Propagation and Maintenance of Cancer Stem Cells: A Major Influence of the Long Non-Coding RNA H19

Abstract

Cancer stem cells (CSCs) represent a rare population of tumor cells that exhibit stem cell properties with the abilities of self-renewal and differentiation. These cells are now widely accepted to be responsible for tumor initiation, development, resistance to conventional therapies, and recurrence. Thus, a better understanding of the molecular mechanisms involved in the control of CSCs is essential to improve patient management in terms of diagnostics and therapies. CSCs are regulated by signals of the tumor microenvironment as well as intrinsic genetic and epigenetic modulators. H19, the first identified lncRNA is involved in the development and progression of many different cancer types. Recently, H19 has been demonstrated to be implicated in the regulation of CSCs in different types of cancers. The aim of this review is to provide an overview of the role and mechanisms of action of H19 in the regulation of CSCs. We summarize how H19 may regulate CSC division and cancer cell reprogramming, thus affecting metastasis and drug resistance. We also discuss the potential clinical implications of H19.

Keywords: H19; cancer stem cells; exosomes; lncRNA; non-coding RNA; reprogramming factors; tumorigenicity.

Figure 1

The long non-coding RNA H19 promotes symmetric division of cancer stem cells (CSCs). (A) The activation of ERβ by the binding of its ligand (estradiol; E2) enhances H19 expression, thus favoring miR-3126-5p sponging. H19 can in turn promote ERβ to generate an activation loop [55,57]. (B) In breast CSCs, H19 sponges let-7c and allows the de-repression of LIN28. The functional status and symmetric/asymmetric division of CSCs will thus be determined by the balance between H19 and let-7 expressions [55,59]. (C) It has been shown that H19 sequesters p53 to inhibit its activity and enhance gastric cancer cells proliferation [39]. Moreover, inactivation of p53 is associated with symmetric division of SCs [61]. We can thus hypothesize that H19 could inactivate p53 to promote CSCs symmetric division.

Figure 2

The balance between H19 and let-7 expression controls the reprogramming of non-CSCs into CSCs. (A) Under hypoxic conditions HIF-1α expression is enhanced. Combined with the sponging of let-7 by H19, this leads to the enhanced expression of PDK1, which will in turn promote glycogenesis and expression of stemness phenotype [69]. (B) In breast and lung cancers, H19 enhances the expression of the reprogramming factor LIN28 through the sponging of let-7 and miR-196b respectively [67,69]. (C) In breast cancer, the activation of the Wnt signaling pathway increases miR-146a production, which in turn promotes let-7 expression and so, the inhibition of reprogramming factors [55,59].

Figure 3

The long non-coding RNA H19 disseminates into extracellular environment through exosomes, propagating its action in both normal and cancer cells.

Figure 4

The long non-coding RNA H19 promotes cancer stem cells phenotypes. H19 is expressed by cancer stem cells and is exported to the extracellular medium through exosomes [85]. H19 is then captured and internalized by surrounding cells. Within those cells, H19 can act in different ways: H19 can be translocated into the nucleus where it sponges miRNAs such as let-7. This allows the expression of reprogrammation factors and promotes stemness phenotypes [70]. In addition, H19 can regulate the activity of factors such as p53 in order to promote symmetric division of CSCs [39,61]. Downstream, all these mechanisms will lead to the promotion of stem cells phenotype (symmetric division, reprogramming) in order to progress in the tumoral development and to reinforce CSCs’ resistance to therapies. Illustrations of this figure are from Servier Medical Art (https://smart.servier.com/).