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首页> 外文期刊>Cellular Physiology and Biochemistry >Doublecortin-Like Kinase 1 (DCLK1) Regulates B Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (Bmi-1) and is Associated with Metastasis and Prognosis in Pancreatic Cancer
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Doublecortin-Like Kinase 1 (DCLK1) Regulates B Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (Bmi-1) and is Associated with Metastasis and Prognosis in Pancreatic Cancer

机译：Doublecortin样激酶1（DCLK1）调节B细胞特定的莫洛尼鼠白血病病毒插入位点1（Bmi-1），并与胰腺癌的转移和预后相关。

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Background/Aims Cancer stem cells (CSCs) are largely responsible for tumor relapse and metastatic behavior. Doublecortin-like kinase 1 (DCLK1) was recently reported to be a biomarker for gastrointestinal CSCs and involved in the epithelial-mesenchymal transition (EMT) and tumor progression. B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1) is a crucial regulator of CSC self-renewal, malignant transformation and EMT, and a previous study from our group showed that Bmi-1 is upregulated in pancreatic cancer progression and participates in EMT. However, it remains unclear whether DCLK1 is involved in pancreatic cancer or whether DCLK1 is associated with the altered level of Bmi-1 expression. Methods The correlation of DCLK1 expression and clinical features of pancreatic cancer was analyzed in 210 paraffin-embedded archived pancreatic cancer specimens by immunohistochemical analysis. The biological effects of DCLK1 siRNA on cells were investigated by examining cell proliferation using a cell counting kit and cell colony assays, cell migration by wound healing assay and cell invasion by Transwell invasion assay. We further investigated the effect of therapeutic siRNA targeting DCLK1 on pancreatic cancer cell growth in vivo. Moreover, the molecular mechanism by which DCLK1 upregulates Bmi-1 expression was explored using real-time PCR, western blotting and Co-immunoprecipitation assay. Results DCLK1 is overexpressed in pancreatic cancer and is related to metastasis and prognosis. Knockdown of DCLK1 markedly suppressed cell growth in vitro and in vivo and also inhibited the migration and invasion of pancreatic cancer cells. Furthermore, we found that DCLK1 silencing could inhibit EMT in cancer cells via downregulation of Bmi-1 and the mesenchymal markers Snail and Vimentin and upregulation of the epithelial marker E-cadherin. Moreover, high DCLK1 expression in human pancreatic cancer samples was associated with a mesenchymal phenotype and increased cell proliferation. Further co-immunoprecipitation indicated that DCLK1 did not interact with Bmi-1 directly. Conclusion Our data suggest that upregulation of DCLK1 may contribute to pancreatic cancer metastasis and poor prognosis by increasing Bmi-1 expression indirectly. The findings indicate that inhibiting DCLK1 expression might be a novel strategy for pancreatic cancer therapy.
机译：背景/目的癌症干细胞（CSC）在很大程度上负责肿瘤的复发和转移行为。最近报道，双皮质素样激酶1（DCLK1）是胃肠道CSCs的生物标志物，参与上皮-间质转化（EMT）和肿瘤进展。 B细胞特异性莫洛尼氏鼠白血病病毒插入位点1（Bmi-1）是CSC自我更新，恶性转化和EMT的关键调节剂，我们小组先前的研究表明Bmi-1在胰腺癌的进展和转移过程中被上调。参加EMT。但是，尚不清楚DCLK1是否参与胰腺癌或DCLK1是否与Bmi-1表达水平的改变有关。方法采用免疫组织化学方法分析210例石蜡包埋的胰腺癌标本中DCLK1表达与胰腺癌临床特征的相关性。通过使用细胞计数试剂盒和细胞集落分析，通过伤口愈合分析进行细胞迁移以及通过Transwell入侵分析进行细胞入侵检查细胞增殖，研究了DCLK1 siRNA对细胞的生物学效应。我们进一步研究了靶向DCLK1的治疗性siRNA对胰腺癌细胞在体内生长的影响。此外，使用实时荧光定量PCR，蛋白质印迹和免疫共沉淀试验探索了DCLK1上调Bmi-1表达的分子机制。结果DCLK1在胰腺癌中过表达，与转移和预后有关。敲低DCLK1显着抑制了体内和体外的细胞生长，并且还抑制了胰腺癌细胞的迁移和侵袭。此外，我们发现DCLK1沉默可以通过下调Bmi-1和间充质标记Snail和Vimentin以及上皮标记E-cadherin的表达来抑制癌细胞中的EMT。此外，人胰腺癌样品中高DCLK1表达与间充质表型和细胞增殖增加有关。进一步的共免疫沉淀表明DCLK1没有直接与Bmi-1相互作用。结论我们的数据表明DCLK1的上调可能通过间接增加Bmi-1表达来促进胰腺癌转移和预后不良。这些发现表明抑制DCLK1表达可能是胰腺癌治疗的一种新策略。

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