Primary mediastinal large B-cell lymphoma: transcriptional regulation by miR-92a through FOXP1 targeting

Abstract

BackgroundPrimary mediastinal large B-cell lymphoma (PMBL) shares pathological features with diffuse large B-cell lymphoma (DLBCL), and molecular features with classical Hodgkin lymphoma (cHL). The miR-17∼92 oncogenic cluster, located at chromosome 13q31, is a region that is amplified in DLBCL.MethodsHere we compared the expression of each member of the miR-17∼92 oncogenic cluster in samples from 40 PMBL patients versus 20 DLBCL and 20 cHL patients, and studied the target genes linked to deregulated miRNA in PMBL.ResultsWe found a higher level of miR-92a in PMBL than in DLBCL, but not in cHL. A combination of in silico prediction and transcriptomic analyses enabled us to identify FOXP1 as a main miR-92a target gene in PMBL, a result so far not established. This was confirmed by 3UTR, and RNA and protein expressions in transduced cell lines. In vivo studies using the transduced cell lines in mice enabled us to demonstrate a tumor suppressor effect of miR-92a and an oncogenic effect of FOXP1.A higher expression of miR-92a and the down-regulation of FOXP1 mRNA and protein expression were also found in human samples of PMBL, while miR-92a expression was low and FOXP1 was high in DLBCL.ConclusionsWe concluded to a post-transcriptional regulation by miR-92a through FOXP1 targeting in PMBL, with a clinico-pathological relevance for better characterisation of PMBL.

Inhibition of microRNA‐92a increases blood vessels and satellite cells in skeletal muscle but does not improve duchenne muscular dystrophy–related phenotype in mdx mice

“…Because mdx mice undergo muscle ischemia after muscle contraction, functional improvement of vasculature, including increased blood flow in ischemic conditions, is crucial, in which Antagomir‐92a treatment can be combined with phosphodiesterase‐5 (PDE5) inhibitor therapy . Other studies also demonstrated the oncogenic effects of miR‐92a, including promotion of cancer growth and inhibition of apoptosis via suppression of p21, KLF2, KLF4, p63, DKK3, PTEN, FOXP1, RBM4, and BCL2L11 genes . In particular, DKK3 has been identified as a diagnostic marker and as a therapeutic target for age‐related muscle atrophy, suggesting that upregulation of DKK3 via Antagomir‐92a administration may induce worsened dystrophic phenotype in mdx mice.…”

“…8 Other studies also demonstrated the oncogenic effects of miR-92a, including promotion of cancer growth and inhibition of apoptosis via suppression of p21, KLF2, KLF4, p63, DKK3, PTEN, FOXP1, RBM4, and BCL2L11 genes. 33,34,[39][40][41][42][43][44] In particular, DKK3 has been identified as a diagnostic marker and as a therapeutic target for age-related muscle atrophy, 25 suggesting that upregulation of DKK3 via Antagomir-92a administration may induce worsened dystrophic phenotype in mdx mice.…”

Exosomes: Insights from Retinoblastoma and Other Eye Cancers

“…In the miRNAs that are downregulated in RB, miR-let-7a, a tumor suppressor, inhibits cellular proliferation and suppresses tumor growth by inhibiting E2F2 in osteosarcoma cells [ 127 ]. miR-92a, a tumor suppressor, regulates primary mediastinal large B-cell lymphoma (PMBL) by targeting FOXP1, known to deliver an oncogenic effect [ 128 ]. miR-216a plays a role in the inhibition of gastric cancer metastasis via targeting JAK2/STAT3-mediated EMT, thereby suggesting its role in tumor suppression and, ultimately, gastric cancer development [ 129 ].…”

MiRNA Dysregulation in Childhood Hematological Cancer

“…Later, Iqbal et al [ 104 ] described an miRNA signature that allowed the distinction between PMLBCL from other DLBCL, including upregulation of miR-193b and miR-365, and underexpression of miR-629, miR-423-5p, and miR-15a. Higher levels of miR-92a were also described as a classifier of PMBLBCL [ 169 ]. Moreover, a recent study by Malpeli et al [ 170 ] showed that the polycistron miR-17–92 cluster, miR-29 family, miR-150, and miR-497 had the highest power of discrimination between B-cell NHL types, though only eight PMLBCL samples were included.…”