1,721,304 research outputs found
Associazione Italiana per la Ricerca sul Cancro AIRC 5xmille 2011: A research platform for miRNA-based treatment of multiple myeloma and chronic lymphocytic leukemia
No full textThe aim of our project is to exploit miRNAs as drugs or targets in innovative therapeutic strategies for CLL and MM based on biological driven hypothesis, novel in vitro and in vivo preclinical models and delivery nanotechnologies. We propose an experimental platform which includes all steps from target identification (Task 1-2), bioreagent development (Task 3), in vivo preclinical validation (Task 4) and translation to clinical setting for assessment of the safety profile (Task 5) and final development as investigational new drug for FIRST in HUMAN studies (Task 6)
AIRC Investigator Grant 2008 - Functional and biological characterization of miR-221 and miR-483 in human cancer
No full textExperimental evidences indicate that miRNAs play a key role in human tumorigenesis. In fact, as many miRNAs are aberrantly expressed in human neoplasms, proper post-transcriptional regulation of oncogenes or tumor suppressors expression may be prevented. As a result, various physiological functions, such as differentiation, cell cycle control, apoptosis regulation may stop working, and cell motility and invasion may increase. At present, several miRNAs aberrantly expressed in human cancer have not yet been thoroughly investigated and understanding their role in human cancer is thus still at the beginning. Aim of the project is to assess the role of two microRNAs, miR-221 and miR-483, as oncogenes in human cancer. We have accumulated preliminary results that support the hypothesis that these miRNAs possess oncogenic functions. In fact, miR-221 is over-expressed in more than 70% of hepatocellular carcinomas, as well as in other human neoplasms, and it can stimulate cell proliferation by inhibiting the expression of the cyclin-dependent kinase inhibitors p27 and p57. miR-483 is instead over-expressed in 100% of Wilms’tumors, preliminary results indicate that it is controlled by the -catenin oncogene and it can possibly modulate the expression of genes, like PUMA, involved in the control of the intrinsic apoptotic pathway. Based on these preliminary results, we set two main objectives: (i) validate the oncogenic role of miR-221 in HCC, and (ii) validate the oncogenic role of miR-483 in Wilms’ tumors and other human neoplasms. To achieve these goals, four different tasks were set up. (1) Identification of the molecular network responsible for the oncogenic properties of miR-221 in hepatocellular carcinomas by (a) identifying and validating upstream regulators, in particular the role of MYC and E2F1 transcription factors, and (b) identifying and validating downstream gene targets, in particular elements of cell cycle control, such as the CDKIs p27 and p57 and other potential targets identified through genome-wide transcriptome analyses. (2) Assessment of in vivo oncogenic properties of miR-221 by developing a transgenic mouse strain over-expressing miR-221 in the liver. (3) Identification of the molecular network responsible for the oncogenic properties of miR-483 in Wilms’ tumors by (a) identifying and validating upstream regulators, in particular elements of the -catenin pathway, and (b) identifying and validating downstream gene targets, in particular those involved in the control of the apoptotic intrinsic pathway. (4) Assessment of in vivo oncogenic properties of miR-483 by developing a transgenic mouse strain over-expressing miR-483 in kidney and several other tissues. By achieving the proposed objectives, the project will improve our knowledge on the role of miRNAs in human tumorigenesis and produce precious tools to investigate novel and unconventional therapeutic approaches based on anti-microRNA oligonucleotides (AMOs)
FIRB Accordi di Programma 2011: Nanosistemi avanzati per una nuova oncologia molecolare (NEWTON)
No full textObiettivo della proposta della Unità Operativa dell’Università di Ferrara (UNIFE) è di investigare l’espressione di miRNA in biopsie tumorali e nel plasma di un’ampia casistica di pazienti affetti da neoplasia mammaria. Attraverso queste analisi, ci proponiamo di identificare profili di espressione in grado di predire le potenzialità metastatiche del tumore primitivo e la presenza di marcatori circolanti in grado di evidenziare tale rischio
Ministero della Salute – New pathogenetic and therapeutic targets in Cutaneous Lymphoma
No full textThe Unit will investigate role and function of miRNAs over-expressed in Sezary syndrome and other cutaneous T-cell lymphoma (CTCL). In particular, the Unit will provide the facilities (Agilent microarray platform and analytical bioinformatic expertise) for investigating:
(i) expression of miRNA during disease progression; (ii) expression of miRNA modulated by treatment with Vorinostat, a histone deacetylase inhibitor for the treatment of cutaneous T cell lymphoma.
In addition, since preliminary studies have already indicated the over-expression of various miRNAs, such as miR-18a, miR-106b and miR-21 among others, in comparison with the normal cellular counterpart, we plan to investigate their role in disease progression and drug responsiveness using cellular models. In fact, several studies have indicated that the identified upregulated miRNAs have a role in suppressing apoptosis and, at least for miR-21, its inhibition by anti-miRNA oligonucleotides (AMOs) increases sensitivity to the chemotherapeutic agent gemcitabine (Meng et al Gastroenterology,2006,130:2113). Thus, it is possible that the identified over-expressed miRNA might be involved in resistance to drug treatment and may therefore represent important targets for treatment. The effectiveness and safety of the in vivo use of AMOs has been proven in primates (Elmen et al., 2008), suggesting that AMOs may potentially represent a new form of anti-cancer agents, either as a single agent or through the potentiation of conventional anti-cancer drugs.
In summary, specific aims of the unit are: (i) expression of miRNA during cutaneous lymphoma disease progression; (ii) expression of miRNA modulated by treatment with the histone deacetylase inhibitor Vorinostat; (iii) assessment of cellular and molecular changes by modulation of miR-21 and/or miR-18/miR-106.
Achievement of the objectives will improve our understanding on the molecular basis of cutaneous lymphoma. In particular, the contribution of aberrant miRNA expression will be clarified. This understanding could be translated into diagnostic approaches important for choosing the most appropriate therapy and, since efficacy and safety of anti-microRNA oligonucleotides has already been proved, it may open the way to the development of novel unconventional therapeutic approaches
Ministero della Salute Progetti Finalizzati 2009: New pathogenetic and therapeutic targets in Cutaneous Lymphoma
No full textThe Unit will investigate role and function of miRNAs over-expressed in Sezary syndrome and other cutaneous T-cell lymphoma (CTCL). In particular, the Unit will provide the facilities (Agilent microarray platform and analytical bioinformatic expertise) for investigating:
(i) expression of miRNA during disease progression; (ii) expression of miRNA modulated by treatment with Vorinostat, a histone deacetylase inhibitor for the treatment of cutaneous T cell lymphoma.
In addition, since preliminary studies have already indicated the over-expression of various miRNAs, such as miR-18a, miR-106b and miR-21 among others, in comparison with the normal cellular counterpart, we plan to investigate their role in disease progression and drug responsiveness using cellular models. In fact, several studies have indicated that the identified upregulated miRNAs have a role in suppressing apoptosis and, at least for miR-21, its inhibition by anti-miRNA oligonucleotides (AMOs) increases sensitivity to the chemotherapeutic agent gemcitabine (Meng et al Gastroenterology,2006,130:2113). Thus, it is possible that the identified over-expressed miRNA might be involved in resistance to drug treatment and may therefore represent important targets for treatment. The effectiveness and safety of the in vivo use of AMOs has been proven in primates (Elmen et al., 2008), suggesting that AMOs may potentially represent a new form of anti-cancer agents, either as a single agent or through the potentiation of conventional anti-cancer drugs.
In summary, specific aims of the unit are: (i) expression of miRNA during cutaneous lymphoma disease progression; (ii) expression of miRNA modulated by treatment with the histone deacetylase inhibitor Vorinostat; (iii) assessment of cellular and molecular changes by modulation of miR-21 and/or miR-18/miR-106.
Achievement of the objectives will improve our understanding on the molecular basis of cutaneous lymphoma. In particular, the contribution of aberrant miRNA expression will be clarified. This understanding could be translated into diagnostic approaches important for choosing the most appropriate therapy and, since efficacy and safety of anti-microRNA oligonucleotides has already been proved, it may open the way to the development of novel unconventional therapeutic approaches
microRNAs and control of cancer-associated molecular pathways
No full textNumerous miRNAs are deregulated in human cancers and may act either as oncogenes or tumor suppressor genes. Similarly to other cancer genes, deregulation of miRNA-coding genes may be associated with genetic or epigenetic alterations, such as deletions, amplifications, point mutations and aberrant DNA methylation. However, the most frequent mechanism for miRNA deregulation is through aberrant transcriptional control. Aberrant miRNA expression has been linked to cell cycle progression, loss of differentiation, increased survival, invasion and metastasis. The discovery that miRNAs interacts with known oncogenes and tumor suppressor genes has established links with molecular pathways implicated in malignant transformation. These findings hold the promise that miRNAs could become important diagnostic and therapeutic tools
Micromarkers 2.0: An update on the role of microRNAs in cancer diagnosis and prognosis
No full textThe identification of reliable diagnostic or prognostic biomarkers is one of the most pressing goals in oncological research. MicroRNAs have proven to be very promising cancer biomarkers because they are resistant to degradation in many tissue types (including FFPE specimens and body fluids), easily measured and, most importantly, their amount correlates with the presence of the tumor or with clinically relevant cancer features. In addition, our knowledge of microRNA genetic alterations in familial and sporadic cancer has recently improved. This review presents an update on cancer diagnostic and prognostic microRNAs, discusses novel tools for prognostic microRNAs identification and evaluates the possible translation of these discoveries to the clinic
Breast cancer metastasis: a microRNA story
No full textMicroRNAs (miRNAs) are small noncoding RNAs with regulatory functions, which play an important role in breast cancer. Several studies have shown that miRNAs can act either as tumor suppressors or as oncogenes, and that measurement of miRNA expression in malignancies may have diagnostic and prognostic implications. This article highlights a series of three recent studies that prove the involvement of miRNAs in breast cancer metastases. The first proves that miR-10b indirectly activates the pro-metastatic gene RHOC by suppressing HOXD10, thus leading to tumor invasion and metastasis. The second proves that miR-373 and miR-520c can also promote tumor invasion and metastasis, at least in part by regulating the gene CD44. The third identifies miR-335, miR-206, and miR-126 as suppressors of breast cancer metastasis. Loss of miR-335 leads to the activation of SOX4 and TNC (encoding tenascin C), which are responsible for the acquisition of metastatic properties. Altogether, these remarkable findings are important for our understanding of malignant transformation in the breast and may have implications for the management of patients with advanced breast cancer. The use of miRNAs as anticancer therapeutic agents is promising, and such fine molecular studies certainly help in bringing miRNAs closer to clinical practice
EARLY DIAGNOSIS AND EXPRESSION PROFILING CLASSIFICATION OF COLORECTAL AND LIVER TUMORS. AIRC Regional Grant.
No full textCancer was expected to be one of the human health problems that could benefit from the
completion of the human genome information. To address the expectation, this project brings
together clinicians and molecular biologists to investigate health problems associated with
colorectal and liver cancer. The best known and, so far, most effective instrument to generate
genome-wide information has been the use of microarrays for gene expression profiling that,
together with the bioinformatic strategies for analyzing microarray data, have allowed to put
expression aberrations into a global perspective and allowed to compare pathologic versus
normal profiles. Cancer has been analyzed using this technology to define tumor molecular
classifications, discover diagnostic methods for the prediction of cancer susceptibility and
prediction to drug response. Here, we intend to use this technology for the study colorectal and
liver cancer features. In addition, aberrant DNA methylation has proven to be a tumor marker
that can be detected with high sensitivity and specificity. Here, we intend to identify a panel of
highly informative methylation markers and use them as screening tools for the early diagnosis
of colorectal and hepatocellular carcinoma.
The project is organized in four interlaced Tasks, each one leaded by one of the
participating groups. Each task is defined by specific objectives. The first two tasks involve the
oncogenomic classification of colorectal and liver cancer through the use of EST and microRNA
microarrays. Their specific objectives are: (i) discovery of gene expression signatures with
prognostic significance in colorectal cancer; (ii) integration of EST and micro RNA microarrays,
microsatellite and DNA methylation data into a molecular classification of colorectal carcinomas;
(iii) identification of gene expression signatures predicting response to preoperative
chemoradiation therapy in rectal carcinomas; (iv) identification of expression signatures
differentiating cirrhotic liver associated or not associated with hepatocellular carcinoma, with the
aim of identifying molecular markers predicting cancer risk in liver cirrhosis; (v) apply the newly
discovered markers of cancer risk for the screening of serum of liver cirrhotic patients for the
early detection of HCC. The third task involves the use of DNA methylation markers for the early
diagnosis of colorectal and liver carcinomas, whose specific objectives are: (i) discovery of new
methylation markers; (ii) use of an optimized panel of DNA methylation markers for the follow-up
of colorectal and hepatocellular cancer patients; (iii) use of an optimized panel of DNA
methylation markers for the screening of colorectal cancer patients’ first-grade relatives and
patients with liver cirrhosis. The entire project is supported by a bioinformatic infrastructure
(Task 4) for data management, mining and validation of microarray results to define molecular
signatures in cancer, whose specific objectives are: (i) storage and management of microarray
experiments; (ii) mining of microarray profiles: data normalization, quality control and validation
of gene signatures; (iii) communication with clinical data.
Through the identification of molecular markers that are able to predict the clinical course
of colorectal and liver cancer and the response to preoperative therapeutic regimens in rectal
cancer, a significant improvement on patients’ clinical management can be achieved. In addition,
by defining the most useful DNA methylation markers and the most effective approaches for their
identification in body fluids of colorectal and hepatocellular cancer patients, the project can
provide highly sensitive and specific screening instruments, whose application could potentially
improve long-term clinical outcome
Genomic organization of the ATM locus involved in ataxia-telangiectasia
No full textThe ATM gene, involved in the genetic disorder ataxia-telangiectasia (AT), has been identified recently. This gene is suspected to predispose to malignancy and is located in a chromosomal region that we have recently found deleted in 50 to 60% of breast and lung carcinomas. Because of its location and its function, the ATM gene is a strong candidate tumor suppressor or modifier gene of chromosome region 11q23. In this study, we define its genomic structure. The aim was to establish the basis for the development of mutation scanning methods based on DNA instead of RNA. We found that the gene spans a region of approximately 70-80 kb and is composed of 37 exons, ranging in size from 64 to 324 bp. Nucleotide sequences of all exon/intron boundaries were determined. With this information, it will be possible to develop simple genetic tests for the identification of homozygotes and heterozygotes, as well as determine whether the gene is involved in the pathogenesis of breast and other carcinomas
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