MicroRNA-449a maintains self-renewal in liver cancer stem-like cells by targeting Tcf3

// Qianzhen Zhang 1, 2, * , Zhi Yang 3, * , Juanjuan Shan 3 , Limei Liu 3 , Chungang Liu 3 , Junjie Shen 3 , Xuejiao Chen 3 , Yanmin Xu 3 , Jun Chen 3 , Qinghua Ma 3 , Li Yang 1, 2 and Cheng Qian 3 1 Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, 400044, China 2 College of Bioengineering, Chongqing University, Chongqing, 400044, China 3 Center of Biological Therapy, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China * These authors contributed equally to this work Correspondence to: Cheng Qian, email: cqian8634@gmail.com Li Yang, email: yanglibme@126.com Keywords: cancer stem cells; MicroRNA-449a; self-renewal; Nanog; TCF3 Received: October 07, 2017      Accepted: October 29, 2017      Published: November 27, 2017 ABSTRACT Cancer stem cells (CSCs) are thought to be responsible for tumor invasion, metastasis, and recurrence. We previously showed that the pluripotency factor Nanog not only serves as a novel biomarker of CSCs but also potentially plays a crucial role in maintaining the self-renewal ability of liver CSCs. However, how CSCs maintain Nanog gene expression has not been elucidated. Here, we demonstrated that microRNA-449a (miR-449a) is overexpressed in poorly differentiated hepatocellular carcinoma tissues, drug-resistant liver cancer cells, cultured liver tumorspheres, and Nanog-positive liver cancer cells. The upregulation of miR-449a in non-CSCs increased stemness, whereas the downregulation of miR-449a in Nanog-positive CSCs reduced stemness. Furthermore, transcription factor 3 (TCF3), a target of miR-449a, could downregulate Nanog expression, and restoring TCF3 expression in miR-449a-expressing Nanog-negative cells abrogated cellular stemness. These data establish that the miR449a-TCF3-Nanog axis maintains stemness in liver CSCs.