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miR-483-3p and drug resistance in Hepatocarcinoma

Final Report Summary - VEROMIRNA (miR-483-3p and drug resistance in Hepatocarcinoma)

Hepatocellular carcinoma (HCC) is the fifth most common form of cancer worldwide and the third cause of cancer-related deaths. Current therapies are limited, mostly ineffective and chemoresistence often occurs after treatment. Therefore a clear need is to identify new druggable molecular targets for the development of improved therapeutics. The project entitled “miR-483-3p and drug resistance in Hepatocarcinoma” (VeromiRNA), stems from the idea that miR-483-3p, a well known oncogene in liver cancer, is involved in chemoresistance and that chemotherapeutic agents, already used in the management of cancer patients, could lower the expression of this miR, thereby sensitising tumoral cells to death.
The results demonstrated that miR-483-3p expression is regulated by cellular glucose availability with a mechanism that involves the O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). This enzyme stabilises factors that directly activate the transcription of the miR-483 proteins depending on the availability of the glucose metabolite UDP-N-acetylglucosamine. Moreover, the inhibitor of glycolysis 2-Deoxy-D-glucose (2-DG), a molecule well tolerated by the tissues, was able to reduce the miR-483-3p expression in hepatocarcinoma cell lines. Despite promising preliminary data, studies in animal models proved that the 2-DG was unable to enhance the effect of 5-Fluoruracil which is used in HCC treatments. This is explainable by the fact that the miR-483-3p did not decrease in tumor cells from mice after 2-DG treatment, on the contrary, almost all the tumors generated showed increased expression of the microRNA and decreased protein expression of its pro-apoptotic target PUMA. Although there were differences in the number and total weight of the xenograft tumors induced, their molecular profile, regarding the miR-483-3p signalling, were similar. This consideration fits with the possibility that selective pressures lead to expansion of resistant clones with higher expression of the miR-483-3p. Indeed, in this project we demonstrated that in HCC cells expressing the P53 up-regulator of apoptosis (BBC3/PUMA) the steady activation of the TP53/miR-145-5p signalling, in the condition of high availability of glucose, selected clones resistant to apoptosis via up-regulation of the oncogenic miR-483-3p.
Overall the project suggests that the clinical translatability of the results could be exploited considering:
1) the use of miR-145-5p in therapy with simultaneous inhibition of miR-483-3p;
2) the use of 2-DG in a non-tumoral cirrhotic context in preventive rather than therapeutic settings.

“VeromiRNA” contributes to develop an independent laboratory with 2 team members consisting of the PI and one PhD student trained by the PI of the project into the laboratories of Dr. Visone’s and Prof. Mariani-Costantini (2 PI, 2 researchers, 2 Post-doctoral fellow, 3 PhD students and 3 under-graduated students). Successful collaborations were established with several laboratories at the University of Chieti.