Experimental 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).
AIRC Investigator Grant 2008 - Functional and biological characterization of miR-221 and miR-483 in human cancer
NEGRINI, Massimo
2009
Abstract
Experimental 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).I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
