ABSTRACT
5S rRNA plays an important part in ribosome biology and is over-expression in multiple cancers. In this study, we found that 5S rRNA is a direct target of miR-150 and miR-383 in esophageal squamous cell carcinoma (ESCC). Overexpression of miR-150 and miR-383 inhibited ESCC cell proliferation in vitro and in vivo. Moreover, 5S rRNA silencing by miR-150 and miR-383 might intensify rpL11-c-Myc interaction, which attenuated role of c-Myc as an oncogenic transcriptional factor and dysregulation of multiple c-Myc target genes. Taken together, our results highlight the involvement of miRNAs in ribosomal regulation during tumorigenesis.
Subject(s)
Carcinoma, Squamous Cell/metabolism , Esophageal Neoplasms/metabolism , MicroRNAs/metabolism , Proto-Oncogene Proteins c-myc/agonists , RNA Interference , RNA, Ribosomal, 5S/antagonists & inhibitors , Ribosomal Proteins/agonists , Animals , Carcinogenesis , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cell Proliferation , Down-Regulation , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma , Female , Gene Expression Regulation, Neoplastic , Humans , Mice, Nude , Neoplasm Proteins/agonists , Neoplasm Proteins/metabolism , Neoplasm Transplantation , Proto-Oncogene Proteins c-myc/metabolism , RNA/metabolism , RNA, Neoplasm/antagonists & inhibitors , RNA, Neoplasm/metabolism , RNA, Ribosomal, 5S/metabolism , Ribosomal Proteins/metabolism , Tumor BurdenABSTRACT
In Xenopus laevis chromatin histone H1 selectively inhibits the transcription of oocyte 5 S RNA genes while not affecting the transcription of somatic 5 S RNA genes (Schlissel, M. S., and Brown, D. D. (1984) Cell 37, 903-913; Wolffe, A. P. (1989) EMBO J. 8, 527-537). To explore possible mechanisms of this specific action of H1 we analyzed the in vitro transcription of H1.DNA complexes. We found that the selective inhibitory effect of H1 in this system depends entirely on the flanking sequences of 5 S RNA genes and not on the coding sequence itself. At an H1:DNA ratio above approximately 0.4, H1 strongly inhibited the transcription of the gene surrounded by the A + T-rich flanks characteristic of oocyte 5 S RNA genes, whereas it did not prevent transcription of the genes surrounded by G + C-rich somatic-type flanks. This was reflected by strongly preferential binding of H1 to isolated 5 S RNA genes contained within A + T-rich flanks. We also showed that superphosphorylation of H1 with growth-associated (mitotic) H1 kinase invariably decreased H1's ability to inhibit transcription in an in vitro system.
