The H19 Long non-coding RNA in cancer initiation, progression and metastasis - a proposed unifying theory

Abstract

The imprinted oncofetal long non-coding RNA (lncRNA) H19 is expressed in the embryo, down-regulated at birth and then reappears in tumors. Its role in tumor initiation and progression has long been a subject of controversy, although accumulating data suggest that H19 is one of the major genes in cancer. It is actively involved in all stages of tumorigenesis and is expressed in almost every human cancer. In this review we delineate the various functions of H19 during the different stages in the complex process of tumor progression. H19 up-regulation allows cells to enter a "selfish" survival mode in response to stress conditions, such as destabilization of the genome and hypoxia, by accelerating their proliferation rate and increasing overall cellular resistance to stress. This response is tightly correlated with nullification, dysfunction or significant down-regulation of the master tumor suppressor gene P53. The growing evidence of H19's involvement in both proliferation and differentiation processes, together with its involvement in epithelial to mesenchymal transition (EMT) and also mesenchymal to epithelial transition (MET), has led us to conclude that some of the recent disputes and discrepancies arising from current research findings can be resolved from a viewpoint supporting the oncogenic properties of H19. According to a holistic approach, the versatile, seemingly contradictory functions of H19 are essential to, and differentially harnessed by, the tumor cell depending on its context within the process of tumor progression.

Fig. 1

H19 in genomic instability. Cells maintain their normal ploidy state depending on normal expression of P53, possibly in a Parp-1 dependent manner. Reduction of P53 level (when Parp-1 is impaired?), leads either to polyploidy (attenuated track that prevents cancer progression) or to H19 upregulation (fast track to cancer, lower panel). PTEN > PI3K/Akt may be the basis of both routes. Since polyploidy (upper panel) is a common gateway to chromosomal loss/aneuploidy, which is usually accompanied with deleterious, tumorigenic mutations, it may eventually re-elicit H19 expression with its oncogenic properties

Fig. 2

H19 in proliferation and in response to hypoxic stress. Hypoxia induces H19 expression under hypoxic stress in p53 mutated cells, in which HIF1α, which is essential to H19 upregulation, as well as H19 itself, are not repressed by P53. Since hypoxia is a mutagenic condition per se, it can also induce p53 mutations and cause the H19 response. H19 promotes cell cycle progression through Rb suppression by its miR-675 or by p57^kip2 (CDKN1C) suppression or c-Myc activation

Fig. 3

H19 in metastasis. H19 plays a role in both epithelial to mesenchymal transition in the primary tumor and colonization and re-differentiation/accommodation to niche in the secondary site. As delineated above, various contradictory pathways are controlled by H19 in the two scenarios. H19 is consolidated into the process active at that time, which is a function of the micro-environmental factors, and may find other partners in each of the scenarios (miR-200 and let-7 in EMT and putative alternative partners such as histone acetylases in MET)

Fig. 4

Outlines for H19 functions during tumor progression. Various stress conditions drive genomic instability in its wide meaning of mutation and chromosomal abnormalities. In some cases, such as severe reduction in P53 levels, H19 upregulation in sub-clones of stressed cells is a direct cancerous reaction to stress that drives proliferation and accelerates mutational rate. H19 acts to enable a selfish cellular survival plan and reacts to stress conditions by accelerating proliferation rate. H19 subsequently promotes the metastatic cascade from EMT in the primary tumor to metastasizing in secondary sites, depending on extracellular and intercellular context