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17 pages, 4428 KiB

Open AccessArticle

MiR-486-5p Targets CD133+ Lung Cancer Stem Cells through the p85/AKT Pathway

by Massimo Moro, Orazio Fortunato, Giulia Bertolini, Mavis Mensah, Cristina Borzi, Giovanni Centonze, Francesca Andriani, Daniela Di Paolo, Patrizia Perri, Mirco Ponzoni, Ugo Pastorino, Gabriella Sozzi and Mattia Boeri

Pharmaceuticals 2022, 15(3), 297; https://doi.org/10.3390/ph15030297 - 28 Feb 2022

Cited by 11 | Viewed by 3041

Abstract

Despite improvements in therapies and screening strategies, lung cancer prognosis still remains dismal, especially for metastatic tumors. Cancer stem cells (CSCs) are endowed with properties such as chemoresistance, dissemination, and stem-like features, that make them one of the main causes of the poor [...] Read more.

Despite improvements in therapies and screening strategies, lung cancer prognosis still remains dismal, especially for metastatic tumors. Cancer stem cells (CSCs) are endowed with properties such as chemoresistance, dissemination, and stem-like features, that make them one of the main causes of the poor survival rate of lung cancer patients. MicroRNAs (miRNAs), small molecules regulating gene expression, have a role in lung cancer development and progression. In particular, miR-486-5p is an onco-suppressor miRNA found to be down-modulated in the tumor tissue of lung cancer patients. In this study, we investigate the role of this miRNA in CD133+ lung CSCs and evaluate the therapeutic efficacy of coated cationic lipid-nanoparticles entrapping the miR-486-5p miRNA mimic (CCL-486) using lung cancer patient-derived xenograft (PDX) models. In vitro, miR-486-5p overexpression impaired the PI3K/Akt pathway and decreased lung cancer cell viability. Moreover, miR-486-5p overexpression induced apoptosis also in CD133+ CSCs, thus affecting the in vivo tumor-initiating properties of these cells. Finally, we demonstrated that in vivo CCL-486 treatment decreased CD133+ percentage and inhibited tumor growth in PDX models. In conclusion, we provided insights on the efficacy of a novel miRNA-based compound to hit CD133+ lung CSCs, setting the basis for new combined therapeutic strategies. Full article

(This article belongs to the Special Issue MiRNA-Based Therapeutics in Cancer)

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15 pages, 2960 KiB

Open AccessArticle

miR-34a-Mediated Survivin Inhibition Improves the Antitumor Activity of Selinexor in Triple-Negative Breast Cancer

by Silvia Martini, Valentina Zuco, Monica Tortoreto, Stefano Percio, Elisa Campi, Rihan El Bezawy, Valentina Doldi, Yosef Landesman, Marzia Pennati and Nadia Zaffaroni

Pharmaceuticals 2021, 14(6), 523; https://doi.org/10.3390/ph14060523 - 29 May 2021

Cited by 7 | Viewed by 2677

Abstract

Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Here, we pursued a combinatorial therapeutic approach to enhance the activity of selinexor, the first-in-class XPO1 inhibitor, by miR-34a ectopic expression in human TNBC experimental models. Anti-proliferative activity induced by selinexor [...] Read more.

Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Here, we pursued a combinatorial therapeutic approach to enhance the activity of selinexor, the first-in-class XPO1 inhibitor, by miR-34a ectopic expression in human TNBC experimental models. Anti-proliferative activity induced by selinexor and miR-34a expression, singly and in combination, was evaluated by MTS assay and cell counting. The effect of treatments on survivin and apoptosis-related proteins was assessed by western blotting and ELISA. The antitumor and toxic effects of individual and combined treatments were evaluated on TNBC orthotopic xenografts in SCID mice. Selinexor consistently showed anti-proliferative activity, although to a variable extent, in the different TNBC cell lines and caused the impairment of survivin expression and intracellular distribution, accompanied by apoptosis induction. Consistent with in vitro data, the XPO1 inhibitor variably affected the growth of TNBC orthotopic xenografts. miR-34a cooperated with selinexor to reduce survivin expression and improved its anti-proliferative activity in TNBC cells. Most importantly, miR-34a expression markedly enhanced selinexor antitumor activity in the less sensitive TNBC xenograft model, in absence of toxicity. Our data form a solid foundation for promoting the use of a miR-34a-based approach to improve the therapeutic efficacy of selinexor in TNBC patients. Full article

(This article belongs to the Special Issue MiRNA-Based Therapeutics in Cancer)

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29 pages, 8020 KiB

Open AccessArticle

Adipose MSCs Suppress MCF7 and MDA-MB-231 Breast Cancer Metastasis and EMT Pathways Leading to Dormancy via Exosomal-miRNAs Following Co-Culture Interaction

by Norlaily Mohd Ali, Swee Keong Yeap, Wan Yong Ho, Lily Boo, Huynh Ky, Dilan Amila Satharasinghe, Sheau Wei Tan, Soon Keng Cheong, Hsien Da Huang, Kuan Chun Lan, Men Yee Chiew and Han Kiat Ong

Pharmaceuticals 2021, 14(1), 8; https://doi.org/10.3390/ph14010008 - 24 Dec 2020

Cited by 20 | Viewed by 4758

Abstract

Globally, breast cancer is the most frequently diagnosed cancer in women, and it remains a substantial clinical challenge due to cancer relapse. The presence of a subpopulation of dormant breast cancer cells that survived chemotherapy and metastasized to distant organs may contribute to [...] Read more.

Globally, breast cancer is the most frequently diagnosed cancer in women, and it remains a substantial clinical challenge due to cancer relapse. The presence of a subpopulation of dormant breast cancer cells that survived chemotherapy and metastasized to distant organs may contribute to relapse. Tumor microenvironment (TME) plays a significant role as a niche in inducing cancer cells into dormancy as well as involves in the reversible epithelial-to-mesenchymal transition (EMT) into aggressive phenotype responsible for cancer-related mortality in patients. Mesenchymal stem cells (MSCs) are known to migrate to TME and interact with cancer cells via secretion of exosome- containing biomolecules, microRNA. Understanding of interaction between MSCs and cancer cells via exosomal miRNAs is important in determining the therapeutic role of MSC in treating breast cancer cells and relapse. In this study, exosomes were harvested from a medium of indirect co-culture of MCF7-luminal and MDA-MB-231-basal breast cancer cells (BCCs) subtypes with adipose MSCs. The interaction resulted in different exosomal miRNAs profiles that modulate essential signaling pathways and cell cycle arrest into dormancy via inhibition of metastasis and epithelial-to-mesenchymal transition (EMT). Overall, breast cancer cells displayed a change towards a more dormant-epithelial phenotype associated with lower rates of metastasis and higher chemoresistance. The study highlights the crucial roles of adipose MSCs in inducing dormancy and identifying miRNAs-dormancy related markers that could be used to identify the metastatic pattern, predict relapses in cancer patients and to be potential candidate targets for new targeted therapy. Full article

(This article belongs to the Special Issue MiRNA-Based Therapeutics in Cancer)

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16 pages, 2512 KiB

Open AccessArticle

Silencing of Exosomal miR-181a Reverses Pediatric Acute Lymphocytic Leukemia Cell Proliferation

by Shabirul Haque and Sarah R. Vaiselbuh

Pharmaceuticals 2020, 13(9), 241; https://doi.org/10.3390/ph13090241 - 11 Sep 2020

Cited by 25 | Viewed by 2852

Abstract

Exosomes are cell-generated nano-vesicles found in most biological fluids. Major components of their cargo are lipids, proteins, RNA, DNA, and non-coding RNAs. The miRNAs carried within exosomes reveal real-time information regarding disease status in leukemia and other cancers, and therefore exosomes have been [...] Read more.

Exosomes are cell-generated nano-vesicles found in most biological fluids. Major components of their cargo are lipids, proteins, RNA, DNA, and non-coding RNAs. The miRNAs carried within exosomes reveal real-time information regarding disease status in leukemia and other cancers, and therefore exosomes have been studied as novel biomarkers for cancer. We investigated the impact of exosomes on cell proliferation in pediatric acute lymphocytic leukemia (PALL) and its reversal by silencing of exo-miR-181a. We isolated exosomes from the serum of PALL patients (Exo-PALL) and conditioned medium of leukemic cell lines (Exo-CM). We found that Exo-PALL promotes cell proliferation in leukemic B cell lines by gene regulation. This exosome-induced cell proliferation is a precise event with the up-regulation of proliferative (PCNA, Ki-67) and pro-survival genes (MCL-1, and BCL2) and suppression of pro-apoptotic genes (BAD, BAX). Exo-PALL and Exo-CM both show over expression of miR-181a compared to healthy donor control exosomes (Exo-HD). Specific silencing of exosomal miR-181a using a miR-181a inhibitor confirms that miR-181a inhibitor treatment reverses Exo-PALL/Exo-CM-induced leukemic cell proliferation in vitro. Altogether, this study suggests that exosomal miR-181a inhibition can be a novel target for growth suppression in pediatric lymphatic leukemia. Full article

(This article belongs to the Special Issue MiRNA-Based Therapeutics in Cancer)

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Review

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18 pages, 2111 KiB

Open AccessReview

The Ambivalent Role of miRNAs in Carcinogenesis: Involvement in Renal Cell Carcinoma and Their Clinical Applications

by Federica Spadaccino, Margherita Gigante, Giuseppe Stefano Netti, Maria Teresa Rocchetti, Rossana Franzin, Loreto Gesualdo, Giuseppe Castellano, Giovanni Stallone and Elena Ranieri

Pharmaceuticals 2021, 14(4), 322; https://doi.org/10.3390/ph14040322 - 02 Apr 2021

Cited by 9 | Viewed by 2413

Abstract

The analysis of microRNA (miRNAs), small, non-coding endogenous RNA, plays a crucial role in oncology. These short regulatory sequences, acting on thousands of messenger RNAs (mRNAs), modulate gene expression at the transcriptional and post-transcriptional level leading to translational repression or degradation of target [...] Read more.

The analysis of microRNA (miRNAs), small, non-coding endogenous RNA, plays a crucial role in oncology. These short regulatory sequences, acting on thousands of messenger RNAs (mRNAs), modulate gene expression at the transcriptional and post-transcriptional level leading to translational repression or degradation of target molecules. Although their function is required for several physiological processes, such as proliferation, apoptosis and cell differentiation, miRNAs are also responsible for development and/or progression of several cancers, since they may interact with classical tumor pathways. In this review, we highlight recent advances in deregulated miRNAs in cancer focusing on renal cell carcinoma (RCC) and provide an overview of the potential use of miRNA in their clinical settings, such as diagnostic and prognostic markers. Full article

(This article belongs to the Special Issue MiRNA-Based Therapeutics in Cancer)

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23 pages, 1236 KiB

Open AccessReview

Aberrant Expression of microRNA Clusters in Head and Neck Cancer Development and Progression: Current and Future Translational Impacts

by Li-Jie Li, Wei-Min Chang and Michael Hsiao

Pharmaceuticals 2021, 14(3), 194; https://doi.org/10.3390/ph14030194 - 27 Feb 2021

Cited by 3 | Viewed by 2681

Abstract

MicroRNAs are small non-coding RNAs known to negative regulate endogenous genes. Some microRNAs have high sequence conservation and localize as clusters in the genome. Their coordination is regulated by simple genetic and epigenetic events mechanism. In cells, single microRNAs can regulate multiple genes [...] Read more.

MicroRNAs are small non-coding RNAs known to negative regulate endogenous genes. Some microRNAs have high sequence conservation and localize as clusters in the genome. Their coordination is regulated by simple genetic and epigenetic events mechanism. In cells, single microRNAs can regulate multiple genes and microRNA clusters contain multiple microRNAs. MicroRNAs can be differentially expressed and act as oncogenic or tumor suppressor microRNAs, which are based on the roles of microRNA-regulated genes. It is vital to understand their effects, regulation, and various biological functions under both normal and disease conditions. Head and neck squamous cell carcinomas are some of the leading causes of cancer-related deaths worldwide and are regulated by many factors, including the dysregulation of microRNAs and their clusters. In disease stages, microRNA clusters can potentially control every field of oncogenic function, including growth, proliferation, apoptosis, migration, and intercellular commutation. Furthermore, microRNA clusters are regulated by genetic mutations or translocations, transcription factors, and epigenetic modifications. Additionally, microRNA clusters harbor the potential to act therapeutically against cancer in the future. Here, we review recent advances in microRNA cluster research, especially relative to head and neck cancers, and discuss their regulation and biological functions under pathological conditions as well as translational applications. Full article

(This article belongs to the Special Issue MiRNA-Based Therapeutics in Cancer)

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23 pages, 3860 KiB

Open AccessReview

The Role of miRNA-7 in the Biology of Cancer and Modulation of Drug Resistance

by Ewa Gajda, Małgorzata Grzanka, Marlena Godlewska and Damian Gawel

Pharmaceuticals 2021, 14(2), 149; https://doi.org/10.3390/ph14020149 - 12 Feb 2021

Cited by 12 | Viewed by 2899

Abstract

MicroRNAs (miRNAs, miRs) are small non-coding RNA (ncRNA) molecules capable of regulating post-transcriptional gene expression. Imbalances in the miRNA network have been associated with the development of many pathological conditions and diseases, including cancer. Recently, miRNAs have also been linked to the phenomenon [...] Read more.

MicroRNAs (miRNAs, miRs) are small non-coding RNA (ncRNA) molecules capable of regulating post-transcriptional gene expression. Imbalances in the miRNA network have been associated with the development of many pathological conditions and diseases, including cancer. Recently, miRNAs have also been linked to the phenomenon of multidrug resistance (MDR). MiR-7 is one of the extensively studied miRNAs and its role in cancer progression and MDR modulation has been highlighted. MiR-7 is engaged in multiple cellular pathways and acts as a tumor suppressor in the majority of human neoplasia. Its depletion limits the effectiveness of anti-cancer therapies, while its restoration sensitizes cells to the administered drugs. Therefore, miR-7 might be considered as a potential adjuvant agent, which can increase the efficiency of standard chemotherapeutics. Full article

(This article belongs to the Special Issue MiRNA-Based Therapeutics in Cancer)

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17 pages, 1739 KiB

Open AccessReview

MicroRNA-Based Therapeutics for Drug-Resistant Colorectal Cancer

by Eunsun Jung, Jinhyeon Choi, Jang-Seong Kim and Tae-Su Han

Pharmaceuticals 2021, 14(2), 136; https://doi.org/10.3390/ph14020136 - 08 Feb 2021

Cited by 14 | Viewed by 2705

Abstract

Although therapeutic approaches for patients with colorectal cancer (CRC) have improved in the past decades, the problem of drug resistance still persists and acts as a major obstacle for effective therapy. Many studies have shown that drug resistance is related to reduced drug [...] Read more.

Although therapeutic approaches for patients with colorectal cancer (CRC) have improved in the past decades, the problem of drug resistance still persists and acts as a major obstacle for effective therapy. Many studies have shown that drug resistance is related to reduced drug uptake, modification of drug targets, and/or transformation of cell cycle checkpoints. A growing body of evidence indicates that several microRNAs (miRNAs) may contribute to the drug resistance to chemotherapy, targeted therapy, and immunotherapy by regulating the drug resistance-related target genes in CRC. These drug resistance-related miRNAs may be used as promising biomarkers for predicting drug response or as potential therapeutic targets for treating patients with CRC. In this review, we summarized the recent discoveries regarding anti-cancer drug-related miRNAs and their molecular mechanisms in CRC. Furthermore, we discussed the challenges associated with the clinical application of miRNAs as biomarkers for the diagnosis of drug-resistant patients and as therapeutic targets for CRC treatment. Full article

(This article belongs to the Special Issue MiRNA-Based Therapeutics in Cancer)

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19 pages, 730 KiB

Open AccessReview

miRNA-Based Therapeutics in the Era of Immune-Checkpoint Inhibitors

by Florian Huemer, Michael Leisch, Roland Geisberger, Nadja Zaborsky and Richard Greil

Pharmaceuticals 2021, 14(2), 89; https://doi.org/10.3390/ph14020089 - 26 Jan 2021

Cited by 10 | Viewed by 2704

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by binding to complementary target regions on gene transcripts. Thus, miRNAs fine-tune gene expression profiles in a cell-type-specific manner and thereby regulate important cellular functions, such as cell growth, proliferation and cell death. [...] Read more.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by binding to complementary target regions on gene transcripts. Thus, miRNAs fine-tune gene expression profiles in a cell-type-specific manner and thereby regulate important cellular functions, such as cell growth, proliferation and cell death. MiRNAs are frequently dysregulated in cancer cells by several mechanisms, which significantly affect the course of the disease. In this review, we summarize the current knowledge on how dysregulated miRNAs contribute to cancer and how miRNAs can be exploited as predictive factors and therapeutic targets, particularly in regard to immune-checkpoint inhibitor therapies. Full article

(This article belongs to the Special Issue MiRNA-Based Therapeutics in Cancer)

12 pages, 599 KiB

Open AccessReview

The Therapeutic Potential of MicroRNAs in Cancer: Illusion or Opportunity?

by Orazio Fortunato and Marilena V. Iorio

Pharmaceuticals 2020, 13(12), 438; https://doi.org/10.3390/ph13120438 - 01 Dec 2020

Cited by 14 | Viewed by 2214

Abstract

The functional involvement of microRNAs in human neoplasia has raised in the last years an increasing interest in the scientific community toward the potential application in clinics as therapeutic tools. Indeed, the possibility to modulate their expression to re-establish a lost equilibrium and [...] Read more.

The functional involvement of microRNAs in human neoplasia has raised in the last years an increasing interest in the scientific community toward the potential application in clinics as therapeutic tools. Indeed, the possibility to modulate their expression to re-establish a lost equilibrium and counteract tumor growth and dissemination, and/or to improve responsiveness to standard therapies, is promising and fascinating. However, several issues need to be taken into account such as factors related to miRNA stability in the blood, tissue penetration and potential off-target effects, which might affect safety, tolerability and efficacy of an miRNA-based therapy. Here we describe the most relevant challenges related to miRNA-based therapy, review the delivery strategies exploited to date and the on-going clinical trials. Full article

(This article belongs to the Special Issue MiRNA-Based Therapeutics in Cancer)

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