miR-30-5p Functions as a Tumor Suppressor and Novel Therapeutic Tool by Targeting the Oncogenic Wnt/β-Catenin/BCL9 Pathway

Abstract

Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, including the deadly plasma cell cancer multiple myeloma (MM). In this study, we report that downregulation of the tumor suppressor microRNA miR-30-5p is a frequent pathogenetic event in MM. Evidence was developed that miR-30-5p downregulation occurs as a result of interaction between MM cells and bone marrow stromal cells, which in turn enhances expression of BCL9, a transcriptional co-activator of the Wnt signaling pathway known to promote MM cell proliferation, survival, migration, drug resistance and formation of MM cancer stem cells. The potential for clinical translation of strategies to re-express miR-30-5p as a therapeutic approach was further encouraged by the capacity of miR-30c and miR-30mix to reduce tumor burden and metastatic potential in vivo, in three murine xenograft models of human MM, without adversely affecting associated bone disease. Together, our findings offer a preclinical rationale to explore miR-30-5p delivery as an effective therapeutic strategy to eradicate MM cells in vivo.

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

“…In the last few years, a wealth of studies has shown deep dysregulation of miRNAs in human cancers, including multiple myeloma (3). Importantly, replacement of downregulated tumor suppressor (TS) miRNAs (4,5) or inhibition of oncogenic miRNAs (6)(7)(8) have demonstrated therapeutic value in multiple myeloma preclinical settings. A subclass of TSmiRNAs, named epi-miRNAs, is emerging as novel epigenetic regulators, which target and downregulate the expression of DNA methyltransferases (DNMT), histone deacetylases (HDAC), or components of the polycomb repressor complexes, thus representing relevant tools to revert epigenetic aberrations.…”

PCDH10 inhibits cell proliferation of multiple myeloma via the negative regulation of the Wnt/β-catenin/BCL-9 signaling pathway

“…BCL-9 is broadly associated with MM cell proliferation, survival, migration and drug resistance. More importantly, BCL-9 regulates Wnt target genes that control transition and stem cell-like behavior with a negligible effect on the homeostatic role of Wnt signaling in mammalian (24,27). These results suggest that the strategies employed on the restoration of PCDH10 can be a potential therapy to refractory and recurrent patients without a particular effect on normal tissues.…”

“…The absorbance (A) at 450 nm was measured using a spectrophotometer (Bio-Rad, Richmond, CA, uSA). For Wnt treatment, the cells were pretreated with Licl for 48 h to activate Wnt/β-catenin signaling (27). Experiments were performed at least three times with representative data presented.…”

“…Nuclear localization of the β-catenin is translocated from the cytoplasm into the nucleus to stimulate Wnt/β-catenin signaling and then to accelerate tumor cell proliferation (27,30). Since we have confirmed that PCDH10 suppresses MM cell growth by targeting Wnt signaling, we investigated whether the functional PCDH10 disturbed the nuclear translocation of β-catenin and its coactivator BCL-9.…”

MicroRNAs: A Puzzling Tool in Cancer Diagnostics and Therapy

“…The manipulation of miRNAs has been showed to undermine cancer progression. The reactivation of tumor suppressor miRNAs, such as miR-29b or miRNA-30-5p, in myeloma cells, has therapeutic effects (40,41). On the other hand, miR-21 has been demonstrated to have an oncogenic feature (42).…”