Plos One：发现新的肝癌治疗靶点miR-148a

乙肝病毒编码的X抗原(HBx)是一个反式调节蛋白，实验表明，它能够改变特定的转录因子以及细胞质信号转导通路的活性。

HBx通过上调一个独特的基因-URG11的表达，反过来上调β-链蛋白(β-catenin)，从而促进了肝癌的发生。

此外，HBx和URG11也改变了多种microRNAs的表达。通过miRNA 阵列分析发现，它们都促进了miR-148a的表达。在感染者的HBx阳性肝脏标本，miR-148a的表达升高。

为了研究miR-148a的功能，美国天普大学的研究人员将anti-148a被导入到稳定表达HBx或者稳定的过表达URG11的HepG2及Hep3B细胞。

结果发现，Anti-miR-148a抑制了细胞增殖、细胞周期的前进，细胞迁移、在软琼脂的停泊非依赖性生长及SCID老鼠皮下肿瘤的形成。

引入anti-miR-148a提升了PTEN蛋白及mRNA的表达，这表明了miR-148a对PTEN的定向作用。

然而，当与PTEN mRNA 3′UTR报告基因突变体联合转染时，Anti-miR-148a却不能抑制PTEN的表达 。

实验还发现，引入anti-miR-148a通过HBx和URG11也导致Akt 信号下调，致使β-catenin表达减少。

因此，miR-148a可能在HBx/URG11介导的肝细胞癌（HCC）中起到了重要作用。它可能成为一个早期诊断标记物，或者是这些癌症类型的一个新的治疗靶点。相关论文发表在4月9日的Plos One。（生物谷Deepblue编译）

doi: 10.1371/journal.pone.0035331
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Role of miR-148a in Hepatitis B Associated Hepatocellular Carcinoma

Ke Yuan, Zhaorui Lian, Bill Sun, Marcia M. Clayton, Irene O. L. Ng, Mark A. Feitelson.

Hepatitis B virus encoded X antigen (HBx) is a trans-regulatory protein that alters the activity of selected transcription factors and cytoplasmic signal transduction pathways.HBx transcriptionally up-regulates the expression of a unique gene, URG11, which in turn transcriptionally up-regulates β-catenin, thereby contributing importantly to hepatocarcinogenesis. HBx and URG11 also alter the expression of multiple microRNAs, and by miRNA array analysis, both were shown to promote the expression of miR-148a. Elevated miR-148a was also seen in HBx positive liver samples from infected patients. To study the function of miR-148a, anti-148a was introduced into HepG2 and Hep3B cells stably expressing HBx or stably over-expressing URG11. Anti-miR-148a suppressed cell proliferation, cell cycle progression, cell migration, anchorage independent growth in soft agar and subcutaneous tumor formation in SCID mice.Introduction of anti-miR-148a increased PTEN protein and mRNA expression, suggesting that PTEN was targeted by miR-148a.Anti-miR-148a failed to suppress PTEN expression when co-transfected with reporter gene mutants in the 3′UTR of PTEN mRNA.Introduction of anti-miR-148a also resulted in depressed Akt signaling by HBx and URG11, resulting in decreased expression of β-catenin. Thus, miR-148a may play a central role in HBx/URG11 mediated HCC, and may be an early diagnostic marker and/or therapeutic target associated with this tumor type.