Keratin 19: a key role player in the invasion of human hepatocellular carcinomas.
Keratin 19: a key role player in the invasion of human hepatocellular carcinomas.
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DOI：
10.1136/gutjnl-2012-304351
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发表时间：
2014-04
期刊：
影响因子：
24.5
通讯作者：
Roskams T
中科院分区：
文献类型：
--
作者：
Govaere O;Komuta M;Berkers J;Spee B;Janssen C;de Luca F;Katoonizadeh A;Wouters J;van Kempen LC;Durnez A;Verslype C;De Kock J;Rogiers V;van Grunsven LA;Topal B;Pirenne J;Vankelecom H;Nevens F;van den Oord J;Pinzani M;Roskams T
角蛋白（K）19是一种胆管/肝祖细胞（HPC）标志物，在预后不良的肝细胞癌（HCC）中表达。驱动K19阳性HCC的这种表型的潜在机制仍然难以捉摸。在242例具有不同潜在病因的连续患者（167例手术标本，75例针吸活检）的高加索队列中，比较了K19与EpCAM和甲胎蛋白的临床病理学价值。使用微阵列和microRNA分析鉴定K19阳性HCC的分子表型。临床原发性肝癌样本被提交进行体外侵袭测定和侧群分析。用针对KRT 19的合成siRNA转染HCC细胞系，并进行侵袭和细胞毒性测定。在手术标本队列中，K19表达与肿瘤大小增加（p<0.01）、肿瘤分化降低（p<0.001）、转移（p<0.05）和微血管浸润（p<0.001）相关性最强。K19的预后价值也在一组75针活检中得到证实。分析显示，K19阳性HCC高度表达侵袭/转移相关标志物（例如，VASP、TACSTD 2、LAMB 1、LAMC 2、PDGFRA）、胆汁/HPC标志物（例如，CD 133、GST P1、NOTCH 2、JAG 1）和miRNA家族200成员（例如，miR-141、miR-200 c）。在体外，原代人K19阳性肿瘤细胞显示出增加的侵袭性，并存在于耐药侧群中。在功能上，K19/KRT 19敲低导致侵袭减少、侵袭伪足形成丧失以及对多柔比星、5-氟尿嘧啶和索拉非尼的抗性降低。由于K19阳性HCC具有不同的侵袭性、不同的分子特征和预后不良，因此K19阳性HCC应被视为HCC的一个独立实体。
Keratin (K)19, a biliary/hepatic progenitor cell (HPC) marker, is expressed in a subset of hepatocellular carcinomas (HCC) with poor prognosis. The underlying mechanisms driving this phenotype of K19-positive HCC remain elusive. Clinicopathological value of K19 was compared with EpCAM, and α-fetoprotein, in a Caucasian cohort of 242 consecutive patients (167 surgical specimens, 75 needle biopsies) with different underlying aetiologies. Using microarrays and microRNA profiling the molecular phenotype of K19-positive HCCs was identified. Clinical primary HCC samples were submitted to in vitro invasion assays and to side population analysis. HCC cell lines were transfected with synthetic siRNAs against KRT19 and submitted to invasion and cytotoxicity assays. In the cohort of surgical specimens, K19 expression showed the strongest correlation with increased tumour size (p<0.01), decreased tumour differentiation (p<0.001), metastasis (p<0.05) and microvascular invasion (p<0.001). The prognostic value of K19 was also confirmed in a set of 75 needle biopsies. Profiling showed that K19-positive HCCs highly express invasion-related/metastasis-related markers (eg, VASP, TACSTD2, LAMB1, LAMC2, PDGFRA), biliary/HPC markers (eg, CD133, GSTP1, NOTCH2, JAG1) and members of the miRNA family 200 (eg, miR-141, miR-200c). In vitro, primary human K19-positive tumour cells showed increased invasiveness, and reside in the chemoresistant side population. Functionally, K19/KRT19 knockdown results in reduced invasion, loss of invadopodia formation and decreased resistance to doxorubicin, 5-fluorouracil and sorafenib. Giving the distinct invasive properties, the different molecular profile and the poor prognostic outcome, K19-positive HCCs should be considered as a seperate entity of HCCs.
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影响因子：
11.2
作者：
Hoshida Y;Nijman SM;Kobayashi M;Chan JA;Brunet JP;Chiang DY;Villanueva A;Newell P;Ikeda K;Hashimoto M;Watanabe G;Gabriel S;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
6.7
作者：
Borght, Sara Vander;Komuta, Mina;Roskams, Tania
通讯作者：
Roskams, Tania
影响因子：
24.5
作者：
Lorenzini S;Bird TG;Boulter L;Bellamy C;Samuel K;Aucott R;Clayton E;Andreone P;Bernardi M;Golding M;Alison MR;Iredale JP;Forbes SJ
通讯作者：
Forbes SJ
影响因子：
3.5
作者：
Tsuchiya, Kaoru;Komuta, Mina;Izumi, Namiki
通讯作者：
Izumi, Namiki