Regulation and function of the cholesterol biosynthesis inhibitors INSIG1 and INSIG2 in hepatocellular carcinoma

• Applicant: Dr. Peter Dietrich, Ph.D.
• Subject Area: Gastroenterology ; Anatomy and Physiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 468408687

Hepatocellular carcinoma (HCC) ranges amongst the most common cancer-related causes of death. In the majority of cases, HCC emerges in the presence of chronic low-level inflammation and resulting liver cirrhosis, which constitutes the most important predisposing condition. In light of increasing HCC incidence rates in the Western world, dysregulation of lipid and cholesterol homeostasis and associated metabolic disorders such as diabetes, obesity, metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) have been recognized as crucial and strongly emerging risk factors for HCC. The homologous proteins insulin-induced gene 1 and 2 (INSIG1, INSIG2) represent master regulators of physiological cholesterol homeostasis in the liver which were described to fulfill complementary and even redundant functions, but their potential function in HCC development and progression remains elusive. Strikingly, preliminary, unpublished data revealed that the appetite-regulating Neuropeptide Y (NPY)-system (which was shown to be majorly involved in metabolic disorders, liver cirrhosis and in HCC progression by the applicant) specifically reduced INSIG1 (but not INSIG2) in HCC. Moreover, we newly identified an "INSIG-isoform-switch" in HCC which affects overall survival in cancer patients. Next to NPY-mediated downregulation of INSIG1, specific de-repression of INSIG2 by loss of microRNA-622 as well as hypoxia-mediated inverse regulation of INSIGs might further drive the observed INSIG-switch in HCC. We hypothesize that the INSIG-switch might strongly promote (liver) cancer development and progression. The (overall) goal of this project is to characterize the regulation of the INSIG-switch as well as to unravel the functional and potential therapeutic role of both INSIG isoforms in HCC which will be addressed within two aims following a straight-forward approach. The first aim of this project is to characterize the expression as well as the regulatory (i.e. upstream) mechanisms (NPY-system, microRNA-622, hypoxia, fatty liver disease) driving the INSIG-switch in HCC. The second aim is to unravel the functional and potential therapeutic role (i.e. the downstream effects) of INSIG1 and INSIG2 in HCC.

• DFG Programme: Research Grants