeutic efficacy of miRNA modulators, while at the same time reducing their toxicities. Several delivery vehicles for miRNA modulators have been shown to be effective in vitro and in vivo. In this review, we will discuss the role and importance of miRNAs in cancer and provide perspectives on currently available carriers for miRNA modulation. We will also summarize the challenges and prospects for the clinical translation of miRNA-based therapeutic strategies.
Collapse
Affiliation(s)
- Nahid Arghiani
- Center for Stem Cell and Translational Immunotherapy (CSTI), Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Khalid Shah
- Center for Stem Cell and Translational Immunotherapy (CSTI), Harvard Medical School, Boston, MA 02115, USA
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| |
Collapse
|
|
27
|
MicroRNAs in Pancreatic Cancer and Chemoresistance. Pancreas 2021; 50:1334-1342. [PMID: 35041330 DOI: 10.1097/mpa.0000000000001934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading malignancies affecting human health, largely because of the development of resistance to chemotherapy/radiotherapy. There are many mechanisms that mediate the development of drug resistance, such as the transport of antineoplastic agents into cells, shifts in energy metabolism and environment, antineoplastic agent-induced DNA damage, and genetic mutations. MicroRNAs are short, noncoding RNAs that are 20 to 24 nucleotides in length and serve several biological functions. They bind to the 3'-untranslated regions of target genes and induce target degradation or translational inhibition. MicroRNAs can regulate several target genes and mediate PDAC chemotherapy/radiotherapy resistance. The detection of novel microRNAs would not only reveal the molecular mechanisms of PDAC and resistance to chemotherapy/radiotherapy but also provide new approaches to PDAC therapy. MicroRNAs are thus potential therapeutic targets for PDAC and might be essential in uncovering new mechanisms of the disease.
Collapse
|
|
28
|
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
|
|
29
|
Xia T, Chen XY, Zhang YN. MicroRNAs as biomarkers and perspectives in the therapy of pancreatic cancer. Mol Cell Biochem 2021; 476:4191-4203. [PMID: 34324119 DOI: 10.1007/s11010-021-04233-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/20/2021] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer is considered as one of the most aggressive tumor types, representing over 45,750 mortality cases annually in the USA solely. The aggressive nature and late identification of pancreatic cancer, combined with the restrictions of existing chemotherapeutics, present the mandatory need for the advancement of novel treatment systems. Ongoing reports have shown an important role of microRNAs (miRNAs) in the initiation, migration, and metastasis of malignancies. Besides, abnormal transcriptional levels of miRNAs have regularly been related with etiopathogenesis of pancreatic malignancy, underlining the conceivable utilization of miRNAs in the management of pancreatic disease patients. In this review article, we give a concise outline of molecular pathways involved in etiopathogenesis of pancreatic cancer patients as well as miRNA implications in pancreatic cancer patients. Ensuing sections describe the involvement of miRNAs in the diagnosis, prognosis, and therapy of pancreatic cancer patients. The involvement of miRNAs in the chemoresistance of pancreatic cancers was also discussed. End area portrays the substance of survey with future headings.
Collapse
Affiliation(s)
- Tao Xia
- Department of Gastrointestinal-Pancreatic Surgery, General Surgery, Zhejiang Provincial People's Hospital, Affiliated Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang Province, People's Republic of China.,Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated Hospital of Hangzhou Medical College, Hangzhou, 310014, Zhejiang Province, People's Republic of China
| | - Xiao-Yi Chen
- Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated Hospital of Hangzhou Medical College, No. 158 Shangtang Road, Hangzhou, 310014, Zhejiang Province, People's Republic of China.
| | - You-Ni Zhang
- Department of Laboratory Medicine, Tiantai People's Hospital of Zhejiang Province (Tiantai Branch of Zhejiang People's Hospital), Kangning Middle Road, Shifeng Street, Tiantai County, Taizhou, 317200, Zhejiang Province, People's Republic of China.
| |
Collapse
|
|
30
|
Association analysis of miRNA-related genetic polymorphisms in miR-143/145 and KRAS with colorectal cancer susceptibility and survival. Biosci Rep 2021; 41:228219. [PMID: 33825830 PMCID: PMC8062955 DOI: 10.1042/bsr20204136] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 03/20/2021] [Accepted: 04/06/2021] [Indexed: 12/29/2022] Open
Abstract
Background: There is accumulating evidence of aberrant expression of miR-143 and miR-145 and their target gene KRAS in colorectal cancer (CRC). We hypothesize that single nucleotide polymorphisms (SNPs) within or near mRNA–microRNA (miRNA) binding sites may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and promoting the development and progression of CRC. Methods: We conducted a case–control study of 507 patients with CRC recruited from a tertiary hospital and 497 population-based controls to assess the association of genetic polymorphisms in miR-143/145 and the KRAS 3′ untranslated region (3′UTR) with susceptibility to CRC and patients’ survival. In addition, genetic variations of genomic regions located from 500 bp upstream to 500 bp downstream of the miR-143/miR-145 gene and the 3′UTR of KRAS were selected for analysis using the Haploview and HaploReg software. Results: Using publicly available expression profiling data, we found that miR-143/145 and KRAS expression were all reduced in rectal cancer tissue compared with adjacent non-neoplastic large intestinal mucosa. The rs74693964 C/T variant located 65 bp downstream of miR-145 genomic regions was observed to be associated with susceptibility to CRC (adjusted odds ratio (OR): 2.414, 95% CI: 1.385–4.206). Cumulative effects of miR-143 and miR-145 on CRC risk were observed (Ptrend=0.03). Patients having CRC carrying variant genotype TT of KRAS rs712 had poorer survival (log-rank P=0.044, adjusted hazard ratio (HR): 4.328, 95% CI: 1.236–15.147). Conclusions: Our results indicate that miRNA-related polymorphisms in miR-143/145 and KRAS are likely to be deleterious and represent potential biomarkers for susceptibility to CRC and patients’ survival.
Collapse
|
|
31
|
Xu R, Shen X, Xie H, Zhang H, Liu D, Chen X, Fu Y, Zhang P, Yang Y, Cheng J, Jiang H. Identification of the canonical and noncanonical role of miR-143/145 in estrogen-deficient bone loss. Theranostics 2021; 11:5491-5510. [PMID: 33859759 PMCID: PMC8039936 DOI: 10.7150/thno.55041] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 02/24/2021] [Indexed: 12/16/2022] Open
Abstract
Rationale: Postmenopausal-induced bone loss is mainly caused by declining core transcription factors (TFs) of bone mesenchymal stem cells (BMSCs), but little is known about how miRNAs regulate chromatin structure remodeling of TFs gene to maintain BMSCs function in bone homeostasis. Methods: We examined the serum, salivary and bone samples from Pre- and Post-menopause women by paired analysis and confirmed canonical ceRNA role of MIR143HG and miR-143/145 complexes in cytoplasm and noncanonical role for SOX2 transcription in nucleus (FISH, qRT-PCR, immunostaining, Luciferase assays and ChIP). Moreover, we took advantage of transgenic mice under OVX-induced osteoporosis, studying the in vitro and in vivo effect of miR-143/145 deletion on BMSCs function and bone homeostasis. Last, using miRNA antagonism, antagomiR-143/145 were delivered into bone marrow to treat estrogen-deficient bone loss. Results: Here, we identified miR-143/145 as potential diagnostic candidates for postmenopausal osteoporosis, and miR-143/145 overexpression impaired BMSCs self-renewing and differentiation function. Mechanistically, we confirmed that cytoplasmic miR-143/145 and LncRNA MIR143HG, that controlled by ERβ, cooperatively regulated pluripotency genes translation via canonical ceRNA pathway, and MIR143HG cooperates with miR‑143 to nuclear translocation for co-activation of SOX2 transcription via opening promoter chromatin. Meanwhile, miR‑143/145 were shuttled into osteoclasts in extracellular vesicles and triggered osteoclastic activity by targeting Cd226 and Srgap2. Furthermore, miR-143/145-/- mice or using chemically‑modified antagomiR-143/145 significantly alleviated estrogen-deficient osteoporosis. Conclusions: Our findings reveal a canonical and noncanonical role of miR-143/145 in controlling BMSCs pluripotency and unfold their dual effect on bone formation and bone resorption, suggesting miR-143/145 as promising therapeutic targets for treating estrogen-deficient bone loss.
Collapse
Affiliation(s)
- Rongyao Xu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Xin Shen
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Hanyu Xie
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Hengguo Zhang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Dingshan Liu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Xin Chen
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Yu Fu
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Ping Zhang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Yi Yang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
- Department of Dental Implantology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Jie Cheng
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Hongbing Jiang
- Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| |
Collapse
|
|
32
|
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC.
Collapse
|
|
33
|
ATF3-Induced Mammary Tumors Exhibit Molecular Features of Human Basal-Like Breast Cancer. Int J Mol Sci 2021; 22:ijms22052353. [PMID: 33652981 PMCID: PMC7956570 DOI: 10.3390/ijms22052353] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 02/19/2021] [Accepted: 02/21/2021] [Indexed: 12/30/2022] Open
Abstract
Basal-like breast cancer (BLBC) is an aggressive and deadly subtype of human breast cancer that is highly metastatic, displays stem-cell like features, and has limited treatment options. Therefore, developing and characterizing preclinical mouse models with tumors that resemble BLBC is important for human therapeutic development. ATF3 is a potent oncogene that is aberrantly expressed in most human breast cancers. In the BK5.ATF3 mouse model, overexpression of ATF3 in the basal epithelial cells of the mammary gland produces tumors that are characterized by activation of the Wnt/β-catenin signaling pathway. Here, we used RNA-Seq and microRNA (miRNA) microarrays to better define the molecular features of BK5.ATF3-derived mammary tumors. These analyses showed that these tumors share many characteristics of human BLBC including reduced expression of Rb1, Esr1, and Pgr and increased expression of Erbb2, Egfr, and the genes encoding keratins 5, 6, and 17. An analysis of miRNA expression revealed reduced levels of Mir145 and Mir143, leading to the upregulation of their target genes including both the pluripotency factors Klf4 and Sox2 as well as the cancer stem-cell-related gene Kras. Finally, we show through knock-down experiments that ATF3 may directly modulate MIR145/143 expression. Taken together, our results indicate that the ATF3 mouse mammary tumor model could provide a powerful model to define the molecular mechanisms leading to BLBC, identify the factors that contribute to its aggressiveness, and, ultimately, discover specific genes and gene networks for therapeutic targeting.
Collapse
|
|
34
|
López-Jiménez E, Andrés-León E. The Implications of ncRNAs in the Development of Human Diseases. Noncoding RNA 2021; 7:17. [PMID: 33668203 PMCID: PMC8006041 DOI: 10.3390/ncrna7010017] [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] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/14/2021] [Accepted: 02/19/2021] [Indexed: 12/12/2022] Open
Abstract
The mammalian genome comprehends a small minority of genes that encode for proteins (barely 2% of the total genome in humans) and an immense majority of genes that are transcribed into RNA but not encoded for proteins (ncRNAs). These non-coding genes are intimately related to the expression regulation of protein-coding genes. The ncRNAs subtypes differ in their size, so there are long non-coding genes (lncRNAs) and other smaller ones, like microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs). Due to their important role in the maintenance of cellular functioning, any deregulation of the expression profiles of these ncRNAs can dissemble in the development of different types of diseases. Among them, we can highlight some of high incidence in the population, such as cancer, neurodegenerative, or cardiovascular disorders. In addition, thanks to the enormous advances in the field of medical genomics, these same ncRNAs are starting to be used as possible drugs, approved by the FDA, as an effective treatment for diseases.
Collapse
Affiliation(s)
- Elena López-Jiménez
- Centre for Haematology, Immunology and Inflammation Department, Faculty of Medicine, Imperial College London, London W12 0NN, UK
| | - Eduardo Andrés-León
- Unidad de Bioinformática, Instituto de Parasitología y Biomedicina “López-Neyra”, Consejo Superior de Investigaciones Científicas, 18016 Granada, Spain
| |
Collapse
|
|
35
|
Kane LE, Mellotte GS, Conlon KC, Ryan BM, Maher SG. Multi-Omic Biomarkers as Potential Tools for the Characterisation of Pancreatic Cystic Lesions and Cancer: Innovative Patient Data Integration. Cancers (Basel) 2021; 13:769. [PMID: 33673153 PMCID: PMC7918773 DOI: 10.3390/cancers13040769] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 01/27/2021] [Accepted: 02/09/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) is regarded as one of the most lethal malignant diseases in the world, with GLOBOCAN 2020 estimates indicating that PC was responsible for almost half a million deaths worldwide in 2020. Pancreatic cystic lesions (PCLs) are fluid-filled structures found within or on the surface of the pancreas, which can either be pre-malignant or have no malignant potential. While some PCLs are found in symptomatic patients, nowadays many PCLs are found incidentally in patients undergoing cross-sectional imaging for other reasons-so called 'incidentalomas'. Current methods of characterising PCLs are imperfect and vary hugely between institutions and countries. As such, there is a profound need for improved diagnostic algorithms. This could facilitate more accurate risk stratification of those PCLs that have malignant potential and reduce unnecessary surveillance. As PC continues to have such a poor prognosis, earlier recognition and risk stratification of PCLs may lead to better treatment protocols. This review will focus on the importance of biomarkers in the context of PCLs and PCand outline how current 'omics'-related work could contribute to the identification of a novel integrated biomarker profile for the risk stratification of patients with PCLs and PC.
Collapse
Affiliation(s)
- Laura E. Kane
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin D08 W9RT, Ireland;
| | - Gregory S. Mellotte
- Department of Gastroenterology, Tallaght University Hospital, Dublin D24 NR0A, Ireland; (G.S.M.); (B.M.R.)
| | - Kevin C. Conlon
- Discipline of Surgery, School of Medicine, Trinity College Dublin, Dublin D02 PN40, Ireland;
| | - Barbara M. Ryan
- Department of Gastroenterology, Tallaght University Hospital, Dublin D24 NR0A, Ireland; (G.S.M.); (B.M.R.)
| | - Stephen G. Maher
- Department of Surgery, Trinity St. James’s Cancer Institute, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin D08 W9RT, Ireland;
| |
Collapse
|
|
36
|
Bhatt AB, Patel S, Matossian MD, Ucar DA, Miele L, Burow ME, Flaherty PT, Cavanaugh JE. Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling. Biomolecules 2021; 11:biom11020183. [PMID: 33572742 PMCID: PMC7911413 DOI: 10.3390/biom11020183] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/17/2021] [Accepted: 01/26/2021] [Indexed: 12/12/2022] Open
Abstract
Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-β (TGF-β), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription factors SNAIL, SLUG, and β-catenin. Moreover, ERK5 activation increases the release of extracellular matrix metalloproteinases (MMPs), facilitating breakdown of the extracellular matrix (ECM) and local tumor invasion. Targeting the ERK5 signaling pathway using small molecule inhibitors, microRNAs, and knockdown approaches decreases EMT, cell invasion, and metastases via several mechanisms. The focus of the current review is to highlight the mechanisms which are known to mediate cancer EMT via ERK5 signaling. Several therapeutic approaches that can be undertaken to target the ERK5 pathway and inhibit or reverse EMT and metastases are discussed.
Collapse
Affiliation(s)
- Akshita B. Bhatt
- Department of Pharmacology, School of Pharmacy, Duquesne University, Pittsburgh, PA 15282, USA;
| | - Saloni Patel
- Department of Medicinal Chemistry, School of Pharmacy, Duquesne University, Pittsburgh, PA 15282, USA; (S.P.); (P.T.F.)
| | - Margarite D. Matossian
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; (M.D.M.); (M.E.B.)
| | - Deniz A. Ucar
- Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; (D.A.U.); (L.M.)
| | - Lucio Miele
- Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; (D.A.U.); (L.M.)
| | - Matthew E. Burow
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; (M.D.M.); (M.E.B.)
| | - Patrick T. Flaherty
- Department of Medicinal Chemistry, School of Pharmacy, Duquesne University, Pittsburgh, PA 15282, USA; (S.P.); (P.T.F.)
| | - Jane E. Cavanaugh
- Department of Pharmacology, School of Pharmacy, Duquesne University, Pittsburgh, PA 15282, USA;
- Correspondence: ; Tel.: +1-412-760-3503
| |
Collapse
|
|
37
|
Qiu X, Shi Q, Huang Y, Jiang H, Qin S. miR-143/145 inhibits Th9 cell differentiation by targeting NFATc1. Mol Immunol 2021; 132:184-191. [PMID: 33446394 DOI: 10.1016/j.molimm.2021.01.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 11/19/2020] [Accepted: 01/03/2021] [Indexed: 12/24/2022]
Abstract
Th9 cells are a defined CD4+ helper T cell subgroup found to promote or suppress oncogenesis in a context-dependent manner. How microRNAs (miRNAs) shape Th9 cell functionality, however, remains to be studied. Herein, we determined that miR-143/145 is downregulated during Th9 differentiation. When these miRNAs were upregulated, this inhibited Th9 differentiation, proliferation, and IL-9 production. Overexpressing miR-143/145 in Th9 cells further suppressed NFATc1 expression at the protein and mRNA level, whereas the opposite phenotype was observed when miR-143/145 was downregulated in these cells. NFATc1 silencing markedly inhibited Th9 cell differentiation, whereas overexpressing this transcription factor was sufficient to reverse miR-143/145-associated phenotypes in these cells. These findings thus indicate that the ability of miR-143/145 to inhibit Th9 cell differentiation is attributable to their ability to target and suppress NFATc1 expression. Overall, our results highlight a novel mode of action whereby miR-143/145 controls Th9 differentiation, suggesting that this pathway may be amenable to therapeutic targeting in the context of anti-cancer treatment in the future.
Collapse
Affiliation(s)
- Xin Qiu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qiuyue Shi
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Youyi Huang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Haixing Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Shanyu Qin
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
| |
Collapse
|
|
38
|
MiRNAs directly targeting the key intermediates of biological pathways in pancreatic cancer. Biochem Pharmacol 2020; 189:114357. [PMID: 33279497 DOI: 10.1016/j.bcp.2020.114357] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 11/27/2020] [Accepted: 12/01/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic Cancer (PC) is a severe form of malignancy all over the world. Delayed diagnosis and chemoresistance are the major factors contributing to its poor prognosis and high mortality rate. The genetic and epigenetic regulations of biological pathways further complicate the progression and chemotherapy response to this cancer. MicroRNAs (MiRNAs) involvement has been observed in all types of cancers including PC. The understanding and categorization of miRNAs according to their specific targets are very important to develop early diagnostic and therapeutic interventions. The current review, emphasizing recent research findings, has categorized miRNAs that directly target the potential onco-factors that act as central converging signal-nodes in five major cancer-related pathways i.e., MAPK/ERK, JAK/STAT, Wnt/β-catenin, AKT/mTOR, and TGFβ in PC. The therapeutic perspectives of miRNAs in PC have also been discussed. This will help to understand the interplay of various miRNAs within foremost signaling pathways and develop a multifactorial approach to treat difficult-to-treat PC.
Collapse
|
|
39
|
Zeinali T, Karimi L, Hosseinahli N, Shanehbandi D, Mansoori B, Mohammadi A, Hajiasgharzadeh K, Babaloo Z, Majidi-Zolbanin J, Baradaran B. Overexpression of miRNA-145 induces apoptosis and prevents proliferation and migration of MKN-45 gastric cancer cells. EXCLI JOURNAL 2020; 19:1446-1458. [PMID: 33250681 PMCID: PMC7689247 DOI: 10.17179/excli2020-2777] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 10/28/2020] [Indexed: 12/11/2022]
Abstract
MiR-145 is a tumor suppressor miRNA that its ubiquitously expressed in the body but in numerous types of cancers such as GC, its expression became reduced or sometimes ceased in many subjects. This study aimed at restoring the function of the miR-145 in MKN-45 cells and investigating the function of this miRNA in proliferation, apoptosis, and migration of GC cells. MKN-45 cells were transfected using the PCMV-miR-145 plasmid vector. The MTT, DAPI staining, and wound healing assays were applied to estimate the impacts of ectopic expression of miR-145 in vitro. Moreover, alterations in the expression levels of K-Ras, c-Myc, caspase-3, caspase-9, Bax, Bcl-2, and MMP-9 mRNA were measured by qRT-PCR analysis. The findings designated that high expression of miR-145 reduced the proliferation and migration and increased the apoptosis of the MKN-45 cells. These effects occur with concurrent suppression of c-Myc, K-Ras, Bcl-2, and MMP-9 as well as induction of caspase-3, caspase-9, and Bax expression. Exogenous miR-145 influences multiple oncogenic pathways and can be regarded as a promising avenue of future therapeutic interventions for GC therapy.
Collapse
Affiliation(s)
- Tahereh Zeinali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Leila Karimi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nayer Hosseinahli
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Zohreh Babaloo
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
40
|
Chung DJ, Wu YL, Yang MY, Chan KC, Lee HJ, Wang CJ. Nelumbo nucifera leaf polyphenol extract and gallic acid inhibit TNF-α-induced vascular smooth muscle cell proliferation and migration involving the regulation of miR-21, miR-143 and miR-145. Food Funct 2020; 11:8602-8611. [PMID: 33084700 DOI: 10.1039/d0fo02135k] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Nelumbo nucifera leaf water extract (NLE) attenuates high-fat diet (HFD)-induced rabbit atherosclerosis, but its mechanism of action and the relevant compounds remain unclear. Modulating the proliferation and migration of vascular smooth muscle cells (VSMCs) may be an enforceable strategy for atherosclerosis prevention. Therefore, we investigated the potential mechanisms of N. nucifera leaf polyphenol extract (NLPE) and its active ingredient gallic acid (GA) in VSMC proliferation and migration. A7r5 rat aortic VSMCs were provoked using 50 ng mL-1 tumor necrosis factor (TNF)-α; the NLPE or GA reduced the TNF-α-induced migration by inhibiting the transforming protein RhoA/cell division cycle protein 42 pathway. The NLPE or GA suppressed the TNF-α-induced VSMC proliferation by inhibiting the Ras pathway and increasing the expression of phosphatase and tensin homolog (PTEN), kinase suppressor of Ras 2, and inducible nitric oxide synthase. The NLPE or GA increased PTEN expression by downregulating microRNA (miR)-21 expression and reduced Ras and RhoA expression by upregulating miR-143 and miR-145 expression. The NLPE and GA use potentially prevents atherosclerosis by inhibiting the VSMC migration and proliferation. The mechanisms involve the regulation of the miRNA in PTEN, the Ras/extracellular-signal-regulated kinase pathway, and Rho family proteins.
Collapse
Affiliation(s)
- Dai-Jung Chung
- Institute of Biochemistry, Microbiology, and Immunology, Chung Shan Medical University, No. 110, Section 1, Jianguo N. Road, Taichung 40201, Taiwan
| | - Yi-Liang Wu
- Division of Cardiovascular Surgery, Surgical Department, Chung Shan Medical University Hospital, No. 110, Section 1, Jianguo N. Road, Taichung 40201, Taiwan and Department of Surgery, School of Medicine, Chung-Shan Medical University, No. 110, Section, Jianguo N. Road, Taichung 40201, Taiwan
| | - Mon-Yuan Yang
- Institute of Biochemistry, Microbiology, and Immunology, Chung Shan Medical University, No. 110, Section 1, Jianguo N. Road, Taichung 40201, Taiwan
| | - Kuei-Chuan Chan
- Department of Internal Medicine, Chung-Shan Medical University Hospital, No. 110, Section 1, Jianguo N. Road, Taichung 40201, Taiwan and Department of Internal Medicine, School of Medicine, Chung-Shan Medical University, No. 110, Section, Jianguo N. Road, Taichung 40201, Taiwan
| | - Huei-Jane Lee
- Department of Biochemistry, School of Medicine, Chung Shan Medical University, No. 110, Section 1, Jianguo N. Road, Taichung 40201, Taiwan. and Department of Clinical Biochemistry, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N Road, Taichung 40201, South District, Taiwan
| | - Chau-Jong Wang
- Department of Medical Research, Chung Shan Medical University Hospital, No. 110, Section 1, Jianguo N. Road, Taichung 40201, Taiwan. and Department of Health Diet and Industry Management, Chung Shan Medical University, No. 110, Section 1, Jianguo N. Road, Taichung 40201, Taiwan
| |
Collapse
|
|
41
|
Non-coding RNA biomarkers in pancreatic ductal adenocarcinoma. Semin Cancer Biol 2020; 75:153-168. [PMID: 33049362 DOI: 10.1016/j.semcancer.2020.10.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 09/20/2020] [Accepted: 10/02/2020] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, which is usually diagnosed at an advanced stage. The late disease diagnosis, the limited availability of effective therapeutic interventions and lack of robust diagnostic biomarkers, are some of the primary reasons for the dismal 5-year survival rates (∼8%) in patients with PDAC. The pancreatic cancer develops through accumulation of a series of genomic and epigenomic alterations which lead to the transformation of normal pancreatic epithelium into an invasive carcinoma - a process that can take up to 15-20 years to develop, from the occurrence of first initiating mutational event. These facts highlight a unique window of opportunity for the earlier detection of PDAC, which could allow timely disease interception and improvement in the overall survival outcomes in patients suffering from this fatal malignancy. Non-coding RNAs (ncRNAs) have been recognized to play a central role in PDAC pathogenesis and are emerging as attractive candidates for biomarker development in various cancers, including PDAC. More specifically, the ncRNAs play a pivotal role in PDAC biology as they affect tumor growth, migration, and invasion by regulating cellular processes including cell cycle, apoptosis, and epithelial-mesenchymal transition. In this review, we focus on three types of well-established ncRNAs - microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) - and discuss their potential as diagnostic, prognostic and predictive biomarkers in PDAC.
Collapse
|
|
42
|
Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes. Nat Commun 2020; 11:4673. [PMID: 32938917 PMCID: PMC7495420 DOI: 10.1038/s41467-020-18483-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 08/25/2020] [Indexed: 12/17/2022] Open
Abstract
RAS-MAPK signaling mediates processes critical to normal development including cell proliferation, survival, and differentiation. Germline mutation of RAS-MAPK genes lead to the Noonan-spectrum of syndromes. Here, we present a patient affected by a 6p-interstitial microdeletion with unknown underlying molecular etiology. Examination of 6p-interstitial microdeletion cases reveals shared clinical features consistent with Noonan-spectrum disorders including short stature, facial dysmorphia and cardiovascular abnormalities. We find the RAS-responsive element binding protein-1 (RREB1) is the common deleted gene in multiple 6p-interstitial microdeletion cases. Rreb1 hemizygous mice display orbital hypertelorism and cardiac hypertrophy phenocopying the human syndrome. Rreb1 haploinsufficiency leads to sensitization of MAPK signaling. Rreb1 recruits Sin3a and Kdm1a to control H3K4 methylation at MAPK pathway gene promoters. Haploinsufficiency of SIN3A and mutations in KDM1A cause syndromes similar to RREB1 haploinsufficiency suggesting genetic perturbation of the RREB1-SIN3A-KDM1A complex represents a new category of RASopathy-like syndromes arising through epigenetic reprogramming of MAPK pathway genes.
Collapse
|
|
43
|
Sharma PC, Gupta A. MicroRNAs: potential biomarkers for diagnosis and prognosis of different cancers. Transl Cancer Res 2020; 9:5798-5818. [PMID: 35117940 PMCID: PMC8798648 DOI: 10.21037/tcr-20-1294] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 06/12/2020] [Indexed: 12/14/2022]
Abstract
A thorough understanding of the tumor environment and underlying genetic factors helps in the better formulation of cancer management strategies. Availability of efficient diagnostic and prognostic biomarkers facilitates early detection and progression of the disease. MicroRNAs affect different biological processes participating in tumorigenesis through regulation of their target genes. An expanding list of unique RNAs and understanding of their regulatory role has opened up a new field in cancer research. Based on a comprehensive literature search, we identified 728 miRNAs dysregulated in sixteen cancer types namely bladder cancer (BC), breast cancer (BrC), cervical cancer (CC), colorectal cancer (CRC), esophageal cancer (EC), endometrial cancer (EnC), gastric cancer (GC), hepatocellular cancer (HCC), head and neck squamous cell cancer (HNSCC), lung cancer (LC), ovarian cancer (OC), pancreatic cancer (PC), prostate cancer (PrC), renal cell cancer (RCC), skin cancer (SC), and thyroid cancer (TC). Expression of 43 miRNAs was either upregulated or downregulated in six or more of these cancers. Finally, seven miRNAs namely mir-18a, mir-21, mir-143/145, mir-210, mir-218, mir-221, showing maximum dysregulation, either up- or down-regulation in the majority of cancers, were selected for a detailed presentation of their expression and evaluation of their potential as biomarkers in the diagnosis and prognosis of different cancers.
Collapse
Affiliation(s)
- Prakash Chand Sharma
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| | - Alisha Gupta
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| |
Collapse
|
|
44
|
Sawant D, Klevenow E, Baeten JT, Thomas S, Manivannan S, Conway SJ, Lilly B. Generation of transgenic mice that conditionally express microRNA miR-145. Genesis 2020; 58:e23385. [PMID: 32648361 PMCID: PMC7672654 DOI: 10.1002/dvg.23385] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/05/2020] [Accepted: 06/11/2020] [Indexed: 01/05/2023]
Abstract
MicroRNAs are modulators of cellular phenotypes and their functions contribute to development, homeostasis, and disease. miR-145 is a conserved microRNA that has been implicated in regulating an array of phenotypes. These include supporting smooth muscle differentiation, repression of stem cell pluripotency, and inhibition of tumor growth and metastasis. Previously, our lab demonstrated that miR-145 acts to suppress cardiac fibrosis through inhibition of the TGF-β signaling pathway. The range of effects that miR-145 has on different cell types makes it an attractive microRNA for further study. Here we describe the generation of transgenic mice that conditionally express miR-145 through Cre recombinase-mediated activation. Characterization of individual founder lines indicates that overexpression of miR-145 in the developing cardiovascular system has detrimental effects, with three independent miR-145 transgenic lines exhibiting Cre-dependent lethality. Expression analysis demonstrates that the transgene is robustly expressed and our analysis reveals a novel downstream target of miR-145, Tnnt2. The miR-145 transgenic mice represent a valuable tool to understand the role of miR-145 in diverse cell types and to address its potential as a therapeutic mediator for the treatment of disease.
Collapse
Affiliation(s)
- Dwitiya Sawant
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Emilie Klevenow
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
- Current address: Department of Physical Therapy, Marquette University
| | - Jeremy T. Baeten
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
- Current address: University of Chicago School of Medicine
| | - Shelby Thomas
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Sathiyanarayanan Manivannan
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
| | - Simon J. Conway
- HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana
| | - Brenda Lilly
- Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, USA
- Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA
| |
Collapse
|
|
45
|
Combined treatment with CBP and BET inhibitors reverses inadvertent activation of detrimental super enhancer programs in DIPG cells. Cell Death Dis 2020; 11:673. [PMID: 32826850 PMCID: PMC7442654 DOI: 10.1038/s41419-020-02800-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 07/15/2020] [Accepted: 07/15/2020] [Indexed: 12/19/2022]
Abstract
Diffuse intrinsic pontine gliomas (DIPG) are the most aggressive brain tumors in children with 5-year survival rates of only 2%. About 85% of all DIPG are characterized by a lysine-to-methionine substitution in histone 3, which leads to global H3K27 hypomethylation accompanied by H3K27 hyperacetylation. Hyperacetylation in DIPG favors the action of the Bromodomain and Extra-Terminal (BET) protein BRD4, and leads to the reprogramming of the enhancer landscape contributing to the activation of DIPG super enhancer-driven oncogenes. The activity of the acetyltransferase CREB-binding protein (CBP) is enhanced by BRD4 and associated with acetylation of nucleosomes at super enhancers (SE). In addition, CBP contributes to transcriptional activation through its function as a scaffold and protein bridge. Monotherapy with either a CBP (ICG-001) or BET inhibitor (JQ1) led to the reduction of tumor-related characteristics. Interestingly, combined treatment induced strong cytotoxic effects in H3.3K27M-mutated DIPG cell lines. RNA sequencing and chromatin immunoprecipitation revealed that these effects were caused by the inactivation of DIPG SE-controlled tumor-related genes. However, single treatment with ICG-001 or JQ1, respectively, led to activation of a subgroup of detrimental super enhancers. Combinatorial treatment reversed the inadvertent activation of these super enhancers and rescued the effect of ICG-001 and JQ1 single treatment on enhancer-driven oncogenes in H3K27M-mutated DIPG, but not in H3 wild-type pedHGG cells. In conclusion, combinatorial treatment with CBP and BET inhibitors is highly efficient in H3K27M-mutant DIPG due to reversal of inadvertent activation of detrimental SE programs in comparison with monotherapy.
Collapse
|
|
46
|
Dissecting miRNA facilitated physiology and function in human breast cancer for therapeutic intervention. Semin Cancer Biol 2020; 72:46-64. [PMID: 32497683 DOI: 10.1016/j.semcancer.2020.05.017] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 05/17/2020] [Accepted: 05/27/2020] [Indexed: 12/12/2022]
Abstract
MicroRNAs (miRNAs) are key epigenomic regulators of biological processes in animals and plants. These small non coding RNAs form a complex networks that regulate cellular function and development. MiRNAs prevent translation by either inactivation or inducing degradation of mRNA, a major concern in post-transcriptional gene regulation. Aberrant regulation of gene expression by miRNAs is frequently observed in cancer. Overexpression of various 'oncomiRs' and silencing of tumor suppressor miRNAs are associated with various types of human cancers, although overall downregulation of miRNA expression is reported as a hallmark of cancer. Modulations of the total pool of cellular miRNA by alteration in genetic and epigenetic factors associated with the biogenesis of miRNA machinery. It also depends on the availability of cellular miRNAs from its store in the organelles which affect tumor development and cancer progression. Here, we have dissected the roles and pathways of various miRNAs during normal cellular and molecular functions as well as during breast cancer progression. Recent research works and prevailing views implicate that there are two major types of miRNAs; (i) intracellular miRNAs and (ii) extracellular miRNAs. Concept, that the functions of intracellular miRNAs are driven by cellular organelles in mammalian cells. Extracellular miRNAs function in cell-cell communication in extracellular spaces and distance cells through circulation. A detailed understanding of organelle driven miRNA function and the precise role of extracellular miRNAs, pre- and post-therapeutic implications of miRNAs in this scenario would open several avenues for further understanding of miRNA function and can be better exploited for the treatment of breast cancers.
Collapse
|
|
47
|
Urdinez J, Boro A, Mazumdar A, Arlt MJ, Muff R, Botter SM, Bode-Lesniewska B, Fuchs B, Snedeker JG, Gvozdenovic A. The miR-143/145 Cluster, a Novel Diagnostic Biomarker in Chondrosarcoma, Acts as a Tumor Suppressor and Directly Inhibits Fascin-1. J Bone Miner Res 2020; 35:1077-1091. [PMID: 32027760 DOI: 10.1002/jbmr.3976] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/24/2020] [Accepted: 01/29/2020] [Indexed: 12/17/2022]
Abstract
Chondrosarcoma is the second most frequent bone sarcoma. Due to the inherent chemotherapy and radiotherapy resistance and absence of known therapeutic targets, clinical management is limited to surgical resection. Consequently, patients with advanced disease face a poor prognosis. Hence, elucidating regulatory networks governing chondrosarcoma pathogenesis is vital for development of effective therapeutic strategies. Here, miRNA and mRNA next generation sequencing of different subtypes of human chondrogenic tumors in combination with in silico bioinformatics tools were performed with the aim to identify key molecular factors. We identified miR-143/145 cluster levels to inversely correlate with tumor grade. This deregulation was echoed in the miRNA plasma levels of patients and we provided the first evidence that circulating miR-145 is a potential noninvasive diagnostic biomarker and can be valuable as an indicator to improve the currently challenging diagnosis of cartilaginous bone tumors. Additionally, artificial upregulation of both miRNAs impelled a potent tumor suppressor effect in vitro and in vivo in an orthotopic xenograft mouse model. A combined in silico/sequencing approach revealed FSCN1 as a direct target of miR-143/145, and its depletion phenotypically resembled miR-143/145 upregulation in vitro. Last, FSCN1 is a malignancy-promoting factor associated with aggressive chondrosarcoma progression. Our findings underscore miR-143/145/FSCN1 as important players in chondrosarcoma and may potentially open new avenues for specific therapeutic intervention options. © 2020 American Society for Bone and Mineral Research.
Collapse
Affiliation(s)
- Joaquin Urdinez
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Aleksandar Boro
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland
| | - Alekhya Mazumdar
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Matthias Je Arlt
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Roman Muff
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland
| | - Sander M Botter
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Beata Bode-Lesniewska
- Institute for Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Bruno Fuchs
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland
| | - Jess G Snedeker
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| | - Ana Gvozdenovic
- Department of Orthopedics, Balgrist University Hospital, Zurich, Switzerland.,Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
| |
Collapse
|
|
48
|
Danbaran GR, Aslani S, Sharafkandi N, Hemmatzadeh M, Hosseinzadeh R, Azizi G, Jadidi-Niaragh F, Babaie F, Mohammadi H. How microRNAs affect the PD-L1 and its synthetic pathway in cancer. Int Immunopharmacol 2020; 84:106594. [PMID: 32416456 DOI: 10.1016/j.intimp.2020.106594] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/27/2020] [Accepted: 05/08/2020] [Indexed: 12/17/2022]
Abstract
Programmed cell death-ligand 1 (PD-L1) is a glycoprotein that is expressed on the cell surface of both hematopoietic and nonhematopoietic cells. PD-L1 play a role in the immune tolerance and protect self-tissues from immune system attack. Dysfunction of this molecule has been highlighted in the pathogenesis of tumors, autoimmunity, and infectious disorders. MicroRNAs (miRNAs) are endogenous molecules that are classified as small non-coding RNA with approximately 20-22 nucleotides (nt) length. The function of miRNAs is based on complementary interactions with target mRNA via matching completely or incompletely. The result of this function is decay of the target mRNA or preventing mRNA translation. In the past decades, several miRNAs have been discovered which play an important role in the regulation of PD-L1 in various malignancies. In this review, we discuss the effect of miRNAs on PD-L1 expression and consider the effect of miRNAs on the synthetic pathway of PD-L1, especially during cancers.
Collapse
Affiliation(s)
| | - Saeed Aslani
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nadia Sharafkandi
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Maryam Hemmatzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Hosseinzadeh
- Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Babaie
- Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
| |
Collapse
|
|
49
|
Huang YY, Jiang HX, Shi QY, Qiu X, Wei X, Zhang XL, Qin SY. miR-145 Inhibits Th9 Cell Differentiation by Suppressing Activation of the PI3K/Akt/mTOR/p70S6K/HIF-1α Pathway in Malignant Ascites from Liver Cancer. Onco Targets Ther 2020; 13:3789-3800. [PMID: 32440147 PMCID: PMC7211301 DOI: 10.2147/ott.s245346] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 04/10/2020] [Indexed: 12/14/2022] Open
Abstract
Purpose Our previous experiments confirmed that T helper type 9 (Th9) cells were involved in the occurrence and development of malignant ascites caused by liver cancer. The current study investigated the mechanism underlying microRNA (miR-145)-mediated inhibition of Th9 cells in an malignant ascites model with liver cancer. Materials and Methods CD4+ T cells were induced to differentiate Th9 cells after transfection with miR-145 mimics or negative control. A malignant ascites mouse model was transfected with miR-145agomir or negative control. Th9 cells were detected by flow cytometry. Enzyme-linked immunosorbent assay was applied to detect the interleukin 9 (IL-9) cytokine and hypoxia-inducible factor 1 alpha (HIF-1α). RT-PCR was used to detect the expression of miR-145 and phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin/p70 ribosomal protein S6 kinase/HIF-1α (PI3K/Akt/mTOR/p70S6K/HIF-1α) mRNA. Western blotting and immunofluorescence were performed to detect the expression of PI3K/Akt/mTOR/p70S6K/HIF-1α-related proteins. Results In vitro experiments showed that miR-145 inhibited Th9 cell polarization, HIF-1α expression, and PI3K/Akt/mTOR/p70S6K pathway activation. In the malignant ascites mouse model, miR-145 also demonstrated inhibitory effects on Th9 cell differentiation through the PI3K/Akt/mTOR/p70S6K/HIF-1α pathway. Conclusion miR-145 may inhibit Th9 cell differentiation through the PI3K/Akt/mTOR/p70S6K/HIF-1α pathway. These findings suggest a novel therapeutic target for malignant ascites from liver cancer.
Collapse
Affiliation(s)
- You-Yi Huang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Hai-Xing Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Qiu-Yue Shi
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Xin Qiu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Xi Wei
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Xiang-Lian Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| | - Shan-Yu Qin
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China
| |
Collapse
|
|
50
|
Gong R, Jiang Y. Non-coding RNAs in Pancreatic Ductal Adenocarcinoma. Front Oncol 2020; 10:309. [PMID: 32257946 PMCID: PMC7089935 DOI: 10.3389/fonc.2020.00309] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 02/20/2020] [Indexed: 12/15/2022] Open
Abstract
Non-coding RNAs (ncRNAs) are reported to be expressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). These ncRNAs affect the growth, migration and invasion of tumor cells by regulating cell cycle and apoptosis, as well as playing important roles in epigenetic processes, transcription and post-transcriptional regulation. It is still unclear whether alterations in ncRNAs influence PDAC development and progression. Because of this, analysis based on existing data on ncRNAs, which are crucial for modulating pancreatic tumorigenesis, will be important for future research on PDAC. Here, we summarize ncRNAs with tumor-promoting functions: HOTAIR, HOTTIP, MALAT1, lncRNA H19, lncRNA PVT1, circ-RNA ciRS-7, circ-0030235, circ-RNA_100782, circ-LDLRAD3, circ-0007534, circRHOT1, circZMYM2, circ-IARS, circ-RNA PDE8A, miR-21, miR-155, miR-221/222, miR-196b, miR-10a. While others including GAS5, MEG3, and lncRNA ENST00000480739, has_circ_0001649, miR-34a, miR-100, miR-217, miR-143 inhibit the proliferation and invasion of PDAC. Hence, we summarize the functions of ncRNAs in the occurrence, development and metastasis of PDAC, with the goal to provide guidance in the clinical diagnosis and treatment of PDAC.
Collapse
Affiliation(s)
- Ruining Gong
- Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yueping Jiang
- Department of Gastroenterology, Affiliated Hospital of Qingdao University, Qingdao, China
| |
Collapse
|