Publications by authors named "Gianpiero Di Leva"

42 Publications

Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition.

EMBO Mol Med 2020 07 17;12(7):e11099. Epub 2020 Jun 17.

Transcriptional Networks in Lung Cancer Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.

A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on-target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4-ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti-apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propose a new treatment strategy for a subset of patients with acquired resistance to first-, second- and third-generation ALK inhibitors.
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http://dx.doi.org/10.15252/emmm.201911099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338803PMC
July 2020

Telomerase inhibition, telomere attrition and proliferation arrest of cancer cells induced by phosphorothioate ASO-NLS conjugates targeting hTERC and siRNAs targeting hTERT.

Nucleosides Nucleotides Nucleic Acids 2020 ;39(1-3):407-425

Department of Biological & Environmental Chemistry, Faculty of Humanity Oriented Science and Engineering, Kindai University, Iizuka, Japan.

Telomerase activity has been regarded as a critical step in cellular immortalization and carcinogenesis and because of this, regulation of telomerase represents an attractive target for anti-tumor specific therapeutics. Recently, one avenue of cancer research focuses on antisense strategy to target the oncogenes or cancer driver genes, in a sequence specific fashion to down-regulate the expression of the target gene. The protein catalytic subunit, human telomerase reverse transcriptase (hTERT) and the template RNA component (hTERC) are essential for telomerase function, thus theoretically, inhibition of telomerase activity can be achieved by interfering with either the gene expression of hTERT or the hTERC of the telomerase enzymatic complex. The present study showed that phosphorothioate antisense oligonucleotide (sASO)-nuclear localization signal (NLS) peptide conjugates targeting hTERC could inhibit telomerase activity very efficiently at 5 μM concentration but less efficiently at 1 μM concentration. On the other hand, siRNA targeting hTERT mRNA could strongly suppress hTERT expression at 200 nM concentration. It was also revealed that siRNA targeting hTERT could induce telomere attrition and then irreversible arrest of proliferation of cancer cells.
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http://dx.doi.org/10.1080/15257770.2020.1713357DOI Listing
September 2020

Author Correction: Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface.

Nat Commun 2019 Jul 18;10(1):3151. Epub 2019 Jul 18.

Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, M20 4BX, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-11220-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639354PMC
July 2019

Heterogeneity in Circulating Tumor Cells: The Relevance of the Stem-Cell Subset.

Cancers (Basel) 2019 Apr 5;11(4). Epub 2019 Apr 5.

Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy.

The release of circulating tumor cells (CTCs) into vasculature is an early event in the metastatic process. The analysis of CTCs in patients has recently received widespread attention because of its clinical implications, particularly for precision medicine. Accumulated evidence documents a large heterogeneity in CTCs across patients. Currently, the most accepted view is that tumor cells with an intermediate phenotype between epithelial and mesenchymal have the highest plasticity. Indeed, the existence of a meta-stable or partial epithelial⁻mesenchymal transition (EMT) cell state, with both epithelial and mesenchymal features, can be easily reconciled with the concept of a highly plastic stem-like state. A close connection between EMT and cancer stem cells (CSC) traits, with enhanced metastatic competence and drug resistance, has also been described. Accordingly, a subset of CTCs consisting of CSC, present a stemness profile, are able to survive chemotherapy, and generate metastases after xenotransplantation in immunodeficient mice. In the present review, we discuss the current evidence connecting CTCs, EMT, and stemness. An improved understanding of the CTC/EMT/CSC connections may uncover novel therapeutic targets, irrespective of the tumor type, since most cancers seem to harbor a pool of CSCs, and disclose important mechanisms underlying tumorigenicity.
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http://dx.doi.org/10.3390/cancers11040483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521045PMC
April 2019

miRNAs in bone metastasis.

Expert Rev Endocrinol Metab 2017 11 10;12(6):451-461. Epub 2017 Oct 10.

b Biomedical Research Centre, School of Environment and Life Sciences , University of Salford , Salford , UK.

Introduction: Bone metastasis is one of the most common forms of metastasis from a number of different primary carcinomas. MicroRNAs (miRNAs) are short, endogenous RNAs that negatively regulate gene expression to control essential pathways, including those involved in bone organogenesis and homeostasis. As these pathways are often hijacked during bone metastasis, it is not surprising that miRNAs can also influence bone metastasis formation. Areas covered: In this review, we first summarize the major signalling pathways involved in normal bone development and bone metastasis. We will then discuss the overall roles of miRNAs in cancer metastasis and highlight the recent findings on the effects of miRNAs in bone metastasis. To this aim, we have performed a literature search in PubMed by using the search words 'miRNAs' and 'bone metastasis', selecting relevant scientific articles published between 2010 and 2016. Seminal publications before 2010 on the metastatic role of miRNAs have also been considered. Expert commentary: With the lack of current diagnostic biomarkers and effective targeted therapies for bone metastasis, the significant role of miRNAs in the regulation of bone homeostasis and bone metastasis may support the future use of miRNAs as diagnostic biomarkers and therapeutic targets.
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http://dx.doi.org/10.1080/17446651.2017.1383893DOI Listing
November 2017

Circulating Micrornas Predict Survival of Patients with Tumors of Glial Origin.

EBioMedicine 2018 Apr 21;30:105-112. Epub 2018 Mar 21.

Dept. of Cancer Biology and Genetics (CBG), The Ohio State University, Columbus, OH, United States. Electronic address:

The World Health Organization has recently introduced molecular prognostic-diagnostic biomarkers in the classification of Central Nervous System (CNS) tumors. In order to characterize subclasses of tumors that cannot find a precise location in the current classification, and, or cannot be tested because of scant material, it is important to find new molecular biomarkers in tissue and, or biological fluid samples. In this study, we identified serum microRNAs that could serve as biomarkers for the diagnosis and prognosis of patients with tumors of glial origin. We retrospectively analyzed microRNA expression in the serum extracellular vesicles of patients with tumors of glial origin. Extracellular vesicles RNA was analyzed by Nanostring. qRT-PCR confirmed 6 overexpressed microRNAs: hsa-miR-4443, hsa-miR-422a, hsa-miR-494-3p, hsa-miR-502-5p, hsa-miR-520f-3p, and hsa-miR-549a. Hsa-miR-4443 was the only microRNA that showed significant differences in most comparisons. In situ hybridization (ISH), confirmed that our signature was mostly expressed in cancer cells. Importantly, hsa-miR-549a and hsa-miR-502-5p expression predicted prognosis in patients with tumors of glial origin. Although more studies are needed, we demonstrated that serum vesicles microRNA profiles are promising diagnostic and prognostic molecular biomarkers that will find an actual application in the clinical practice of CNS tumors.
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http://dx.doi.org/10.1016/j.ebiom.2018.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952410PMC
April 2018

Loss of miR-204 expression is a key event in melanoma.

Mol Cancer 2018 03 9;17(1):71. Epub 2018 Mar 9.

LTTA, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121, Ferrara, Italy.

Cutaneous melanoma (CM) is a malignancy with increasing occurrence. Its microRNA repertoire has been defined in a number studies, leading to candidates for biological and clinical relevance: miR-200a/b/c, miR-203, miR-205, miR-204, miR-211, miR-23b and miR-26a/b. Our work was aimed to validate the role of these candidate miRNAs in melanoma, using additional patients cohorts and in vitro cultures. miR-26a, miR-204 and miR-211 were more expressed in normal melanocytes, while miR-23b, miR-200b/c, miR-203 and miR-205 in epidermis and keratinocytes. None of the keratinocyte-related miRNAs was associated with any known mutation or with clinical covariates in melanoma. On the other hand, the loss of miR-204 was enriched in melanomas with NRAS sole mutation (Fisher exact test, P = 0.001, Log Odds = 1.67), and less frequent than expected in those harbouring CDKN2A mutations (Fisher exact test, P = 0.001, Log Odds - 1.09). Additionally, miR-204 was associated with better prognosis in two independent melanoma cohorts and its exogenous expression led to growth impairment in melanoma cell lines. Thus, miR-204 represents a relevant mechanism in melanoma, with potential prognostic value and its loss seems to act in the CDKN2A pathway, in cooperation with NRAS.
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http://dx.doi.org/10.1186/s12943-018-0819-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844115PMC
March 2018

Deregulation of miRNAs in malignant pleural mesothelioma is associated with prognosis and suggests an alteration of cell metabolism.

Sci Rep 2017 06 9;7(1):3140. Epub 2017 Jun 9.

Department of Biology, University of Pisa, Pisa, Italy.

Malignant pleural mesothelioma (MPM) is an aggressive human cancer and miRNAs can play a key role for this disease. In order to broaden the knowledge in this field, the miRNA expression was investigated in a large series of MPM to discover new pathways helpful in diagnosis, prognosis and therapy. We employed nanoString nCounter system for miRNA profiling on 105 MPM samples and 10 healthy pleura. The analysis was followed by the validation of the most significantly deregulated miRNAs by RT-qPCR in an independent sample set. We identified 63 miRNAs deregulated in a statistically significant way. MiR-185, miR-197, and miR-299 were confirmed differentially expressed, after validation study. In addition, the results of the microarray analysis corroborated previous findings concerning miR-15b-5p, miR-126-3p, and miR-145-5p. Kaplan-Meier curves were used to explore the association between miRNA expression and overall survival (OS) and identified a 2-miRNA prognostic signature (Let-7c-5p and miR-151a-5p) related to hypoxia and energy metabolism respectively. In silico analyses with DIANA-microT-CDS highlighted 5 putative targets in common between two miRNAs. With the present work we showed that the pattern of miRNAs expression is highly deregulated in MPM and that a 2-miRNA signature can be a new useful tool for prognosis in MPM.
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http://dx.doi.org/10.1038/s41598-017-02694-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466648PMC
June 2017

Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface.

Nat Commun 2017 04 18;8:14909. Epub 2017 Apr 18.

Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.

Lysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking the extracellular matrix. LOX overexpression is associated with poor cancer outcomes. Here, we find that LOX regulates the epidermal growth factor receptor (EGFR) to drive tumour progression. We show that LOX regulates EGFR by suppressing TGFβ1 signalling through the secreted protease HTRA1. This increases the expression of Matrilin2 (MATN2), an EGF-like domain-containing protein that traps EGFR at the cell surface to facilitate its activation by EGF. We describe a pharmacological inhibitor of LOX, CCT365623, which disrupts EGFR cell surface retention and delays the growth of primary and metastatic tumour cells in vivo. Thus, we show that LOX regulates EGFR cell surface retention to drive tumour progression, and we validate the therapeutic potential of inhibiting this pathway with the small molecule inhibitor CCT365623.
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http://dx.doi.org/10.1038/ncomms14909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399287PMC
April 2017

miR-9 and miR-200 Regulate PDGFRβ-Mediated Endothelial Differentiation of Tumor Cells in Triple-Negative Breast Cancer.

Cancer Res 2016 09 11;76(18):5562-72. Epub 2016 Jul 11.

Start Up Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Organization of cancer cells into endothelial-like cell-lined structures to support neovascularization and to fuel solid tumors is a hallmark of progression and poor outcome. In triple-negative breast cancer (TNBC), PDGFRβ has been identified as a key player of this process and is considered a promising target for breast cancer therapy. Thus, we aimed at investigating the role of miRNAs as a therapeutic approach to inhibit PDGFRβ-mediated vasculogenic properties of TNBC, focusing on miR-9 and miR-200. In MDA-MB-231 and MDA-MB-157 TNBC cell lines, miR-9 and miR-200 promoted and inhibited, respectively, the formation of vascular-like structures in vitro Induction of endogenous miR-9 expression, upon ligand-dependent stimulation of PDGFRβ signaling, promoted significant vascular sprouting of TNBC cells, in part, by direct repression of STARD13. Conversely, ectopic expression of miR-200 inhibited this sprouting by indirectly reducing the protein levels of PDGFRβ through the direct suppression of ZEB1. Notably, in vivo miR-9 inhibition or miR-200c restoration, through either the generation of MDA-MB-231-stable clones or peritumoral delivery in MDA-MB-231 xenografted mice, strongly decreased the number of vascular lacunae. Finally, IHC and immunofluorescence analyses in TNBC specimens indicated that PDGFRβ expression marked tumor cells engaged in vascular lacunae. In conclusion, our results demonstrate that miR-9 and miR-200 play opposite roles in the regulation of the vasculogenic ability of TNBC, acting as facilitator and suppressor of PDGFRβ, respectively. Moreover, our data support the possibility to therapeutically exploit miR-9 and miR-200 to inhibit the process of vascular lacunae formation in TNBC. Cancer Res; 76(18); 5562-72. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0140DOI Listing
September 2016

Repression of Esophageal Neoplasia and Inflammatory Signaling by Anti-miR-31 Delivery In Vivo.

J Natl Cancer Inst 2015 Nov 18;107(11). Epub 2015 Aug 18.

Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (CT, MG, GDL, HA, PF, JM, CMC); Kimmel Cancer Center (HC, YJ, KJS, LYF) and Department of Pathology, Anatomy, and Cell Biology (YJ, JLF, LYF), Thomas Jefferson University, Philadelphia, PA; Center for Genome Research (CT, GMT), Department of Life Sciences (TS), University of Modena and Reggio Emilia, Modena, Italy (CT, GMT); Transcriptional Networks in Lung Cancer Group, Manchester Institute, University of Manchester, UK (MG, SN).

Background: Overexpression of microRNA-31 (miR-31) is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary zinc deficiency. Using a rat model that recapitulates features of human ESCC, the mechanism whereby Zn regulates miR-31 expression to promote ESCC is examined.

Methods: To inhibit in vivo esophageal miR-31 overexpression in Zn-deficient rats (n = 12-20 per group), locked nucleic acid-modified anti-miR-31 oligonucleotides were administered over five weeks. miR-31 expression was determined by northern blotting, quantitative polymerase chain reaction, and in situ hybridization. Physiological miR-31 targets were identified by microarray analysis and verified by luciferase reporter assay. Cellular proliferation, apoptosis, and expression of inflammation genes were determined by immunoblotting, caspase assays, and immunohistochemistry. The miR-31 promoter in Zn-deficient esophagus was identified by ChIP-seq using an antibody for histone mark H3K4me3. Data were analyzed with t test and analysis of variance. All statistical tests were two-sided.

Results: In vivo, anti-miR-31 reduced miR-31 overexpression (P = .002) and suppressed the esophageal preneoplasia in Zn-deficient rats. At the same time, the miR-31 target Stk40 was derepressed, thereby inhibiting the STK40-NF-κΒ-controlled inflammatory pathway, with resultant decreased cellular proliferation and activated apoptosis (caspase 3/7 activities, fold change = 10.7, P = .005). This same connection between miR-31 overexpression and STK40/NF-κΒ expression was also documented in human ESCC cell lines. In Zn-deficient esophagus, the miR-31 promoter region and NF-κΒ binding site were activated. Zn replenishment restored the regulation of this genomic region and a normal esophageal phenotype.

Conclusions: The data define the in vivo signaling pathway underlying interaction of Zn deficiency and miR-31 overexpression in esophageal neoplasia and provide a mechanistic rationale for miR-31 as a therapeutic target for ESCC.
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http://dx.doi.org/10.1093/jnci/djv220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4675101PMC
November 2015

A set of NF-κB-regulated microRNAs induces acquired TRAIL resistance in lung cancer.

Proc Natl Acad Sci U S A 2015 Jun 15;112(26):E3355-64. Epub 2015 Jun 15.

Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210;

TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. However, TRAIL can also stimulate the proliferation of cancer cells through the activation of NF-κB, but the exact mechanism is still poorly understood. In this study, we show that chronic exposure to subtoxic concentrations of TRAIL results in acquired resistance. This resistance is associated with the increase in miR-21, miR-30c, and miR-100 expression, which target tumor-suppressor genes fundamental in the response to TRAIL. Importantly, down-regulation of caspase-8 by miR-21 blocks receptor interacting protein-1 cleavage and induces the activation of NF-κB, which regulates these miRNAs. Thus, TRAIL activates a positive feedback loop that sustains the acquired resistance and causes an aggressive phenotype. Finally, we prove that combinatory treatment of NF-κB inhibitors and TRAIL is able to revert resistance and reduce tumor growth, with important consequences for the clinical practice.
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http://dx.doi.org/10.1073/pnas.1504630112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491797PMC
June 2015

miRNA clusters as therapeutic targets for hormone-resistant breast cancer.

Expert Rev Endocrinol Metab 2015 13;10(6):607-617. Epub 2015 Oct 13.

Department of Molecular Virology Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.

MicroRNAs are small non coding RNAs that typically inhibit the translation and stability of messenger RNAs, controlling genes involved in cellular processes such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis, and migration. Not surprisingly, microRNAs are also aberrantly expressed in cancer and promote tumorigenesis by disrupting these vital cellular functions. In this review, we first broadly summarize the role of microRNAs in breast cancer and Estrogen Receptor alpha signaling. Then we focus on what is currently known about the role of microRNAs in anti-hormonal therapy or resistance to endocrine agents. Specifically, we will discuss key miRNAs involved in tamoxifen (miR-221/222, 181, 101, 519a, 301, 375, 342, 451, and the let-7 family), fulvestrant (miR-221/222, miR-200 family), and aromatase inhibitor (miR-128 and the let-7 family) resistance.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053393PMC
http://dx.doi.org/10.1586/17446651.2015.1099430DOI Listing
October 2015

Pluripotent stem cell miRNAs and metastasis in invasive breast cancer.

J Natl Cancer Inst 2014 Dec 11;106(12). Epub 2014 Oct 11.

Department of Molecular Virology, Immunology and Molecular Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (SV, GN, AD, SC, MiG, RAe, RG, GDL, PG, PD, TW, SEW, FP, NZ, HA, KFH, CMC); Biosystems Analysis, LTTA, Deptartment of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy, (SV, MES, JM, MaG, MM, CZ, FC, MP, JP, MN); Fate Therapeutics, San Diego, CA (RAb); Department of Chemistry, The Scripps Research Institute, La Jolla, CA (CD); Department of Urology, Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA (RB); Comprehensive Cancer Center, The Ohio State University, Columbus, OH (KM); Deptartment of Internal Medicine, James Cancer Hospital and Ohio State University Comprehensive Cancer Center, The Ohio State University (CLS); Division of Pathology, II University of Rome "La Sapienza," Ospedale Santo Andrea, Rome, Italy (AV); Department of Surgery, Thomas Jefferson University Medical College, Philadelphia, PA (ALR).

Background: The purpose of this study is to determine whether microRNA for pluripotent stem cells are also expressed in breast cancer and are associated with metastasis and outcome.

Methods: We studied global microRNA profiles during differentiation of human embryonic stem cells (n =26) and in breast cancer patients (n = 33) and human cell lines (n = 35). Using in situ hybridization, we then investigated MIR302 expression in 318 untreated breast cancer patients (test cohort, n = 22 and validation cohort, n = 296). In parallel, using next-generation sequencing data from breast cancer patients (n = 684), we assessed microRNA association with stem cell markers. All statistical tests were two-sided.

Results: In healthy tissues, the MIR302 (high)/MIR203 (low) asymmetry was exclusive for pluripotent stem cells. MIR302 was expressed in a small population of cancer cells within invasive ductal carcinoma, but not in normal breast (P < .001). Furthermore, MIR302 was expressed in the tumor cells together with stem cell markers, such as CD44 and BMI1. Conversely, MIR203 expression in 684 breast tumors negatively correlated with CD44 (Spearman correlation, Rho = -0.08, P = .04) and BMI1 (Rho = -0.11, P = .004), but positively correlated with differentiation marker CD24 (Rho = 0.15, P < .001). Primary tumors with lymph node metastasis had cancer cells showing scattered expression of MIR302 and widespread repression of MIR203. Finally, overall survival was statistically significantly shorter in patients with MIR302-positive cancer cells (P = .03).

Conclusions: In healthy tissues the MIR302(high)/MIR203(low) asymmetry was characteristic of embryonic and induced pluripotency. In invasive ductal carcinoma, the MIR302/MIR203 asymmetry was associated with stem cell markers, metastasis, and shorter survival.
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http://dx.doi.org/10.1093/jnci/dju324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334797PMC
December 2014

MicroRNA profiles discriminate among colon cancer metastasis.

PLoS One 2014 12;9(6):e96670. Epub 2014 Jun 12.

MVIMG, Ohio State University, Columbus, Ohio, United States of America.

MicroRNAs are being exploited for diagnosis, prognosis and monitoring of cancer and other diseases. Their high tissue specificity and critical role in oncogenesis provide new biomarkers for the diagnosis and classification of cancer as well as predicting patients' outcomes. MicroRNAs signatures have been identified for many human tumors, including colorectal cancer (CRC). In most cases, metastatic disease is difficult to predict and to prevent with adequate therapies. The aim of our study was to identify a microRNA signature for metastatic CRC that could predict and differentiate metastatic target organ localization. Normal and cancer tissues of three different groups of CRC patients were analyzed. RNA microarray and TaqMan Array analysis were performed on 66 Italian patients with or without lymph nodes and/or liver recurrences. Data obtained with the two assays were analyzed separately and then intersected to identify a primary CRC metastatic signature. Five differentially expressed microRNAs (hsa-miR-21, -103, -93, -31 and -566) were validated by qRT-PCR on a second group of 16 American metastatic patients. In situ hybridization was performed on the 16 American patients as well as on three distinct commercial tissues microarray (TMA) containing normal adjacent colon, the primary adenocarcinoma, normal and metastatic lymph nodes and liver. Hsa-miRNA-21, -93, and -103 upregulation together with hsa-miR-566 downregulation defined the CRC metastatic signature, while in situ hybridization data identified a lymphonodal invasion profile. We provided the first microRNAs signature that could discriminate between colorectal recurrences to lymph nodes and liver and between colorectal liver metastasis and primary hepatic tumor.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0096670PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055753PMC
October 2015

MicroRNAs as anti-cancer therapy.

Curr Pharm Des 2014 ;20(33):5328-35

The Ohio State University, 992, Biomedical Research Tower, 460 W 12th Avenue, Columbus, OH 43210.

MicroRNAs (miRNAs) are endogenously expressed and evolutionarily conserved small non-coding RNAs, which regulate gene expression. Several studies have shown that they are involved in fundamental biological processes, such as proliferation and apoptosis. MicroRNA dysregulation plays an important role in cancer onset and progression where miRs can function as both tumor promoters (oncomiRs) or tumor suppressors by targeting numerous biomolecules that are important in carcinogenesis. MicroRNA molecules are already entering the clinic as diagnostic and prognostic biomarkers for patient stratification and also as therapeutic targets and agents. Their role as biomarkers and therapeutic targets is appealing but several obstacles have as yet limited our ability to translate this potential into a clinical reality. This review provides a comprehensive overview of miRNAs with established functional relevance in cancer. Furthermore, approaches towards therapeutic miRNA-based intervention are discussed. Those include viral or non-viral approaches of miRNA replacement therapy in the case of tumor-suppressing miRNAs and strategies for the inhibition of oncogenic miRNAs.
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http://dx.doi.org/10.2174/1381612820666140128211346DOI Listing
May 2015

Idiopathic pulmonary fibrosis is strongly associated with productive infection by herpesvirus saimiri.

Mod Pathol 2014 Jun 15;27(6):851-62. Epub 2013 Nov 15.

1] Satellite Laboratory, Ohio State Univ Comprehensive Cancer Center, Powell, Columbus, OH, USA [2] Phylogeny Inc, Powell, OH, USA.

Idiopathic pulmonary fibrosis is a fatal disease without effective therapy or diagnostic test. To investigate a potential role for γ-herpesviruses in this disease, 21 paraffin-embedded lung biopsies from patients diagnosed with idiopathic pulmonary fibrosis and 21 lung biopsies from age-matched controls with pulmonary fibrosis of known etiology were examined for a series of γ-herpesviruses' DNA/RNA and related proteins using in situ hybridization and reverse transcriptase-polymerase chain reaction (RT-PCR)-based methods. We detected four proteins known to be in the genome of several γ-herpesviruses (cyclin D, thymidylate synthase, dihydrofolate reductase, and interleukin-17) that were strongly co-expressed in the regenerating epithelial cells of each of the 21 idiopathic pulmonary fibrosis cases and not in the benign epithelia of the controls. Among the γ-herpesviruses, only herpesvirus saimiri expresses all four of these 'pirated' mammalian proteins. We found herpesvirus saimiri DNA in the regenerating epithelial cells of 21/21 idiopathic pulmonary fibrosis cases using four separate probe sets but not in the 21 controls. RT-PCR showed that the source of the cyclin D RNA in active idiopathic pulmonary fibrosis was herpesvirus saimiri and not human. We cloned and sequenced part of genome corresponding to the DNA polymerase herpesvirus saimiri gene from an idiopathic pulmonary fibrosis sample and it matched 100% with the published viral sequence. These data are consistent with idiopathic pulmonary fibrosis representing herpesvirus saimiri-induced pulmonary fibrosis. Thus, treatment directed against viral proliferation and/or viral-associated proteins may halt disease progression. Further, demonstration of the viral nucleic acids or proteins may help diagnose the disease.
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http://dx.doi.org/10.1038/modpathol.2013.198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050527PMC
June 2014

MicroRNAs in cancer.

Annu Rev Pathol 2014 25;9:287-314. Epub 2013 Sep 25.

Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210; email: ,

MicroRNAs (miRNAs) are small noncoding RNAs that typically inhibit the translation and stability of messenger RNAs (mRNAs), controlling genes involved in cellular processes such as inflammation, cell-cycle regulation, stress response, differentiation, apoptosis, and migration. Thus, miRNAs have been implicated in the regulation of virtually all signaling circuits within a cell, and their dysregulation has been shown to play an essential role in the development and progression of cancer. Here, after a brief description of miRNA genomics, biogenesis, and function, we discuss the effects of miRNA dysregulation in the cellular pathways that lead to the progressive conversion of normal cells into cancer cells and the potential to develop new molecular miRNA-targeted therapies.
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http://dx.doi.org/10.1146/annurev-pathol-012513-104715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4009396PMC
March 2014

MiR-34a/c-Dependent PDGFR-α/β Downregulation Inhibits Tumorigenesis and Enhances TRAIL-Induced Apoptosis in Lung Cancer.

PLoS One 2013 21;8(6):e67581. Epub 2013 Jun 21.

Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, the Ohio State University, Columbus, Ohio, United States of America.

Lung cancer is the leading cause of cancer mortality in the world today. Although some advances in lung cancer therapy have been made, patient survival is still poor. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family consists of tumor-suppressive miRNAs, and its reduced expression has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we found that miR-34a and miR-34c target platelet-derived growth factor receptor alpha and beta (PDGFR-α and PDGFR-β), cell surface tyrosine kinase receptors that induce proliferation, migration and invasion in cancer. MiR-34a and miR-34c were downregulated in lung tumors compared to normal tissues. Moreover, we identified an inverse correlation between PDGFR-α/β and miR-34a/c expression in lung tumor samples. Finally, miR-34a/c overexpression or downregulation of PDGFR-α/β by siRNAs, strongly augmented the response to TNF-related apoptosis inducing ligand (TRAIL) while reducing migratory and invasive capacity of NSCLC cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067581PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689725PMC
October 2017

The Role of microRNAs in the Tumorigenesis of Ovarian Cancer.

Front Oncol 2013 13;3:153. Epub 2013 Jun 13.

Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University Columbus, OH, USA.

Epithelial ovarian cancer (EOC) is a complex disease, with multiple histological subtypes recognized. There have been major advances in the understanding of the cellular and molecular biology of this human malignancy, however the survival rate of women with EOC has changed little since platinum-based-treatment was introduced more than 30 years ago. Since 2006, an increasing number of studies have indicated an essential role for microRNAs (miRNAs) in ovarian-cancer tumorigenesis. Several miRNA profiling studies have shown that they associate with different aspects of ovarian cancer (tumor subtype, stage, histological grade, prognosis, and therapy resistance) and pointed to a critical role for miRNAs in the pathogenesis and progression of EOC. In this review, we discuss the current data concerning the accumulating evidence of the modulated expression of miRNAs in EOC, their role in diagnosis, prognosis, and prediction of response to therapy. Given the heterogeneity of this disease, it is likely that increases in long-term survival might be also achieved by translating the recent insights of miRNAs involvement in EOC into novel targeted therapies that will have a major impact on the management of ovarian cancer.
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http://dx.doi.org/10.3389/fonc.2013.00153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682193PMC
June 2013

MicroRNAs.

Clin Biochem 2013 Jul;46(10-11):840-1

Ohio State University, Comprehensive Cancer Center, Department of Molecular Virology, Immunology and Medical Genetics, BRT1072 460W 12th avenue Columbus, OH 43210, USA.

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http://dx.doi.org/10.1016/j.clinbiochem.2013.05.060DOI Listing
July 2013

Estrogen mediated-activation of miR-191/425 cluster modulates tumorigenicity of breast cancer cells depending on estrogen receptor status.

PLoS Genet 2013 7;9(3):e1003311. Epub 2013 Mar 7.

Department of Molecular Virology, Immunology, and Medical Genetics, School of Medicine, The Ohio State University, Columbus, Ohio, United States of America.

MicroRNAs (miRNAs), single-stranded non-coding RNAs, influence myriad biological processes that can contribute to cancer. Although tumor-suppressive and oncogenic functions have been characterized for some miRNAs, the majority of microRNAs have not been investigated for their ability to promote and modulate tumorigenesis. Here, we established that the miR-191/425 cluster is transcriptionally dependent on the host gene, DALRD3, and that the hormone 17β-estradiol (estrogen or E2) controls expression of both miR-191/425 and DALRD3. MiR-191/425 locus characterization revealed that the recruitment of estrogen receptor α (ERα) to the regulatory region of the miR-191/425-DALRD3 unit resulted in the accumulation of miR-191 and miR-425 and subsequent decrease in DALRD3 expression levels. We demonstrated that miR-191 protects ERα positive breast cancer cells from hormone starvation-induced apoptosis through the suppression of tumor-suppressor EGR1. Furthermore, enforced expression of the miR-191/425 cluster in aggressive breast cancer cells altered global gene expression profiles and enabled us to identify important tumor promoting genes, including SATB1, CCND2, and FSCN1, as targets of miR-191 and miR-425. Finally, in vitro and in vivo experiments demonstrated that miR-191 and miR-425 reduced proliferation, impaired tumorigenesis and metastasis, and increased expression of epithelial markers in aggressive breast cancer cells. Our data provide compelling evidence for the transcriptional regulation of the miR-191/425 cluster and for its context-specific biological determinants in breast cancers. Importantly, we demonstrated that the miR-191/425 cluster, by reducing the expression of an extensive network of genes, has a fundamental impact on cancer initiation and progression of breast cancer cells.
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http://dx.doi.org/10.1371/journal.pgen.1003311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591271PMC
June 2013

miRNA profiling of cancer.

Curr Opin Genet Dev 2013 Feb 4;23(1):3-11. Epub 2013 Mar 4.

Ohio State University, Comprehensive Cancer Center, Department of Molecular Virology, Immunology and Medical Genetics, BRT1072 460W. 12th Avenue, Columbus, OH 43210, USA.

A steadily growing number of studies have shown that microRNAs have key roles in the regulation of cellular processes and that their dysregulation is essential to keep the malignant phenotype of cancer cells. The distorted and unique expression profile of microRNAs in different types and subsets of tumor coupled with their presence in biological fluids make of microRNAs an attractive source of sensitive biomarkers. Here, we will discuss how microRNA profiles are altered in cancer, highlighting their potential as sensitive biomarkers for cancer risk stratification, outcome prediction and classification of histological subtypes. We will also evaluate the current knowledge on the use of microRNAs as circulating biomarkers, hoping that further studies will lead to the application of microRNA signature in prognostic and predictive markers that can improve patient health.
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http://dx.doi.org/10.1016/j.gde.2013.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632255PMC
February 2013

MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non-small-cell lung cancer through BIM down-regulation.

Proc Natl Acad Sci U S A 2012 Oct 24;109(41):16570-5. Epub 2012 Sep 24.

Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Studio di Diagnostica Nucleare (SDN), 80143 Naples, Italy.

MicroRNAs (miRNAs) have an important role in the development of chemosensitivity or chemoresistance in different types of cancer. Activation of the ERK1/2 pathway is a major determinant of diverse cellular processes and cancer development and is responsible for the transcription of several important miRNAs. Here we show a link between the ERK1/2 pathway and BIM expression through miR-494. We blocked ERK1/2 nuclear activity through the overexpression of an ERK1/2 natural interactor, the protein PED/PEA15, and we performed a microRNA expression profile. miR-494 was the most down-regulated microRNA after ERK1/2 inactivation. Moreover, we found that miR-494 induced Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resistance in non-small-cell lung cancer (NSCLC) through the down-modulation of BIM. Elucidation of this undiscovered ERK1/2 pathway that regulates apoptosis and cell proliferation through miR-494 in NSCLC will greatly enhance our understanding of the mechanisms responsible for TRAIL resistance and will provide an additional arm for the development of anticancer therapies.
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http://dx.doi.org/10.1073/pnas.1207917109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478630PMC
October 2012

Oncosuppressive role of p53-induced miR-205 in triple negative breast cancer.

Mol Oncol 2012 Aug 19;6(4):458-72. Epub 2012 Apr 19.

Departments of Molecular Virology, Immunology and Human Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.

An increasing body of evidence highlights an intriguing interaction between microRNAs and transcriptional factors involved in determining cell fate, including the well known "genome guardian" p53. Here we show that miR-205, oncosuppressive microRNA lost in breast cancer, is directly transactivated by oncosuppressor p53. Moreover, evaluating miR-205 expression in a panel of cell lines belonging to the highly aggressive triple negative breast cancer (TNBC) subtype, which still lacks an effective targeted therapy and characterized by an extremely undifferentiated and mesenchymal phenotype, we demonstrated that this microRNA is critically down-expressed compared to a normal-like cell line. Re-expression of miR-205 where absent strongly reduces cell proliferation, cell cycle progression and clonogenic potential in vitro, and inhibits tumor growth in vivo, and this tumor suppressor activity is at least partially exerted through targeting of E2F1, master regulator of cell cycle progression, and LAMC1, component of extracellular matrix involved in cell adhesion, proliferation and migration.
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http://dx.doi.org/10.1016/j.molonc.2012.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679926PMC
August 2012

MicroRNA in cancer: new hopes for antineoplastic chemotherapy.

Ups J Med Sci 2012 May 21;117(2):202-16. Epub 2012 Feb 21.

Department of Molecular Virology, Immunology and Human Genetics, Ohio State University, Columbus, OH 43210, USA.

MicroRNAs (miRNAs) are a class of endogenous non-coding small RNAs that are evolutionarily conserved and widely distributed among species. Their major function is to negatively regulate mRNA target genes, and miRNA expression has been found to be deregulated in all human cancers, where miRNAs play critical roles in tumorigenesis, functioning either as tumor suppressors or as oncogenes. This review provides a current overview of the connection between miRNAs and cancer by covering the recent advances in miRNA involvement in human cancer including initiation, growth, invasion, and metastasis. We will also highlight the literature where application of miRNAs has created the foundation for the development of potential future miRNA therapy.
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http://dx.doi.org/10.3109/03009734.2012.660551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339552PMC
May 2012

EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers.

Nat Med 2011 Dec 11;18(1):74-82. Epub 2011 Dec 11.

Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.

The involvement of the MET oncogene in de novo and acquired resistance of non-small cell lung cancers (NSCLCs) to tyrosine kinase inhibitors (TKIs) has previously been reported, but the precise mechanism by which MET overexpression contributes to TKI-resistant NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand their role in TKI-resistant NSCLCs, we examined changes in miRNA that are mediated by tyrosine kinase receptors. Here we report that miR-30b, miR-30c, miR-221 and miR-222 are modulated by both epidermal growth factor (EGF) and MET receptors, whereas miR-103 and miR-203 are controlled only by MET. We showed that these miRNAs have important roles in gefitinib-induced apoptosis and epithelial-mesenchymal transition of NSCLC cells in vitro and in vivo by inhibiting the expression of the genes encoding BCL2-like 11 (BIM), apoptotic peptidase activating factor 1 (APAF-1), protein kinase C ɛ (PKC-ɛ) and sarcoma viral oncogene homolog (SRC). These findings suggest that modulation of specific miRNAs may provide a therapeutic approach for the treatment of NSCLCs.
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http://dx.doi.org/10.1038/nm.2577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467100PMC
December 2011

Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development.

Cancer Cell 2010 Oct;18(4):367-81

Department of Molecular Virology, Comprehensive Cancer Center, Ohio State University, Columbus, 43210, USA.

In multiple myeloma (MM), an incurable B cell neoplasm, mutation or deletion of p53 is rarely detected at diagnosis. Using small-molecule inhibitors of MDM2, we provide evidence that miR-192, 194, and 215, which are downregulated in a subset of newly diagnosed MMs, can be transcriptionally activated by p53 and then modulate MDM2 expression. Furthermore, ectopic re-expression of these miRNAs in MM cells increases the therapeutic action of MDM2 inhibitors in vitro and in vivo by enhancing their p53-activating effects. In addition, miR-192 and 215 target the IGF pathway, preventing enhanced migration of plasma cells into bone marrow. The results suggest that these miRNAs are positive regulators of p53 and that their downregulation plays a key role in MM development.
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http://dx.doi.org/10.1016/j.ccr.2010.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561766PMC
October 2010