MiR-212-3p functions as a tumor suppressor gene in group 3 medulloblastoma via targeting nuclear factor I/B (NFIB)

Abstract

Haploinsufficiency of chromosome 17p and c-Myc amplification distinguish group 3 medulloblastomas which are associated with early metastasis, rapid recurrence, and swift mortality. Tumor suppressor genes on this locus have not been adequately characterized. We elucidated the role of miR-212-3p in the pathophysiology of group 3 tumors. First, we learned that miR-212-3p undergoes epigenetic silencing by histone modifications in group 3 tumors. Restoring its expression reduced cancer cell proliferation, migration, colony formation, and wound healing in vitro and attenuated tumor burden and improved survival in vivo. MiR-212-3p also triggered c-Myc destabilization and degradation, leading to elevated apoptosis. We then isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors and associated with poor survival. NFIB silencing reduced cancer cell proliferation, migration, and invasion. Concurrently, reduced medullosphere formation and stem cell markers (Nanog, Oct4, Sox2, CD133) were noted. These results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and identify a novel oncogenic target implicated in metastasis and tumor recurrence.

Integration of miRNA:mRNA Co-Expression Revealed Crucial Mechanisms Modulated in Immunogenic Cancer Cell Death

“…These studies postulated that detection of these miRNAs may have diagnostic or prognostic value in several neoplastic diseases. In support of this notion, their expression has been linked to several hallmarks of cancer development and progression: tumorigenicity, proliferation, migration, invasion, angiogenesis, and therapy-promoted cell death [ 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. In contrast, no information is available regarding their involvement in ICD.…”

Noncoding RNA therapeutics for substance use disorder

“…In preclinical studies, researchers have demonstrated the effectiveness of antimiRs in animal models of alcohol ( 19 , 164 – 166 ), cocaine ( 25 , 124 ), and opioid ( 167 ) use disorders via intrathecal or direct brain injections. In other disease models, SUD-relevant miRs (miR-34, miR-145, miR-212) have been targeted with miR mimics ( 168 – 170 ). Although miR-based therapeutics have yet to be tested clinically in SUD patients, several miR mimic and antimiR formulations are being tested in animals or clinical trials for other diseases ( 171 – 175 ).…”

Subgroup-Specific Diagnostic, Prognostic, and Predictive Markers Influencing Pediatric Medulloblastoma Treatment

“…Aside from being downregulated in medulloblastoma, forced expression of miR-22 in MB cell lines resulted in reduced tumorigenesis by downregulating 3′-phosphoadenosine 5′-phosphosulfate transporters 1 (PAPST1) [ 159 , 173 ]. Similarly, we have uncovered transcriptional silencing of miR-212 via histone modification in group 3 MB [ 174 ]. Specifically, in HDMB03 and D425 cells with baseline-reduced miR-212-3p expression, we showed enriched methylated H3K27 and high EZH2 activity, which, as discussed prior, are epigenetic markers consistent with a stem/progenitor cell-like identity [ 127 ].…”

“…Induction of miR-212 within orthotopic tumors led to a significant augmentation of longevity in animal models concurrent with smaller tumor sizes. We also identified an important oncogenic target of miR-212, Nuclear Factor I/B, a target of c-Myc whose amplification in group 3 tumors is a cardinal high-risk feature [ 174 ]. Finally, on the terminal end of this locus lies miR-1253.…”