Non-alcoholic fatty liver disease (NAFLD) is present in approximately 25% of the population worldwide. It begins with the accumulation of lipids in hepatocytes (steatosis), which with time become toxic for the liver, leading to the development of steatohepatitis and fibrosis. A further progression to cirrhosis causes significant risk of death for the patient due to portal hypertension and overall liver failure. Cirrhosis and earlier steps of NAFLD often lead to the development of hepatocellular carcinoma (HCC), which is among the deadliest cancers worldwide.
AU-rich elements-binding proteins (AUBPs) are a family of RNA-binding proteins recognizing AU-rich motifs in non-coding regions of mRNAs. Depending on the protein, the consequences of their binding may vary. Some AUBPs, like TTP, sentence transcripts for degradation, while others, like HuR, stabilize them and protect from the degrading machinery. Finally, proteins like TIA1 contribute to a transient translational inhibition, which is reversible. Many AUBPs, like TTP, HuR and TIA1, associate with processing bodies (P-bodies) and/or stress granules (SGs) to execute their functions. Studies on the role of AUBPs in liver diseases are starting to gain attention, however, not much is yet known about the role of TTP and TIA1.
In the first part of the study, we focused on TTP, a well-known anti-inflammatory protein and a tumor suppressor. We characterized its function in a panel of hepatic cell lines and using mice bearing a liver-specific knockout of TTP (LTTPKO). While TTP displays a tumor-suppressive effect on hepatic cancer cells, its knock-out in vivo unexpectedly contributes to the reduction of tumor burden in diethylnitrosamine (DEN)-treated mice, thus suggesting a dual function of TTP depending on the state of the disease. Correspondingly, LTTPKO mice develop less steatosis, fibrosis, and inflammation than the respective control mice. We also showed that TTP decreases on protein level with the advancement of HCC and that it is regulated by the HNF4a/EGR1 axis.
Since many AUBPs work in concert to carry out their cellular functions, in the second part of the study, we investigated another AUBP, TIA1, which was shown to display tumor-suppressive characteristics in various cancers e.g., gastric, colorectal, thyroid, etc. TIA1 facilitates cell proliferation and migration of hepatic cell lines and has a tumor suppressive effect in LPTENKO mice partially lacking this protein. We demonstrated that it protects the liver against a methionine and choline deficient (MCD) diet induced steatosis and fibrosis. In agreement, accordingly to a translatome-based approach, TIA1 silencing deregulates many tumor suppressors, oncogenes and genes related to lipid metabolism, underlining its role as a key regulator of liver diseases.
Our study demonstrates that both TTP and TIA1 exert important roles in the development of fatty liver disease and hepatocellular carcinoma. Depending on the cellular context and the models used in the study, they behave as a tumor suppressor or oncogene, which calls for caution when envisaging therapeutic targeting of these proteins. However, due to their downregulation in HCC, they may serve as a potential biomarker for this liver cancer. Finally, our results revealed networks of potential targets of both proteins, which opens the path for future investigations.
