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首页> 外文期刊>Oncogene >The PDGFRα-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma
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The PDGFRα-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma

机译:PDGFRα-lamininB1-Keratin 19级联反应在人类肝细胞癌浸润性前端驱动肿瘤进展

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摘要

Human hepatocellular carcinomas (HCCs) expressing the biliary/hepatic progenitor cell marker keratin 19 (K19) have been linked with a poor prognosis and exhibit an increase in platelet-derived growth factor receptor a (PDGFRα) and laminin beta 1 (LAMB1) expression. PDGFRα has been reported to induce de novo synthesis of LAMB1 protein in a Sjogren syndrome antigen B (La/SSB)- dependent manner in a murine metastasis model. However, the role of this cascade in human HCC remains unclear. This study focused on the functional role of the PDGFRα-La/SSB-LAMB1 pathway and its molecular link to K19 expression in human HCC In surgical HCC specimens from a cohort of 136 patients, PDGFRα expression correlated with K19 expression, microvascular invasion and metastatic spread. In addition, PDGFRα expression in pre-operative needle biopsy specimens predicted poor overall survival during a 5-year follow-up period. Consecutive histological staining demonstrated that the signaling components of the PDGFRα-La/ SSB-LAMB1 pathway were strongly expressed at the invasive front. K19-positive HCC cells displayed high levels of α2β1 integrili (HG) receptor, both in vitro and in vivo. In vitro activation of PDGFRα signaling triggered the translocation of nuclear La/SSB into the cytoplasm, enhanced the protein synthesis of LAMB1 by activating its internal ribosome entry site, which in turn led to increased secretion of laminin-111. This effect was abrogated by the PDGFRα-specific inhibitor crenolanib. Importantly LAMB1 stimulated ITG- dependent focal adhesion kinase/Src proto-oncogene non-receptor tyrosine kinase signaling. It also promoted the ITG-specific downstream target Rho-associated coiled-coil containing protein kinase 2, induced K19 expression in an autocrine manner, invadopodia formation and cell invasion. Finally, we showed that the knockdown of LAMB1 or K19 in subcutaneous xenograft mouse models resulted in significant loss of cells invading the surrounding stromal tissue and reduced HepG2 colonization into lung and liver after tail vein injection. The PDGFRα-LAMBI pathway supports tumor progression at the invasive front of human HCC through K19 expression.
机译:表达胆汁/肝祖细胞标志物角蛋白19(K19)的人类肝细胞癌(HCC)与不良预后相关,并且血小板衍生生长因子受体a(PDGFRα)和层粘连蛋白beta 1(LAMB1)表达增加。已经报道PDGFRα在鼠转移模型中以干燥综合征抗原B(La / SSB)依赖性方式诱导LAMB1蛋白的从头合成。然而,这种级联在人类肝癌中的作用仍不清楚。这项研究的重点是PDGFRα-La/ SSB-LAMB1通路的功能作用及其与人HCC中K19表达的分子联系在来自136例患者的外科手术HCC标本中,PDGFRα表达与K19表达,微血管浸润和转移扩散相关。此外,术前穿刺活检标本中PDGFRα的表达预示了5年随访期的总体生存率较差。连续的组织学染色表明,PDGFRα-La/ SSB-LAMB1途径的信号传导成分在侵袭性前沿强烈表达。在体外和体内,K19阳性HCC细胞均显示高水平的α2β1整合(HG)受体。 PDGFRα信号的体外激活触发了核La / SSB进入细胞质的转运,通过激活其内部核糖体进入位点增强了LAMB1的蛋白质合成,进而导致层粘连蛋白111的分泌增加。 PDGFRα特异性抑制剂crenolanib消除了这种作用。重要的是,LAMB1刺激了ITG依赖性粘着斑激酶/ Src原癌基因非受体酪氨酸激酶信号传导。它也促进了ITG特异性下游靶标Rho相关的含有蛋白激酶2的卷曲螺旋,以自分泌方式诱导K19表达,侵袭伪足形成和细胞侵袭。最后,我们显示在皮下异种移植小鼠模型中,LAMB1或K19的敲低导致尾静脉注射后侵袭周围基质组织的细胞大量丢失,并减少了HepG2定植在肺和肝脏中。 PDGFRα-LAMBI途径通过K19表达支持人类HCC侵袭性前端的肿瘤进展。

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