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.