Carlo M Croce

The Ohio State University, Columbus, Ohio, United States

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Publications (700)6355.9 Total impact

  • Source
    Veronica Balatti · Yuri Pekarky · Carlo M Croce ·
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    ABSTRACT: B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia occurring as indolent or aggressive form. CLL clinical features and genetic abnormalities are well documented, but molecular details are still under investigation. MicroRNAs are small non-coding RNAs involved in several cellular processes and expressed in a tissue-specific manner. MicroRNAs regulate gene expression, and their deregulation can alter expression levels of genes involved in development/progression of tumors. In CLL, microRNAs can function as oncogenes or tumor suppressors and can also serve as markers for CLL onset/progression. Here, we discuss the most recent findings about the role of microRNAs in CLL and how this knowledge can be used to identify new biomarkers and treatment approaches.
    Journal of Hematology & Oncology 12/2015; 8(1). DOI:10.1186/s13045-015-0112-x · 4.81 Impact Factor
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    ABSTRACT: Cancer stem cells (CSCs) are a small part of the heterogeneous tumor cell population possessing self-renewal and multilineage differentiation potential as well as a great ability to sustain tumorigenesis. The molecular pathways underlying CSC phenotype are not yet well characterized. MicroRNAs (miRs) are small noncoding RNAs that play a powerful role in biological processes. Early studies have linked miRs to the control of self-renewal and differentiation in normal and cancer stem cells. We aimed to study the functional role of miRs in human breast cancer stem cells (BCSCs), also named mammospheres. We found that miR-221 was upregulated in BCSCs compared to their differentiated counterpart. Similarly, mammospheres from T47D cells had an increased level of miR-221 compared to differentiated cells. Transfection of miR-221 in T47D cells increased the number of mammospheres and the expression of stem cell markers. Among miR-221's targets, we identified DNMT3b. Furthermore, in BCSCs we found that DNMT3b repressed the expression of various stemness genes, such as Nanog and Oct 3/4, acting on the methylation of their promoters, partially reverting the effect of miR-221 on stemness. We hypothesize that miR-221 contributes to breast cancer tumorigenicity by regulating stemness, at least in part through the control of DNMT3b expression.
    Oncotarget 11/2015; DOI:10.18632/oncotarget.5979 · 6.36 Impact Factor
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    ABSTRACT: 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. 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. 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. 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. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
    JNCI Journal of the National Cancer Institute 10/2015; 107(11). DOI:10.1093/jnci/djv220 · 12.58 Impact Factor
  • Gianpiero Di Leva · Douglas G Cheung · Carlo M Croce ·
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    ABSTRACT: 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.
    Expert Review of Endocrinology &amp Metabolism 10/2015; 10(6):1-11. DOI:10.1586/17446651.2015.1099430
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    Alessandro Laganà · Alfredo Ferro · Carlo Maria Croce ·

    Frontiers in Bioengineering and Biotechnology 10/2015; 3. DOI:10.3389/fbioe.2015.00156
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    ABSTRACT: The central role of the microRNA (miR) 15a/16-1 cluster in B-cell oncogenesis has been extensively demonstrated, with over two-thirds of B-cell chronic lymphocytic leukemia characterized by the deletion of the miR-15a/16-1 locus at 13q14. Despite the well-established understanding of the molecular mechanisms occurring during miR-15a/16-1 dysregulation, the oncogenic role of other miR-15/16 family members, such as the miR-15b/16-2 cluster (3q25), is still far from being elucidated. Whereas miR-15a is highly similar to miR-15b, miR-16-1 is identical to miR-16-2; thus, it could be speculated that both clusters control a similar set of target genes and may have overlapping functions. However, the biological role of miR-15b/16-2 is still controversial. We generated miR-15b/16-2 knockout mice to better understand the cluster's role in vivo. These mice developed B-cell malignancy by age 15-18 mo with a penetrance of 60%. At this stage, mice showed significantly enlarged spleens with abnormal B cell-derived white pulp enlargement. Flow cytometric analysis demonstrated an expanded CD19+ CD5+ population in the spleen of 40% knockout mice, a characteristic of the chronic lymphocytic leukemia-associated phenotype found in humans. Of note, miR-15b/16-2 modulates the CCND2 (Cyclin D2), CCND1 (Cyclin D1), and IGF1R (insulin-like growth factor 1 receptor) genes involved in proliferation and antiapoptotic pathways in mouse B cells. These results are the first, to our knowledge, to suggest an important role of miR-15b/16-2 loss in the pathogenesis of B-cell chronic lymphocytic leukemia.
    Proceedings of the National Academy of Sciences 08/2015; 112(37). DOI:10.1073/pnas.1514954112 · 9.67 Impact Factor
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    ABSTRACT: Quaking (QKI) is a tumor-suppressor gene encoding a conserved RNA-binding protein, whose expression is downregulated in several solid tumors. Here we report that QKI plays an important role in the immune response and suppression of leukemogenesis. We show that the expression of Qki is reduced in lipopolysaccharide (LPS)-challenged macrophages, suggesting that Qki is a key regulator of LPS signaling pathway. Furthermore, LPS-induced downregulation of Qki expression is miR-155-dependent. Qki overexpression impairs LPS-induced phosphorylation of JNK and particularly p38 MAPKs, in addition to increasing the production of anti-inflammatory cytokine IL-10. In contrast, Qki ablation decreases Fas expression and the rate of Caspase3/7 activity, while increasing the levels of IL-1α, IL-1β and IL-6, and p38 phosphorylation. Similarly, the p38 pathway is also a target of QKI activity in chronic lymphocytic leukemia (CLL)-derived MEC2 cells. Finally, B-CLL patients show lower levels of QKI expression compared with B cells from healthy donor, and Qki is similarily downregulated with the progression of leukemia in Eµ-miR-155 transgenic mice. Altogether, these data implicate QKI in the pathophysiology of inflammation and oncogenesis where miR-155 is involved.
    Oncotarget 08/2015; 6(28). DOI:10.18632/oncotarget.5248 · 6.36 Impact Factor
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    ABSTRACT: We recently reported that miR-224 was significantly up-regulated in non-small cell lung cancer (NSCLC) tissues, in particular in resected NSCLC metastasis. We further demonstrated that miR-224 functions as an oncogene in NSCLC by directly targeting TNFAIP1 and SMAD4. However, the biological functions of miR-224 in NSCLC are controversial and underlying mechanisms of miR-224 in the progression and metastasis of lung cancer remain to be further explored. Here we report that caspase3 (CASP3) and caspase7 (CASP7) are previously unidentified targets of miR-224 in NSCLC, and that miR-224 promotes lung cancer cells proliferation and migration in part by directly targeting CASP7 and down-regulating its expression. In addition, miR-224 attenuated TNF-α induced apoptosis by direct targeting of CASP3 resulting in reduction of cleaved PARP1 expression in lung cancer cells. Furthermore, the expression of miR-224 negatively correlates with the expression of CASP7 and CASP3 in tissue samples from patients with lung cancer. Finally, we found that activated NF-κB signaling is involved in the regulation of miR-224 expression in lung cancer. Our study provides new insight in understanding of oncogenic role of miR-224 in the lung cancer pathogenesis and suggests that NF-κB/miR-224/CASP3, 7 pathway could be a putative therapeutic target in lung cancer.
    Oncotarget 08/2015; 6(26). DOI:10.18632/oncotarget.5224 · 6.36 Impact Factor
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  • Cancer Research 08/2015; 75(15 Supplement):LB-289-LB-289. DOI:10.1158/1538-7445.AM2015-LB-289 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):LB-164-LB-164. DOI:10.1158/1538-7445.AM2015-LB-164 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):3974-3974. DOI:10.1158/1538-7445.AM2015-3974 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):3126-3126. DOI:10.1158/1538-7445.AM2015-3126 · 9.33 Impact Factor
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    ABSTRACT: Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advancements and improvements in surgical and medical treatments, the survival rate of lung cancer patients remains frustratingly poor. Local control for early-stage nonsmall cell lung cancer (NSCLC) has dramatically improved over the last decades for both operable and inoperable patients. However, the molecular mechanisms of NSCLC invasion leading to regional and distant disease spread remain poorly understood. Here, we identify microRNA-224 (miR-224) to be significantly up-regulated in NSCLC tissues, particularly in resected NSCLC metastasis. Increased miR-224 expression promotes cell migration, invasion, and proliferation by directly targeting the tumor suppressors TNFα-induced protein 1 (TNFAIP1) and SMAD4. In concordance with in vitro studies, mouse xenograft studies validated that miR-224 functions as a potent oncogenic miRNA in NSCLC in vivo. Moreover, we found promoter hypomethylation and activated ERK signaling to be involved in the regulation of miR-224 expression in NSCLC. Up-regulated miR-224, thus, facilitates tumor progression by shifting the equilibrium of the partially antagonist functions of SMAD4 and TNFAIP1 toward enhanced invasion and growth in NSCLC. Our findings indicate that targeting miR-224 could be effective in the treatment of certain lung cancer patients.
    Proceedings of the National Academy of Sciences 07/2015; 112(31). DOI:10.1073/pnas.1502068112 · 9.67 Impact Factor
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    Mario Acunzo · Carlo M. Croce ·
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    ABSTRACT: MicroRNAs (miRNAs) are short noncoding RNAs with a length of approximately 22 nucleotides that are involved in posttranscriptional regulation of gene expression. miRNAs cover an important role in all biological processes, and aberrant miRNA expression is commonly associated with cancer. Recent discoveries have associated the involvement of miRNA in an increasingly large number of biological processes, including cachexia. The cachexia syndrome is a debilitating state of cancer that is, at least in part, associated with apoptosis. The mechanism through which tumors promote the characteristic distal loss of muscle and fat mass during the cachectic process is still not deeply investigated. In this review, we briefly describe the role of miRNAs in cancer development and cachexia. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:
    The Journal of Infectious Diseases 07/2015; 212(suppl 1). DOI:10.1093/infdis/jiv197 · 6.00 Impact Factor
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    ABSTRACT: Nucleolin (NCL) is a nucleocytoplasmic protein involved in many biological processes, such as ribosomal assembly, rRNA processing, and mRNA stabilization. NCL also regulates the biogenesis of specific microRNAs (miRNAs) involved in tumor development and aggressiveness. Interestingly, NCL is expressed on the surface of actively proliferating cancer cells, but not on their normal counterparts. Therefore, NCL is an attractive target for antineoplastic treatments. Taking advantage of phage-display technology, we engineered a fully human single-chain fragment variable, named 4LB5. This immunoagent binds NCL on the cell surface, it is translocated into the cytoplasm of target cells, and it abrogates the biogenesis of NCL-dependent miRNAs. Binding of 4LB5 to NCL on the cell surface of a variety of breast cancer and hepatocellular carcinoma cell lines, but not to normal-like MCF-10a breast cells, dramatically reduces cancer cell viability and proliferation. Finally, in orthotopic breast cancer mouse models, 4LB5 administration results in a significant reduction of the tumor volume without evident side effects. In summary, here we describe, to our knowledge, the first anti-NCL single-chain fragment variable displaying antineoplastic activity against established solid tumors, which could represent the prototype of novel immune-based NCL-targeting drugs with clinical potential as diagnostic and therapeutic tools in a wide variety of human cancers.
    Proceedings of the National Academy of Sciences 07/2015; 112(30):201507087. DOI:10.1073/pnas.1507087112 · 9.67 Impact Factor
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    ABSTRACT: P19 H-Ras, a second product derived from the H-Ras gene by alternative splicing, induces a G1/S phase delay, thereby maintaining cells in a reversible quiescence state. When P21 H-Ras is mutated in tumour cells, the alternative protein P19 H-Ras is also mutated. The H-Ras mutation Q61L is frequently detected in different tumours, which acts as constitutive activator of Ras functions and is considered to be a strong activating mutant. Additionally, a rare congenital disorder named Costello Syndrome, is described as a H-Ras disorder in children, mainly due to mutation G12S in p19 and p21 H-Ras proteins, which is present in 90 % of the Costello Syndrome patients. Our aim is to better understand the role of p19 and p21 H-Ras proteins in the cancer and Costello Syndrome development, concerning the miRNAs expression. Total miRNAs expression regulated by H-Ras proteins were first analyzed in human miRNA microarrays assays. Previously selected miRNAs, were further analyzed in developed cell lines containing H-Ras protein mutants, that included the G12S Costello Syndrome mutant, with PCR Real-Time Taq Man miRNA Assays primers. This study describes how p19 affects the RNA world and shows that: i) miR-342, miR-206, miR-330, miR-138 and miR-99b are upregulated by p19 but not by p19W164A mutant; ii) anti-miR-206 can restore the G2 phase in the presence of p19; iii) p19 and p21Q61L regulate their own alternative splicing; iv) miR-206 and miR-138 are differentially regulated by p19 and p21 H-Ras and v) P19G12S Costello mutants show a clear upregulation of miR-374, miR-126, miR-342, miR-330, miR-335 and let-7. These results allow us to conclude that the H-Ras G12S mutation plays an important role in miRNA expression and open up a new line of study to understand the consequences of this mutation on Costello syndrome. Furthermore, they suggest that oncogenes may have a sufficiently important impact on miRNA expression to promote the development of numerous cancers.
    BMC Medical Genetics 07/2015; 16(1):46. DOI:10.1186/s12881-015-0184-z · 2.08 Impact Factor
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    ABSTRACT: 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.
    Proceedings of the National Academy of Sciences 06/2015; 112(26). DOI:10.1073/pnas.1504630112 · 9.67 Impact Factor
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    ABSTRACT: The involvement of microRNAs (miRNAs) in chronic lymphocytic leukemia (CLL) pathogenesis suggests the possibility of anti-CLL therapeutic approaches based on miRNAs. Here, we used the Eµ-TCL1 transgenic mouse model, which reproduces leukemia with a similar course and distinct immunophenotype as human B-CLL, to test miR-181b as a therapeutic agent.In vitro enforced expression of miR-181b mimics induced significant apoptotic effects in human B-cell lines (RAJI, EHEB), as well as in mouse Eµ-TCL1 leukemic splenocytes. Molecular analyses revealed that miR-181b not only affected the expression of TCL1, Bcl2 and Mcl1 anti-apoptotic proteins, but also reduced the levels of Akt and phospho-Erk1/2. Notably, a siRNA anti-TCL1 could similarly down-modulate TCL1, but exhibited a reduced or absent activity in other relevant proteins, as well as a reduced effect on cell apoptosis and viability. In vivo studies demonstrated the capability of miR-181b to reduce leukemic cell expansion and to increase survival of treated mice.These data indicate that miR-181b exerts a broad range of actions, affecting proliferative, survival and apoptotic pathways, both in mice and human cells, and can potentially be used to reduce expansion of B-CLL leukemic cells.
    Oncotarget 06/2015; 6(23). DOI:10.18632/oncotarget.4415 · 6.36 Impact Factor
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    ABSTRACT: Central Nervous System malignancies often require stereotactic biopsy or biopsy for differential diagnosis, and for tumor staging and grading. Furthermore, stereotactic biopsy can be non-diagnostic or underestimate grading. Hence, there is a compelling need of new diagnostic biomarkers to avoid such invasive procedures. Several biological markers have been proposed, but they can only identify specific prognostic subtype of Central Nervous System tumors, and none of them has found a standardized clinical application.The aim of the study was to identify a Cerebro-Spinal Fluid microRNA signature that could differentiate among Central Nervous System malignancies.CSF total RNA of 34 neoplastic and of 14 non-diseased patients was processed by NanoString. Comparison among groups (Normal, Benign, Glioblastoma, Medulloblastoma, Metastasis and Lymphoma) lead to the identification of a microRNA profile that was further confirmed by RT-PCR and in situ hybridization.Hsa-miR-451, -711, 935, -223 and -125b were significantly differentially expressed among the above mentioned groups, allowing us to draw an hypothetical diagnostic chart for Central Nervous System malignancies.This is the first study to employ the NanoString technique for Cerebro-Spinal Fluid microRNA profiling. In this article, we demonstrated that Cerebro-Spinal Fluid microRNA profiling mirrors Central Nervous System physiologic or pathologic conditions. Although more cases need to be tested, we identified a diagnostic Cerebro-Spinal Fluid microRNA signature with good perspectives for future diagnostic clinical applications.
    Oncotarget 05/2015; 6(25). DOI:10.18632/oncotarget.4096 · 6.36 Impact Factor

Publication Stats

76k Citations
6,355.90 Total Impact Points


  • 2004-2015
    • The Ohio State University
      • • Department of Molecular Virology, Immunology and Medical Genetics
      • • The James Comprehensive Cancer Center
      Columbus, Ohio, United States
    • University of Aberdeen
      Aberdeen, Scotland, United Kingdom
  • 2007-2014
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
    • Universita' degli Studi "Magna Græcia" di Catanzaro
      Catanzaro, Calabria, Italy
  • 2004-2013
    • Sapienza University of Rome
      Roma, Latium, Italy
  • 1995-2013
    • Universita degli studi di Ferrara
      • Department of Morphology, Surgery and Experimental Medicine
      Ferrare, Emilia-Romagna, Italy
  • 2008-2012
    • University of Massachusetts Medical School
      • Department of Cancer Biology
      Worcester, Massachusetts, United States
  • 2011
    • University of Padova
      Padua, Veneto, Italy
  • 1999-2011
    • Weizmann Institute of Science
      • Department of Molecular Cell Biology
    • The Philadelphia Center
      Philadelphia, Pennsylvania, United States
  • 1995-2011
    • Thomas Jefferson University
      • • Department of Microbiology & Immunology
      • • Kimmel Cancer Center
      Filadelfia, Pennsylvania, United States
  • 2007-2010
    • Istituto Superiore di Sanità
      • Department of Haematology, Oncology and Molecular Medicine
      Roma, Latium, Italy
  • 2003-2007
    • University of Naples Federico II
      • Department of Molecular Medicine and Health Biotechnology
      Napoli, Campania, Italy
  • 2006
    • University of Verona
      • Department of Surgical and Gastroenterological Sciences
      Verona, Veneto, Italy
  • 1995-2005
    • Jefferson College
      Хиллсборо, Missouri, United States
  • 1993-2002
    • Thomas Jefferson University Hospitals
      Philadelphia, Pennsylvania, United States
  • 2000
    • The Children's Hospital of Philadelphia
      • Department of Pediatrics
      Philadelphia, Pennsylvania, United States
  • 1997
    • National Cancer Institute (USA)
      • Laboratory of Experimental Carcinogenesis
      Maryland, United States
  • 1989-1991
    • Temple University
      • • Department of Medicine
      • • Fels Institute for Cancer Research and Molecular Biology
      Filadelfia, Pennsylvania, United States
  • 1973-1989
    • Wistar Institute
      • Melanoma Research Center
      Filadelfia, Pennsylvania, United States
  • 1976
    • Albert Einstein College of Medicine
      New York City, New York, United States