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Open accessJournal ArticleDOI: 10.1016/J.OMTN.2021.01.016

ncRNA therapy with miRNA-22-3p suppresses the growth of triple-negative breast cancer.

05 Mar 2021-Molecular therapy. Nucleic acids (Nature Publishing Group)-Vol. 23, pp 930-943
Abstract: Deregulation of noncoding RNAs, including microRNAs (miRs), is implicated in the pathogenesis of many human cancers, including breast cancer. Through extensive analysis of The Cancer Genome Atlas, we found that expression of miR-22-3p is markedly lower in triple-negative breast cancer (TNBC) than in normal breast tissue. The restoration of miR-22-3p expression led to significant inhibition of TNBC cell proliferation, colony formation, migration, and invasion. We demonstrated that miR-22-3p reduces eukaryotic elongation factor 2 kinase (eEF2K) expression by directly binding to the 3′ untranslated region of eEF2K mRNA. Inhibition of EF2K expression recapitulated the effects of miR-22-3p on TNBC cell proliferation, motility, invasion, and suppression of phosphatidylinositol 3-kinase/Akt and Src signaling. Systemic administration of miR-22-3p in single-lipid nanoparticles significantly suppressed tumor growth in orthotopic MDA-MB-231 and MDA-MB-436 TNBC models. Evaluation of the tumor response, following miR-22-3p therapy in these models using a novel mathematical model factoring in various in vivo parameters, demonstrated that the therapy is highly effective against TNBC. These findings suggest that miR-22-3p functions as a tumor suppressor by targeting clinically significant oncogenic pathways and that miR-22-3p loss contributes to TNBC growth and progression. The restoration of miR-22-3p expression is a potential novel noncoding RNA-based therapy for TNBC.

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Topics: Triple-negative breast cancer (54%), microRNA (53%), Gene silencing (53%) ... show more
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6 results found


Open accessJournal ArticleDOI: 10.3892/OL.2021.12773
Meghana Manjunath1, Bibha Choudhary1Institutions (1)
05 May 2021-Oncology Letters
Abstract: Breast cancer is the most prevalent cancer in women worldwide. Triple-negative breast cancer (TNBC) is characterized by the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. It is the most aggressive subtype of breast cancer and accounts for 12-20% of all breast cancer cases. TNBC is associated with younger age of onset, greater metastatic potential, higher incidence of relapse, and lower overall survival rates. Based on molecular phenotype, TNBC has been classified into six subtypes (BL1, BL2, M, MES, LAR, and IM). TNBC treatment is challenging due to its heterogeneity, highly invasive nature, and relatively poor therapeutics response. Chemotherapy and radiotherapy are conventional strategies for the treatment of TNBC. Recent research in TNBC and mechanistic understanding of disease pathogenesis using cutting-edge technologies has led to the unfolding of new lines of therapies that have been incorporated into clinical practice. Poly (ADP-ribose) polymerase and immune checkpoint inhibitors have made their way to the current TNBC treatment paradigm. This review focuses on the classification, features, and treatment progress in TNBC. Histological subtypes connected to recurrence, molecular classification of TNBC, targeted therapy for early and advanced TNBC, and advances in non-coding RNA in therapy are the key highlights in this review.

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Topics: Triple-negative breast cancer (58%), Breast cancer (57%), Cancer (55%) ... show more

3 Citations


Journal ArticleDOI: 10.1016/J.LFS.2021.119541
Aysegul Gorur1, Miguel Patino2, Hideaki Takahashi1, German Corrales1  +4 moreInstitutions (2)
27 Apr 2021-Life Sciences
Abstract: Aims In vitro and in vivo studies suggest that the mu-opioid receptor (MOR) is involved in tumorigenesis, and metastasis in cancer. In humans, the use of MOR agonists (opioids) is associated with head and neck squamous cell carcinoma (HNSCC) progression. In the present study, we aimed to examine the role of MOR activation in MOR (+) HNSCC. Main methods FaDu, MDA686Tu and UMSCC47 cell lines were used in in vitro and in vivo experiments. Cells and animals were treated with a highly selective MOR agonist DAMGO, [D-Ala (2), Me Phe (4), Glycol (5)]-enkephalin] or saline 0.9%. Key findings MOR activation significantly increased the proliferation, colony formation, invasion, and migration of FaDu and MDA6868Tu cells and promoted tumor growth in vivo. Significance These findings suggest that MOR is implicated in tumorigenesis of HNSCC. Overall, our findings identify that MOR could be used as a potential therapeutic target in patients with MOR (+) HNSCC.

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1 Citations


Open accessPosted ContentDOI: 10.1101/2021.10.19.21265154
26 Oct 2021-medRxiv
Abstract: The downregulation of miRNA-22 in triple negative breast cancer (TNBC) is associated with upregulation of eukaryotic elongation 2 factor kinase (eEF2K) protein, which regulates tumor growth, chemoresistance, and tumor immunosurveillance. Moreover, exogenous administration of miRNA-22, loaded in nanoparticles to prevent degradation and improve tumor delivery (termed miRNA-22 nanotherapy), to suppress eEF2K production has shown potential as an investigational therapeutic agent in vivo. To evaluate the translational potential of miRNA-22 nanotherapy, we developed a multiscale mechanistic model, calibrated to published in vivo data and extrapolated to the human scale, to describe and quantify the pharmacokinetics and pharmacodynamics of miRNA-22 in virtual patient populations. Our analysis revealed the dose-response relationship, suggested optimal treatment frequency for miRNA-22 nanotherapy, and highlighted key determinants of therapy response, from which combination with immune checkpoint inhibitors was identified as a candidate strategy for improving treatment outcomes. More importantly, drug synergy was identified between miRNA-22 and standard-of-care drugs for TNBC, providing a basis for rational therapeutic combinations for improved response.

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Open accessJournal ArticleDOI: 10.1002/JCLA.23952
Min Wei1, Jie Wang1, Qi He1, Lei Liu2  +1 moreInstitutions (2)
Abstract: Background Increasing studies reported that long non-coding RNAs are involved in regulating breast cancer (BRCA) progression. However, the specific roles and mechanisms of lncRNAs in BRCA remain largely unknown. Here, we sought to explore the functions and mechanisms of AC016405.3 in BRCA progression. Methods Bioinformatic analysis for AC016405.3, miR-22-3p, and ERBB3 were performed on starBase. The expressions of AC016405.3, miR-22-3p, and ERBB3 were examined by RT-qPCR. The functions of AC016405.3 on the proliferation, migration, and invasion of cells were evaluated by conducting CCK-8, colony formation, wound-healing, and Transwell assays. The subcellular distribution of AC016405.3 in BRCA cells was identified by performing fluorescence in situ hybridization (FISH) and subcellular fractionation techniques. Dual-luciferase assay was applied to validate the interactions of miR-22-3p with AC016405.3 or ERBB3. The interaction between ERBB3 and miR-22-3p was also tested by Anti-Ago2 RNA immunoprecipitation (RIP) assay. Results The results showed that AC016405.3 is highly expressed in BRCA tissues as well as cells and positively correlated with poor prognosis in BRCA patients. Silencing AC016405.3 obviously repressed the malignant behaviors of BRCA cells. Mechanistically, AC016405.3 functioned as a competing endogenous RNA (ceRNA) for miR-22-3p in the cytoplasm and sponged miR-22-3p to release its suppression of ERBB3. Rescue experiments revealed that the suppression role induced by AC016405.3 depletion on malignant behaviors of BRCA cells could be obviously counter by inhibiting miR-22-3p or overexpressing ERBB3. Conclusion AC016405.3 promotes BRCA progression by the derepression of ERBB3 via sponging miR-22-3p, which may represent a potential target for BRCA treatment.

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Journal ArticleDOI: 10.1021/ACS.JMEDCHEM.0C02218
Shiou Zhu1, Minru Liao1, Huidan Tan1, Lingjuan Zhu1  +3 moreInstitutions (1)
Abstract: Eukaryotic elongation factor 2 kinase (eEF2K), a member of the atypical protein kinase family of alpha-kinases, is well-known as a negative regulator of protein synthesis by phosphorylating eEF2. Notably, eEF2K functions as a key regulator of several cellular processes, leading to tumorigenesis. To date, some small-molecule compounds have been reported as potential eEF2K inhibitors in cancer drug discovery. However, an ideal targeted drug design still faces huge challenges. Alternatively, other design strategies, such as repurposed drugs, dual-target drugs, and drug combination strategies, provide insights into the improvement of cancer treatment. Here, we summarize the crucial eEF2K-modulating pathways in cancer, including AMPK, REDD1, and Src. Moreover, we discuss the inhibition of eEF2K with single-target inhibitors, repurposed drugs, dual-target inhibitors, drug combination strategies, and other emerging technologies for therapeutic purposes. Together, these inspiring findings provide insights into a promising strategy for inhibiting eEF2K with small-molecule compounds to improve potential cancer therapy.

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Topics: EEF2 (54%)

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24 results found


Open accessJournal ArticleDOI: 10.1016/S0092-8674(04)00045-5
David P. Bartel1Institutions (1)
23 Jan 2004-Cell
Abstract: MicroRNAs (miRNAs) are endogenous ∼22 nt RNAs that can play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression. Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.

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Topics: MicroRNA 34a (63%), Lin-4 microRNA precursor (56%), MicroRNA sequencing (55%) ... show more

30,422 Citations


Open accessJournal ArticleDOI: 10.3322/CAAC.21332
Abstract: Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Cancer Registries. Mortality data were collected by the National Center for Health Statistics. In 2016, 1,685,210 new cancer cases and 595,690 cancer deaths are projected to occur in the United States. Overall cancer incidence trends (13 oldest SEER registries) are stable in women, but declining by 3.1% per year in men (from 2009-2012), much of which is because of recent rapid declines in prostate cancer diagnoses. The cancer death rate has dropped by 23% since 1991, translating to more than 1.7 million deaths averted through 2012. Despite this progress, death rates are increasing for cancers of the liver, pancreas, and uterine corpus, and cancer is now the leading cause of death in 21 states, primarily due to exceptionally large reductions in death from heart disease. Among children and adolescents (aged birth-19 years), brain cancer has surpassed leukemia as the leading cause of cancer death because of the dramatic therapeutic advances against leukemia. Accelerating progress against cancer requires both increased national investment in cancer research and the application of existing cancer control knowledge across all segments of the population.

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Topics: Cancer Death Rate (74%), Epidemiology of cancer (72%), Cancer (63%) ... show more

13,496 Citations


Journal ArticleDOI: 10.1038/NRD.2016.246
Rajesha Rupaimoole1, Frank J. Slack1Institutions (1)
Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic. In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.

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2,209 Citations


Open accessJournal ArticleDOI: 10.1111/J.1365-2559.2007.02889.X
13 Dec 2007-Histopathology
Abstract: Breast cancer is a heterogeneous disease that encompasses several distinct entities with remarkably different biological characteristics and clinical behaviour. Currently, breast cancer patients are managed according to algorithms based on a constellation of clinical and histopathological parameters in conjunction with assessment of hormone receptor (oestrogen and progesterone receptor) status and HER2 overexpression/gene amplification. Although effective tailored therapies have been developed for patients with hormone receptor-positive or HER2+ disease, chemotherapy is the only modality of systemic therapy for patients with breast cancers lacking the expression of these markers (triple-negative cancers). Recent microarray expression profiling analyses have demonstrated that breast cancers can be systematically characterized into biologically and clinically meaningful groups. These studies have led to the re-discovery of basal-like breast cancers, which preferentially show a triple-negative phenotype. Both triple-negative and basal-like cancers preferentially affect young and African-American women, are of high histological grade and have more aggressive clinical behaviour. Furthermore, a significant overlap between the biological and clinical characteristics of sporadic triple-negative and basal-like cancers and breast carcinomas arising in BRCA1 mutation carriers has been repeatedly demonstrated. In this review, we critically address the characteristics of basal-like and triple-negative cancers, their similarities and differences, their response to chemotherapy as well as strategies for the development of novel therapeutic targets for these aggressive types of breast cancer. In addition, the possible mechanisms are discussed leading to BRCA1 pathway dysfunction in sporadic triple-negative and basal-like cancers and animal models for these tumour types.

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Topics: Breast cancer (63%), CA15-3 (60%), Cancer (59%) ... show more

835 Citations


Open accessJournal ArticleDOI: 10.1111/J.1432-1033.1990.TB19169.X
Ulf Carlberg1, Anders Nilsson1, Odd Nygård1Institutions (1)
01 Aug 1990-FEBS Journal
Abstract: The effect of phosphorylation on the functional activity of eukaryotic elongation factor 2 (eEF-2) was studied using a purified phosphorylated factor. The modified factor was unable to stimulate protein synthesis in an eEF-2-dependent rabbit reticulocyte lysate. The functional alteration was further analyzed by measuring the effects of phosphorylation on the ability of the factor to catalyse the ribosome-dependent hydrolysis of GTP. Kinetic analysis showed that both phosphorylated and unmodified factor was able to hydrolyse GTP with approximately the same maximum rate, indicating that the rate of nucleotide exchange was not impaired by the modification. However, the phosphorylated factor showed a marked reduction in the second-order rate constant, suggesting that the phosphorylation interfered with ribosome · eEF-2 complex formation by reducing the affinity of eEF-2 for the ribosome. This assumption was confirmed by direct measurements of the dissociation constants for the ribosomal complexes containing unmodified and phosphorylated eEF-2.

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Topics: Protein phosphorylation (62%), Elongation factor (59%), EEF2 (57%) ... show more

249 Citations