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Saadh MJ, Muhammad FA, Alazzawi TS, Fahdil AA, Athab ZH, Tuxtayev J, Alsaikhan F, Farhood B. Regulation of Apoptotic Pathways by MicroRNAs: A Therapeutic Strategy for Alzheimer's Disease. Mol Neurobiol 2025:10.1007/s12035-025-04833-5. [PMID: 40220245 DOI: 10.1007/s12035-025-04833-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 03/09/2025] [Indexed: 04/14/2025]
Abstract
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder marked by a gradual decline in memory and cognitive functions. It is characterized by the presence of senile plaques, neurofibrillary tangles, and neuronal degeneration, affecting a significant portion of the human population. A key feature of various nervous system disorders, including AD, is extensive cellular death caused by apoptosis, which affects not only neurons but also glial cells. While apoptosis plays a vital role in eliminating certain cells and supporting normal development, alterations or disruptions in apoptotic pathways can lead to harmful neurodegenerative conditions such as AD. Thus, targeting apoptosis presents a promising therapeutic approach for these diseases. MicroRNAs (miRNAs), a class of non-coding RNA, play diverse roles in cellular functions, including proliferation, gene expression regulation, programmed cell death, intercellular communication, and angiogenesis. By modulating regulatory genes, miRNAs can influence apoptosis, either promoting or inhibiting it. Aberrant expression of miRNAs can impact multiple apoptotic pathways, potentially driving the progression of AD and related health issues. This review summarizes recent research on miRNAs and their dual role in exacerbating or protecting against neural cell damage in AD by altering apoptotic pathways. The regulation of apoptosis by miRNAs offers a prospective therapeutic strategy for Alzheimer's disease.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | | | - Tuqa S Alazzawi
- College of Dentist, National University of Science and Technology, Dhi Qar, Iraq
| | - Ali A Fahdil
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Jamshid Tuxtayev
- Department of Surgical Diseases, Faculty of Pediatrics, Samarkand State Medical Institute, Samarkand, Uzbekistan
| | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
- School of Pharmacy, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia.
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Karaca Dogan B, Salman Yilmaz S, Izgi GN, Ozen M. Circulating non-coding RNAs as a tool for liquid biopsy in solid tumors. Epigenomics 2025; 17:335-358. [PMID: 40040488 PMCID: PMC11970797 DOI: 10.1080/17501911.2025.2467021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 02/10/2025] [Indexed: 03/06/2025] Open
Abstract
Solid tumors are significant causes of global mortality and morbidity. Recent research has primarily concentrated on finding pathology-specific molecules that can be acquired non-invasively and that can change as the disease progresses or in response to treatment. The focus of research has moved to RNA molecules that are either freely circulating in body fluids or bundled in microvesicles and exosomes because of their great stability in challenging environments, ease of accessibility, and changes in level in response to therapy. In this context, there are many non-coding RNAs that can be used for this purpose in liquid biopsies. Out of these, microRNAs have been extensively studied. However, there has been an increase of interest in studying long non-coding RNAs, piwi interacting RNAs, circular RNAs, and other small non-coding RNAs. In this article, an overview of the most researched circulating non-coding RNAs in solid tumors will be reviewed, along with a discussion of the significance of these molecules for early diagnosis, prognosis, and therapeutic targets. The publications analyzed were extracted from the PubMed database between 2008 and June 2024.
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Affiliation(s)
- Beyza Karaca Dogan
- Department of Medical Genetics, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkiye
| | - Seda Salman Yilmaz
- Department of Medical Genetics, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkiye
- Department of Medical Services and Techniques Medical Monitoring Techniques Pr. Vocational School of Health Services, Istanbul University-Cerrahpaşa, Istanbul, Turkiye
| | - Gizem Nur Izgi
- Department of Medical Genetics, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkiye
| | - Mustafa Ozen
- Department of Medical Genetics, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkiye
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA
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Wnuk J, Hudy D, Strzelczyk JK, Michalecki Ł, Dybek K, Gisterek-Grocholska I. Serum hsa-miR-22-3p, hsa-miR-885-5p, Lipase-to-Amylase Ratio, C-Reactive Protein, CA19-9, and Neutrophil-to-Lymphocyte Ratio as Prognostic Factors in Advanced Pancreatic Ductal Adenocarcinoma. Curr Issues Mol Biol 2025; 47:27. [PMID: 39852142 PMCID: PMC11763715 DOI: 10.3390/cimb47010027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/28/2024] [Accepted: 01/01/2025] [Indexed: 01/26/2025] Open
Abstract
Pancreatic cancer (PC) is the seventh most common cause of cancer-related death worldwide. The low survival rate may be due to late diagnosis and asymptomatic early-stage disease. Most patients are diagnosed at an advanced stage of the disease. The search for novel prognostic factors is still needed. Two miRNAs, miR-22-3p and miR-885-5p, which show increased expression in PC, were selected for this study. The aim of this study was to evaluate the utility of these miRNAs in the prognosis of PC. Other prognostic factors such as lipase-to-amylase ratio (LAR), neutrophil-to-lymphocyte ratio (NLR), and carbohydrate antigen 19-9 (CA19-9) were also evaluated in this study. This study was conducted in 50 patients previously diagnosed with pancreatic ductal adenocarcinoma in clinical stage (CS) III and IV. All patients underwent a complete medical history, physical examination, and routine laboratory tests including a complete blood count, C-reactive protein (CRP), CA19-9, lipase, and amylase. Two additional blood samples were taken from each patient to separate plasma and serum. Isolation of miRNA was performed using TRI reagent with cel-miR-39-3p as a spike-in control. Reverse transcription of miRNA was performed using a TaqMan Advanced miRNA cDNA Synthesis Kit. The relative expression levels of miR-22-3p and miR-885-5p were measured using RT-qPCR. Serum hsa-miR-22-3p was detected in 22 cases (44%), while hsa-miR-885-5p was detected in 33 cases (66%). There were no statistically significant differences in serum or plasma miRNA expression levels between patient groups based on clinical stage, gender, or BMI. There were no statistically significant differences in LAR between patients with different CS. For NLR, CRP and CA19-9 thresholds were determined using ROC analysis (6.63, 24.7 mg/L and 4691 U/mL, respectively). Cox's F test for overall survival showed statistically significant differences between groups (p = 0.002 for NLR, p = 0.007 for CRP and p = 0.007 for CA19-9). Utility as prognostic biomarkers was confirmed in univariate and multivariate analysis for CA19-9, CRP, and NLR. The selected miRNAs and LAR were not confirmed as reliable prognostic markers in PC.
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Affiliation(s)
- Jakub Wnuk
- Department of Oncology and Radiotherapy, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 35 Ceglana St., 40-515 Katowice, Poland; (J.W.)
| | - Dorota Hudy
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana St., 41-808 Zabrze, Poland; (D.H.); (J.K.S.)
| | - Joanna Katarzyna Strzelczyk
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana St., 41-808 Zabrze, Poland; (D.H.); (J.K.S.)
| | - Łukasz Michalecki
- Department of Oncology and Radiotherapy, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 35 Ceglana St., 40-515 Katowice, Poland; (J.W.)
| | - Kamil Dybek
- Central Laboratory, University Clinical Center, Medical University of Silesia in Katowice, 14 Medyków St., 40-752 Katowice, Poland
| | - Iwona Gisterek-Grocholska
- Department of Oncology and Radiotherapy, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 35 Ceglana St., 40-515 Katowice, Poland; (J.W.)
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Hasani F, Masrour M, Khamaki S, Jazi K, Hosseini S, Heidarpour H, Namazee M. Diagnostic and Prognostic Accuracy of MiRNAs in Pancreatic Cancer: A Systematic Review and Meta-Analysis. J Cell Mol Med 2025; 29:e70337. [PMID: 39855897 PMCID: PMC11761000 DOI: 10.1111/jcmm.70337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 11/30/2024] [Accepted: 12/20/2024] [Indexed: 01/27/2025] Open
Abstract
Pancreatic cancer (PC) remains a significant contributor to global cancer mortality, with limited effective diagnostic and prognostic tools. MicroRNAs (miRNAs) have emerged as promising biomarkers for PC diagnosis and prognosis. A comprehensive literature search was conducted in PubMed, Web of Science, and Scopus. Studies reporting sensitivity, specificity or area under the curve (AUC) for miRNAs in PC diagnosis, as well as hazard ratios (HRs) for survival evaluations, were included. Data extraction and quality assessment followed PRISMA guidelines. Meta-analyses were conducted using appropriate statistical methods. The protocol is registered in PROSPERO. Diagnostic analysis included 290 evaluations, revealing an overall AUC of 0.8226 for PC diagnosis. Subgroup analyses showed varying accuracies, with blood and tissue specimens yielding higher AUC values. Promising miRNAs with AUC values above 0.8 included miR-320, miR-1290, miR-93, miR-25, miR-451, miR-20, miR-21, miR-223 and miR-122. Prognostic analysis encompassed 46 studies, indicating significant associations between miRNA expression and overall survival (OS) and progression-free survival (PFS). The combined HR for studies reporting OS HRs higher than one was 1.7613 (95% CI: 1.5394-2.0152, p < 0.0001; I2 = 81.7%). Notable miRNAs with prognostic significance included miR-10, miR-21 and miR-221. Studies reporting OS HRs less than one had a pooled HR of 0.6805 (95% CI: 0.5862-0.7901, p < 0.0001; I2 = 65.4%). MiRNAs hold promise as diagnostic and prognostic biomarkers for PC. Blood and tissue specimens offer superior diagnostic accuracy, and several miRNAs show potential for predicting patient outcomes.
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Affiliation(s)
- Fatemeh Hasani
- Golestan Research Center of Gastroenterology and HepatologyGolestan University of Medical SciencesGorganIran
| | - Mahdi Masrour
- School of MedicineTehran University of Medical SciencesTehranIran
| | - Sina Khamaki
- Golestan Research Center of Gastroenterology and HepatologyGolestan University of Medical SciencesGorganIran
| | - Kimia Jazi
- Student Research Committee, Faculty of MedicineQom University of Medical SciencesQomIran
| | - Saba Hosseini
- Golestan Research Center of Gastroenterology and HepatologyGolestan University of Medical SciencesGorganIran
| | - Hadiseh Heidarpour
- Golestan Research Center of Gastroenterology and HepatologyGolestan University of Medical SciencesGorganIran
| | - Mehrad Namazee
- School of MedicineShiraz University of Medical SciencesShirazIran
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Tu W, Guo M, Zhang Z, Li C. Pathogen-induced apoptosis in echinoderms: A review. FISH & SHELLFISH IMMUNOLOGY 2024; 155:109990. [PMID: 39481501 DOI: 10.1016/j.fsi.2024.109990] [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: 08/04/2024] [Revised: 10/16/2024] [Accepted: 10/26/2024] [Indexed: 11/02/2024]
Abstract
Echinoderms possess unique biological traits that make them valuable models in immunology, regeneration, and developmental biology studies. As a class rich in active substances with significant nutritional and medicinal value, echinoderms face threats from marine pathogens, including bacteria, viruses, fungi, protozoa, and parasites, which have caused substantial economic losses in echinoderm aquaculture. Echinoderms counteract pathogen invasion through innate immunity and programmed cell death, in particular, with apoptosis being essential for eliminating infected or damaged cells and maintaining homeostasis in many echinoderm cell types. Despite the importance of this process, there is a lack of comprehensive and updated reviews on this topic. This review underscores that echinoderm apoptotic pathways exhibit a complexity comparable to that of vertebrates, featuring proteins with unique domains that may indicate the presence of novel signaling mechanisms. We synthesize current knowledge on how echinoderms utilize diverse transcriptional and post-transcriptional mechanisms to regulate apoptosis in response to pathogen infections and explore how pathogens have evolved strategies to manipulate echinoderm apoptosis, either by inhibiting it to create survival niches or by inducing excessive apoptosis to weaken the host. By elucidating the primary apoptotic pathways in echinoderms and the host-pathogen interactions that modulate these pathways, this review aims to reveal new mechanisms of apoptosis in animal immune defense and provide insights into the evolutionary arms race between hosts and pathogens.
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Affiliation(s)
- Weitao Tu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Ming Guo
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China.
| | - Zhen Zhang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Chenghua Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266071, China.
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6
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Gao H, Chen Z, Yao Y, He Y, Hu X. Common biological processes and mutual crosstalk mechanisms between cardiovascular disease and cancer. Front Oncol 2024; 14:1453090. [PMID: 39634266 PMCID: PMC11614734 DOI: 10.3389/fonc.2024.1453090] [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: 06/22/2024] [Accepted: 10/31/2024] [Indexed: 12/07/2024] Open
Abstract
Cancer and cardiovascular disease (CVD) are leading causes of mortality and thus represent major health challenges worldwide. Clinical data suggest that cancer patients have an increased likelihood of developing cardiovascular disease, while epidemiologic studies have shown that patients with cardiovascular disease are also more likely to develop cancer. These observations underscore the increasing importance of studies exploring the mechanisms underlying the interaction between the two diseases. We review their common physiological processes and potential pathophysiological links. We explore the effects of chronic inflammation, oxidative stress, and disorders of fatty acid metabolism in CVD and cancer, and also provide insights into how cancer and its treatments affect heart health, as well as present recent advances in reverse cardio-oncology using a new classification approach.
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Affiliation(s)
- Hanwei Gao
- Department of Cardiology, China–Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin, China
| | - Zhongyu Chen
- Department of Cardiology, China–Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin, China
- CJUH-JLU-China iGEM Team, Jilin University, Changchun, Jilin, China
| | - Yutong Yao
- Department of Cardiology, China–Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin, China
- CJUH-JLU-China iGEM Team, Jilin University, Changchun, Jilin, China
| | - Yuquan He
- Department of Cardiology, China–Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin, China
- CJUH-JLU-China iGEM Team, Jilin University, Changchun, Jilin, China
| | - Xin Hu
- Department of Cardiology, China–Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin, China
- CJUH-JLU-China iGEM Team, Jilin University, Changchun, Jilin, China
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Saadh MJ, Faisal A, Adil M, Zabibah RS, Mamadaliev AM, Jawad MJ, Alsaikhan F, Farhood B. Parkinson's Disease and MicroRNAs: A Duel Between Inhibition and Stimulation of Apoptosis in Neuronal Cells. Mol Neurobiol 2024; 61:8552-8574. [PMID: 38520611 DOI: 10.1007/s12035-024-04111-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 02/03/2024] [Accepted: 02/27/2024] [Indexed: 03/25/2024]
Abstract
Parkinson's disease (PD) is one of the most prevalent diseases of central nervous system that is caused by degeneration of the substantia nigra's dopamine-producing neurons through apoptosis. Apoptosis is regulated by initiators' and executioners' caspases both in intrinsic and extrinsic pathways, further resulting in neuronal damage. In that context, targeting apoptosis appears as a promising therapeutic approach for treating neurodegenerative diseases. Non-coding RNAs-more especially, microRNAs, or miRNAs-are a promising target for the therapy of neurodegenerative diseases because they are essential for a number of cellular processes, including signaling, apoptosis, cell proliferation, and gene regulation. It is estimated that a substantial portion of coding genes (more than 60%) are regulated by miRNAs. These small regulatory molecules can have wide-reaching consequences on cellular processes like apoptosis, both in terms of intrinsic and extrinsic pathways. Furthermore, it was recommended that a disruption in miRNA expression levels could also result in perturbation of typical apoptosis pathways, which may be a factor in certain diseases like PD. The latest research on miRNAs and their impact on neural cell injury in PD models by regulating the apoptosis pathway is summarized in this review article. Furthermore, the importance of lncRNA/circRNA-miRNA-mRNA network for regulating apoptosis pathways in PD models and treatment is explored. These results can be utilized for developing new strategies in PD treatment.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | - Ahmed Faisal
- Department of Pharmacy, Al-Noor University College, Nineveh, Iraq
| | - Mohaned Adil
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
| | - Rahman S Zabibah
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | | | | | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia.
- School of Pharmacy, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia.
| | - Bagher Farhood
- Department of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Helen H, Gunawan MC, Halim P, Dinata MR, Ahmed A, Dalimunthe A, Marianne M, Ribeiro RIMDA, Hasibuan PAZ, Nurkolis F, Hey-Hawkins E, Park MN, Harahap U, Kim SH, Kim B, Syahputra RA. Flavonoids as modulators of miRNA expression in pancreatic cancer: Pathways, Mechanisms, And Therapeutic Potential. Biomed Pharmacother 2024; 179:117347. [PMID: 39241569 DOI: 10.1016/j.biopha.2024.117347] [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: 06/14/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/09/2024] Open
Abstract
Pancreatic cancer (PC) is a complex malignancy, distinguished by its aggressive characteristics and unfavorable prognosis. Recent developments in understanding the molecular foundations of this disease have brought attention to the noteworthy involvement of microRNAs (miRNAs) in disease development, advancement, and treatment resistance. The anticancer capabilities of flavonoids, which are a wide range of phytochemicals present in fruits and vegetables, have attracted considerable interest because of their ability to regulate miRNA expression. This review provides the effects of flavonoids on miRNA expression in PC, explains the underlying processes, and explores the possible therapeutic benefits of flavonoid-based therapies. Flavonoids inhibit PC cell proliferation, induce apoptosis, and enhance chemosensitivity via the modulation of miRNAs involved in carcinogenesis. Additionally, this review emphasizes the significance of certain miRNAs as targets of flavonoid action. These miRNAs have a role in regulating important signaling pathways such as the phosphoinositide-3-kinase-protein kinase B/Protein kinase B (Akt), mitogen activated protein kinase (MAPK), Janus kinase/signal transducers and activators of transcription (JAK/STAT), and Wnt/β-catenin pathways. This review aims to consolidate current knowledge on the interaction between flavonoids and miRNAs in PC, providing a comprehensive analysis of how flavonoid-mediated modulation of miRNA expression could influence cancer progression and therapy. It highlights the use of flavonoid nanoformulations to enhance stability, increase absorption, and maximize anti-PC activity, improving patient outcomes. The review calls for further research to optimize the use of flavonoid nanoformulations in clinical trials, leading to innovative treatment strategies and more effective approaches for PC.
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Affiliation(s)
- Helen Helen
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Mega Carensia Gunawan
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Princella Halim
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Muhammad Riza Dinata
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Amer Ahmed
- Department of Bioscience, Biotechnology and Environment, University of Bari, Bari, Italy
| | - Aminah Dalimunthe
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Marianne Marianne
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Rosy Iara Maciel De Azambuja Ribeiro
- Experimental Pathology Laboratory, Federal University of São João del Rei (UFSJ), 400, Sebastião Gonçalves Coelho, Chanadour, Divinópolis 35501-296, MG, Brazil
| | | | - Fahrul Nurkolis
- Biological Sciences, Faculty of Sciences and Technology, UIN Sunan Kalijaga, Yogyakarta, Indonesia
| | - Evamarie Hey-Hawkins
- Leipzig University, Faculty of Chemistry and Mineralogy, Centre for Biotechnology and Biomedicine (BBZ), Institute of Bioanalytical Chemistry, Deutscher Platz 5, 04103 Leipzig, Germany
| | - Moon Nyeo Park
- Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea; College of Korean Medicine, Kyung Hee University, Hoegidong, Dongdaemungu, Seoul, 05253, Republic of Korea
| | - Urip Harahap
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Sung-Hoon Kim
- Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Bonglee Kim
- Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea; College of Korean Medicine, Kyung Hee University, Hoegidong, Dongdaemungu, Seoul, 05253, Republic of Korea
| | - Rony Abdi Syahputra
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia.
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Saadh MJ, Ahmed HH, Singh A, Mustafa MA, Al Zuhairi RAH, Ghildiyal P, Jawad MJ, Alsaikhan F, Khalilollah S, Akhavan-Sigari R. Small molecule and big function: MicroRNA-mediated apoptosis in rheumatoid arthritis. Pathol Res Pract 2024; 261:155508. [PMID: 39116571 DOI: 10.1016/j.prp.2024.155508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 07/24/2024] [Accepted: 07/29/2024] [Indexed: 08/10/2024]
Abstract
Rheumatoid arthritis (RA) is a common autoimmune condition and chronic inflammatory disease, mostly affecting synovial joints. The complex pathogenesis of RA is supportive of high morbidity, disability, and mortality rates. Pathological changes a common characteristic in RA synovial tissue is attributed to the inadequacy of apoptotic pathways. In that regard, apoptotic pathways have been the center of attention in RA therapeutic approaches. As the regulators in the complex network of apoptosis, microRNAs (miRNAs) are found to be vital modulators in both intrinsic and extrinsic pathways through altering their regulatory genes. Indeed, miRNA, a member of the family of non-coding RNAs, are found to be an important player in not even apoptosis, but proliferation, gene expression, signaling pathways, and angiogenesis. Aberrant expression of miRNAs is implicated in attenuation and/or intensification of various apoptosis routes, resulting in culmination of human diseases including RA. Considering the need for more studies focused on the underlying mechanisms of RA in order to elevate the unsatisfactory clinical treatments, this study is aimed to delineate the importance of apoptosis in the pathophysiology of this disease. As well, this review is focused on the critical role of miRNAs in inducing or inhibiting apoptosis of RA-synovial fibroblasts and fibroblast-like synoviocytes and how this mechanism can be exerted for therapeutic purposes for RA.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan.
| | | | - Anamika Singh
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Mohammed Ahmed Mustafa
- School of Pharmacy-Adarsh Vijendra Institute of Pharmaceutical Sciences, Shobhit University, Gangoh, Uttar Pradesh-247341, India; Department of Pharmacy, Arka Jain University, Jamshedpur, Jharkhand- 831001, India.
| | | | - Pallavi Ghildiyal
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India.
| | | | - Fahad Alsaikhan
- College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj, Saudi Arabia; School of Pharmacy, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia.
| | - Shayan Khalilollah
- Department of Neurosurgery, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Germany; Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University Warsaw, Poland
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10
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Singh VK, Rajak N, Singh Y, Singh AK, Giri R, Garg N. Role of MicroRNA-21 in Prostate Cancer Progression and Metastasis: Molecular Mechanisms to Therapeutic Targets. Ann Surg Oncol 2024; 31:4795-4808. [PMID: 38758485 DOI: 10.1245/s10434-024-15453-z] [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: 06/22/2023] [Accepted: 04/29/2024] [Indexed: 05/18/2024]
Abstract
The role of noncoding RNA has made remarkable progress in understanding progression, metastasis, and metastatic castration-resistant prostate cancer (mCRPC). A better understanding of the miRNAs has enhanced our knowledge of their targeting mainly at the therapy level in solid tumors, such as prostate cancer (PCa). microRNAs (miRNAs) belong to a class of endogenous RNA that deficit encoded proteins. Therefore, the role of miRNAs has been well-coined in the progression and development of PCa. miR-21 has a dual nature in its work both as a tumor suppressor and oncogenic role, but most of the recent studies showed that miR-21 is a tumor promoter and also is involved in castration-resistant prostate cancer (CRPC). Upregulation of miR-21 suppresses programmed cell death and inducing metastasis and castration resistant in PCa. miR-21 is involved in the different stages, such as proliferation, angiogenesis, migration, and invasion, and plays an important role in the progression, metastasis, and advanced stages of PCa. Recently, various studies directly linked the role of high levels of miR-21 with a poor therapeutic response in the patient of PCa. In the present review, we have explained the molecular mechanisms/pathways of miR-21 in PCa progression, metastasis, and castration resistant and summarized the role of miR-21 in diagnosis and therapeutic levels in PCa. In addition, we have spotlighted the recent therapeutic strategies for targeting different stages of PCa.
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Affiliation(s)
- Vipendra Kumar Singh
- School of Biosciences and Bioengineering, Indian Institute of Technology Mandi, VPO Kamand, Mandi, Himachal Pradesh, India
- Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, D.C., DC, USA
| | - Naina Rajak
- Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India
| | - Yashasvi Singh
- Department of Urology, Faculty of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India
| | - Ankit Kumar Singh
- University Department of Botany Lalit Narayan Mithila University, Darbhanga, Bihar, India
| | - Rajanish Giri
- School of Biosciences and Bioengineering, Indian Institute of Technology Mandi, VPO Kamand, Mandi, Himachal Pradesh, India
| | - Neha Garg
- Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India.
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11
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Vahidi S, Agah S, Mirzajani E, Asghari Gharakhyli E, Norollahi SE, Rahbar Taramsari M, Babaei K, Samadani AA. microRNAs, oxidative stress, and genotoxicity as the main inducers in the pathobiology of cancer development. Horm Mol Biol Clin Investig 2024; 45:55-73. [PMID: 38507551 DOI: 10.1515/hmbci-2023-0012] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 03/06/2024] [Indexed: 03/22/2024]
Abstract
Cancer is one of the most serious leading causes of death in the world. Many eclectic factors are involved in cancer progression including genetic and epigenetic alongside environmental ones. In this account, the performance and fluctuations of microRNAs are significant in cancer diagnosis and treatment, particularly as diagnostic biomarkers in oncology. So, microRNAs manage and control the gene expression after transcription by mRNA degradation, or also they can inhibit their translation. Conspicuously, these molecular structures take part in controlling the cellular, physiological and pathological functions, which many of them can accomplish as tumor inhibitors or oncogenes. Relatively, Oxidative stress is defined as the inequality between the creation of reactive oxygen species (ROS) and the body's ability to detoxify the reactive mediators or repair the resulting injury. ROS and microRNAs have been recognized as main cancer promoters and possible treatment targets. Importantly, genotoxicity has been established as the primary reason for many diseases as well as several malignancies. The procedures have no obvious link with mutagenicity and influence the organization, accuracy of the information, or fragmentation of DNA. Conclusively, mutations in these patterns can lead to carcinogenesis. In this review article, we report the impressive and practical roles of microRNAs, oxidative stress, and genotoxicity in the pathobiology of cancer development in conjunction with their importance as reliable cancer biomarkers and their association with circulating miRNA, exosomes and exosomal miRNAs, RNA remodeling, DNA methylation, and other molecular elements in oncology.
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Affiliation(s)
- Sogand Vahidi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shahram Agah
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ebrahim Mirzajani
- Department of Biochemistry and Biophysics, School of Medicine, 37554 Guilan University of Medical Sciences , Rasht, Iran
| | | | - Seyedeh Elham Norollahi
- Cancer Research Center and Department of Immunology, Semnan University of Medical Sciences, Semnan, Iran
| | - Morteza Rahbar Taramsari
- Department of Forensic Medicine, School of Medicine, 37554 Guilan University of Medical Sciences , Rasht, Iran
| | - Kosar Babaei
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences, Rasht, Iran
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12
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Popov A, Hrudka J, Szabó A, Oliverius M, Šubrt Z, Vránová J, Ciprová V, Moravcová J, Mandys V. Expression of Selected miRNAs in Undifferentiated Carcinoma with Osteoclast-like Giant Cells (UCOGC) of the Pancreas: Comparison with Poorly Differentiated Pancreatic Ductal Adenocarcinoma. Biomedicines 2024; 12:962. [PMID: 38790924 PMCID: PMC11117927 DOI: 10.3390/biomedicines12050962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 04/18/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC) of the pancreas represents a rare subtype of pancreatic ductal adenocarcinoma (PDAC). Despite a distinct morphology and specific clinical behavior, UCOGCs exhibit unexpected similarities in regard to DNA mutational profiles with conventional PDAC. Treating pancreatic ductal adenocarcinoma is particularly challenging, with limited prospects for cure. As with many other malignant neoplasms, the exploration of microRNAs (miRNAs, miRs) in regulating the biological characteristics of pancreatic cancer is undergoing extensive investigation to enhance tumor diagnostics and unveil the therapeutic possibilities. Herein, we evaluated the expression of miR-21, -96, -148a, -155, -196a, -210, and -217 in UCOGCs and poorly differentiated (grade 3, G3) PDACs. The expression of miR-21, miR-155, and miR-210 in both UCOGCs and G3 PDACs was significantly upregulated compared to the levels in normal tissue, while the levels of miR-148a and miR-217 were downregulated. We did not find any significant differences between cancerous and normal tissues for the expression of miR-96 and miR-196a in G3 PDACs, whereas miR-196a was slightly, but significantly, downregulated in UCOGCs. On the other hand, we have not observed significant differences in the expression of the majority of miRNAs between UCOGC and G3 PDAC, with the exception of miR-155. UCOGC samples demonstrated lower mean levels of miR-155 in comparison with those in G3 PDACs.
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Affiliation(s)
- Alexey Popov
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
| | - Jan Hrudka
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
| | - Arpád Szabó
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
| | - Martin Oliverius
- Department of Surgery, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (M.O.); (Z.Š.)
| | - Zdeněk Šubrt
- Department of Surgery, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (M.O.); (Z.Š.)
| | - Jana Vránová
- Department of Medical Biophysics and Medical Informatics, 3rd Faculty of Medicine, Charles University, 100 00 Prague, Czech Republic;
| | - Vanda Ciprová
- Institute of Pathology, 1st Faculty of Medicine, Charles University, General University Hospital, 100 00 Prague, Czech Republic
| | - Jana Moravcová
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
- Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, 140 00 Prague, Czech Republic
| | - Václav Mandys
- Department of Pathology, 3rd Faculty of Medicine, Charles University, University Hospital Královské Vinohrady, 100 00 Prague, Czech Republic; (A.P.); (A.S.)
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13
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Madadjim R, An T, Cui J. MicroRNAs in Pancreatic Cancer: Advances in Biomarker Discovery and Therapeutic Implications. Int J Mol Sci 2024; 25:3914. [PMID: 38612727 PMCID: PMC11011772 DOI: 10.3390/ijms25073914] [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: 02/20/2024] [Revised: 03/28/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
Pancreatic cancer remains a formidable malignancy characterized by high mortality rates, primarily attributable to late-stage diagnosis and a dearth of effective therapeutic interventions. The identification of reliable biomarkers holds paramount importance in enhancing early detection, prognostic evaluation, and targeted treatment modalities. Small non-coding RNAs, particularly microRNAs, have emerged as promising candidates for pancreatic cancer biomarkers in recent years. In this review, we delve into the evolving role of cellular and circulating miRNAs, including exosomal miRNAs, in the diagnosis, prognosis, and therapeutic targeting of pancreatic cancer. Drawing upon the latest research advancements in omics data-driven biomarker discovery, we also perform a case study using public datasets and address commonly identified research discrepancies, challenges, and limitations. Lastly, we discuss analytical approaches that integrate multimodal analyses incorporating clinical and molecular features, presenting new insights into identifying robust miRNA-centric biomarkers.
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Affiliation(s)
| | | | - Juan Cui
- School of Computing, University of Nebraska—Lincoln, Lincoln, NE 68588, USA; (R.M.); (T.A.)
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14
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Damiescu R, Efferth T, Dawood M. Dysregulation of different modes of programmed cell death by epigenetic modifications and their role in cancer. Cancer Lett 2024; 584:216623. [PMID: 38246223 DOI: 10.1016/j.canlet.2024.216623] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/19/2023] [Accepted: 01/07/2024] [Indexed: 01/23/2024]
Abstract
Modifications of epigenetic factors affect our lives and can give important information regarding one's state of health. In cancer, epigenetic modifications play a crucial role, as they influence various programmed cell death types. The purpose of this review is to investigate how epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNAs, influence various cell death processes in suppressing or promoting cancer development. Autophagy and apoptosis are the most investigated programmed cell death modes, as based on the tumor stage these cell death types can either promote or prevent cancer evolution. Therefore, our discussion focuses on how epigenetic modifications affect autophagy and apoptosis, as well as their diagnostic and therapeutical potential in combination with available chemotherapeutics. Additionally, we summarize the available data regarding the role of epigenetic modifications on other programmed cell death modes, such as ferroptosis, necroptosis, and parthanatos in cancer and discuss current advancements.
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Affiliation(s)
- R Damiescu
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, Mainz, Germany
| | - T Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, Mainz, Germany
| | - M Dawood
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, Mainz, Germany.
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15
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Vahabi M, Xu G, Avan A, Peters GJ, Giovannetti E. Pharmacological mechanisms underlying the interaction of the nucleoside analogue gemcitabine with the c-MET inhibitor tivantinib in pancreatic cancer. NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2024; 43:837-850. [PMID: 38420938 DOI: 10.1080/15257770.2024.2319215] [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: 12/01/2023] [Revised: 02/06/2024] [Accepted: 02/11/2024] [Indexed: 03/02/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with limited treatment options, highlighting the urgent need for innovative approaches. A promising target for new anticancer therapies across various tumor types is the receptor tyrosine kinase c-MET. Here, we examined the impact of the c-MET inhibitor tivantinib in combination with gemcitabine on both primary and immortalized PDAC cells, and we investigated the mechanism underlying this combined treatment's effects. Our findings demonstrate that tivantinib is synergistic with gemcitabine, which is not related to cytidine deaminase but to inhibition of the polymerization of tubulin. Moreover, these drugs affected the expression of microRNAs miR-21 and miR-34, which regulate key oncogenic pathways. These findings might have an impact on the selection of patients for future trials.
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Affiliation(s)
- Mahrou Vahabi
- Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Geng Xu
- Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Godefridus J Peters
- Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
| | - Elisa Giovannetti
- Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Fondazione Pisana per la Scienza, Pisa, Italy
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16
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Yang M, Li T, Guo S, Song K, Gong C, Huang N, Pang D, Xiao H. CVD phenotyping in oncologic disorders: cardio-miRNAs as a potential target to improve individual outcomes in revers cardio-oncology. J Transl Med 2024; 22:50. [PMID: 38216965 PMCID: PMC10787510 DOI: 10.1186/s12967-023-04680-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 10/28/2023] [Indexed: 01/14/2024] Open
Abstract
With the increase of aging population and prevalence of obesity, the incidence of cardiovascular disease (CVD) and cancer has also presented an increasing tendency. These two different diseases, which share some common risk factors. Relevant studies in the field of reversing Cardio-Oncology have shown that the phenotype of CVD has a significant adverse effect on tumor prognosis, which is mainly manifested by a positive correlation between CVD and malignant progression of concomitant tumors. This distal crosstalk and the link between different diseases makes us aware of the importance of diagnosis, prediction, management and personalized treatment of systemic diseases. The circulatory system bridges the interaction between CVD and cancer, which suggests that we need to fully consider the systemic and holistic characteristics of these two diseases in the process of clinical treatment. The circulating exosome-miRNAs has been intrinsically associated with CVD -related regulation, which has become one of the focuses on clinical and basic research (as biomarker). The changes in the expression profiles of cardiovascular disease-associated miRNAs (Cardio-miRNAs) may adversely affect concomitant tumors. In this article, we sorted and screened CVD and tumor-related miRNA data based on literature, then summarized their commonalities and characteristics (several important pathways), and further discussed the conclusions of Cardio-Oncology related experimental studies. We take a holistic approach to considering CVD as a risk factor for tumor malignancy, which provides an in-depth analysis of the various regulatory mechanisms or pathways involved in the dual attribute miRNAs (Cardio-/Onco-miRNAs). These mechanisms will be key to revealing the systemic effects of CVD on tumors and highlight the holistic nature of different diseases. Therefore, the Cardio-miRNAs should be given great attention from researchers in the field of CVD and tumors, which might become new targets for tumor treatment. Meanwhile, based on the principles of precision medicine (such as the predictive preventive personalized medicine, 3PM) and reverse Cardio-oncology to better improve individual outcomes, we should consider developing personalized medicine and systemic therapy for cancer from the perspective of protecting cardiovascular function.
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Affiliation(s)
- Ming Yang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- The Lab of Aging Research, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Tiepeng Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shujin Guo
- Department of Health Management & Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Kangping Song
- Rehabilitation Medicine Center, West China Hospital, Sichuan University, Chengdu, China
| | - Chuhui Gong
- The Lab of Aging Research, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Ning Huang
- The Lab of Aging Research, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Dejiang Pang
- Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatric, West China Hospital, Sichuan University, Chengdu, China.
| | - Hengyi Xiao
- The Lab of Aging Research, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
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17
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Abulsoud AI, Elshaer SS, Abdelmaksoud NM, Zaki MB, El-Mahdy HA, Ismail A, Al-Noshokaty TM, Fathi D, Abdel-Reheim MA, Mohammed OA, Doghish AS. Investigating the regulatory role of miRNAs as silent conductors in the management of pathogenesis and therapeutic resistance of pancreatic cancer. Pathol Res Pract 2023; 251:154855. [PMID: 37806169 DOI: 10.1016/j.prp.2023.154855] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 09/16/2023] [Accepted: 10/02/2023] [Indexed: 10/10/2023]
Abstract
Pancreatic cancer (PC) has the greatest mortality rate of all the main malignancies. Its advanced stage and poor prognosis place it at the bottom of all cancer sites. Hence, emerging biomarkers can enable precision medicine where PC therapy is tailored to each patient. This highlights the need for new, highly sensitive and specific biomarkers for early PC diagnosis. Prognostic indicators are also required to stratify PC patients. To avoid ineffective treatment, adverse events, and expenses, biomarkers are also required for patient monitoring and identifying responders to treatment. There is substantial evidence that microRNAs (miRs, miRNAs) play a critical role in regulating mRNA and, as a consequence, protein expression in normal and malignant tissues. Deregulated miRNA profiling in PC can help with diagnosis, treatment planning, and prognosis. Furthermore, knowledge of the primary effector genes and downstream pathways in PC can help pinpoint potential miRNAs for use in treatment. Different miRNA expression profiles may serve as diagnostic, prognostic markers, and therapeutic targets across the spectrum of malignant pancreatic illness. Dysregulation of miRNAs has been linked to the malignant pathophysiology of PC through affecting many cellular functions such as increasing invasive and proliferative prospect, supporting angiogenesis, cell cycle aberrance, apoptosis elusion, metastasis promotion, and low sensitivity to particular treatments. Accordingly, in the current review, we summarize the recent advances in the roles of oncogenic and tumor suppressor (TS) miRNAs in PC and discuss their potential as worthy diagnostic and prognostic biomarkers for PC, as well as their significance in PC pathogenesis and anticancer drug resistance.
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Affiliation(s)
- Ahmed I Abulsoud
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt; Department of Biochemistry and Biotechnology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Shereen Saeid Elshaer
- Department of Biochemistry and Biotechnology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Department of Biochemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr city, Cairo 11823, Egypt
| | - Nourhan M Abdelmaksoud
- Department of Biochemistry and Biotechnology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt
| | - Hesham A El-Mahdy
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt.
| | - Ahmed Ismail
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt
| | - Tohada M Al-Noshokaty
- Department of Biochemistry and Biotechnology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Doaa Fathi
- Department of Biochemistry and Biotechnology, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef 62521, Egypt.
| | - Osama A Mohammed
- Department of Clinical Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231 Cairo, Egypt.
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18
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Harman RM, Das SP, Kanke M, Sethupathy P, Van de Walle GR. miRNA-214-3p stimulates carcinogen-induced mammary epithelial cell apoptosis in mammary cancer-resistant species. Commun Biol 2023; 6:1006. [PMID: 37789172 PMCID: PMC10547694 DOI: 10.1038/s42003-023-05370-4] [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: 10/25/2022] [Accepted: 09/18/2023] [Indexed: 10/05/2023] Open
Abstract
Mammary cancer incidence varies greatly across species and underlying mechanisms remain elusive. We previously showed that mammosphere-derived epithelial cells from species with low mammary cancer incidence, such as horses, respond to carcinogen 7, 12-Dimethylbenz(a)anthracene-induced DNA damage by undergoing apoptosis, a postulated anti-cancer mechanism. Additionally, we found that miR-214-3p expression in mammosphere-derived epithelial cells is lower in mammary cancer-resistant as compared to mammary cancer-susceptible species. Here we show that increasing miR-214 expression and decreasing expression of its target gene nuclear factor kappa B subunit 1 in mammosphere-derived epithelial cells from horses abolishes 7,12-Dimethylbenz(a)anthracene-induced apoptosis. A direct interaction of miR-214-3p with another target gene, unc-5 netrin receptor A, is also demonstrated. We propose that relatively low levels of miR-214 in mammosphere-derived epithelial cells from mammals with low mammary cancer incidence, allow for constitutive gene nuclear factor kappa B subunit 1 expression and apoptosis in response to 7, 12-Dimethylbenz(a)anthracene. Better understanding of the mechanisms regulating cellular responses to carcinogens improves our overall understanding of mammary cancer resistance mechanisms.
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Affiliation(s)
- Rebecca M Harman
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Sanjna P Das
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Matt Kanke
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Praveen Sethupathy
- Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA
| | - Gerlinde R Van de Walle
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
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19
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Vahabi M, Dehni B, Antomás I, Giovannetti E, Peters GJ. Targeting miRNA and using miRNA as potential therapeutic options to bypass resistance in pancreatic ductal adenocarcinoma. Cancer Metastasis Rev 2023; 42:725-740. [PMID: 37490255 PMCID: PMC10584721 DOI: 10.1007/s10555-023-10127-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 07/12/2023] [Indexed: 07/26/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with poor prognosis due to early metastasis, low diagnostic rates at early stages, and resistance to current therapeutic regimens. Despite numerous studies and clinical trials, the mortality rate for PDAC has shown limited improvement. Therefore, there is a pressing need to attain. a more comprehensive molecular characterization to identify biomarkers enabling early detection and evaluation of treatment response. MicroRNA (miRNAs) are critical regulators of gene expression on the post-transcriptional level, and seem particularly interesting as biomarkers due to their relative stability, and the ability to detect them in fixed tissue specimens and biofluids. Deregulation of miRNAs is common and affects several hallmarks of cancer and contribute to the oncogenesis and metastasis of PDAC. Unique combinations of upregulated oncogenic miRNAs (oncomiRs) and downregulated tumor suppressor miRNAs (TsmiRs), promote metastasis, characterize the tumor and interfere with chemosensitivity of PDAC cells. Here, we review several oncomiRs and TsmiRs involved in chemoresistance to gemcitabine and FOLFIRINOX in PDAC and highlighted successful/effective miRNA-based therapy approaches in vivo. Integrating miRNAs in PDAC treatment represents a promising therapeutic avenue that can be used as guidance for personalized medicine for PDAC patients.
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Affiliation(s)
- Mahrou Vahabi
- Department of Medical Oncology, Amsterdam UMC, location VUMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Bilal Dehni
- Department of Medical Oncology, Amsterdam UMC, location VUMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Inés Antomás
- Department of Medical Oncology, Amsterdam UMC, location VUMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Elisa Giovannetti
- Department of Medical Oncology, Amsterdam UMC, location VUMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana per La Scienza, Pisa, Italy
| | - Godefridus J Peters
- Department of Medical Oncology, Amsterdam UMC, location VUMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands.
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland.
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20
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Gupta J, Suliman M, Ali R, Margiana R, Hjazi A, Alsaab HO, Qasim MT, Hussien BM, Ahmed M. Double-edged sword role of miRNA-633 and miRNA-181 in human cancers. Pathol Res Pract 2023; 248:154701. [PMID: 37542859 DOI: 10.1016/j.prp.2023.154701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 07/16/2023] [Accepted: 07/18/2023] [Indexed: 08/07/2023]
Abstract
Understanding the function and mode of operation of microRNAs (miRNAs) in cancer is of growing interest. The short non-coding RNAs known as miRNAs, which target mRNA in multicellular organisms, are described as controlling essential cellular processes. The miR-181 family and miR-633 are well-known miRNAs that play a key role in the development and metastasis of tumor cells. They may facilitate either tumor-suppressive or oncogenic function in malignant cells, according to mounting evidence. Metastatic cells that are closely linked to cancer cell migration, invasion, and angiogenesis can be identified by abnormal levels of miR-181 and miR-633. Numerous studies have demonstrated their capacity to control drug resistance, cell growth, apoptosis, and the epithelial-mesenchymal transition (EMT) and metastasis process. Interestingly, the levels of miR-181 and miR-633 and their potential target genes in the basic cellular process can vary depending on the type of cancer cells and their gene expression profile. Such miRNAs' interactions with other non-coding RNAs such as long non-coding RNAs and circular RNAs can influence tumor behaviors. Herein, we concentrated on the multifaceted roles of miR-181 and miR-633 and potential targets in human tumorigenesis, ranging from cell growth and metastasis to drug resistance.
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Affiliation(s)
- Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura 281406, U. P., India.
| | - Muath Suliman
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Rida Ali
- Rawalpindi Medical University, Rawalpindi, Pakistan
| | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; Dr. Soetomo General Academic Hospital, Surabaya, Indonesia.
| | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Beneen M Hussien
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Muhja Ahmed
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
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21
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Tazeoglu D, Benli S, Colak T, Apaydin FD. Comparative analysis of the sarcopenia and HALP score on postoperative outcomes in pancreatic cancer patients after pancreatoduodenectomy. Pancreatology 2023; 23:530-536. [PMID: 37210304 DOI: 10.1016/j.pan.2023.05.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 04/13/2023] [Accepted: 05/14/2023] [Indexed: 05/22/2023]
Abstract
BACKGROUND Sarcopenia and HALP (Hemoglobin, Albumin, Lymphocyte, and Platelet) scores are factors commonly associated with postoperative outcomes used in cancer patients. This study aims to evaluate the effect of these two prognostic factors on postoperative outcomes in operated pancreatic cancer patients and their correlation with each other. METHODS The study is a single-center, retrospective study conducted with 179 patients diagnosed with pancreatic adenocarcinoma after pancreatoduodenectomy (PD) between January 2012 and January 2022. The Psoas muscular index (PMI) and HALP scores of the patients were calculated. Cut-off values were determined in order to determine the nutritional status of the patients and to group them. The cut-off value of the HALP score was determined according to survival status. In addition, the clinical data and pathological findings of tumors were collected. These two parameters were evaluated in terms of length of hospital stay, postoperative complication rates, fistula development, and overall survival, and their correlations with each other were examined. RESULTS Of the patients, 74 (41.3%) were female, and 105 (58.7%) were male. According to PMI cut-off values, 83 (46.4%) patients were in the sarcopenia group. According to the HALP score cut-off values, 77 (43.1%) patients were in the low HALP group. Sarcopenia and Low HALP group had a higher risk of death (respectively Hazard ratio:5.67, CI:3.58-8.98, Hazard ratio:5.95, CI: 3.72-9.52) (p < 0.001). There was a moderate correlation between PMI and HALP score (rs = 0.34, p = 0.01). The correlation in these values was higher in the female gender. CONCLUSIONS In line with the data obtained from our study, HALP score and sarcopenia are among the important parameters used to evaluate postoperative complications and provide information about survival. Patients with a low HALP score and sarcopenic have an increased likelihood of developing postoperative complications and a lower survival.
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Affiliation(s)
- Deniz Tazeoglu
- Department of General Surgery, Faculty of Medicine, Mersin University, Mersin, Turkey.
| | - Sami Benli
- Department of General Surgery, Faculty of Medicine, Mersin University, Mersin, Turkey.
| | - Tahsin Colak
- Department of General Surgery, Faculty of Medicine, Mersin University, Mersin, Turkey.
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22
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Wei L, Sun J, Wang X, Huang Y, Huang L, Han L, Zheng Y, Xu Y, Zhang N, Yang M. Noncoding RNAs: an emerging modulator of drug resistance in pancreatic cancer. Front Cell Dev Biol 2023; 11:1226639. [PMID: 37560164 PMCID: PMC10407809 DOI: 10.3389/fcell.2023.1226639] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/17/2023] [Indexed: 08/11/2023] Open
Abstract
Pancreatic cancer is the eighth leading cause of cancer-related deaths worldwide. Chemotherapy including gemcitabine, 5-fluorouracil, adriamycin and cisplatin, immunotherapy with immune checkpoint inhibitors and targeted therapy have been demonstrated to significantly improve prognosis of pancreatic cancer patients with advanced diseases. However, most patients developed drug resistance to these therapeutic agents, which leading to shortened patient survival. The detailed molecular mechanisms contributing to pancreatic cancer drug resistance remain largely unclear. The growing evidences have shown that noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are involved in pancreatic cancer pathogenesis and development of drug resistance. In the present review, we systematically summarized the new insight on of various miRNAs, lncRNAs and circRNAs on drug resistance of pancreatic cancer. These results demonstrated that targeting the tumor-specific ncRNA may provide novel options for pancreatic cancer treatments.
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Affiliation(s)
- Ling Wei
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jujie Sun
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Xingwu Wang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yizhou Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Linying Huang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Linyu Han
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yanxiu Zheng
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yuan Xu
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Nasha Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
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23
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Kunwar A, Ablordeppey KK, Mireskandari A, Sheinerman K, Kiefer M, Umansky S, Kumar G. Analytical Validation of a Novel MicroRNA Panel for Risk Stratification of Cognitive Impairment. Diagnostics (Basel) 2023; 13:2170. [PMID: 37443567 DOI: 10.3390/diagnostics13132170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
We have been developing a novel approach to identify cognitive impairment-related biomarkers by profiling brain-enriched and inflammation-associated microRNA (miRNA) in plasma specimens of cognitively unimpaired and cognitively impaired patients. Here, we present an analytical validation of the novel miRNA panel, CogniMIR®, using two competing quantitative PCR technologies for the expression analysis of 24 target miRNAs. Total RNA from the plasma specimens was isolated using the MagMAX mirVana Kit, and RT-qPCR was performed using stem-loop-based TaqMan and LNA-based qPCR assays. Evaluation of RNA dilution series for our target 24 miRNAs, performed by two operators on two different days, demonstrated that all CogniMIR® panel miRNAs can be reliably and consistently detected by both qPCR technologies, with sample input as low as 20 copies in a qPCR reaction. Intra-run and inter-run repeatability and reproducibility analyses using RNA specimens demonstrated that both operators generated repeatable and consistent Cts, with R2 values of 0.94 to 0.99 and 0.96 to 0.97, respectively. The study results clearly indicate the suitability of miRNA profiling of plasma specimens using either of the qPCR technologies. However, the LNA-based qPCR technology appears to be more operationally friendly and better suited for a CAP/CLIA-certified clinical laboratory.
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Affiliation(s)
- Arzu Kunwar
- DiamiR Biosciences Laboratory, 2 Church Street South, Suite B05, New Haven, CT 06519, USA
| | | | - Alidad Mireskandari
- DiamiR Biosciences Laboratory, 2 Church Street South, Suite B05, New Haven, CT 06519, USA
| | - Kira Sheinerman
- DiamiR Biosciences Laboratory, 2 Church Street South, Suite B05, New Haven, CT 06519, USA
| | - Michael Kiefer
- DiamiR Biosciences Laboratory, 2 Church Street South, Suite B05, New Haven, CT 06519, USA
| | - Samuil Umansky
- DiamiR Biosciences Laboratory, 2 Church Street South, Suite B05, New Haven, CT 06519, USA
| | - Gyanendra Kumar
- DiamiR Biosciences Laboratory, 2 Church Street South, Suite B05, New Haven, CT 06519, USA
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24
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Roy JW, Wajnberg G, Ouellette A, Boucher JE, Lacroix J, Chacko S, Ghosh A, Ouellette RJ, Lewis SM. Small RNA sequencing analysis of peptide-affinity isolated plasma extracellular vesicles distinguishes pancreatic cancer patients from non-affected individuals. Sci Rep 2023; 13:9251. [PMID: 37286718 DOI: 10.1038/s41598-023-36370-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 06/02/2023] [Indexed: 06/09/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a high fatality rate, mainly due to its asymptomatic nature until late-stage disease and therefore delayed diagnosis that leads to a lack of timely treatment intervention. Consequently, there is a significant need for better methods to screen populations that are at high risk of developing PDAC. Such advances would result in earlier diagnosis, more treatment options, and ultimately better outcomes for patients. Several recent studies have applied the concept of liquid biopsy, which is the sampling of a biofluid (such as blood plasma) for the presence of disease biomarkers, to develop screening approaches for PDAC; several of these studies have focused on analysis of extracellular vesicles (EVs) and their cargoes. While these studies have identified many potential biomarkers for PDAC that are present within EVs, their application to clinical practice is hindered by the lack of a robust, reproducible method for EV isolation and analysis that is amenable to a clinical setting. Our previous research has shown that the Vn96 synthetic peptide is indeed a robust and reproducible method for EV isolation that has the potential to be used in a clinical setting. We have therefore chosen to investigate the utility of the Vn96 synthetic peptide for this isolation of EVs from human plasma and the subsequent detection of small RNA biomarkers of PDAC by Next-generation sequencing (NGS) analysis. We find that analysis of small RNA from Vn96-isolated EVs permits the discrimination of PDAC patients from non-affected individuals. Moreover, analyses of all small RNA species, miRNAs, and lncRNA fragments are most effective at segregating PDAC patients from non-affected individuals. Several of the identified small RNA biomarkers have been previously associated with and/or characterized in PDAC, indicating the validity of our findings, whereas other identified small RNA biomarkers may have novel roles in PDAC or cancer in general. Overall, our results provide a basis for a clinically-amendable detection and/or screening strategy for PDAC using a liquid biopsy approach that relies on Vn96-mediated isolation of EVs from plasma.
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Affiliation(s)
- Jeremy W Roy
- Atlantic Cancer Research Institute, Moncton, NB, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
| | | | | | | | | | - Simi Chacko
- Atlantic Cancer Research Institute, Moncton, NB, Canada
| | - Anirban Ghosh
- Atlantic Cancer Research Institute, Moncton, NB, Canada
| | - Rodney J Ouellette
- Atlantic Cancer Research Institute, Moncton, NB, Canada
- Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
- Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB, Canada
- Dr. Georges-L.-Dumont University Hospital Centre, Moncton, NB, Canada
| | - Stephen M Lewis
- Atlantic Cancer Research Institute, Moncton, NB, Canada.
- Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada.
- Department of Chemistry and Biochemistry, Université de Moncton, Moncton, NB, Canada.
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25
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Amaral MJ, Oliveira RC, Donato P, Tralhão JG. Pancreatic Cancer Biomarkers: Oncogenic Mutations, Tissue and Liquid Biopsies, and Radiomics-A Review. Dig Dis Sci 2023:10.1007/s10620-023-07904-6. [PMID: 36988759 DOI: 10.1007/s10620-023-07904-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 02/24/2023] [Indexed: 03/30/2023]
Abstract
Pancreatic cancer is one of the most fatal malignancies, as approximately 80% of patients are at advanced stages by the time of diagnosis. The main reason for the poor overall survival is late diagnosis that is partially due to the lack of tools for early-stage detection. In addition, there are several challenges in evaluating response to treatment and predicting prognosis. In this article, we do a review of the most common pancreatic cancer biomarkers with emphasis in new and promising approaches. Liquid biopsies seem to have important clinical applications in early detection, screening, prognosis, and longitudinal monitoring of on-treatment patients. Together with biomarkers in imaging, can represent valuable alternative non-invasive tools in order to achieve a more effective management of pancreatic cancer patients.
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Affiliation(s)
- Maria João Amaral
- General Surgery Department, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
| | - Rui Caetano Oliveira
- Pathology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Paulo Donato
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Radiology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - José Guilherme Tralhão
- General Surgery Department, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075, Coimbra, Portugal
- Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Coimbra Institute for Clinical and Biomedical Research (iCBR) Area of Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Biophysics Institute, University of Coimbra, Coimbra, Portugal
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26
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Li Y, Wu S, Zhao X, Hao S, Li F, Wang Y, Liu B, Zhang D, Wang Y, Zhou H. Key events in cancer: Dysregulation of SREBPs. Front Pharmacol 2023; 14:1130747. [PMID: 36969840 PMCID: PMC10030587 DOI: 10.3389/fphar.2023.1130747] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/22/2023] [Indexed: 03/11/2023] Open
Abstract
Lipid metabolism reprogramming is an important hallmark of tumor progression. Cancer cells require high levels of lipid synthesis and uptake not only to support their continued replication, invasion, metastasis, and survival but also to participate in the formation of biological membranes and signaling molecules. Sterol regulatory element binding proteins (SREBPs) are core transcription factors that control lipid metabolism and the expression of important genes for lipid synthesis and uptake. A growing number of studies have shown that SREBPs are significantly upregulated in human cancers and serve as intermediaries providing a mechanistic link between lipid metabolism reprogramming and malignancy. Different subcellular localizations, including endoplasmic reticulum, Golgi, and nucleus, play an indispensable role in regulating the cleavage maturation and activity of SREBPs. In this review, we focus on the relationship between aberrant regulation of SREBPs activity in three organelles and tumor progression. Because blocking the regulation of lipid synthesis by SREBPs has gradually become an important part of tumor therapy, this review also summarizes and analyzes several current mainstream strategies.
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Affiliation(s)
- Yunkuo Li
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Shouwang Wu
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Xiaodong Zhao
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Shiming Hao
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Faping Li
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Yuxiong Wang
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Bin Liu
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Difei Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
- *Correspondence: Yishu Wang, Honglan Zhou,
| | - Honglan Zhou
- Department of Urology, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Yishu Wang, Honglan Zhou,
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27
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Wnuk J, Strzelczyk JK, Gisterek I. Clinical Value of Circulating miRNA in Diagnosis, Prognosis, Screening and Monitoring Therapy of Pancreatic Ductal Adenocarcinoma-A Review of the Literature. Int J Mol Sci 2023; 24:ijms24065113. [PMID: 36982210 PMCID: PMC10049684 DOI: 10.3390/ijms24065113] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 02/28/2023] [Accepted: 03/04/2023] [Indexed: 03/30/2023] Open
Abstract
Pancreatic cancer (PC) is considered to be the seventh most common cause of cancer-related deaths. The number of deaths caused by PC is estimated to increase in the future. An early diagnosis of PC is crucial for improving treatment outcomes. The most common histopathological subtype of PC is pancreatic ductal adenocarcinoma (PDAC). MicroRNAs (miRNAs)-which are endogenous non-coding RNAs involved in the posttranscriptional regulation of multiple gene expression-constitute useful diagnostic and prognostic biomarkers in various neoplasms, including PDAC. Circulating miRNAs detected in a patient's serum or plasma are drawing more and more attention. Hence, this review aims at evaluating the clinical value of circulating miRNA in the screening, diagnosis, prognosis and monitoring of pancreatic ductal adenocarcinoma therapy.
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Affiliation(s)
- Jakub Wnuk
- Department of Oncology and Radiotherapy, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 35 Ceglana St., 40-515 Katowice, Poland
| | - Joanna Katarzyna Strzelczyk
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana St., 41-808 Zabrze, Poland
| | - Iwona Gisterek
- Department of Oncology and Radiotherapy, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 35 Ceglana St., 40-515 Katowice, Poland
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28
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Extracellular Vesicles and MicroRNA in Myelodysplastic Syndromes. Cells 2023; 12:cells12040658. [PMID: 36831325 PMCID: PMC9955013 DOI: 10.3390/cells12040658] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/09/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
The bone marrow niche plays an increasing role in the pathophysiogenesis of myelodysplastic syndromes. More specifically, mesenchymal stromal cells, which can secrete extracellular vesicles and their miRNA contents, modulate the fate of hematopoietic stem cells leading to leukemogenesis. Extracellular vesicles can mediate their miRNA and protein contents between nearby cells but also in the plasma of the patients, being potent tools for diagnosis and prognostic markers in MDS. They can be targeted by antisense miRNA or by modulators of the secretion of extracellular vesicles and could lead to future therapeutic directions in MDS.
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29
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Funamizu N, Honjo M, Tamura K, Sakamoto K, Ogawa K, Takada Y. microRNAs Associated with Gemcitabine Resistance via EMT, TME, and Drug Metabolism in Pancreatic Cancer. Cancers (Basel) 2023; 15:1230. [PMID: 36831572 PMCID: PMC9953943 DOI: 10.3390/cancers15041230] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Despite extensive research, pancreatic cancer remains a lethal disease with an extremely poor prognosis. The difficulty in early detection and chemoresistance to therapeutic agents are major clinical concerns. To improve prognosis, novel biomarkers, and therapeutic strategies for chemoresistance are urgently needed. microRNAs (miRNAs) play important roles in the development, progression, and metastasis of several cancers. During the last few decades, the association between pancreatic cancer and miRNAs has been extensively elucidated, with several miRNAs found to be correlated with patient prognosis. Moreover, recent evidence has revealed that miRNAs are intimately involved in gemcitabine sensitivity and resistance through epithelial-to-mesenchymal transition, the tumor microenvironment, and drug metabolism. Gemcitabine is the gold standard drug for pancreatic cancer treatment, but gemcitabine resistance develops easily after chemotherapy initiation. Therefore, in this review, we summarize the gemcitabine resistance mechanisms associated with aberrantly expressed miRNAs in pancreatic cancer, especially focusing on the mechanisms associated with epithelial-to-mesenchymal transition, the tumor microenvironment, and metabolism. This novel evidence of gemcitabine resistance will drive further research to elucidate the mechanisms of chemoresistance and improve patient outcomes.
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Affiliation(s)
- Naotake Funamizu
- Department of Hepatobiliary Pancreatic and Transplantation Surgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
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30
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Ali A, Jamieson NB, Khan IN, Chang D, Giovannetti E, Funel N, Frampton AE, Morton J, Sansom O, Evans TRJ, Duthie F, McKay CJ, Samra J, Gill AJ, Biankin A, Oien KA. Prognostic implications of microRNA-21 overexpression in pancreatic ductal adenocarcinoma: an international multicenter study of 686 patients. Am J Cancer Res 2022; 12:5668-5683. [PMID: 36628279 PMCID: PMC9827095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/27/2022] [Indexed: 01/12/2023] Open
Abstract
Despite progress in genomic characterization, no single prognostic marker that can be evaluated using an easy-to-perform and relatively inexpensive method is available for pancreatic ductal adenocarcinoma (PDAC). MicroRNAs, which are stable, tumor- and tissue-specific molecules, are potentially ideal biomarkers, and we established an inter-laboratory validated method to investigate miR-21 as a prognostic biomarker in PDAC. The study samples of PDAC patients were recruited from a test cohort of Glasgow (n = 189) and three validation cohorts of Pisa (n = 69), Sydney (n = 249), and International Cancer Genome Consortium (ICGC) (n = 249). Tissue microarrays were used for miR-21 staining by chromogenic in situ hybridization (CISH). The patients were subdivided into no/low and high miR-21 staining groups using a specific histoscore. Furthermore, miR-21 staining was evaluated against clinicopathological variables and follow-up data by Fisher/log-rank test and Cox proportional models. The prognostic variables found to be significant in univariate analysis (P value < 0.10) were included in multivariate analysis in a backward-stepwise fashion. MiR-21 expression was cytoplasmic, with more consistent staining in the malignant ductal epithelium than in the stroma. The expression of miR-21 was significantly associated with tumor size and lymph node metastasis, whereas no association was observed with other clinicopathological variables. High miR-21 staining (histoscore ≥ 45 [median score]) was an independent predictor of survival in the Glasgow test cohort (HR 2.37, 95% CI: 1.42-3.96, P < 0.0001) and three validation cohorts (Pisa, HR 2.03, 95% CI: 1.21-3.39, P = 0.007; Sydney, HR 2.58, 95% CI (1.21-3.39), P < 0.0001; and ICGC, HR 3.34, 95% CI: 2.07-5.84, P = 0.002) when adjusted for clinical variables in a multivariate model. In comparison to the patients with low miR-21, the patients with high miR-21 expression had significant increase in OS as they benefit from gemcitabine-based adjuvant chemotherapy (Glasgow 16.5 months [with chemotherapy] vs 10.5 months [without chemotherapy]); Sydney 25.0 vs 10.6; ICGC 25.2 vs 11.9. These results indicated that miR-21 is a predictor of survival, prompting prospective trials. Evaluation of miR-21 offers new opportunities for the stratification of patients with PDAC and might facilitate the implementation of clinical management and therapeutic interventions for this devastating disease.
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Affiliation(s)
- Asif Ali
- Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of GlasgowUK
- Institute of Pathology and Diagnostic Medicine, Khyber Medical UniversityPeshawar, Pakistan
- Gulf Medical UniversityAjman, United Arab Emirates
| | - Nigel Balfour Jamieson
- Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of GlasgowUK
| | - Ishaq N Khan
- Department of Pharmaceutical Sciences, Texas A&M Health Science Center, Joe H. Reynolds Medical Bld, Texas A&M University, College StationUnited States
- Cancer Cell Culture & Precision Oncomedicine Lab, Institute of Basic Medical Sciences, Khyber Medical UniversityPeshawar, Pakistan
| | - David Chang
- Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of GlasgowUK
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical CenterAmsterdam, The Netherlands
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of PisaPisa, Italy
| | - Nicola Funel
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of PisaPisa, Italy
| | - Adam E Frampton
- Department of Surgery & Cancer, Imperial College, Hammersmith Hospital CampusDu Cane Road, London, UK
- Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County HospitalEgerton Road, Guildford, Surrey, GU2 7XX, UK
- Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of SurreyGuildford, Surrey, UK
| | - Jennifer Morton
- Beatson Institute for Cancer Research, University of GlasgowUK
| | - Owen Sansom
- Beatson Institute for Cancer Research, University of GlasgowUK
| | | | - Fraser Duthie
- Department of Pathology, Laboratory Medicine Building, Queen Elizabeth University HospitalGreater Glasgow & Clyde NHS
| | - Colin J McKay
- West of Scotland Pancreatic Unit and Glasgow Royal InfirmaryAlexandra Parade, Glasgow
| | - Jas Samra
- Department of Upper Gastrointestinal Surgery, Royal North Shore HospitalPacific Highway St Leonards, Australia
| | - Anthony J Gill
- Sydney Medical School, University of SydneySydney, Australia
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, and Health Pathology Department of Anatomical Pathology, Royal North Shore HospitalSt Leonards, NSW, Australia
- The Kinghorn Cancer Centre, The Garvan Institute of Medical ResearchDarlinghurst, Sydney, Australia
- The Australian Pancreatic Genome InitiativeDarlinghurst NSW 2010, Australia
| | - Andrew Biankin
- Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of GlasgowUK
| | - Karin A Oien
- Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of GlasgowUK
- Department of Pathology, Laboratory Medicine Building, Queen Elizabeth University HospitalGreater Glasgow & Clyde NHS
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31
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Yu YC, Ahmed A, Lai HC, Cheng WC, Yang JC, Chang WC, Chen LM, Shan YS, Ma WL. Review of the endocrine organ-like tumor hypothesis of cancer cachexia in pancreatic ductal adenocarcinoma. Front Oncol 2022; 12:1057930. [PMID: 36465353 PMCID: PMC9713001 DOI: 10.3389/fonc.2022.1057930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 10/26/2022] [Indexed: 08/30/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of solid tumors, associated with a high prevalence of cachexia (~80%). PDAC-derived cachexia (PDAC-CC) is a systemic disease involving the complex interplay between the tumor and multiple organs. The endocrine organ-like tumor (EOLT) hypothesis may explain the systemic crosstalk underlying the deleterious homeostatic shifts that occur in PDAC-CC. Several studies have reported a markedly heterogeneous collection of cachectic mediators, signaling mechanisms, and metabolic pathways, including exocrine pancreatic insufficiency, hormonal disturbance, pro-inflammatory cytokine storm, digestive and tumor-derived factors, and PDAC progression. The complexities of PDAC-CC necessitate a careful review of recent literature summarizing cachectic mediators, corresponding metabolic functions, and the collateral impacts on wasting organs. The EOLT hypothesis suggests that metabolites, genetic instability, and epigenetic changes (microRNAs) are involved in cachexia development. Both tumors and host tissues can secrete multiple cachectic factors (beyond only inflammatory mediators). Some regulatory molecules, metabolites, and microRNAs are tissue-specific, resulting in insufficient energy production to support tumor/cachexia development. Due to these complexities, changes in a single factor can trigger bi-directional feedback circuits that exacerbate PDAC and result in the development of irreversible cachexia. We provide an integrated review based on 267 papers and 20 clinical trials from PubMed and ClinicalTrials.gov database proposed under the EOLT hypothesis that may provide a fundamental understanding of cachexia development and response to current treatments.
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Affiliation(s)
- Ying-Chun Yu
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, Center for Tumor Biology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Azaj Ahmed
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
| | - Hsueh-Chou Lai
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Wei-Chung Cheng
- Graduate Institute of Biomedical Sciences, Center for Tumor Biology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Juan-Chern Yang
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Wei-Chun Chang
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, Center for Tumor Biology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Lu-Min Chen
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
| | - Yan-Shen Shan
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Chen Kung University, Tainan, Taiwan
| | - Wen-Lung Ma
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, Center for Tumor Biology, School of Medicine, China Medical University, Taichung, Taiwan
- Department of Nursing, Asia University, Taichung, Taiwan
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32
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Zhao Y, Dhani S, Zhivotovsky B. Unveiling caspase-2 regulation by non-coding RNAs. Cell Death Dis 2022; 13:834. [PMID: 36171196 PMCID: PMC9519946 DOI: 10.1038/s41419-022-05270-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 09/13/2022] [Accepted: 09/14/2022] [Indexed: 01/23/2023]
Abstract
Non-coding RNAs (ncRNAs) are a group of RNA molecules, such as small nucleolar RNAs, circular RNAs (circRNAs), microRNAs (miRNAs) and long-noncoding RNAs (ncRNAs), that do not encode proteins. Although their biofunctions are not well-understood, many regulatory ncRNAs appear to be highly involved in regulating the transcription and translation of several genes that have essential biological roles including cell differentiation, cell death, metabolism, tumorigenesis and so on. A growing number of studies have revealed the associations between dysregulated ncRNAs and caspases involved in cell death in numerous human diseases. As one of the initiator and executor caspases, caspase-2 is the most evolutionally conserved caspase in mammals, exerting both apoptotic and non-apoptotic functions. A great deal of studies has shown the involvement of caspase-2 as a tumor suppressor in multiple oncogene-driven cancers, and yet a comprehensive understanding of its biological roles remains largely unknown. In this review, we highlight a compilation of studies focused on the interaction between caspase-2 and miRNAs/lncRNAs in the context of different diseases in order to deepen our knowledge on the regulatory biofunctions of caspase-2 and, furthermore, provide more insight into understanding the role that ncRNAs/caspase-2 axis plays in the development of human diseases.
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Affiliation(s)
- Yun Zhao
- Institute of Environmental Medicine, Karolinska Institutet, Box 210, 17177, Stockholm, Sweden
| | - Shanel Dhani
- Institute of Environmental Medicine, Karolinska Institutet, Box 210, 17177, Stockholm, Sweden
| | - Boris Zhivotovsky
- Institute of Environmental Medicine, Karolinska Institutet, Box 210, 17177, Stockholm, Sweden.
- Faculty of Medicine, MV Lomonosov Moscow State University, 119991, Moscow, Russia.
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Rhim J, Baek W, Seo Y, Kim JH. From Molecular Mechanisms to Therapeutics: Understanding MicroRNA-21 in Cancer. Cells 2022; 11:cells11182791. [PMID: 36139366 PMCID: PMC9497241 DOI: 10.3390/cells11182791] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 11/29/2022] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that play an important role in regulating gene expression at a posttranscriptional level. As one of the first discovered oncogenic miRNAs, microRNA-21 (miR-21) has been highlighted for its critical role in cancers, such as glioblastoma, pancreatic adenocarcinoma, non-small cell lung cancer, and many others. MiR-21 targets many vital components in a wide range of cancers and acts on various cellular processes ranging from cancer stemness to cell death. Expression of miR-21 is elevated within cancer tissues and circulating miR-21 is readily detectable in biofluids, making it valuable as a cancer biomarker with significant potential for use in diagnosis and prognosis. Advances in RNA-based therapeutics have revealed additional avenues by which miR-21 can be utilized as a promising target in cancer. The purpose of this review is to outline the roles of miR-21 as a key modulator in various cancers and its potential as a therapeutic target.
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Affiliation(s)
- Jiho Rhim
- Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Korea
- Department of Cancer Biomedical Science, National Cancer Center, Graduate School of Cancer Science and Policy, Goyang 10408, Korea
| | - Woosun Baek
- Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Korea
- Department of Cancer Biomedical Science, National Cancer Center, Graduate School of Cancer Science and Policy, Goyang 10408, Korea
| | - Yoona Seo
- Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Korea
- Department of Cancer Biomedical Science, National Cancer Center, Graduate School of Cancer Science and Policy, Goyang 10408, Korea
| | - Jong Heon Kim
- Cancer Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Korea
- Department of Cancer Biomedical Science, National Cancer Center, Graduate School of Cancer Science and Policy, Goyang 10408, Korea
- Correspondence: ; Tel.: +82-31-920-2204
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Guo J, Jin K, Tang T, Liu HM, Xie YA. A new biomarker to enhance the radiosensitivity of hepatocellular cancer: miRNAs. Future Oncol 2022; 18:3217-3228. [PMID: 35968820 DOI: 10.2217/fon-2022-0136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aims: This review summarizes findings regarding miRNAs that modulate radiation in hepatocellular carcinoma (HCC) and evaluates their potential clinical therapeutic uses. Materials & methods: We searched the relevant English-language medical databases for papers on miRNAs and radiation therapy for tumors to identify miRNAs that are linked with radiosensitivity and radioresistance, focusing on those associated with HCC radiation. Results: There were 88 papers assessed for miRNAs associated with tumor radiation, 56 of which dealt with radiosensitization, 21 with radioresistance and 11 with radiosensitization for HCC. Conclusion: Further work in this area would enable future evaluation of radiation responses and the potential use of miRNAs as therapeutic agents in HCC patients.
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Affiliation(s)
- Ju Guo
- Graduate School of Guangxi Traditional Chinese Medical University, Nanning, Guangxi, 530299, PR China.,Guangxi Key Laboratory of Reproductive Health & Birth Defects Prevention, Nanning, Guangxi, 530002, PR China
| | - Kai Jin
- Graduate School of Guangxi Traditional Chinese Medical University, Nanning, Guangxi, 530299, PR China
| | - Ting Tang
- Graduate School of Guangxi Traditional Chinese Medical University, Nanning, Guangxi, 530299, PR China
| | - Hong-Mei Liu
- Department of Radiation Oncology, Affiliated Cancer Hospital of Guangxi Medical University & Cancer Institute of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, PR China
| | - Yu-An Xie
- Graduate School of Guangxi Traditional Chinese Medical University, Nanning, Guangxi, 530299, PR China.,Guangxi Key Laboratory of Reproductive Health & Birth Defects Prevention, Nanning, Guangxi, 530002, PR China.,Experimental Research Department, Affiliated Cancer Hospital of Guangxi Medical University & Cancer Institute of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, PR China.,Guangxi Zhuang Autonomous Region Women & Children Care Hospital, Nanning, Guangxi, 530002, PR China
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Yu L, Lu J, Xie H, Ni J, Chen S, Zhao Q, Xie N, Lu L, Wang X, Li B. RELA-induced MiR-21 Exerts Oncogenic Effects on PDAC via Targeting of ARHGAP24. J Cancer 2022; 13:2781-2797. [PMID: 35812178 PMCID: PMC9254878 DOI: 10.7150/jca.73690] [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: 04/06/2022] [Accepted: 05/25/2022] [Indexed: 11/05/2022] Open
Abstract
Inflammation is one of the inducing factors of pancreatic ductal adenocarcinoma (PDAC), and microRNAs have been confirmed to be involved in the occurrence and development of PDAC. However, whether RELA, an inflammatory regulator, is involved in the regulation of PDAC by miRNA remains to be further studied. In the present study miR-21 was characterized and its upstream regulatory mechanism was investigated, as well as its functional effects and target genes in pancreatic ductal adenocarcinoma (PDAC). In situ hybridization analysis confirmed increased miR-21 expression levels in PDAC tissues. The results of the chromatin immunoprecipitation and dual-luciferase reporter assays demonstrated that transcription factor RELA modulated miR-21 transcription in the PDAC, PANC-1 and MIA PaCa-2 cell lines. Subsequently, a cell viability assay, EdU staining assay and flow cytometry analysis, demonstrated that miR-21 promoted cell proliferation and cell cycle progression, but inhibited cell apoptosis in vitro. Furthermore, a xenograft assay demonstrated that miR-21 accelerated tumor growth in vivo. Mechanistically, miR-21 directly regulated the expression of Rho GTPase activating protein 24 (ARHGAP24), which was indicated to be a tumor suppressor gene. Moreover, both miR-21 and ARHGAP24 were strongly associated with clinical features and may therefore serve as valuable biomarkers in PDAC prognosis.
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Affiliation(s)
- Lanting Yu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Jiawei Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Haoran Xie
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Jianbo Ni
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Sumin Chen
- Department of Gastroenterology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China
| | - Qiuyan Zhao
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Ni Xie
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Lungen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Xingpeng Wang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Baiwen Li
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.,Shanghai Key Laboratory of Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
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36
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miRNAs as therapeutic predictors and prognostic biomarkers of neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat 2022; 194:483-505. [PMID: 35727379 DOI: 10.1007/s10549-022-06642-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 05/30/2022] [Indexed: 11/02/2022]
Abstract
PURPOSE Accumulating evidence has shown that microRNAs (miRNAs) are promising biomarkers of neoadjuvant chemotherapy (NAC) response in breast cancer (BC). However, their predictive roles remain controversial. Thus, this systematic review and meta-analysis aimed to describe the role of miRNA expression in NAC response and prognosis in BC to increase statistical power and improve translation. METHODS A systematic review of electronic databases for relevant studies was conducted following PRISMA guidelines. Data were extracted, collated, and combined by odds ratio (OR) and hazard ratio (HR) with 95% confidence intervals (CIs) to estimate the strength of the associations. RESULTS Of the 560 articles screened, 59 studies were included in our systematic review, and 5 studies were included in the subsequent meta-analysis. Sixty of 123 miRNAs were found to be related with NAC response and an elevated baseline miR-7 level in tissues was associated with a higher pathological complete response rate (OR 5.63; 95% CI 2.15-14.79; P = 0.0004). The prognostic value of 39 miRNAs was also studied. Of them, 26 miRNAs were found to be associated with survival. Pooled HRs indicated that patients with increased levels of serum miR-21 from baseline to the end of the second NAC cycle and from baseline to the end of NAC had a worse disease-free survival than those with decreased levels. CONCLUSION Our results highlight that a large number of miRNAs have possible associations with NAC response and prognosis in BC patients. Further well-designed studies are needed to elucidate the molecular mechanisms underlying these associations.
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Pekarek L, Fraile-Martinez O, Garcia-Montero C, Saez MA, Barquero-Pozanco I, Del Hierro-Marlasca L, de Castro Martinez P, Romero-Bazán A, Alvarez-Mon MA, Monserrat J, García-Honduvilla N, Buján J, Alvarez-Mon M, Guijarro LG, Ortega MA. Clinical Applications of Classical and Novel Biological Markers of Pancreatic Cancer. Cancers (Basel) 2022; 14:1866. [PMID: 35454771 PMCID: PMC9029823 DOI: 10.3390/cancers14081866] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/02/2022] [Accepted: 04/06/2022] [Indexed: 01/27/2023] Open
Abstract
The incidence and prevalence of pancreatic adenocarcinoma have increased in recent years. Pancreatic cancer is the seventh leading cause of cancer death, but it is projected to become the second leading cause of cancer-related mortality by 2040. Most patients are diagnosed in an advanced stage of the disease, with very limited 5-year survival. The discovery of different tissue markers has elucidated the underlying pathophysiology of pancreatic adenocarcinoma and allowed stratification of patient risk at different stages and assessment of tumour recurrence. Due to the invasive capacity of this tumour and the absence of screening markers, new immunohistochemical and serological markers may be used as prognostic markers for recurrence and in the study of possible new therapeutic targets because the survival of these patients is low in most cases. The present article reviews the currently used main histopathological and serological markers and discusses the main characteristics of markers under development.
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Affiliation(s)
- Leonel Pekarek
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Oncology Service, Guadalajara University Hospital, 19002 Guadalajara, Spain
| | - Oscar Fraile-Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Cielo Garcia-Montero
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Miguel A Saez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Pathological Anatomy Service, Central University Hospital of Defence-UAH Madrid, 28801 Alcala de Henares, Spain
| | - Ines Barquero-Pozanco
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Laura Del Hierro-Marlasca
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Patricia de Castro Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Adoración Romero-Bazán
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Miguel A Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Jorge Monserrat
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Julia Buján
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Melchor Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Immune System Diseases-Rheumatology, Oncology Service an Internal Medicine (CIBEREHD), University Hospital Príncipe de Asturias, 28806 Alcala de Henares, Spain
| | - Luis G Guijarro
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Unit of Biochemistry and Molecular Biology, Department of System Biology (CIBEREHD), University of Alcalá, 28801 Alcala de Henares, Spain
| | - Miguel A Ortega
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Cancer Registry and Pathology Department, Principe de Asturias University Hospital, 28806 Alcala de Henares, Spain
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Soliman HAN, Toso EA, Darwish IE, Ali SM, Kyba M. Antiapoptotic Protein FAIM2 is targeted by miR-3202, and DUX4 via TRIM21, leading to cell death and defective myogenesis. Cell Death Dis 2022; 13:405. [PMID: 35468884 PMCID: PMC9038730 DOI: 10.1038/s41419-022-04804-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 03/23/2022] [Accepted: 03/30/2022] [Indexed: 11/25/2022]
Abstract
Inappropriate expression of DUX4, a transcription factor that induces cell death at high levels of expression and impairs myoblast differentiation at low levels of expression, leads to the development of facioscapulohumeral muscular dystrophy (FSHD), however, the pathological mechanisms downstream of DUX4 responsible for muscle loss are poorly defined. We performed a screen of 1972 miR inhibitors for their ability to interfere with DUX4-induced cell death of human immortalized myoblasts. The most potent hit identified by the screen, miR-3202, is known to target the antiapoptotic protein FAIM2. Inhibition of miR-3202 led to the upregulation of FAIM2, and remarkably, expression of DUX4 led to reduced cellular levels of FAIM2. We show that the E3 ubiquitin ligase and DUX4 target gene, TRIM21, is responsible for FAIM2 degradation downstream of DUX4. Human myoblasts overexpressing FAIM2 showed increased resistance to DUX4-induced cell death, whereas in wild-type cells FAIM2 knockdown resulted in increased apoptosis and failure to differentiate into myotubes. The necessity of FAIM2 for myogenic differentiation of WT cells led us to test the effect of FAIM2 overexpression on the impairment of myogenesis by DUX4. Strikingly, FAIM2 overexpression rescued the myogenic differentiation defect caused by low-level expression of DUX4. These data implicate FAIM2 levels, modulated by DUX4 through TRIM21, as an important factor mediating the pathogenicity of DUX4, both in terms of cell viability and myogenic differentiation, and thereby open a new avenue of investigation towards drug targets in FSHD. ![]()
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Kanagasabai T, Li G, Shen TH, Gladoun N, Castillo-Martin M, Celada SI, Xie Y, Brown LK, Mark ZA, Ochieng J, Ballard BR, Cordon-Cardo C, Adunyah SE, Jin R, Matusik RJ, Chen Z. MicroRNA-21 deficiency suppresses prostate cancer progression through downregulation of the IRS1-SREBP-1 signaling pathway. Cancer Lett 2022; 525:46-54. [PMID: 34610416 DOI: 10.1016/j.canlet.2021.09.041] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 09/21/2021] [Accepted: 09/29/2021] [Indexed: 12/24/2022]
Abstract
Sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor in lipogenesis and lipid metabolism, is critical for disease progression and associated with poor outcomes in prostate cancer (PCa) patients. However, the mechanism of SREBP-1 regulation in PCa remains elusive. Here, we report that SREBP-1 is transcriptionally regulated by microRNA-21 (miR-21) in vitro in cultured cells and in vivo in mouse models. We observed aberrant upregulation of SREBP-1, fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC) in Pten/Trp53 double-null mouse embryonic fibroblasts (MEFs) and Pten/Trp53 double-null mutant mice. Strikingly, miR-21 loss significantly reduced cell proliferation and suppressed the prostate tumorigenesis of Pten/Trp53 mutant mice. Mechanistically, miR-21 inactivation decreased the levels of SREBP-1, FASN, and ACC in human PCa cells through downregulation of insulin receptor substrate 1 (IRS1)-mediated transcription and induction of cellular senescence. Conversely, miR-21 overexpression increased cell proliferation and migration; as well as the levels of IRS1, SREBP-1, FASN, and ACC in human PCa cells. Our findings reveal that miR-21 promotes PCa progression by activating the IRS1/SREBP-1 axis, and targeting miR-21/SREBP-1 signaling pathway can be a novel strategy for controlling PCa malignancy.
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Affiliation(s)
- Thanigaivelan Kanagasabai
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, 37208, USA
| | - Guoliang Li
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, 37208, USA
| | - Tian Huai Shen
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, 10032, USA
| | - Nataliya Gladoun
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, 10032, USA
| | - Mireia Castillo-Martin
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, 10032, USA
| | - Sherly I Celada
- Department of Biological Sciences, Tennessee State University, Nashville, TN, 37209, USA
| | - Yingqiu Xie
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, 37208, USA
| | - Lakendria K Brown
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, 37208, USA
| | - Zaniya A Mark
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, 37208, USA
| | - Josiah Ochieng
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, 37208, USA
| | - Billy R Ballard
- Department of Pathology, Anatomy and Cell Biology, Meharry Medical College, Nashville, TN, 37208, USA
| | - Carlos Cordon-Cardo
- Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, 10032, USA
| | - Samuel E Adunyah
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, 37208, USA
| | - Renjie Jin
- Department of Urology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Robert J Matusik
- Department of Urology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Zhenbang Chen
- Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN, 37208, USA.
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40
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Spectrum of microRNAs and their target genes in cancer: intervention in diagnosis and therapy. Mol Biol Rep 2022; 49:6827-6846. [PMID: 35031927 DOI: 10.1007/s11033-021-07040-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 11/30/2021] [Indexed: 12/11/2022]
Abstract
Till date, several groups have studied the mechanism of microRNA (miRNA) biogenesis, processing, stability, silencing, and their dysregulation in cancer. The miRNA coding genes recurrently go through abnormal amplification, deletion, transcription, and epigenetic regulation in cancer. Some miRNAs function as tumor promoters while few others are tumor suppressors based on the transcriptional regulation of target genes. A review of miRNAs and their target genes in a wide range of cancers is attempted in this article, which may help in the development of new diagnostic tools and intervention therapies. The contribution of miRNAs for drug sensitivity or resistance in cancer therapy and opportunities of miRNAs in cancer prognosis or diagnosis and therapy is also presented in detail.
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Osei-Bordom DC, Sachdeva G, Christou N. Liquid Biopsy as a Prognostic and Theranostic Tool for the Management of Pancreatic Ductal Adenocarcinoma. Front Med (Lausanne) 2022; 8:788869. [PMID: 35096878 PMCID: PMC8795626 DOI: 10.3389/fmed.2021.788869] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 12/02/2021] [Indexed: 12/24/2022] Open
Abstract
Pancreatic ductal adenocarcinomas (PDAC) represent one of the deadliest cancers worldwide. Survival is still low due to diagnosis at an advanced stage and resistance to treatment. Herein, we review the main types of liquid biopsy able to help in both prognosis and adaptation of treatments.
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Affiliation(s)
- Daniel C Osei-Bordom
- Department of General Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, United Kingdom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, Birmingham, United Kingdom
| | - Gagandeep Sachdeva
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Niki Christou
- Department of General Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, United Kingdom
- Department of General Surgery, University Hospital of Limoges, Limoges, France
- EA3842 CAPTuR Laboratory "Cell Activation Control, Tumor Progression and Therapeutic Resistance", Faculty of Medicine, Limoges, France
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Dashti F, Mirazimi SMA, Rabiei N, Fathazam R, Rabiei N, Piroozmand H, Vosough M, Rahimian N, Hamblin MR, Mirzaei H. The role of non-coding RNAs in chemotherapy for gastrointestinal cancers. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:892-926. [PMID: 34760336 PMCID: PMC8551789 DOI: 10.1016/j.omtn.2021.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.
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Affiliation(s)
- Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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TÜNCEL Ö, KARA M, YAYLAK B, ERDOĞAN İ, AKGÜL B. Noncoding RNAs in apoptosis: identification and function. Turk J Biol 2021; 46:1-40. [PMID: 37533667 PMCID: PMC10393110 DOI: 10.3906/biy-2109-35] [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: 09/11/2021] [Revised: 02/08/2022] [Accepted: 11/14/2021] [Indexed: 08/04/2023] Open
Abstract
Apoptosis is a vital cellular process that is critical for the maintenance of homeostasis in health and disease. The derailment of apoptotic mechanisms has severe consequences such as abnormal development, cancer, and neurodegenerative diseases. Thus, there exist complex regulatory mechanisms in eukaryotes to preserve the balance between cell growth and cell death. Initially, protein-coding genes were prioritized in the search for such regulatory macromolecules involved in the regulation of apoptosis. However, recent genome annotations and transcriptomics studies have uncovered a plethora of regulatory noncoding RNAs that have the ability to modulate not only apoptosis but also many other biochemical processes in eukaryotes. In this review article, we will cover a brief summary of apoptosis and detection methods followed by an extensive discussion on microRNAs, circular RNAs, and long noncoding RNAs in apoptosis.
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Affiliation(s)
- Özge TÜNCEL
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
| | - Merve KARA
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
| | - Bilge YAYLAK
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
| | - İpek ERDOĞAN
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
| | - Bünyamin AKGÜL
- Non-coding RNA Laboratory, Department of Molecular Biology and Genetics, Faculty of Science, İzmir Institute of Technology, İzmir,
Turkey
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The Role of Circulating MicroRNAs in Patients with Early-Stage Pancreatic Adenocarcinoma. Biomedicines 2021; 9:biomedicines9101468. [PMID: 34680585 PMCID: PMC8533318 DOI: 10.3390/biomedicines9101468] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/10/2021] [Accepted: 10/12/2021] [Indexed: 01/17/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is increasing in incidence and is still associated with a high rate of mortality. Only a minority of patients are diagnosed in the early stage. Radical surgery is the only potential curative procedure. However, radicality is reached in 20% of patients operated on. Despite the multidisciplinary approach in resectable tumors, early tumor recurrences are common. Options on how to select optimal candidates for resection remain limited. Nevertheless, accumulating evidence shows an important role of circulating non-coding plasma and serum microRNAs (miRNAs), which physiologically regulate the function of a target protein. miRNAs also play a crucial role in carcinogenesis. In PDAC patients, the expression levels of certain miRNAs vary and may modulate the function of oncogenes or tumor suppressor genes. As they can be detected in a patient's blood, they have the potential to become promising non-invasive diagnostic and prognostic biomarkers. Moreover, they may also serve as markers of chemoresistance. Thus, miRNAs could be useful for early and accurate diagnosis, prognostic stratification, and individual treatment planning. In this review, we summarize the latest findings on miRNAs in PDAC patients, focusing on their potential use in the early stage of the disease.
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Campos A, Sharma S, Obermair A, Salomon C. Extracellular Vesicle-Associated miRNAs and Chemoresistance: A Systematic Review. Cancers (Basel) 2021; 13:cancers13184608. [PMID: 34572835 PMCID: PMC8472653 DOI: 10.3390/cancers13184608] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 09/04/2021] [Accepted: 09/08/2021] [Indexed: 01/01/2023] Open
Abstract
Simple Summary There is an urgent need for a non-invasive, specific biomarker to identify patients at risk of chemoresistance, which it is the ability of cancer cells to escape the effect of chemotherapy drugs. Extracellular vesicles contain an abundance of miRNAs that demonstrate expression across a range of cancers including breast cancer, renal cell carcinoma, lung cancer, multiple myeloma, and lymphoma. Interestingly, miRNAs encapsulated within extracellular vesicles (EVs) including exosomes display an association with chemoresistance. Here, we performed a systematic revision to evaluate the association between miRNAs within EVs and chemotherapy resistance. The summarized graphical abstract indicates that several exosome-derived miRNAs involved in chemotherapy resistance can be found among different types of cancers, such as colorectal, ovarian, breast, and lung cancer, and lymphoma. Abstract Cancer is a leading public health issue globally, and diagnosis is often associated with poor outcomes and reduced patient survival. One of the major contributors to the fatality resultant of cancer is the development of resistance to chemotherapy, known as chemoresistance. Furthermore, there are limitations in our ability to identify patients that will respond to therapy, versus patients that will develop relapse, and display limited or no response to treatment. This often leads to patients being subjected to multiple futile treatment cycles, and results in a reduction in their quality of life. Therefore, there is an urgent clinical need to develop tools to identify patients at risk of chemoresistance, and recent literature has suggested that small extracellular vesicles, known as exosomes, may be a vital source of information. Extracellular vesicles (EV) are membrane bound vesicles, involved in cell-cell communication, through the transfer of their cargo, which includes proteins, lipids, and miRNAs. A defined exploration strategy was performed in this systematic review in order to provide a compilation of key EV miRNAs which may be predictive of chemoresistance. We searched the PubMed, Science Direct, and Scopus databases using the following keywords: Extracellular vesicles OR exosomes OR EVs AND miRNA AND Chemotherapy OR Chemoresistance OR Cancer Recurrence from 2010 to 2020. We found 31 articles that reported key EV-associated miRNAs involved in cancer recurrence related to chemoresistance. Interestingly, multiple studies of the same tumor type identified different microRNAs, and few studies identified the same ones. Specifically, miR-21, miR-222, and miR-155 displayed roles in response to chemotherapy, and were found to be common in colorectal cancer, ovarian cancer, breast cancer, and diffuse large B cell lymphoma patients (DLBCL). miR-21 and miR-222 were found to favour the development of chemoresistance, whereas miR-155 exhibited a contrasting role, depending on the type of primary tumor. Whilst high levels of miR-155 were found to correlate with chemotherapy resistance in DLBCL, it was found to be predictive of an effective response towards chemotherapy in breast cancer. Thus, further research regarding the roles of these miRNAs would be beneficial in terms of designing novel tools to counteract the progression of cancer in a not-to-distant future.
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Affiliation(s)
- America Campos
- Exosome Biology Laboratory, Center for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women’s Hospital, The University of Queensland, Brisbane, QLD 4029, Australia; (A.C.); (S.S.)
| | - Shayna Sharma
- Exosome Biology Laboratory, Center for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women’s Hospital, The University of Queensland, Brisbane, QLD 4029, Australia; (A.C.); (S.S.)
| | - Andreas Obermair
- Queensland Centre for Gynaecological Cancer Research, The University of Queensland, Centre for Clinical Research, Building 71/918, Royal Brisbane and Women’s Hospital, Herston, QLD 4029, Australia;
| | - Carlos Salomon
- Exosome Biology Laboratory, Center for Clinical Diagnostics, University of Queensland Centre for Clinical Research, Royal Brisbane and Women’s Hospital, The University of Queensland, Brisbane, QLD 4029, Australia; (A.C.); (S.S.)
- Departamento de Investigación, Postgrado y Educación Contínua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago 8370007, Chile
- Correspondence: ; Tel.: +61-7-33465500; Fax: +61-7-3346-5509
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Maleki M, Khelghati N, Alemi F, Younesi S, Asemi Z, Abolhasan R, Bazdar M, Samadi-Kafil H, Yousefi B. Multiple interactions between melatonin and non-coding RNAs in cancer biology. Chem Biol Drug Des 2021; 98:323-340. [PMID: 33905613 DOI: 10.1111/cbdd.13849] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/10/2021] [Indexed: 12/14/2022]
Abstract
The melatonin hormone secreted by the pineal gland is involved in physiological functions such as growth and maturation, circadian cycles, and biological activities including antioxidants, anti-tumor, and anti-ischemia. Melatonin not only interacts with proteins but also has functional effects on regulatory RNAs such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs). In this study, we overview various physiological and pathological conditions affecting melatonin through lncRNA and miRNA. The information compiled herein will serve as a solid foundation to formulate ideas for future mechanistic studies on melatonin. It will also provide a chance to more clarify the emerging functions of the non-coding transcriptome.
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Affiliation(s)
- Masomeh Maleki
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Nafiseh Khelghati
- Department of Clinical Biochemistry, Urmia University of Medical Sciences, Urmia, Iran
| | - Forough Alemi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Simin Younesi
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Vic., Australia
| | - Zatollah Asemi
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Vic., Australia.,Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Rozita Abolhasan
- Stem Cell and Regenerative Medicine Institute (SCARM), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahtab Bazdar
- Department of Clinical Biochemistry, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Bahman Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Serum Exosomal microRNA-21, 222 and 124-3p as Noninvasive Predictive Biomarkers in Newly Diagnosed High-Grade Gliomas: A Prospective Study. Cancers (Basel) 2021; 13:cancers13123006. [PMID: 34203979 PMCID: PMC8232769 DOI: 10.3390/cancers13123006] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/31/2021] [Accepted: 06/11/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Diagnosis of relapse during post-surgery monitoring of patients with High-grade glioma is often challenging. This study was aimed to identify circulating biomarkers providing information about response to therapy and early diagnosis of progression during follow-up of these patients. Our findings, showing upregulation of exosomal miRNAs associated with relapse represent a proof of principle that these biomarkers may be clinically useful tools for diagnosing and monitoring of gliomas. Abstract Background: High-grade gliomas (HGG) are malignant brain tumors associated with frequent recurrent disease. Clinical management of HGG patients is currently devoid of blood biomarkers for early diagnosis, monitoring therapeutic effects and predicting recurrence. Different circulating miRNAs, both free and associated with exosomes, are described in patients with HGG. We previously identified miR-21, miR-222 and miR-124-3p purified from serum exosomes as molecular signature to help pre-operative clinical diagnosis and grading of gliomas. The aim of the present study was to verify this signature as a tool to assess the effect of treatment and for the early identification of progression in newly diagnosed HGG patients. Material and Methods: Major inclusion criteria were newly diagnosed, histologically confirmed HGG patients, no prior chemotherapy, ECOG PS 0-2 and patients scheduled for radiochemotherapy with temozolomide as first-line treatment after surgery. RANO criteria were used for response assessment. Serum was collected at baseline and subsequently at each neuroradiological assessment. mir-21, -222 and -124-3p expression in serum exosomes was measured in all samples. Results: A total number of 57 patients were enrolled; 41 were male, 52 with glioblastoma and 5 with anaplastic astrocytoma; 18 received radical surgery. HGG patients with higher exosomal miRNA expression displayed a statistically significant lower progression-free survival and overall survival. Increased expression of miR-21, -222 and -124-3p during post-operative follow-up was associated with HGG progression. Conclusions: These data indicate that miR-21, -222 and -124-3p in serum exosomes may be useful molecular biomarkers for complementing clinical evaluation of early tumor progression during post-surgical therapy in patients with HGG.
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Yang F, Wang J, Chen Z, Yang Y, Zhang W, Guo S, Yang Q. Role of microRNAs in intervertebral disc degeneration (Review). Exp Ther Med 2021; 22:860. [PMID: 34178133 PMCID: PMC8220656 DOI: 10.3892/etm.2021.10292] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 05/19/2021] [Indexed: 11/14/2022] Open
Abstract
The incidence of lower back pain caused by intervertebral disc degeneration (IDD) is gradually increasing. IDD not only affects the quality of life of the patients, but also poses a major socioeconomic burden. There is currently no optimal method for delaying or reversing IDD, mainly due to its unknown pathogenesis. MicroRNAs (miRNAs/miRs) participate in the development of a number of diseases, including IDD. Abnormal expression of miRNAs in the intervertebral disc is implicated in various pathological processes underlying the development of IDD, including nucleus pulposus (NP) cell (NPC) proliferation, NPC apoptosis, extracellular matrix remodeling, inflammation and cartilaginous endplate changes, among others. The focus of the present review was the advances in research on the involvement of miRNAs in the mechanism underlying IDD. Further research is expected to identify markers for early diagnosis of IDD and new targets for delaying or reversing IDD.
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Affiliation(s)
- Fengguang Yang
- Department of Orthopedics, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Jizu Wang
- Department of Orthopedics, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Zhixin Chen
- Department of Orthopedics, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Yuping Yang
- Department of Orthopedics, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Wenhui Zhang
- Department of Orthopedics, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Shifang Guo
- Department of Orthopedics, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
| | - Qingshan Yang
- Department of Orthopedics, Gansu Provincial Hospital, Lanzhou, Gansu 730000, P.R. China
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The Neutrophil-to-Monocyte Ratio and Platelet-to-White Blood Cell Ratio Represent Novel Prognostic Markers in Patients with Pancreatic Cancer. Gastroenterol Res Pract 2021; 2021:6693028. [PMID: 34122538 PMCID: PMC8169265 DOI: 10.1155/2021/6693028] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 05/02/2021] [Accepted: 05/08/2021] [Indexed: 01/23/2023] Open
Abstract
Background Inflammation plays an important role in the development of tumors. Several serum based-markers and ratios have been investigated for their prognostic value in pancreatic cancer. However, the prognostic value of the neutrophil-to-monocyte ratio (NMR) and platelet-to-white blood cell ratio (PWR) for patients with pancreatic cancer has scarcely been investigated. Methods From October 2013 to November 2018, a retrospective cohort study was performed on 269 pancreatic cancer patients without treatment. Receiver operating characteristic curves were generated, and areas under the curve were compared for the evaluation of the discriminatory ability of inflammation-based prognostic scoring systems. Kaplan-Meier curves and the Cox proportional hazard model were employed to analyze the relationships among NMR, PWR, and overall survival (OS). Results The optimal cutoff values of NMR and PWR were 48 and 6, respectively. In univariate analysis, the survival time of NMR > 48 and PWR ≤ 6 was shorter than that of NMR ≤ 48 and PWR > 6 in patients with pancreatic cancer (P < 0.001). In Cox univariate and multivariate analyses, NMR (hazard ratio (HR), 9.095; 95% confidence interval (CI), 3.64-22.72; P < 0.001) and PWR (HR, 8.230; 95% CI, 3.32-20.43; P < 0.001) were significantly correlated with OS. Conclusions The current study demonstrated that NMR and PWR may serve as novel and promising inflammatory prognostic scores for patients with pancreatic cancer. Elevated NMR (>48) and depressed PWR (<6) were independently associated with poor prognosis in patients with pancreatic cancer.
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Kokkinos J, Jensen A, Sharbeen G, McCarroll JA, Goldstein D, Haghighi KS, Phillips PA. Does the Microenvironment Hold the Hidden Key for Functional Precision Medicine in Pancreatic Cancer? Cancers (Basel) 2021; 13:cancers13102427. [PMID: 34067833 PMCID: PMC8156664 DOI: 10.3390/cancers13102427] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/11/2021] [Accepted: 05/12/2021] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and no significant improvement in patient survival has been seen in the past three decades. Treatment options are limited and selection of chemotherapy in the clinic is usually based on the performance status of a patient rather than the biology of their disease. In recent years, research has attempted to unlock a personalised treatment strategy by identifying actionable molecular targets in tumour cells or using preclinical models to predict the effectiveness of chemotherapy. However, these approaches rely on the biology of PDAC tumour cells only and ignore the importance of the microenvironment and fibrotic stroma. In this review, we highlight the importance of the microenvironment in driving the chemoresistant nature of PDAC and the need for preclinical models to mimic the complex multi-cellular microenvironment of PDAC in the precision medicine pipeline. We discuss the potential for ex vivo whole-tissue culture models to inform precision medicine and their role in developing novel therapeutic strategies that hit both tumour and stromal compartments in PDAC. Thus, we highlight the critical role of the tumour microenvironment that needs to be addressed before a precision medicine program for PDAC can be implemented.
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Affiliation(s)
- John Kokkinos
- Pancreatic Cancer Translational Research Group, School of Medical Sciences, Faculty of Medicine & Health, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia; (J.K.); (G.S.); (D.G.)
- Australian Centre for Nanomedicine, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, UNSW Sydney, Sydney, NSW 2052, Australia;
| | - Anya Jensen
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia;
- School of Women’s and Children’s Health, Faculty of Medicine & Health, UNSW Sydney, Sydney, NSW 2052, Australia
| | - George Sharbeen
- Pancreatic Cancer Translational Research Group, School of Medical Sciences, Faculty of Medicine & Health, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia; (J.K.); (G.S.); (D.G.)
| | - Joshua A. McCarroll
- Australian Centre for Nanomedicine, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, UNSW Sydney, Sydney, NSW 2052, Australia;
- Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia;
- School of Women’s and Children’s Health, Faculty of Medicine & Health, UNSW Sydney, Sydney, NSW 2052, Australia
| | - David Goldstein
- Pancreatic Cancer Translational Research Group, School of Medical Sciences, Faculty of Medicine & Health, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia; (J.K.); (G.S.); (D.G.)
- Prince of Wales Clinical School, Prince of Wales Hospital, UNSW Sydney, Sydney, NSW 2052, Australia;
| | - Koroush S. Haghighi
- Prince of Wales Clinical School, Prince of Wales Hospital, UNSW Sydney, Sydney, NSW 2052, Australia;
| | - Phoebe A. Phillips
- Pancreatic Cancer Translational Research Group, School of Medical Sciences, Faculty of Medicine & Health, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW 2052, Australia; (J.K.); (G.S.); (D.G.)
- Australian Centre for Nanomedicine, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, UNSW Sydney, Sydney, NSW 2052, Australia;
- Correspondence:
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