The novel MKL target gene myoferlin modulates expansion and senescence of hepatocellular carcinoma
The novel MKL target gene myoferlin modulates expansion and senescence of hepatocellular carcinoma
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DOI：
10.1038/onc.2016.496
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发表时间：
2017-06-15
期刊：
影响因子：
8
通讯作者：
Muehlich, S.
中科院分区：
文献类型：
--
作者：
Hermanns, C.;Hampl, V.;Muehlich, S.
巨核母细胞白血病1和2 （MKL1/2）是血清反应因子（SRF）的转录共激活因子，在肝细胞癌（HCC）生长和癌基因诱导的衰老中起重要作用。在本报告中，我们通过基因表达谱和肝癌异种移植物体内验证，确定了myoferlin是一种新的MKL/SRF靶基因。Myoferlin在人和小鼠hcc中过度表达，这是由肝细胞中组成活性SRF-VP16蛋白的条件表达引发的。此外，心肌蛋白是HCC细胞侵袭、增殖和不依赖于锚定的细胞生长所必需的。我们提供的证据表明myoferlin是MKL1/2通过调节EGFR和下游MAPK和p16-/Rb通路的激活状态介导其在癌基因诱导的衰老中的作用的关键基因靶点。srf - vp16来源的小鼠hcc肿瘤细胞中肌钙素的消耗诱导衰老表型。这些发现确定了MKL1/2和myoferlin是通过诱导衰老策略治疗人类HCC的新治疗靶点。
Megakaryoblastic Leukemia 1 and 2 (MKL1/2) are transcriptional coactivators of Serum Response Factor (SRF) with an essential role for hepatocellular carcinoma (HCC) growth and oncogene-induced senescence. In this report, we identified myoferlin as a novel MKL/SRF target gene by gene expression profiling and verification in vivo in HCC xenografts. Myoferlin was overexpressed in human and murine HCCs triggered by conditional expression of constitutively active SRF-VP16 protein in hepatocytes. Furthermore, myoferlin was required for HCC cell invasion, proliferation and anchorage-independent cell growth. We provide evidence that myoferlin is a crucial gene target of MKL1/2 mediating its effect on oncogene-induced senescence by modulating the activation state of the EGFR and downstream MAPK and p16-/Rb pathways. Depletion of myoferlin in tumour cells from SRF-VP16-derived murine HCCs induced a senescence phenotype. These findings identify MKL1/2 and myoferlin as novel therapeutic targets to treat human HCC by a senescence-inducing strategy.