A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer

Abstract

SUMMARY Emerging evidence suggests that microRNAs can initiate asymmetric division, but whether microRNA and protein cell fate determinants coordinate with each other remains unclear. Here we show that miR-34a directly suppresses Numb in early-stage colon cancer stem cells (CCSCs), forming an incoherent feedforward loop (IFFL) targeting Notch to separate stem and non-stem cell fates robustly. Perturbation of the IFFL leads to a new intermediate cell population with plastic and ambiguous identity. Lgr5+ mouse intestinal/colon stem cells (ISCs) predominantly undergo symmetric division, but turn on asymmetric division to curb the number of ISCs when proinflammatory response causes excessive proliferation. Deletion of miR-34a inhibits asymmetric division and exacerbates Lgr5+ ISC proliferation under such stress. Collectively, our data indicate that microRNA and protein cell fate determinants coordinate to enhance robustness of cell fate decision, and they provide a safeguard mechanism against stem cell proliferation induced by inflammation or oncogenic mutation.

Regulation and plasticity of intestinal stem cells during homeostasis and regeneration

“…Another recent study implies that inflammatory signals can affect symmetric division of intestinal stem cells to prevent excessive expansion during repair (Bu et al, 2016). CBCs predominantly undergo symmetric cell divisions while competing for niche space; through neutral competition clones, are eventually either lost or take over the crypt in a stochastic fashion (Snippert et al, 2010).…”

“…Inflammatory signals can, however, enforce asymmetric cell divisions in CBCs. In DSS-induced colitis, the number of asymmetric cell divisions of Lgr5-GFP + cells increases from 2% to 13% (Bu et al, 2016). Shen and colleagues propose that asymmetric stem cell divisions are essential to prevent inflammation-induced increase of stem cell numbers (Bu et al, 2016).…”

“…In DSS-induced colitis, the number of asymmetric cell divisions of Lgr5-GFP + cells increases from 2% to 13% (Bu et al, 2016). Shen and colleagues propose that asymmetric stem cell divisions are essential to prevent inflammation-induced increase of stem cell numbers (Bu et al, 2016). Deletion of miR34a in intestinal organoids reverses this increase in asymmetric cell division following treatment with TNFα, causing a concomitant, rapid expansion of stem cell numbers.…”

“…miR34a is a microRNA that negatively regulates the Notch receptor and its negative regulator Numb. By having both a negative and indirect positive effect on Notch, miR34a installs robust bimodal rather than graded Notch activity, being high in CBCs and low in their offspring (Bu et al, 2016). Deletion of Numb disrupts this binary Notch activity, creating a population of cells with intermediate Notch levels that express both stem cell and differentiated markers.…”

The role of extracellular vesicle microRNAs in cancer biology

“…Cellular microRNAs (ce-miRNAs) can be classified as tumor-suppressive or oncogenic and play important roles in tumor development such as tumor initiation, acquisition of drug resistance, and metastasis [33][34][35]. Likewise, se-miRNAs in exosomes (exosomal miRNAs) are also important for tumor progression and metastasis in multiple cancers [7,9,20,36,37] (Figure 2).…”