关键词: 肝癌, NRAS, CTNNB1, L-丙氨酸

Abstract: Objective To compare the differences in molecular biological characteristics and the signal transduction networks of liver cancer  induced by constitutive activation of NRAS and CTNNB1, as well as to investigate potential therapeutic strategies. Methods The expression of NRAS and CTNNB1 in liver cancer tissues and their relationship with patients prognosis were analyzed using public data. The mixed plasmids of NRasV12/myr⁃Akt/pCMV⁃SB and N90⁃β⁃catenin/myr⁃Akt/pCMV⁃SB were introduced into mice by a hydrodynamic tail vein injection, and the liver cancer tissues were obtained after 4 weeks. Transcriptome sequencing and bioinformatics analysis were employed to analyze the differential genes and signal networks in liver cancer with NRAS and CTNNB1 constitutively activated. NRAS related  liver cancer mice and CTNNB1 related  liver cancer mice were continuously supplemented with 1.5 g/L L⁃alanine through drinking water until the end of the observation period for 90 days , and the corresponding control group mice were given normal drinking water. The survival status, body weight and liver weight of the mice were recorded. Results The expression of NRAS and CTNNB1 in liver cancer tissues was significantly up⁃regulated as compared with those in normal liver tissues (all P<0.001), and the survival rate of patients with high expression of NRAS and CTNNB1 was lower than that of patients with low expression (all P<0.01).  KEGG analysis revealed that the constitutive activation of both oncogenes could regulate the cell cycle, but the alterations in amino acid metabolism were particularly pronounced in NRAS constitutively activated liver cancer tissues. Supplementation with L⁃alanine significantly prolonged the survival time of the mice with NRAS constitutive activation (P<0.001) and reduced the liver⁃to⁃body weight ratio (P<0.05). However, continuous supplementation of L⁃alanine did not significantly improve the survival time and liver⁃to⁃body weight ratio of the mice with CTNNB1 constitutive activation (all P>0.05). Conclusions The molecular biological characteristics induced by constitutive activation of NRAS and CTNNB1 are significantly different in liver cancer. Intervention of  amino acid metabolism may be a potential therapeutic strategy for NRAS related liver cancer, but there is no significant benefit for CTNNB1 related liver cancer.

Key words: Liver cancer, NRAS, CTNNB1, L-alanine