miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple Myeloma

Abstract

miR-125b, ubiquitously expressed and frequently dysregulated in several tumors, has gained special interest in the field of cancer research, displaying either oncogenic or oncosuppressor potential based on tumor type. We have previously demonstrated its tumor-suppressive role in multiple myeloma (MM), but the analysis of molecular mechanisms needs additional investigation. The purpose of this study was to explore the effects of miR-125b and its chemically modified analogs in modulating cell viability and cancer-associated molecular pathways, also focusing on the functional aspects of stress adaptation (autophagy and senescence), as well as programmed cell death (apoptosis). Based on the well-known low microRNA (miRNA) stability in therapeutic application, we designed chemically modified miR-125b mimics, laying the bases for their subsequent investigation in in vivo models. Our study clearly confirmed an oncosuppressive function depending on the repression of multiple targets, and it allowed the identification, for the first time, of miR-125b-dependent miR-34a stimulation as a possible consequence of the inhibitory role on the interleukin-6 receptor (IL-6R)/signal transducer and activator of transcription 3 (STAT3)/miR-34a feedback loop. Moreover, we identified a pattern of miR-125b-co-regulated miRNAs, shedding light on possible new players of anti-MM activity. Finally, functional studies also revealed a sequential activation of senescence, autophagy, and apoptosis, thus indicating, for the first two processes, an early cytoprotective and inhibitory role from apoptosis activation.

LINC02418 promotes colon cancer progression by suppressing apoptosis via interaction with miR-34b-5p/BCL2 axis

“…Bioinformatic analysis revealed that LINC02418 and 3′UTR region of BCL2 contained complementary sequence of miR-34b-5p, implying miR-34b-5p could bind to LINC02418 and BCL2 gene. MiR-34b-5p belongs to the miR-34 family which has been reported to be tumor suppressor and therapeutic candidate in cancer [ 33 – 36 ]. Dual-luciferase activity assays confirmed the interaction between miR-34b-5p and LINC02418 (Fig.…”

Breast Cancer Chemotherapeutic Options: A General Overview on the Preclinical Validation of a Multi-Target Ruthenium(III) Complex Lodged in Nucleolipid Nanosystems

“…Independently form cancer molecular subtypes, BCC that evade therapy-dependent growth inhibition can hypothetically give rise to drug resistant clones, wherein autophagy can be one of the main driver factors in this process. In the case of ER-positive BCs, about the 40% of patients show resistance to targeted anti-estrogen treatments, and this can be frequently correlated with protective autophagy [68]. Remarkably, a significant correlation between ERα and Beclin 1 has been established by recent studies, where the autophagic protein can deactivate the estrogen receptor, making thereby MCF-7 cells less responsive to growth stimulation by estradiol.…”

Role of microRNAs in Diagnosis, Prognosis and Management of Multiple Myeloma

“…Interestingly, miR-125b was found to up-regulate miR-34a, which in turn inhibits the IL-6 receptor/STAT3/miR-34a feedback loop. As a result, these pathways activate cell death machinery in MM [ 140 ]. The up-regulation of miR-33b resulted in significant apoptosis of malignant plasma cells, thus suppressing cancer growth and enhancing survival rates [ 141 ].…”