Fig. 5: AK2 ablation exacerbates tumor formation in HRASG12Vmouse model of HCC.
From: AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis
A Reduced survival of HRASG12V+/− mice by AK2+/− deficiency. Survival curves of HRASG12V+/−:AK2+/+ (n = 12, HRASTg/−; AK2+/+), HRASG12V+/−:AK2+/− (n = 14, HRASTg/−; AK2+/−), and HRASG12V+/+ (n = 11, HRASTg/Tg) mice with median survival of 450, 360, and 300 days, respectively. **p = 0.001172 by log-rank test. B Pathology of liver tumor by AK2+/− deficiency. Gross histology (left) and representative H&E staining of paraffin-embedded liver sections (right) obtained from HRASG12V+/−:AK2+/+ (HRASTg/−; AK2+/+) and HRASG12V+/−:AK2+/− (HRASTg/−; AK2+/−) mice at 8 months of age. C–G High incidence of liver tumor by AK2+/− deficiency. After tumors had grown to the approved size, the liver/body weight ratios (C), liver tumor volumes (D), maximal diameters (E), average tumor burden (F), and circulating blood levels of ALT (G) were quantified. Values are mean ± S.E.M. (n = 12, 14 for each HRASG12V+/−:AK2+/+ and HRASG12V+/−:AK2+/−; *p < 0.05, **p < 0.01, ***p < 0.001, ***p < 0.0001); paired Student’s t-test. H–J Combinations of HRASG12V and AK2+/− alleles amplify the ERK activity. Liver tumor extracts of HRASG12V+/−:AK2+/+ (HRASTg/−; AK2+/+), HRASG12V+/−:AK2+/− (HRASTg/−; AK2+/−), and HRASG12V+/+ (HRASTg/Tg) mice in (B) were analyzed with western blotting (H) and immunoprecipitation (IP) assay (J) followed by kinase reaction with γ-32p-MEK1 (I). Total β-actin was used as a loading control. K−M Sorafenib retards tumor growth in 7-month-old HRASG12V+/−:AK2+/− mice. HRASG12V+/−:AK2+/+ (HRASTg/−; AK2+/+) and HRASG12V+/−:AK2+/− (HRASTg/−; AK2+/−) mice were daily treated with 100 mg kg−1 body weight Sorafenib for 3 weeks. Gross appearances of livers lesions (K) and representative H&E staining of paraffin-embedded liver sections (L) were examined in four groups of the mice. Liver tumor extracts were subjected to western blotting (M). Total β-actin was used as a loading control.
