MicroRNA Therapeutics: Towards a New Era for the Management of Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 63829

Special Issue Editor


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Guest Editor
Precision Health Program, Michigan State University, East Lansing, MI 48824, USA
Interests: non-coding RNAs; microRNAs; tissue-slide-based microRNA biomarkers; animal models; genetic engineering; nanoparticle delivery; breast cancer; pancreatic cancer
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Special Issue Information

Dear Colleagues,

The first microRNA, lin-4, was discovered in the small roundworm Caenorhabditis elegans over 25 years ago. It took seven years for the discovery of the second microRNA, let-7a, also in C. elegans in 2000, but soon after that the evolutionary conservation of let-7a and shared enzymatic machinery between short interfering RNAs (siRNAs) and microRNAs tremendously contributed to accelerating the pace of research on these short, non-coding regulatory RNAs. The field of microRNA cancer research is one that emerged very early on and at a frenetic pace with a number of major scientific discoveries in very short succession, and with the almost immediate realization of the great potential of microRNA-based therapies to replenish the activity of a tumor-suppressing, and/or inhibit the activity of a tumor-promoting, microRNA. Within the last decade, several microRNAs have been positioned as front-runners for microRNA-based therapy in different cancer types, and several compounds from different companies have already entered clinical trials. However, most microRNA-based therapeutics are still in the pre-clinical stage. FDA approval of the first-ever siRNA-based therapy, Onpattro, in August 2018 has provided an immense boost to the development and implementation of additional microRNA-based therapeutics, which face similar challenges for stability and targeted delivery as siRNA-based therapies do.

This Special Issue focuses on microRNA-based viral and non-viral delivery strategies in animal models and first-in-human clinical trials towards a new era in cancer management. Viral strategies will include recent advances in packaging, tissue tropism, and immunogenicity of adeno-associated viruses, lentiviruses, and other viral systems. Non-viral strategies will include recent advances in packaging technologies using native and synthetic exosomes, liposomal encapsulation, and nanoparticle conjugation as well as new RNA formulations and modifications for increased stability and/or image-guided monitoring.

Dr. Sempere Lorenzo
Guest Editor

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Published Papers (14 papers)

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Research

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27 pages, 4551 KiB  
Article
MicroRNA-Based Risk Score for Predicting Tumor Progression Following Radioactive Iodine Ablation in Well-Differentiated Thyroid Cancer Patients: A Propensity-Score Matched Analysis
by Eman A. Toraih, Manal S. Fawzy, Mohammad H. Hussein, Mohamad M. El-Labban, Emmanuelle M. L. Ruiz, Abdallah A. Attia, Shams Halat, Krzysztof Moroz, Youssef Errami, Mourad Zerfaoui and Emad Kandil
Cancers 2021, 13(18), 4649; https://doi.org/10.3390/cancers13184649 - 16 Sep 2021
Cited by 8 | Viewed by 3038
Abstract
To identify molecular markers that can accurately predict aggressive tumor behavior at the time of surgery, a propensity-matching score analysis of archived specimens yielded two similar datasets of DTC patients (with and without RAI). Bioinformatically selected microRNAs were quantified by qRT-PCR. The risk [...] Read more.
To identify molecular markers that can accurately predict aggressive tumor behavior at the time of surgery, a propensity-matching score analysis of archived specimens yielded two similar datasets of DTC patients (with and without RAI). Bioinformatically selected microRNAs were quantified by qRT-PCR. The risk score was generated using Cox regression and assessed using ROC, C-statistic, and Brier-score. A predictive Bayesian nomogram was established. External validation was performed, and causal network analysis was generated. Within the eight-year follow-up period, progression was reported in 51.5% of cases; of these, 48.6% had the T1a/b stage. Analysis showed upregulation of miR-221-3p and miR-222-3p and downregulation of miR-204-5p in 68 paired cancer tissues (p < 0.001). These three miRNAs were not differentially expressed in RAI and non-RAI groups. The ATA risk score showed poor discriminative ability (AUC = 0.518, p = 0.80). In contrast, the microRNA-based risk score showed high accuracy in predicting tumor progression in the whole cohorts (median = 1.87 vs. 0.39, AUC = 0.944) and RAI group (2.23 vs. 0.37, AUC = 0.979) at the cutoff >0.86 (92.6% accuracy, 88.6% sensitivity, 97% specificity) in the whole cohorts (C-statistics = 0.943/Brier = 0.083) and RAI subgroup (C-statistic = 0.978/Brier = 0.049). The high-score group had a three-fold increased progression risk (hazard ratio = 2.71, 95%CI = 1.86–3.96, p < 0.001) and shorter survival times (17.3 vs. 70.79 months, p < 0.001). Our prognostic microRNA signature and nomogram showed excellent predictive accuracy for progression-free survival in DTC. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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17 pages, 2320 KiB  
Article
Allele-Specific MicroRNA-Mediated Regulation of a Glycolysis Gatekeeper PDK1 in Cancer Metabolism
by Sugarniya Subramaniam, Varinder Jeet, Jennifer H. Gunter, Judith A. Clements and Jyotsna Batra
Cancers 2021, 13(14), 3582; https://doi.org/10.3390/cancers13143582 - 17 Jul 2021
Cited by 7 | Viewed by 2861
Abstract
Background: Emerging evidence has revealed that genetic variations in microRNA (miRNA) binding sites called miRSNPs can alter miRNA binding in an allele-specific manner and impart prostate cancer (PCa) risk. Two miRSNPs, rs1530865 (G > C) and rs2357637 (C > A), in the 3′ [...] Read more.
Background: Emerging evidence has revealed that genetic variations in microRNA (miRNA) binding sites called miRSNPs can alter miRNA binding in an allele-specific manner and impart prostate cancer (PCa) risk. Two miRSNPs, rs1530865 (G > C) and rs2357637 (C > A), in the 3′ untranslated region of pyruvate dehydrogenase kinase 1 (PDK1) have been previously reported to be associated with PCa risk. However, these results have not been functionally validated. Methods: In silico analysis was used to predict miRNA–PDK1 interactions and was tested using PDK1 knockdown, miRNA overexpression and reporter gene assay. Results: PDK1 expression was found to be upregulated in PCa metastasis. Further, our results show that PDK1 suppression reduced the migration, invasion, and glycolysis of PCa cells. Computational predictions showed that miR-3916, miR-3125 and miR-3928 had a higher binding affinity for the C allele than the G allele for the rs1530865 miRSNP which was validated by reporter gene assays. Similarly, miR-2116 and miR-889 had a higher affinity for the A than C allele of the rs2357637 miRSNP. Overexpression of miR-3916 and miR-3125 decreased PDK1 protein levels in cells expressing the rs1530865 SNP C allele, and miR-2116 reduced in cells with the rs2357637 SNP A allele. Conclusions: The present study is the first to report the regulation of the PDK1 gene by miRNAs in an allele-dependent manner and highlights the role of PDK1 in metabolic adaption associated with PCa progression. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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17 pages, 2151 KiB  
Article
Inhibition of miR-222 by Oncolytic Adenovirus-Encoded miRNA Sponges Promotes Viral Oncolysis and Elicits Antitumor Effects in Pancreatic Cancer Models
by Giulia Raimondi, Sabrina Gea-Sorlí, Marc Otero-Mateo and Cristina Fillat
Cancers 2021, 13(13), 3233; https://doi.org/10.3390/cancers13133233 - 28 Jun 2021
Cited by 8 | Viewed by 2110
Abstract
Oncolytic adenoviruses (OA) are envisioned as a therapeutic option for patients with cancer, designed to preferentially replicate in cancer cells. However, the high number of genetic alterations in tumors can generate a context in which adenoviruses have difficulties replicating. Abnormal miRNAs expression is [...] Read more.
Oncolytic adenoviruses (OA) are envisioned as a therapeutic option for patients with cancer, designed to preferentially replicate in cancer cells. However, the high number of genetic alterations in tumors can generate a context in which adenoviruses have difficulties replicating. Abnormal miRNAs expression is a trademark of pancreatic cancer, with several oncogenic miRNAs playing essential roles in cancer-associated pathways. The perturbed miRNome induces reprogramming of gene expression in host cells that can impact the complex interplay between cellular processes and viral replication. We have studied the effects of overexpressed miRNAs on oncolytic adenoviral activity and identified miRNAs modulators of adenoviral oncolysis in pancreatic cancer cells. Inhibition of the highly upregulated miR-222 sensitized cancer cells to oncolysis. To provide a therapeutic application to this insight, we engineered the oncolytic adenovirus AdNuPARmE1A with miR-222 binding sites, working as sponges to withdraw the miRNA from the cellular environment. AdNuPAR-E-miR222-S mediated-decrease of miR-222 expression in pancreatic cancer cells strongly improved the viral yield and enhanced the adenoviral cytotoxic effects. Antitumoral studies confirmed a high activity for AdNuPARmE1A-miR222-S in vivo, controlling tumor progression more effectively than the scrambled control virus in xenografts. We demonstrated that the increased antitumor potency of the novel oncolytic virus resulted from the combinatory effects of miR-222 oncomiR inhibition and the restoration of miR-222 target genes activity enhancing viral fitness. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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17 pages, 2141 KiB  
Article
The Possible Influence of Mediterranean Diet on Extracellular Vesicle miRNA Expression in Breast Cancer Survivors
by Yu-Jin Kwon, Young-Eun Cho, A-Ra Cho, Won Jun Choi, Sijung Yun, Hyunki Park, Hyung-Suk Kim, Ann K. Cashion, Jessica Gill, Hyangkyu Lee and Ji-Won Lee
Cancers 2020, 12(6), 1355; https://doi.org/10.3390/cancers12061355 - 26 May 2020
Cited by 9 | Viewed by 3406
Abstract
The Mediterranean diet (MD) has been reported to have beneficial effects on breast cancer and cardiovascular diseases. Recently, microRNAs (miRNAs) have been suggested as biomarkers for the diagnosis and disease prognosis in cancer and cardiovascular diseases. We evaluated the influence of the MD [...] Read more.
The Mediterranean diet (MD) has been reported to have beneficial effects on breast cancer and cardiovascular diseases. Recently, microRNAs (miRNAs) have been suggested as biomarkers for the diagnosis and disease prognosis in cancer and cardiovascular diseases. We evaluated the influence of the MD on the plasma-derived extracellular vesicle miRNA signature of overweight breast cancer survivors. Sixteen participants instructed to adhere to the MD for eight weeks were included in this study. To curate differentially expressed miRNAs after MD intervention, we employed two methods: significance analysis of microarrays and DESeq2. The selected miRNAs were analyzed using ingenuity pathway analysis. After an eight-week intervention, body mass index, waist circumference, fasting glucose, fasting insulin, and homeostatic model assessment for insulin resistance were significantly improved. Expression levels of 798 miRNAs were comprehensively analyzed, and 42 extracellular vesicle miRNAs were significantly differentially regulated after the eight-week MD (36 were up and 6 were down-regulated). We also identified enriched pathways in genes regulated by differentially expressed 42 miRNAs, which include signaling associated with breast cancer, energy metabolism, glucose metabolism, and insulin. Our study indicates that extracellular vesicle miRNAs differentially expressed as a result of the MD might be involved in the mechanisms that relate to cardiometabolic risk factors in overweight breast cancer survivors. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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20 pages, 1551 KiB  
Article
Clinical Theragnostic Potential of Diverse miRNA Expressions in Prostate Cancer: A Systematic Review and Meta-Analysis
by Rama Jayaraj, Greg Raymond, Sunil Krishnan, Katherine S. Tzou, Siddhartha Baxi, M. Ravishankar Ram, Suresh Kumar Govind, Harish C. Chandramoorthy, Faisal N. Abu-Khzam and Peter Shaw
Cancers 2020, 12(5), 1199; https://doi.org/10.3390/cancers12051199 - 9 May 2020
Cited by 20 | Viewed by 4292
Abstract
Background: Prostate cancer (PrC) is the second-most frequent cancer in men, its incidence is emerging globally and is the fifth leading cause of death worldwide. While diagnosis and prognosis of PrC have been studied well, the associated therapeutic biomarkers have not yet been [...] Read more.
Background: Prostate cancer (PrC) is the second-most frequent cancer in men, its incidence is emerging globally and is the fifth leading cause of death worldwide. While diagnosis and prognosis of PrC have been studied well, the associated therapeutic biomarkers have not yet been investigated comprehensively. This systematic review and meta-analysis aim to evaluate the theragnostic effects of microRNA expressions on chemoresistance in prostate cancer and to analyse the utility of miRNAs as clinical theragnostic biomarkers. Methods: A systematic literature search for studies reporting miRNA expressions and their role in chemoresistance in PrC published until 2018 was collected from bibliographic databases. The evaluation of data was performed as per PRISMA guidelines for systematic review and meta-analysis. Meta-analysis was performed using a random-effects model using Comprehensive Meta-Analysis (CMA) software. Heterogeneity between studies was analysed using Cochran’s Q test, I2 and the Tau statistic. Quality assessment of the studies was performed using the Newcastle–Ottawa Scale (NOS) for the methodological assessment of cohort studies. Publication bias was assessed using Egger’s bias indicator test, Orwin and classic fail-safe N test, Begg and Mazumdar rank collection test, and Duval and Tweedie’s trim and fill methods. Findings: Out of 2909 studies retrieved, 79 studies were shortlisted and reviewed. A total of 17 studies met our eligibility criteria, from which 779 PrC patients and 17 chemotherapy drugs were examined, including docetaxel and paclitaxel. The majority of the drug regulatory genes reported were involved in cell survival, angiogenesis and cell proliferation pathways. We studied 42 miRNAs across all studies, out of which two miRNAs were found to be influencing chemosensitivity, while 21 were involved in chemoresistance. However, the remaining 19 miRNAs did not appear to have any theragnostic effects. Besides, the prognostic impact of the miRNAs was evaluated and had a pooled HR value of 1.960 with 95% CI (1.377–2.791). Interpretation: The observation of the current study depicts the significance of miRNA expression as a theragnostic biomarker in medical oncology. This review suggests the involvement of specific miRNAs as predictors of chemoresistance and sensitivity in PrC. Hence, the current systematic review and meta-analysis provide insight on the use of miRNA as PrC biomarkers, which can be harnessed as molecular candidates for therapeutic targeting. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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Review

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35 pages, 1145 KiB  
Review
The miR-200 Family of microRNAs: Fine Tuners of Epithelial-Mesenchymal Transition and Circulating Cancer Biomarkers
by Ilaria Cavallari, Francesco Ciccarese, Evgeniya Sharova, Loredana Urso, Vittoria Raimondi, Micol Silic-Benussi, Donna M. D’Agostino and Vincenzo Ciminale
Cancers 2021, 13(23), 5874; https://doi.org/10.3390/cancers13235874 - 23 Nov 2021
Cited by 69 | Viewed by 4561
Abstract
The miR-200 family of microRNAs (miRNAs) includes miR-200a, miR-200b, miR-200c, miR-141 and miR-429, five evolutionarily conserved miRNAs that are encoded in two clusters of hairpin precursors located on human chromosome 1 (miR-200b, miR-200a and miR-429) and chromosome 12 (miR-200c and miR-141). The mature [...] Read more.
The miR-200 family of microRNAs (miRNAs) includes miR-200a, miR-200b, miR-200c, miR-141 and miR-429, five evolutionarily conserved miRNAs that are encoded in two clusters of hairpin precursors located on human chromosome 1 (miR-200b, miR-200a and miR-429) and chromosome 12 (miR-200c and miR-141). The mature -3p products of the precursors are abundantly expressed in epithelial cells, where they contribute to maintaining the epithelial phenotype by repressing expression of factors that favor the process of epithelial-to-mesenchymal transition (EMT), a key hallmark of oncogenic transformation. Extensive studies of the expression and interactions of these miRNAs with cell signaling pathways indicate that they can exert both tumor suppressor- and pro-metastatic functions, and may serve as biomarkers of epithelial cancers. This review provides a summary of the role of miR-200 family members in EMT, factors that regulate their expression, and important targets for miR-200-mediated repression that are involved in EMT. The second part of the review discusses the potential utility of circulating miR-200 family members as diagnostic/prognostic biomarkers for breast, colorectal, lung, ovarian, prostate and bladder cancers. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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24 pages, 897 KiB  
Review
Extracellular Vesicle-Associated miRNAs and Chemoresistance: A Systematic Review
by America Campos, Shayna Sharma, Andreas Obermair and Carlos Salomon
Cancers 2021, 13(18), 4608; https://doi.org/10.3390/cancers13184608 - 14 Sep 2021
Cited by 27 | Viewed by 3755
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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19 pages, 3422 KiB  
Review
Diagnostic and Prognostic Performance of Liquid Biopsy-Derived Exosomal MicroRNAs in Thyroid Cancer Patients: A Systematic Review and Meta-Analysis
by Eman A. Toraih, Rami M. Elshazli, Lily N. Trinh, Mohammad H. Hussein, Abdallah A. Attia, Emmanuelle M. L. Ruiz, Mourad Zerfaoui, Manal S. Fawzy and Emad Kandil
Cancers 2021, 13(17), 4295; https://doi.org/10.3390/cancers13174295 - 26 Aug 2021
Cited by 16 | Viewed by 3436
Abstract
Circulatory tumor-derived exosomal microRNAs (miRNAs) play key roles in cancer development/progression. We aimed to assess the diagnostic/prognostic value of circulating exosomal miRNA in thyroid cancer (TC). A search in PubMed, Scopus, Web of Science, and Science Direct up to 22 May 2021 was [...] Read more.
Circulatory tumor-derived exosomal microRNAs (miRNAs) play key roles in cancer development/progression. We aimed to assess the diagnostic/prognostic value of circulating exosomal miRNA in thyroid cancer (TC). A search in PubMed, Scopus, Web of Science, and Science Direct up to 22 May 2021 was performed. The true/false positive (TP/FP) and true/false negative (TN/FN) rates were extracted from each eligible study to obtain the pooled sensitivity, specificity, positive/negative likelihood ratios (PLR/NLR), diagnostic odds ratio (DOR), and their 95% confidence intervals (95%CIs). The meta-analysis included 12 articles consisting of 1164 Asian patients and 540 controls. All miRNAs were quantified using qRT-PCR assays. The pooled sensitivity was 82% (95%CI = 77–86%), pooled specificity was 76% (95%CI = 71–80%), and pooled DOR was 13.6 (95%CI = 8.8–21.8). The best biomarkers with high sensitivity were miR-16-2-3p (94%), miR-223-5p (91%), miR-130a-3p (90%), and miR182-5p (94%). Similarly, they showed high specificity, in addition to miR-34c-5p. Six panels of two to four exosomal miRNAs showed higher diagnostic values with an area under the curve (AUC) ranging from 0.906 to 0.981. The best discriminative ability to differentiate between cancer and non-cancer individuals was observed for miR-146b-5p + miR-223-5p + miR-182-5p (AUC = 0.981, sensitivity = 93.8% (84.9–98.3), specificity = 92.9% (76.5–99.1)). In conclusion, the expression levels of exosomal miRNAs could predict TC. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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19 pages, 866 KiB  
Review
Exosomal microRNA in Pancreatic Cancer Diagnosis, Prognosis, and Treatment: From Bench to Bedside
by Md. Hafiz Uddin, Mohammed Najeeb Al-Hallak, Philip A. Philip, Ramzi M. Mohammad, Nerissa Viola, Kay-Uwe Wagner and Asfar S. Azmi
Cancers 2021, 13(11), 2777; https://doi.org/10.3390/cancers13112777 - 3 Jun 2021
Cited by 23 | Viewed by 5036
Abstract
Pancreatic cancer is the fourth leading cause of cancer death among men and women in the United States, and pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of pancreatic cancer cases. PDAC is one of the most lethal gastrointestinal malignancies with an [...] Read more.
Pancreatic cancer is the fourth leading cause of cancer death among men and women in the United States, and pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of pancreatic cancer cases. PDAC is one of the most lethal gastrointestinal malignancies with an overall five-year survival rate of ~10%. Developing effective therapeutic strategies against pancreatic cancer is a great challenge. Novel diagnostic, prognostic, and therapeutic strategies are an immediate necessity to increase the survival of pancreatic cancer patients. So far, studies have demonstrated microRNAs (miRNAs) as sensitive biomarkers because of their significant correlation with disease development and metastasis. The miRNAs have been shown to be more stable inside membrane-bound vesicles in the extracellular environment called exosomes. Varieties of miRNAs are released into the body fluids via exosomes depending on the normal physiological or pathological conditions of the body. In this review, we discuss the recent findings on the diagnostic, prognostic, and therapeutic roles of exosomal miRNAs in pancreatic cancer. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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28 pages, 14222 KiB  
Review
MicroRNA Therapeutics in Cancer: Current Advances and Challenges
by Soha Reda El Sayed, Justine Cristante, Laurent Guyon, Josiane Denis, Olivier Chabre and Nadia Cherradi
Cancers 2021, 13(11), 2680; https://doi.org/10.3390/cancers13112680 - 29 May 2021
Cited by 86 | Viewed by 11963
Abstract
The discovery of microRNAs (miRNAs) in 1993 has challenged the dogma of gene expression regulation. MiRNAs affect most of cellular processes from metabolism, through cell proliferation and differentiation, to cell death. In cancer, deregulated miRNA expression leads to tumor development and progression by [...] Read more.
The discovery of microRNAs (miRNAs) in 1993 has challenged the dogma of gene expression regulation. MiRNAs affect most of cellular processes from metabolism, through cell proliferation and differentiation, to cell death. In cancer, deregulated miRNA expression leads to tumor development and progression by promoting acquisition of cancer hallmark traits. The multi-target action of miRNAs, which enable regulation of entire signaling networks, makes them attractive tools for the development of anti-cancer therapies. Hence, supplementing downregulated miRNA by synthetic oligonucleotides or silencing overexpressed miRNAs through artificial antagonists became a common strategy in cancer research. However, the ultimate success of miRNA therapeutics will depend on solving pharmacokinetic and targeted delivery issues. The development of a number of nanocarrier-based platforms holds significant promises to enhance the cell specific controlled delivery and safety profile of miRNA-based therapies. In this review, we provide among the most comprehensive assessments to date of promising nanomedicine platforms that have been tested preclinically, pertaining to the treatment of selected solid tumors including lung, liver, breast, and glioblastoma tumors as well as endocrine malignancies. The future challenges and potential applications in clinical oncology are discussed. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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22 pages, 1429 KiB  
Review
microRNAs as Novel Therapeutics in Cancer
by Giulia Romano, Mario Acunzo and Patrick Nana-Sinkam
Cancers 2021, 13(7), 1526; https://doi.org/10.3390/cancers13071526 - 26 Mar 2021
Cited by 29 | Viewed by 3797
Abstract
In the last 20 years, the functional roles for miRNAs in gene regulation have been well established. MiRNAs act as regulators in virtually all biological pathways and thus have been implicated in numerous diseases, including cancer. They are particularly relevant in regulating the [...] Read more.
In the last 20 years, the functional roles for miRNAs in gene regulation have been well established. MiRNAs act as regulators in virtually all biological pathways and thus have been implicated in numerous diseases, including cancer. They are particularly relevant in regulating the basic hallmarks of cancer, including apoptosis, proliferation, migration, and invasion. Despite the substantial progress made in identifying the molecular mechanisms driving the deregulation of miRNAs in cancer, the clinical translation of these important molecules to therapy remains in its infancy. The paucity of vehicles available for the safe and efficient delivery of miRNAs and ongoing concerns for toxicity remain major obstacles to clinical application. Novel formulations and the development of new vectors have significantly improved the stability of oligonucleotides, increasing the effectiveness of therapy. Furthermore, the use of specific moieties for delivery in target tissues or cells has increased the specificity of treatment. The use of new technologies has allowed small but important steps toward more specific therapeutic delivery in tumor tissues and cells. Although a long road remains, the path ahead holds great potential. Currently, a few miRNA drugs are under investigation in human clinical trials with promising results ahead. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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23 pages, 1715 KiB  
Review
The Roles of ceRNAs-Mediated Autophagy in Cancer Chemoresistance and Metastasis
by Huilin Zhang and Bingjian Lu
Cancers 2020, 12(10), 2926; https://doi.org/10.3390/cancers12102926 - 11 Oct 2020
Cited by 31 | Viewed by 3213
Abstract
Chemoresistance and metastasis are the main causes of treatment failure and unfavorable outcome in cancers. There is a pressing need to reveal their mechanisms and to discover novel therapy targets. Autophagy is composed of a cascade of steps controlled by different autophagy-related genes [...] Read more.
Chemoresistance and metastasis are the main causes of treatment failure and unfavorable outcome in cancers. There is a pressing need to reveal their mechanisms and to discover novel therapy targets. Autophagy is composed of a cascade of steps controlled by different autophagy-related genes (ATGs). Accumulating evidence suggests that dysregulated autophagy contributes to chemoresistance and metastasis via competing endogenous RNA (ceRNA) networks including lncRNAs and circRNAs. ceRNAs sequester the targeted miRNA expression to indirectly upregulate ATGs expression, and thereof participate in autophagy-mediated chemoresistance and metastasis. Here, we attempt to summarize the roles of ceRNAs in cancer chemoresistance and metastasis through autophagy regulation. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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17 pages, 600 KiB  
Review
Insights into the Role of microRNAs in Colorectal Cancer (CRC) Metabolism
by Kha Wai Hon, Syafiq Asnawi Zainal Abidin, Iekhsan Othman and Rakesh Naidu
Cancers 2020, 12(9), 2462; https://doi.org/10.3390/cancers12092462 - 31 Aug 2020
Cited by 17 | Viewed by 3369
Abstract
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers, with a high mortality rate globally. The pathophysiology of CRC is mainly initiated by alteration in gene expression, leading to dysregulation in multiple signalling pathways and cellular processes. Metabolic reprogramming is one [...] Read more.
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers, with a high mortality rate globally. The pathophysiology of CRC is mainly initiated by alteration in gene expression, leading to dysregulation in multiple signalling pathways and cellular processes. Metabolic reprogramming is one of the important cancer hallmarks in CRC, which involves the adaptive changes in tumour cell metabolism to sustain the high energy requirements for rapid cell proliferation. There are several mechanisms in the metabolic reprogramming of cancer cells, such as aerobic glycolysis, oxidative phosphorylation, lactate and fatty acids metabolism. MicroRNAs (miRNAs) are a class of non-coding RNAs that are responsible for post-transcriptional regulation of gene expression. Differential expression of miRNAs has been shown to play an important role in different aspects of tumorigenesis, such as proliferation, apoptosis, and drug resistance, as well as metabolic reprogramming. Increasing evidence also reports that miRNAs could function as potential regulators of metabolic reprogramming in CRC cells. This review provides an insight into the role of different miRNAs in regulating the metabolism of CRC cells as well as to discuss the potential role of miRNAs as biomarkers or therapeutic targets in CRC tumour metabolism. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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21 pages, 1306 KiB  
Review
A Comprehensive Review of Cancer MicroRNA Therapeutic Delivery Strategies
by Alexis Forterre, Hiroaki Komuro, Shakhlo Aminova and Masako Harada
Cancers 2020, 12(7), 1852; https://doi.org/10.3390/cancers12071852 - 9 Jul 2020
Cited by 143 | Viewed by 7175
Abstract
In the field of molecular oncology, microRNAs (miRNAs) and their role in regulating physiological processes and cancer pathogenesis have been a revolutionary discovery over the last decade. It is now considered that miRNA dysregulation influences critical molecular pathways involved in tumor progression, invasion, [...] Read more.
In the field of molecular oncology, microRNAs (miRNAs) and their role in regulating physiological processes and cancer pathogenesis have been a revolutionary discovery over the last decade. It is now considered that miRNA dysregulation influences critical molecular pathways involved in tumor progression, invasion, angiogenesis and metastasis in a wide range of cancer types. Hence, altering miRNA levels in cancer cells has promising potential as a therapeutic intervention, which is discussed in many other articles in this Special Issue. Some of the most significant hurdles in therapeutic miRNA usage are the stability and the delivery system. In this review, we cover a comprehensive update on the challenges and strategies for the development of therapeutic miRNA delivery systems that includes virus-based delivery, non-viral delivery (artificial lipid-based vesicles, polymer-based or chemical structures), and recently emerged extracellular vesicle (EV)-based delivery systems. Full article
(This article belongs to the Special Issue MicroRNA Therapeutics: Towards a New Era for the Management of Cancer)
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