A microRNA miR-34a-Regulated Bimodal Switch Targets Notch in Colon Cancer Stem Cells

被引：401

作者：

Bu, Pengcheng ^{[1
,2
]}

Chen, Kai-Yuan ^{[1
]}

Chen, Joyce Huan ^{[2
]}

Wang, Lihua ^{[1
,3
]}

Walters, Jewell ^{[4
,5
,6
]}

Shin, Yong Jun ^{[1
]}

Goerger, Julian P. ^{[2
]}

Sun, Jian ^{[7
]}

Witherspoon, Mavee ^{[4
,5
,6
]}

Rakhilin, Nikolai ^{[1
,3
]}

Li, Jiahe ^{[2
]}

Yang, Herman ^{[1
]}

Milsom, Jeff ^{[4
,5
,6
]}

Lee, Sang ^{[4
,5
,6
]}

Zipfel, Warren ^{[2
]}

Jin, Moonsoo M. ^{[2
,8
]}

Guemues, Zeynep H. ^{[7
,9
,10
]}

Lipkin, Steven M. ^{[4
,5
,6
]}

Shen, Xiling ^{[1
,2
,3
]}

机构：

[1] Cornell Univ, Sch Elect & Comp Engn, Ithaca, NY 14853 USA

[2] Cornell Univ, Dept Biomed Engn, Ithaca, NY 14853 USA

[3] Cornell Univ, Dept Biol & Environm Engn, Ithaca, NY 14853 USA

[4] Weill Cornell Med Coll, Dept Med, New York, NY 10021 USA

[5] Weill Cornell Med Coll, Dept Med Genet, New York, NY 10021 USA

[6] Weill Cornell Med Coll, Dept Surg, New York, NY 10021 USA

[7] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA

[8] Weill Cornell Med Coll, Dept Radiol, New York, NY 10021 USA

[9] Weill Cornell Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10021 USA

[10] Weill Cornell Med Coll, Computat Biomed & Canc Ctr, New York, NY 10021 USA

来源：

CELL STEM CELL | 2013年 / 12卷 / 05期

基金：

美国国家科学基金会;

关键词：

TUMOR-INITIATING CELLS; INTESTINAL CRYPTS; MAMMALIAN-CELLS; SELF-RENEWAL; DIVISION; METASTASIS; RNAS; DIFFERENTIATION; MODULATION; REGULATORS;

D O I：

10.1016/j.stem.2013.03.002

中图分类号：

Q813 [细胞工程];

学科分类号：

100113 [医学细胞生物学];

摘要：

microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.

引用

页码：602 / 615

页数：14

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