BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common cancers, whereas the molecular mechanism remains largely unknown. PRAS40 (encoded by AKT1S1) phosphorylation was increased in human melanoma, prostate cancer and lung cancer specimens, which was considered as the results of Akt activation. However the mechanism in detail and its role in HCC stay elusive. METHODS PRAS40 expression and phosphorylation were analyzed in HCC specimens, and the survival rates of patients were investigated. Functional analyses of PRAS40 in HCC were performed in vivo and in vitro. The miR-124-3p binding sites in PRAS40 were investigated using luciferase assay. MiR-124-3p expression in HCC specimens was examined by In Situ hybridization, and the correlation to PRAS40 level was evaluated. FINDINGS The phosphorylation, protein and mRNA levels of PRAS40 were increased significantly in HCC specimens from our cohorts and TCGA database, which was positively correlated to the poor prognosis of HCC patients. Compared to Akt1s1+/+ mice, hepatocarcinogenesis was suppressed in Akt1s1-/- mice, and the activation of Akt was impaired. PRAS40 depletion resulted in the inhibition of HCC cellular proliferation. Tumor suppressor miR-124-3p was found to downregulate PRAS40 expression by targeting its 3'UTR. MiR-124-3p levels were inversely correlated to PRAS40 protein and phosphorylation levels in HCC specimens. The proliferation inhibition by miR-124-3p mimics was partially reversed by exogenous PRAS40 introduction in HCC cells. INTERPRETATION PRAS40 hyperexpression induced by loss of miR-124-3p contributes to PRAS40 hyperphosphorylation and hepatocarcinogenesis. These results could be expected to offer novel clues for understanding hepatocarcinogenesis and developing approaches.

中文翻译：

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PRAS40过表达促进肝癌发生。

背景技术肝细胞癌（HCC）是最常见的癌症之一，但是其分子机制仍然是未知的。人黑素瘤，前列腺癌和肺癌标本中的PRAS40（由AKT1S1编码）磷酸化增加，这被认为是Akt激活的结果。但是，详细的机制及其在HCC中的作用仍然难以捉摸。方法分析肝癌标本中PRAS40的表达及磷酸化情况，探讨患者生存率。在体内和体外进行了肝癌中PRAS40的功能分析。使用荧光素酶测定法研究了PRAS40中的miR-124-3p结合位点。通过原位杂交检测HCC标本中MiR-124-3p的表达，并评估其与PRAS40水平的相关性。结果磷酸化，我们的队列和TCGA数据库中的HCC标本中PRAS40的蛋白和mRNA水平显着增加，这与HCC患者的不良预后呈正相关。与Akt1s1 + / +小鼠相比，Akt1s1-/-小鼠的肝癌发生受到抑制，并且Akt的激活受到损害。PRAS40耗竭导致抑制HCC细胞增殖。发现肿瘤抑制物miR-124-3p通过靶向其3'UTR来下调PRAS40表达。MiR-124-3p水平与HCC标本中的PRAS40蛋白和磷酸化水平呈负相关。miR-124-3p模拟物的增殖抑制被外源PRAS40引入HCC细胞部分逆转。解释由miR-124-3p缺失引起的PRAS40过表达有助于PRAS40过磷酸化和肝癌发生。