Activation of the AKT/mTOR cascade and overexpression of c-Met have been implicated in the development of human hepatocellular carcinoma (HCC). To elucidate the functional crosstalk between the two pathways, we generated a model characterized by the combined expression of activated AKT and c-Met in the mouse liver. Co-expression of AKT and c-Met triggered rapid liver tumor development and mice required to be euthanized within 8 weeks after hydrodynamic injection. At the molecular level, liver tumors induced by AKT/c-Met display activation of AKT/mTOR and Ras/MAPK cascades as well as increased lipogenesis and glycolysis. Since a remarkable lipogenic phenotype characterizes liver lesions from AKT/c-Met mice, we determined the requirement of lipogenesis in AKT/c-Met driven hepatocarcinogenesis using conditional Fatty Acid Synthase (FASN) knockout mice. Of note, hepatocarcinogenesis induced by AKT/c-Met was fully inhibited by FASN ablation. In human HCC samples, coordinated expression of FASN, activated AKT and c-Met proteins was detected in a subgroup of biologically aggressive tumors. Altogether, our study demonstrates that co-activation of AKT and c-Met induces HCC development that depends on the mTORC1/FASN pathway. Suppression of mTORC1 and/or FASN might be highly detrimental for the growth of human HCC subsets characterized by concomitant induction of the AKT and c-Met cascades.

Arsenic trioxide (As₂O₃, ATO), a FDA approved drug for hematologic malignancies, was proved of efficient growth inhibition of cancer cell in vitro or solid tumor in vivo. However, its effect on solid tumor in vivo was hampered by its poor pharmacokinetics and dose-limited toxicity. In this study, a polyacrylic acid capped pH-triggered mesoporous silica nanoparticles was conducted to improve the pharmacokinetics and enhance the antitumor effect of arsenic trioxide. The mesoporous silica nanoparticles loaded with arsenic trioxide was grafted with polyacrylic acid (PAA-ATO-MSN) as a pH-responsive biomaterial on the surface to achieve the release of drug in acidic microenvironment of tumor, instead of burst release action in circulation. The nanoparticles were characterized with uniform grain size (particle sizes of 158.6 ± 1.3 nm and pore sizes of 3.71 nm, respectively), historically comparable drug loading efficiency (11.42 ± 1.75%), pH-responsive and strengthened sustained release features. The cell toxicity of amino groups modified mesoporous silica nanoparticles (NH₂-MSN) was significantly reduced by capping of polyacrylic acid. In pharmacokinetic studies, the half time (t_1/2β) was prolonged by 1.3 times, and the area under curve) was increased by 2.6 times in PAA-ATO-MSN group compared with free arsenic trioxide group. Subsequently, the antitumor efficacy in vitro (SMMC-7721 cell line) and in vivo (H22 xenografts) was remarkably enhanced indicated that PAA-ATO-MSN improved the antitumor effect of the drug. These results suggest that the polyacrylic acid capped mesoporous silica nanoparticles (PAA-MSN) will be a promising nanocarrier for improving pharmacokinetic features and enhancing the anti-tumor efficacy of arsenic trioxide.

Increasing the drug tumor-specific accumulation and controlling their release is considered one of the most effective ways to increase the efficacy of drugs. Here, we developed a vesicle system that can target hepatoma and release drugs rapidly within tumor cells. This non-ionic surfactant vesicle is biodegradable. Galactosylated stearate has been used to glycosylate the vesicles to achieve liver targeting; replacement of a portion (Chol:CHEMS = 1:1) of cholesterol by cholesteryl hemisuccinate (CHEMS) allows for a rapid release of drugs in an acidic environment. In vitro release experiments confirmed that galactose-modified pH-sensitive niosomes loaded with tanshinone IIA had excellent drug release performance in acid medium. In vitro experiments using ovarian cancer cells (A2780), colon cancer cells (HCT8), and hepatoma cell (Huh7, HepG2) confirmed that the preparation had specific targeting ability to hepatoma cells compared with free drugs, and this ability was dependent on the galactose content. Furthermore, the preparation also had a more substantial inhibitory effect on tumor cells, and subsequent apoptosis assays and cell cycle analyses further confirmed its enhanced anti-tumor effect. Results of pharmacokinetic experiments confirmed that the vesicle system could significantly extend the blood circulation time of tanshinone IIA, and the larger area under the curve indicated that the preparation had a better drug effect. Thus, the results of biodistribution experiments confirmed the in vivo liver targeting ability of this preparation. Niosomes designed in this manner are expected to be a safe and effective drug delivery system for liver cancer therapy.

An abnormality in the Lin28/let-7a axis is relevant to the progression of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), which could be a novel therapeutic target for this malignant tumor. The present study aimed to investigate the antiproliferative and anti-invasive effects of urolithin A in a stable full-length HBV gene integrated cell line HepG2.2.15 using CCK-8 and transwell assays. The RNA and protein expressions of targets were assessed by quantitative PCR and western blot, respectively. Results revealed that urolithin A induced cytotoxicity in HepG2.2.15 cells, which was accompanied by the cleavage of caspase-3 protein and down-regulation of Bcl-2/Bax ratio. Moreover, urolithin A suppressed the protein expressions of Sp-1, Lin28a, and Zcchc11, and elevated the expression of microRNA let-7a. Importantly, urolithin A also regulated the Lin28a/let-7a axis in transient HBx-transfected HCC HepG2 cells. Furthermore, urolithin A decelerated the HepG2.2.15 cell invasion, which was involved in suppressing the let-7a downstream factors HMGA2 and K-ras. These findings indicated that urolithin A exerted the antiproliferative effect by regulating the Lin28a/let-7a axis and may be a potential supplement for HBV-infected HCC therapy.