The role of miR-107-dependent signaling networks in hepatocarcinogenesis

• Applicant: Dr. Mirco Castoldi, Ph.D.
• Subject Area: Gastroenterology ; Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 440603844

Hepatocellular carcinoma (HCC) accounts for 90% of all primary liver cancers. It is the third leading cause of cancer-related mortality and the fifth most common cancer worldwide. The incidence of HCC is increasing despite progress in identifying risk factors. Treatment options are limited and survival after diagnosis is poor, in fact, the incidence of HCC is still almost equal to its mortality rate. Epigenetic modifiers, including miRNA-mediated processes, have been identified as important therapeutic objectives for hepatocellular carcinoma. miRNAs, a class of highly conserved small non-coding RNAs, are pivotal participants and regulators in the development and progression of hepatocellular carcinoma (HCC). Although great progress has been made in the studies of miRNAs in HCC, the mechanisms underlying dysregulation of miRNAs-associated networks and their interaction with other regulatory networks in the development of hepatocellular carcinoma have remained unclear.We previously hypothesized that HCC development in murine HCC models might feature more homogenous transcriptional profiles in screening approaches, thus potentially leading to the discovery of previously unrecognized transcriptional networks in HCC. Based on this hypothesis our research group has devised, and recently published, an innovative, system biology-based approach that – starting from the integrated analyses of three different mouse models of hepatocellular carcinoma – led to the discovery of a previously unrecognized miRNA-driven transcriptional networks driving hepatocarcinogenesis in human.In this proposal, we will proceed in further analyzing miRNA-associated pathways originated from our original work. Herewith we propose examining the specific mechanistic role of miR-107-associated signaling in the development and progression of HCC. Preliminary data included in this proposal indicated that miR-107 act as tumor suppressor gene hence leading to the hypothesis that miR-107 might play an important role in the molecular pathogenesis of hepatocellular carcinoma. Therefore, we will use state-of-the-art methodological approaches to discern systematically the role of down- and up-stream signaling pathways of miR-107 in the promotion/inhibition of liver cancer traits. The submitted proposal consist of 5 interconnected work-packages. We expect to establish a new and comprehensive mechanistic view of the role played by miR-107 signaling in hepatocarcinogenesis. Our findings will improve the understanding of the role played by miR-107-associated signaling pathways in the development of HCC by identifying the key players and the underlying signaling pathways. Moreover, the proposed experiments might lead to the identification of promising new candidates for pharmacological targeting of miR-107 signaling, thereby paving the way for new diagnostic and therapeutic approaches in the treatment of HCC in future.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Tom Lüdde, Ph.D.