Overexpression of PER3 Inhibits Self-Renewal Capability and Chemoresistance of Colorectal Cancer Stem-Like Cells via Inhibition of Notch and β-Catenin Signaling.
Overexpression of PER3 Inhibits Self-Renewal Capability and Chemoresistance of Colorectal Cancer Stem-Like Cells via Inhibition of Notch and β-Catenin Signaling.
复制标题
DOI：
10.3727/096504016x14772331883976
复制
发表时间：
2017-05-24
影响因子：
3.1
通讯作者：
Su T
中科院分区：
文献类型：
--
作者：
Zhang F;Sun H;Zhang S;Yang X;Zhang G;Su T
PER 3是一种生物钟基因，在结直肠癌中起着重要作用，但其在结直肠癌干细胞样细胞（CSCs）中的作用及其机制尚不清楚。在这项研究中，结肠直肠CSC富集在结肠直肠HCT-116球形成细胞中，与HCT-116细胞相比，表达较低水平的干细胞标志物CD 133、CD 44、LGR 5和SOX 2。建立了HCT-116耐药株。Western blot和qRT-PCR分析显示，PER 3在结直肠CSC和耐药HCT-116中下调。过表达PER 3可增强5-FU对结肠癌干细胞的抑制作用，而敲低PER 3则可减弱其对结肠癌干细胞的抑制作用。此外，结直肠CSC中PER 3的过表达导致软琼脂培养基中的集落形成效率和自我更新效率降低。抑制，敲除PER 3增强结肠直肠CSC的自我更新。PER 3的过表达降低了结直肠CSC中的干性标志物和Notch 1、Jagged 1、β-catenin、c-Myc和LGR 5。当Notch或β-catenin信号被抑制时，结肠直肠CSCs的化学抗性和自我更新能力降低。研究证实，PER 3可通过抑制Notch和β-catenin信号通路，降低结肠癌干细胞的化疗耐药性和自我更新能力。我们的研究结果表明，PER 3在维持结直肠CSCs的干细胞性方面起着关键作用，并且可能是消除CSCs的有希望的靶点。
PER3, a circadian clock gene, plays an important role in colorectal cancer, but its action and underlying mechanism in colorectal cancer stem-like cells (CSCs) remain unclear. In this study, the colorectal CSCs were enriched in colorectal HCT-116 sphere-forming cells, expressing lower levels of stem cell markers CD133, CD44, LGR5, and SOX2 compared with HCT-116 cells. A drug-resistant strain from HCT-116 was established. Western blot and qRT-PCR analysis showed that PER3 was downregulated in colorectal CSCs and drug-resistant HCT-116. Overexpression of PER3 could strengthen 5-FU-induced inhibitory effects on colorectal CSCs, but knockdown of PER3 decreased its inhibition of colorectal CSCs. In addition, overexpression of PER3 in colorectal CSCs resulted in reduced colony formation efficiency in a soft agar medium and self-renewal efficiency. Inversely, knockdown of PER3 enhanced self-renewal of colorectal CSCs. Overexpression of PER3 decreased stemness markers and Notch1, Jagged1, β-catenin, c-Myc, and LGR5 in colorectal CSCs. When Notch or β-catenin signaling was inhibited, the chemoresistance and self-renewal capability of colorectal CSCs were decreased. It was confirmed that PER3 can reduce chemoresistance and self-renewal capability of colorectal CSCs via inhibition of Notch and β-catenin signaling. Our results reveal that PER3 plays a critical role in maintaining the stemness of colorectal CSCs and may be a promising target for elimination of CSCs.