Koh Hyebin, Park Hyeri, Chandimali Nisansala, Huynh Do Luong, Zhang Jiao Jiao, Ghosh Mrinmoy, Gera Meeta, Kim Nameun, Bak Yesol, Yoon Do-Young, Park Yang Ho, Kwon Taeho, Jeong Dong Kee
Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea.
Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul, Republic of Korea.
Oncotarget. 2017 Nov 30;8(66):110540-110551. doi: 10.18632/oncotarget.22818. eCollection 2017 Dec 15.
The existence of cancer stem cells (CSCs) is the main reason for failure of cancer treatment caused by drug resistance. Therefore, eradicating cancers by targeting CSCs remains a significant challenge. In the present study, because of the important role of BMI-1 proto-oncogene, polycomb ring finger (BMI-1) and C-terminal Mucin1 (MUC1-C) in tumor growth and maintenance of CSCs, we aimed to confirm that microRNA miR-128, as an inhibitor of BMI-1 and MUC1-C, could effectively suppress paclitaxel (PTX)-resistant lung cancer stem cells. We showed that CSCs have significantly higher expression levels of BMI-1, MUC1-C, stemness proteins, signaling factors, and higher malignancy compared with normal tumor cells. After transfection with miR-128, the BMI-1 and MUC1-C levels in CSCs were suppressed. When miR-128 was stably expressed in PTX-resistant lung cancer stem cells, the cells showed decreased proliferation, metastasis, self-renewal, migration, invasive ability, clonogenicity, and tumorigenicity and and increased apoptosis compared with miR-NC (negative control) CSCs. Furthermore, miR-128 effectively decreased the levels of β-catenin and intracellular signaling pathway-related factors in CSCs. MiR-128 also decreased the luciferase activity of MUC1 reporter constructs and reduced the levels of transmembrane MUC1-C and BMI-1. These results suggested miR-128 as an attractive therapeutic strategy for PTX-resistant lung cancer via inhibition of BMI-1 and MUC1-C.
癌症干细胞（CSCs）的存在是导致癌症治疗因耐药性而失败的主要原因。因此，通过靶向癌症干细胞来根除癌症仍然是一项重大挑战。在本研究中，鉴于BMI-1原癌基因、多梳环指蛋白（BMI-1）和C端黏蛋白1（MUC1-C）在肿瘤生长和癌症干细胞维持中的重要作用，我们旨在证实作为BMI-1和MUC1-C抑制剂的微小RNA miR-128能够有效抑制耐紫杉醇（PTX）的肺癌干细胞。我们发现，与正常肿瘤细胞相比，癌症干细胞中BMI-1、MUC1-C、干性蛋白、信号因子的表达水平显著更高，恶性程度也更高。用miR-128转染后，癌症干细胞中BMI-1和MUC1-C的水平受到抑制。当miR-128在耐PTX的肺癌干细胞中稳定表达时，与miR-NC（阴性对照）癌症干细胞相比，这些细胞的增殖、转移、自我更新、迁移、侵袭能力、克隆形成能力和致瘤性降低，凋亡增加。此外，miR-128有效降低了癌症干细胞中β-连环蛋白和细胞内信号通路相关因子的水平。miR-128还降低了MUC1报告基因构建体的荧光素酶活性，并降低了跨膜MUC1-C和BMI-1的水平。这些结果表明，miR-128通过抑制BMI-1和MUC1-C，是一种有吸引力的耐PTX肺癌治疗策略。
