Fig. 8: Clinical importance of TM4SF5 and NCOA3 mRNA expression and serum ALB levels of TCGA patients with LIHC in terms of survival probability.

a The LIHC patient group from the public TCGA dataset (n = 291 with serum ALB level, [ALB]_serum) showed a mean [ALB]_serum of 3.77 g/dl (that is, 37.7 mg/ml). Subgroups depending on the expression levels of TM4SF5 and NCOA3 mRNA showed different [ALB]_serum levels. b The entire LIHC patient group (n = 364 including patients without [ALB]_serum information) was analyzed for the probability of survival depending on the expression levels of TM4SF5 and NCOA3 mRNA. c, d The LIHC group was subclassified into [ALB]_serum >3.77 g/dl (c) or [ALB]_serum ≤3.77 g/dl (d). The subgroups were further subclassified into TM4SF5^low/NCOA3^low (control), TM4SF5^high, NCOA3^high or TM4SF5^high/NCOA3^high categories to analyze the probability of survival depending on their mRNA expression levels. The survival probability of patient groups was analyzed to 1,200 days for statistical comparisons. P values were calculated by one-way ANOVA. e Schematic of the working model: in normal hepatocytes without notable TM4SF5 expression, extracellular ALB might not be efficiently uptaken for cellular energetics due to less macropinocytosis, supported by higher PTEN lipid phosphatase activity via greater NCOA3 localization into the nucleus or degradation in cytosol. Meanwhile, in cancerous hepatocytes with enhanced TM4SF5 expression, TM4SF5 binds to and promotes cytosolic stabilization of NCOA3, leading to an association with and acetylation of PTEN, which could eventually become inactive for PIP₃ accumulation on membranes to allow efficient macropinocytosis-mediated uptake of extracellular ALB. ALB may then be degraded for mitochondrial ATP synthesis, leading to greater energetics for cell migration, presumably during intrahepatic metastasis for tumor nodule expansion or multifocality. See also Supplementary Fig. 7.