Description
It is well-known that urea cycle enzymes (UCEs) are markedly suppressed in liver tumor microenvironments. However, it is still unclear how UCEs are systemically suppressed in liver tumor microenvironments. To address this important question, we tested the potential involvements of oncogene overexpression including (c-Met, ΔN90-β-catenin, and YAP), as well as hypoxia in the regulation processes as urea cycle dysregulation in mouse liver tumors is accompanied by HIF upregulation.Methods: In vivo and in vitro experiments were established to detect urea cycle dysregulation (UCD) using c-Met/ΔN90-β-catenin induced mouse liver tumors and primary hepatocyte transfection. Single or combination of different types of oncogenes are overexpressed using mouse primary hepacotyces. An established hypoxic culture system was designed to exogenously and endogenously promote hypoxic stimulation in cell cultures.
Results: Exogenous expression of c-Met, ΔN90-β-catenin, YAP, or combination of c-Met-ΔN90-β-catenin failed to suppress UCE protein levels including CPS1, ARG1, or ASS1. Furthermore, exogenous hypoxic stimulation activated the expression of HIF1α in five hepatocellular carcinoma (HCC) cell lines and the changes in the expression of the five UCEs depended on the specific HCC cells. ASS1 was the only UCE whose expression was decreased in five HCC cell lines after hypoxic stimulation. Interestingly, endogenous hypoxia stimulation with ETC inhibitors suppressed HIF1α expression in all three HCC cell lines. The detectable changes in UCE expression were dependent on the dosage of ETC inhibitors.
Conclusion: UCE mRNA and protein levels are markedly suppressed in HCC patients and mouse liver tumor tissues. Oncogene overexpression including (c-Met, ΔN90-β-catenin, and YAP) fails to inhibit the protein expression of urea cycle enzymes CPS1, ARG1 or ASS1 in vitro. Hypoxia activates HIF1α and leads to the downregulation of ASS1 at protein level.
| Period | 1 Sept 2023 → 10 Jun 2024 |
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| Degree of Recognition | International |