miR-7977 inhibits the Hippo-YAP signaling pathway in bone marrow mesenchymal stromal cells

Abstract

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.

Differentially Expressed MicroRNAs in Radioresistant and Radiosensitive Atypical Meningioma: A Clinical Study in Chinese Patients

“…Horiguchi H. et al found that miR-7977 was upregulated in acute myeloid leukemia and myelodysplastic syndrome and could reduce the expression of poly(rC) binding protein 1 to interfere with normal hematopoiesis. Moreover, miR-7977 was also reported to regulate the Hippo-YAP pathway, therefore inducing the upregulation of leukemia-supporting stroma growth (24,25). MiR-4286 is another miRNA that was found to be upregulated in the radioresistant group in our study.…”

Bone Marrow Mesenchymal Stem Cells-Derived Exosomal miR-425-5p Inhibits Acute Myeloid Leukemia Cell Proliferation, Apoptosis, Invasion and Migration by Targeting WTAP

“… 46 MiR-7977 represses the Hippo-YAP signaling in BM-MSCs during AML progression. 47 In this study, we found that the expression levels of miR-425-5p were decreased in CD34+CD38− AML cells from primary AML patients compared to that from the bone marrow of healthy cases. The expression levels of miR-425-5p were reduced in the exosomes from primary AML patients compared to those from normal cases.…”

BH3 profiling discriminates the anti‑apoptotic status of 5‑fluorouracil‑resistant colon cancer cells

“…Western blotting was performed as previously described (8). Briefly, separated proteins were transferred to polyvinylidene difluoride membranes and blotted with specific antibodies to detect BCL2 (at dilution of 1:500; Thermo Fisher Scientific, Inc.; #13-8800), BCLW (1:1,000; Cell Signaling Technology; cat.…”