Targeting AKR1B10-S1P Signal Pathway Inhibits The Growth Of Mice Hepatocellular Carcinoma

Objective: Hepatocellular carcinoma(HCC)is one of the most common malignant tumors,more than half of the diagnosed liver cancer occur in China.Due to the progression of this disease without obvious clinical symptoms and lack of early diagnosis methods,most of the patients frequently step into middle and advanced stage when diagnosed and the long term survivals are unsatisfactory.AKR1B10 was first cloned from liver cancer tissue,studies showed that AKR1B10 might be a molecular marker for early diagnosis of HCC.Recently,we found that S1P is a downstream signaling molecule of AKR1B10.Targeted inhibition of AKR1B10 can inhibit tumor cell proliferation,and decrease S1P level.To further investigate the effects of targeted AKR1B10-S1P signaling pathway on HCC treatment,mouse tumor model was used.Additionally,the potential mechanism of these effects was also studied.Methods:1.To establish the subcutaneously transplanted tumor model in nude mice,Hep G2 cells were injected into mice right flank.The nude mice were randomly divided into control group,OA treatment group and FTY720 treatment group.2.When the tumor volume reached 70–100 mm~3,saline ? OA(20mg/kg)or FTY720(10 mg/kg)were administered intraperitoneally every other day for 21 days.After the treatment,the tumors and blood samples were collected.3.Tumor was measured every 2 days and tumor volume was determined according to the formula V = [L × W~2] ÷ 2.Here,V means the volume,L means the length and W means the width.The weights of tumor were measured after collected from mice.4.HE staining was used to show the morphology and structure of tumor tissues from nude mice.5.Western-blot assay was used to detect the expression levels of some related enzymes in the AKR1B10-S1P signaling pathway.6.TUNEL assay.Results:1.AKR1B10 inhibitor OA significantly hindered tumor growth.2.S1P inhibitor FTY720 markedly reduced tumor growth.3.OA and FTY720 inhibited the expression of AKR1B10 in nude mice.4.OA and FTY720 down-regulated the expression of S1P related enzymes.5.Targeted inhibition of AKR1B10-S1P induces apoptosis of hepatocellular carcinoma cells in Vivo.Conclusions:1.Targeted inhibition of AKR1B10-S1P signaling pathway can significantly hinder the growth of HCC.2.OA and FTY720 reduced HCC growth probably by regulation of related enzymes involved in sphingolipid signaling pathway.3.Inhibition of AKR1B10-S1P signaling pathway can inhibit tumor growth by promoting cell apoptosis.