Li Liping, Duan Tingmei, Wang Xin, Zhang Ru-Hua, Zhang Meifang, Wang Suihai, Wang Fen, Wu Yuanzhong, Huang Haojie, Kang Tiebang
State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
School of Biotechnology, Southern Medical University, Guangzhou 510515, China.
Sci Rep. 2016 Feb 5;6:20460. doi: 10.1038/srep20460.
Targeting cancer stem cells (CSCs) in colorectal cancer (CRC) remains a difficult problem, as the regulation of CSCs in CRC is poorly understood. Here we demonstrated that KCTD12, potassium channel tetramerization domain containing 12, is down-regulated in the CSC-like cells of CRC. The silencing of endogenous KCTD12 and the overexpression of ectopic KCTD12 dramatically enhances and represses CRC cell stemness, respectively, as assessed in vitro and in vivo using a colony formation assay, a spheroid formation assay and a xenograft tumor model. Mechanistically, KCTD12 suppresses CRC cell stemness markers, such as CD44, CD133 and CD29, by inhibiting the ERK pathway, as the ERK1/2 inhibitor U0126 abolishes the increase in expression of CRC cell stemness markers induced by the down-regulation of KCTD12. Indeed, a decreased level of KCTD12 is detected in CRC tissues compared with their adjacent normal tissues and is an independent prognostic factor for poor overall and disease free survival in patients with CRC (p = 0.007). Taken together, this report reveals that KCTD12 is a novel regulator of CRC cell stemness and may serve as a novel prognostic marker and therapeutic target for patients with CRC.
在结直肠癌（CRC）中靶向癌症干细胞（CSCs）仍然是一个难题，因为人们对CRC中CSCs的调控了解甚少。在此我们证明，含钾通道四聚化结构域12（KCTD12）在CRC的类CSC细胞中表达下调。使用集落形成试验、球体形成试验和异种移植肿瘤模型在体外和体内评估发现，内源性KCTD12的沉默和异位KCTD12的过表达分别显著增强和抑制CRC细胞的干性。从机制上讲，KCTD12通过抑制ERK途径抑制CRC细胞干性标志物，如CD44、CD133和CD29，因为ERK1/2抑制剂U0126消除了因KCTD12下调诱导的CRC细胞干性标志物表达的增加。实际上，与相邻正常组织相比，在CRC组织中检测到KCTD12水平降低，并且它是CRC患者总体生存和无病生存不良的独立预后因素（p = 0.007）。综上所述，本报告揭示KCTD12是CRC细胞干性的新型调节因子，可能作为CRC患者的新型预后标志物和治疗靶点。
