Oncofetal H19 RNA promotes tumor metastasis

Abstract

The oncofetal H19 gene transcribes a long non-coding RNA(lncRNA) that is essential for tumor growth. Here we found that numerous established inducers of epithelial to mesenchymal transition(EMT) also induced H19/miR-675 expression. Both TGF-β and hypoxia concomitantly induced H19 and miR-675 with the induction of EMT markers. We identified the PI3K/AKT pathway mediating the inductions of Slug, H19 RNA and miR-675 in response to TGF-β treatment, while Slug induction depended on H19 RNA. In the EMT induced multidrug resistance model, H19 level was also induced. In a mouse breast cancer model, H19 expression was tightly correlated with metastatic potential. In patients, we detected high H19 expression in all common metastatic sites tested, regardless of tumor primary origin. H19 RNA suppressed the expression of E-cadherin protein. H19 up-regulated Slug expression concomitant with the suppression of E-cadherin protein through a mechanism that involved miR-675. Slug also up-regulated H19 expression and activated its promoter. Altogether, these results may support the existence of a positive feedback loop between Slug and H19/miR-675, that regulates E-cadherin expression. H19 RNA enhanced the invasive potential of cancer cells in vitro and enhanced tumor metastasis in vivo. Additionally, H19 knockdown attenuated the scattering and tumorigenic effects of HGF/SF. Our results present novel mechanistic insights into a critical role for H19 RNA in tumor progression and indicate a previously unknown link between H19/miR-675, Slug and E-cadherin in the regulation of cancer cell EMT programs.

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

“…Moreover, 2 noncoding RNAs involved in the regulation of EZH2, H19, and HOTAIR (39-41) turned out to be among the RNAs most significantly upregulated in FS-DFSP. This finding suggests that overexpression of H19 and HOTAIR, together with let-7 downregulation, all concur to induce EZH2 and, in turn, chromatin remodeling and mesenchymal transdifferentiation in FS-DFSP (19,(39)(40)(41). A role for epigenetic reprogramming in fibrosarcomatous transformation was also supported by the finding that 66 genes enriched in FS-DFSP versus DFSP are reported to undergo epigenetic regulation (11), and recent evidence is consistent with the involvement of chromatin remodeling in translocation-associated sarcomas (42).…”

Reprogramming during epithelial to mesenchymal transition under the control of TGFβ

“…H19 and Snail2, together with miR-675, repress E-cadherin expression and promote metastasis in vivo. 130 Upregulation of Malat1 lncRNA by TGFb has been described in bladder cancer. Malat1 associates with Suz12, another component of PRC2, and regulates EMT genes, and knockdown of either Malat1 or Suz12 inhibits tumor metastasis.…”

A potential biomarker for colorectal cancer: long non-coding RNA RP1-13P20.6

“…Because lncRNA RP1-13P20.6 and SPRR3 are dysregulated in CRC, and lncRNA RP1-13P20.6 is decreased, and SPRR3 increased, there may be an inverse relationship between lncRNA RP1-13P20.6 and SPRR3. A possible mechanism whereby lncRNA RP1-13P20.6 may regulate SPRR3 are as follows: lncRNAs act as precursors of miRNAs to degrade mRNAs through assembly of RNAinduced silencing complexes (RISC) [45][46] or impair the stability of mRNAs [47]. However, the exact mechanism by which lncRNA RP1-13P20.6 regulates SPRR3 is still unclear and requires further investigation.…”