Hermanns C, Hampl V, Holzer K, Aigner A, Penkava J, Frank N, Martin D E, Maier K C, Waldburger N, Roessler S, Goppelt-Struebe M, Akrap I, Thavamani A, Singer S, Nordheim A, Gudermann T, Muehlich S
Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University Munich, Munich, Germany.
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Oncogene. 2017 Jun 15;36(24):3464-3476. doi: 10.1038/onc.2016.496. Epub 2017 Jan 23.
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.
巨核细胞白血病1和2（MKL1/2）是血清反应因子（SRF）的转录共激活因子，对肝细胞癌（HCC）的生长和癌基因诱导的衰老起着至关重要的作用。在本报告中，我们通过基因表达谱分析和在HCC异种移植瘤中的体内验证，确定肌铁蛋白是一种新的MKL/SRF靶基因。在肝细胞中通过组成型活性SRF-VP16蛋白的条件性表达引发的人类和小鼠HCC中，肌铁蛋白过表达。此外，肌铁蛋白是HCC细胞侵袭、增殖和非锚定依赖性细胞生长所必需的。我们提供的证据表明，肌铁蛋白是MKL1/2的关键基因靶点，通过调节表皮生长因子受体（EGFR）以及下游丝裂原活化蛋白激酶（MAPK）和p16/Rb信号通路的激活状态来介导其对癌基因诱导衰老的影响。在源自SRF-VP16的小鼠HCC肿瘤细胞中，肌铁蛋白的缺失诱导了衰老表型。这些发现确定MKL1/2和肌铁蛋白是通过诱导衰老策略治疗人类HCC的新治疗靶点。
