Ito Hiromitsu, Tanaka Shinji, Akiyama Yoshimitsu, Shimada Shu, Adikrisna Rama, Matsumura Satoshi, Aihara Arihiro, Mitsunori Yusuke, Ban Daisuke, Ochiai Takanori, Kudo Atsushi, Arii Shigeki, Yamaoka Shoji, Tanabe Minoru
Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
PLoS One. 2016 Jan 14;11(1):e0146564. doi: 10.1371/journal.pone.0146564. eCollection 2016.
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.
胰腺癌患者通常在疾病早期就会发生肿瘤侵袭和转移。这些恶性行为可能源于癌症干细胞（CSCs），但对于难以捉摸的CSCs，尤其是其在侵袭和转移过程中的作用靶点，我们了解较少。我们之前检测了CSCs的蛋白酶体活性，并构建了一个用于人类胰腺CSCs的实时可视化系统。在本研究中，我们发现，在肝转移模型中，CSCs具有高度转移性，并且主要定位于侵袭性肿瘤边缘。基因芯片和小干扰RNA（siRNA）筛选分析表明，双皮质素样激酶1（DCLK1）在具有侵袭和转移潜能的胰腺CSCs中，主要与组蛋白修饰一起表达。DCLK1的过表达导致细胞呈阿米巴样形态，促进胰腺癌细胞的迁移。敲低DCLK1可显著抑制胰腺CSCs在体内的肝转移。临床上，DCLK1在胰腺癌患者的转移瘤中呈过表达。我们的研究表明，DCLK1对于CSCs的侵袭和转移特性至关重要，可能是人类胰腺癌一个有前景的表观遗传和治疗靶点。
