1. Oncofetal H19 RNA promotes tumor metastasis.
- Author
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Matouk IJ, Raveh E, Abu-lail R, Mezan S, Gilon M, Gershtain E, Birman T, Gallula J, Schneider T, Barkali M, Richler C, Fellig Y, Sorin V, Hubert A, Hochberg A, and Czerniak A
- Subjects
- Animals, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cadherins genetics, Cadherins metabolism, Cell Hypoxia, Cell Line, Tumor, Drug Resistance, Multiple, Drug Resistance, Neoplasm genetics, Feedback, Physiological, Female, Humans, Mammary Glands, Animal metabolism, Mammary Glands, Animal pathology, Mammary Neoplasms, Experimental genetics, Mammary Neoplasms, Experimental metabolism, Mammary Neoplasms, Experimental pathology, Mice, MicroRNAs metabolism, Neoplasm Metastasis, Oxygen metabolism, Oxygen pharmacology, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, RNA, Long Noncoding metabolism, Signal Transduction, Snail Family Transcription Factors, Transcription Factors metabolism, Transforming Growth Factor beta pharmacology, Breast Neoplasms genetics, Epithelial-Mesenchymal Transition genetics, Gene Expression Regulation, Neoplastic, MicroRNAs genetics, RNA, Long Noncoding genetics, Transcription Factors genetics
- 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., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2014
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