Date Published: March 5, 2019
Publisher: Public Library of Science
Author(s): Masahiro Yoshida, Hiroto Horiguchi, Shohei Kikuchi, Satoshi Iyama, Hiroshi Ikeda, Akari Goto, Yutaka Kawano, Kazuyuki Murase, Kohichi Takada, Koji Miyanishi, Junji Kato, Masayoshi Kobune, Andre van Wijnen.
We and others have demonstrated that various abnormalities of the bone marrow (BM) mesenchymal stromal cells (MSCs) such as aberrant cytokine expression, abnormal hedgehog signaling, and impaired miRNA biogenesis are observed in patients with acute myeloid leukemia (AML). However, underlying mechanisms to induce the dysfunction of BM MSCs have not yet been clarified. We previously showed that AML cells release abundant exosomal miR-7977, which, in turn, enters BM mesenchymal stromal cells (MSCs). However, the precise function of miR-7977 is not known. In this study, we performed transduction of a miR-7977 mimic into MSCs, compared transcriptomes between control-transduced (n = 3) and miR-7977-transduced MSCs (n = 3), and conducted pathway analysis. The array data revealed that the expression of 0.05% of genes was reduced 2-fold and the expression of 0.01% of genes was increased 2-fold. Interestingly, approximately half of these genes possessed a miR-7977 target site, while the other genes did not, suggesting that miR-7977 regulates the gene expression level directly and indirectly. Gene set enrichment analysis showed that the gene sets of Yes-associated protein 1 (YAP1) _up were significantly enriched (p<0.001, q<0.25), suggesting that miR-7977 modulates the Hippo-YAP signaling pathway. Visualization of pathway and network showed that miR-7977 significantly reduced the expression of Hippo core kinase, STK4. miR-7977 inactivated the Hippo-YAP signaling pathway as proven by GFP-tagged YAP nuclear trans localization and TEAD reporter assay. The miR-7977-transduced MSC cell line, HTS-5, showed elevated saturation density and enhanced entry into the cell cycle. These results suggest that miR-7977 is a critical factor that regulates the Hippo-YAP signaling pathway in BM-MSCs and may be involved in the upregulation of leukemia-supporting stroma growth.
We and others have revealed that various abnormalities of the bone marrow (BM) environment such as stromal dysfunction , aberrant cytokine expression  and impaired microRNA (miRNA) biogenesis are observed in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Moreover, these abnormalities may be involved in the development of MDS/AML as shown by studies using mesenchymal progenitor-specific knockout mice that demonstrated impaired miRNA biogenesis in BM mesenchymal stromal cells (MSCs) and the development of MDS .
In the present study, we revealed that transfer of miR-7977 reduced the expression of STK4 and inhibited the Hippo-YAP1 signaling pathway in MSCs. Moreover, miR-7977 inactivated contact inhibition and subsequently promoted proliferation of the HTS-5 mesenchymal cell line.
The miR-7977 is an important factor that inhibits normal hematopoiesis via reduction of several factors in BM MSC and could contribute to propagate functionally-disturbed MSCs via inactivation of Hippo-YAP signaling pathway in AML.