Dominant Expression of DCLK1 in Human Pancreatic Cancer Stem Cells Accelerates Tumor Invasion and Metastasis.
Dominant Expression of DCLK1 in Human Pancreatic Cancer Stem Cells Accelerates Tumor Invasion and Metastasis.
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DCLK1在人胰腺癌干细胞中的主要表达会加速肿瘤侵袭和转移。
DOI：
10.1371/journal.pone.0146564
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Tanabe M
中科院分区：
文献类型：
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作者：
Ito H;Tanaka S;Akiyama Y;Shimada S;Adikrisna R;Matsumura S;Aihara A;Mitsunori Y;Ban D;Ochiai T;Kudo A;Arii S;Yamaoka S;Tanabe M
胰腺癌患者通常会在早期发生肿瘤侵袭和转移。这些恶性行为可能起源于肿瘤干细胞（CSCs），但对于不可见的CSCs，尤其是侵袭和转移的靶点知之甚少。我们先前检查了CSC的蛋白酶体活性，并构建了一个人胰腺CSC的实时可视化系统。在本研究中，我们发现CSC是高度转移性的，并且在肝转移模型中主要定位于侵入的肿瘤边缘。微阵列和siRNA筛选分析表明，双皮质素样激酶1（DCLK1）主要表达与组蛋白修饰的胰腺肿瘤干细胞的侵袭和转移的潜力。DCLK1的过表达导致变形虫形态，这促进了胰腺癌细胞的迁移。DCLK1的敲除可显著抑制胰腺CSC的体内肝转移。临床上，DCLK1在胰腺癌患者的转移性肿瘤中过表达。我们的研究表明，DCLK1是至关重要的肿瘤干细胞的侵袭性和转移性，并可能是一个有前途的表观遗传和治疗靶点在人类胰腺癌。
Patients with pancreatic cancer typically develop tumor invasion and metastasis in the early stage. These malignant behaviors might be originated from cancer stem cells (CSCs), but the responsible target is less known about invisible CSCs especially for invasion and metastasis. We previously examined the proteasome activity of CSCs and constructed a real-time visualization system for human pancreatic CSCs. In the present study, we found that CSCs were highly metastatic and dominantly localized at the invading tumor margins in a liver metastasis model. Microarray and siRNA screening assays showed that doublecortin-like kinase 1 (DCLK1) was predominantly expressed with histone modification in pancreatic CSCs with invasive and metastatic potential. Overexpression of DCLK1 led to amoeboid morphology, which promotes the migration of pancreatic cancer cells. Knockdown of DCLK1 profoundly suppressed in vivo liver metastasis of pancreatic CSCs. Clinically, DCLK1 was overexpressed in the metastatic tumors in patients with pancreatic cancer. Our studies revealed that DCLK1 is essential for the invasive and metastatic properties of CSCs and may be a promising epigenetic and therapeutic target in human pancreatic cancer.