Microrna-324-5p Regulates Stemness, Pathogenesis And Sensitivity To Bortezomib In Multiple Myeloma Cells By Targeting Hedgehog Signaling

Chromosome 17p deletions are present in 10% of patients with newly diagnosed multiple myeloma (MM), and are associated with inferior prognosis. miR-324-5p is located on chromosome 17p, and shows diverse functions in different types of cancers. However, its role in MM is largely unknown. Here we found the expression of miR-324-5p was decreased in MM, especially in del(17p) MM. In contrast, the expression of hedgehog (Hh) signaling components was elevated, indicating a correlation between miR-324-5p and Hh signaling in MM. Hh signaling is important for the pathogenesis of MM and maintenance of MM stem cell compartment. Indeed, overexpression of miR-324-5p significantly decreased Hh signaling components Smo and Gli1, and functionally reduced cell growth, survival as well as stem cell compartment in MM. Moreover, miR-324-5p potentiated the anti-MM efficacy of bortezomib through regulating the activities of multidrug-resistance proteins and the expression of Bcl-2 family genes. Consistent results were obtained in vivo. Finally, miR-324-5p overcame the protective effect of bone marrow stromal cells on MM cells. Taken together, our data demonstrate that miR-324-5p is essential for MM pathogenesis and downregulation of miR-324-5p is a novel mechanism of Hh signaling activation in MM. Therefore, targeting miR-324-5p provides a potential therapeutic strategy for MM.What's new? Although deletions of chromosome 17p13 include the tumor suppressor p53 locus, other tumor suppressor genes in this region may affect cancers associated with the deletion, including multiple myeloma. Here the authors show that a microRNA, miR-324-5p, located in 17p13, is commonly downregulated in multiple myeloma, especially those with del(17p). Overexpression of miR-324-5p inhibited proliferation of multiple myeloma cells and rendered them more sensitive to chemotherapy otherwise poorly effective in del(17p) malignancies, underscoring the relevance of miR-324-5p downregulation in multiple myeloma pathogenesis.