Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, , Leuven, Belgium.
Gut. 2014 Apr;63(4):674-85. doi: 10.1136/gutjnl-2012-304351. Epub 2013 Aug 19.
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.
角蛋白 19（K）19 是胆管/肝祖细胞（HPC）标志物，在预后不良的一部分肝细胞癌（HCC）中表达。驱动这种 K19 阳性 HCC 表型的潜在机制仍不清楚。
在一个由 242 名不同病因的连续患者（167 例手术标本，75 例活检）组成的白种人群中，比较了 K19、EpCAM 和甲胎蛋白的临床病理价值。利用微阵列和 microRNA 分析，确定了 K19 阳性 HCC 的分子表型。将临床原发性 HCC 样本进行体外侵袭试验和侧群分析。将 HCC 细胞系用针对 KRT19 的合成 siRNA 转染，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）和微血管侵犯（p<0.001）相关性最强。在一组 75 例活检中也证实了 K19 的预后价值。分析显示，K19 阳性 HCC 高度表达侵袭相关/转移相关标志物（如 VASP、TACSTD2、LAMB1、LAMC2、PDGFRA）、胆管/ HPC 标志物（如 CD133、GSTP1、NOTCH2、JAG1）和 miRNA 家族 200 的成员（如 miR-141、miR-200c）。在体外，原代人 K19 阳性肿瘤细胞表现出较强的侵袭性，并存在于化疗耐药的侧群中。功能上，K19/KRT19 敲低导致侵袭减少、侵袭小体形成缺失以及对阿霉素、5-氟尿嘧啶和索拉非尼的耐药性降低。
鉴于其独特的侵袭特性、不同的分子谱和不良的预后结果，K19 阳性 HCC 应被视为 HCC 的一个独立实体。
