Abstract
The long non-coding RNA H19 (lncH19) is broadly transcribed in the first stage of development and silenced in most cells of an adult organism; it appears again in several tumors where, through different molecular mediators, promotes cell proliferation, motility and metastases. LncH19 has been associated with hypoxia-inducible factor 1-alpha (HIF-1α) activation and, in some tumors, it has proved to be necessary and required to sustain hypoxic responses. Here we propose to investigate a putative role for the lncH19 in hypoxia induced multiple myeloma (MM) progression. Transcriptional analysis of MM cell lines (RPMI and MM1.S) exposed to normoxia or hypoxia (1% O2) was done in order to evaluate lncH19 levels under hypoxic stimulation. Then, to investigate the role of lncH19 in hypoxia mediated MM progression, transcriptional, protein and functional assays have been performed on hypoxia stimulated MM cell lines, silenced or not for lncH19. Our data demonstrated that hypoxic stimulation in MM cell lines induced the overexpression of lncH19, which, in turn, is required for the expression of the hypoxia induced genes involved in MM dissemination, such as C-X-C Motif Chemokine Receptor 4 (CXCR4) and Snail. Moreover, adhesion assays demonstrated that lncH19 silencing abrogates the increased adhesion on stromal cells induced by the hypoxic condition. Finally, Western blot analysis indicated that lncH19 silencing impaired HIF1α nuclear translocation. The LncH19, required for the induction of hypoxic responses in MM cells, could represent a new therapeutic target for MM.
Highlights
Increasing evidence has demonstrated the involvement of several long non-coding RNAs in the onset and progression of different neoplasms, including multiple myeloma (MM) [1,2] so that, most of them, including long non-coding RNA H19 (lncH19), are recognized as oncogenes [3]
In order to evaluate the effects of hypoxia on MM cells, we made use of three different cellular models: MM1.S, RPMI and H929 cells
We evaluated the effects of hypoxia on lncH19 expression
Summary
Increasing evidence has demonstrated the involvement of several long non-coding RNAs (lncRNAs) in the onset and progression of different neoplasms, including multiple myeloma (MM) [1,2] so that, most of them, including lncH19, are recognized as oncogenes [3]. Concerning the mechanism driving lncH19 expression, among the proposed transcription factors, recent evidence formally demonstrated that the hypoxia master regulator HIF-1α directly binds the lncH19-promoter, inducing its transcription [14]. The molecular mechanisms by which hypoxia controls tumor progression has been largely dissected, while less information is available about this aspect in hematological disease, the contribution of HIFs is consolidated in this context [16,17]. We investigated the correlation between the lncH19 aberrant expression and hypoxic condition in MM cell lines
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