Plasma DCLK1 is a marker of hepatocellular carcinoma (HCC): Targeting DCLK1 prevents HCC tumor xenograft growth via a microRNA-dependent mechanism.
Plasma DCLK1 is a marker of hepatocellular carcinoma (HCC): Targeting DCLK1 prevents HCC tumor xenograft growth via a microRNA-dependent mechanism.
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DOI：
10.18632/oncotarget.5808
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发表时间：
2015-11-10
期刊：
影响因子：
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通讯作者：
Houchen CW
中科院分区：
文献类型：
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作者：
Sureban SM;Madhoun MF;May R;Qu D;Ali N;Fazili J;Weygant N;Chandrakesan P;Ding K;Lightfoot SA;Houchen CW
肿瘤干细胞标志物双皮质素样激酶1 （DCLK1）在几种实体肿瘤中上调。DCLK1在肝细胞癌中的作用尚不清楚。我们对来自HCC、肝硬化对照组（CC）和非肝硬化对照组（NCC）的人肝脏组织进行DCLK1免疫染色。对保存的血浆样本进行DCLK1的Western blot和ELISA分析。我们观察到，与NCC相比，HCC和CC的上皮细胞和间质中免疫反应性DCLK1增加，HCC患者的血浆DCLK1与CC和NCC相比显著增加。对癌症基因组图谱的HCC数据集的分析显示，相对于邻近的正常组织，DCLK1在HCC肿瘤中过表达。高dclk1表达的细胞有更多的上皮-间质转化（EMT）。各种肿瘤抑制mirna在HCC肿瘤中也下调。我们评估了DCLK1敲低对huh7.5衍生的肿瘤异种移植物生长的影响。这与生长停滞和cMYC、EMT转录因子ZEB1、ZEB2、SNAIL和SLUG通过let-7a和miR-200 mirna依赖机制的显著下调有关。此外，我们还观察到miR-143/145上调，多能因子OCT4、NANOG、KLF4和LIN28相应降低，let-7a、miR-143/145和mir -200特异性荧光素酶活性降低。这些研究结果表明，检测血浆DCLK1升高可能为肝硬化临床症状的确认提供一种成本效益高、侵入性小的工具，并可能成为肝硬化和HCC患者的伴随诊断标志物。我们的研究结果支持评估DCLK1作为检测的生物标志物和作为根除HCC的治疗靶点。
Tumor stem cell marker Doublecortin-like kinase1 (DCLK1) is upregulated in several solid tumors. The role of DCLK1 in hepatocellular carcinoma (HCC) is unclear. We immunostained tissues from human livers with HCC, cirrhosis controls (CC), and non-cirrhosis controls (NCC) for DCLK1. Western blot and ELISA analyses for DCLK1 were performed with stored plasma samples. We observed increased immunoreactive DCLK1 in epithelia and stroma in HCC and CCs compared with NCCs, and observed a marked increase in plasma DCLK1 from patients with HCC compared with CC and NCC. Analysis of the Cancer Genome Atlas’ HCC dataset revealed that DCLK1 is overexpressed in HCC tumors relative to adjacent normal tissues. High DCLK1-expressing cells had more epithelial-mesenchymal transition (EMT). Various tumor suppressor miRNAs were also downregulated in HCC tumors. We evaluated the effects of DCLK1 knockdown on Huh7.5-derived tumor xenograft growth. This was associated with growth arrest and a marked downregulation of cMYC, and EMT transcription factors ZEB1, ZEB2, SNAIL, and SLUG via let-7a and miR-200 miRNA-dependent mechanisms. Furthermore, upregulation of miR-143/145, a corresponding decrease in pluripotency factors OCT4, NANOG, KLF4, and LIN28, and a reduction of let-7a, miR-143/145, and miR-200-specific luciferase activity was observed. These findings suggest that the detection of elevated plasma DCLK1 may provide a cost-effective, less invasive tool for confirmation of clinical signs of cirrhosis, and a potential companion diagnostic marker for patients with cirrhosis and HCC. Our results support evaluating DCLK1 as a biomarker for detection and as a therapeutic target for eradicating HCC.