Downregulation of 14q32 microRNAs in Primary Human Desmoplastic Medulloblastoma

Abstract

Medulloblastoma (MB) is one of the most common pediatric cancers, likely originating from abnormal development of cerebellar progenitor neurons. MicroRNA (miRNA) has been shown to play an important role in the development of the central nervous system. Microarray analysis was used to investigate miRNA expression in desmoplastic MB from patients diagnosed at a young age (1 or 2 years old). Normal fetal or newborn cerebellum was used as control. A total of 84 differentially expressed miRNAs (64 downregulated and 20 upregulated) were found. Most downregulated miRNAs (32/64) were found to belong to the cluster of miRNAs at the 14q32 locus, suggesting that this miRNA locus is regulated as a module in MB. Possible mechanisms of 14q32 miRNAs downregulation were investigated by the analysis of publicly available gene expression data sets. First, expression of estrogen-related receptor-γ (ESRRG), a reported positive transcriptional regulator of some 14q32 miRNAs, was found downregulated in desmoplastic MB. Second, expression of the parentally imprinted gene MEG3 was lower in MB in comparison to normal cerebellum, suggesting a possible epigenetic silencing of the 14q32 locus. miR-129-5p (11p11.2/7q32.1), miR-206 (6p12.2), and miR-323-3p (14q32.2), were chosen for functional studies in DAOY cells. Overexpression of miR-129-5p using mimics decreased DAOY proliferation. No effect was found with miR-206 or miR-323 mimics.

MiR-206, a Cerebellum Enriched miRNA Is Downregulated in All Medulloblastoma Subgroups and Its Overexpression Is Necessary for Growth Inhibition of Medulloblastoma Cells

“…MiR-206 expression was found to be downregulated in medulloblastoma tissues belonging to all the four molecular subgroups, as compared to the normal cerebellar tissues. Murine miR-206 expression was also found to be downregulated in SHH subgroup medulloblastomas from Ptch1 (+/−) knockout and Smo +/+ transgenic mouse models that is consistent with reported downregulation of miR-206 expression in desmoplastic medulloblastomas belonging to the SHH subgroup (Lucon et al 2013). MiR-206 expression was also found to be downregulated in all the established medulloblastoma cell lines studied.…”

Genome‐wide small noncoding RNA profiling of pediatric high‐grade gliomas reveals deregulation of several miRNAs, identifies downregulation of snoRNA cluster HBII‐52 and delineates H3F3A and TP53 mutant‐specific miRNAs and snoRNAs

“…Furthermore, the unsupervised hierarchical clustering showed two subsets among the tumors, which were based on the relative underexpression of various 14q32 miRNAs (miR‐431, miR‐433, miR‐380, miR‐323a, miR‐329, miR‐543, miR‐1185, miR‐487b, miR‐539, miR‐487a, miR‐485, miR‐668, miR‐154 and miR‐410) in Group 2 as compared to Group 1. The downregulation of 14q32 miRNAs has also been reported in adult GBMs, medulloblastomas and various other cancers such as renal clear cell cancer, breast cancer and ovarian cancer . Earlier studies showed frequent loss of heterozygosity of 14q region, suggesting that allelic deletion on chromosome 14q plays an important role in the pathogenesis of GBM .…”

“…The downregulation of 14q32 miRNAs has also been reported in adult GBMs, medulloblastomas and various other cancers such as renal clear cell cancer, breast cancer and ovarian cancer. 38,39 Earlier studies showed frequent loss of heterozygosity of 14q region, suggesting that allelic deletion on chromosome 14q plays an important role in the pathogenesis of GBM. 40 Interestingly, some members of 14q32 cluster especially miR-487b and miR-410 have been shown to discriminate highversus low-risk group in neuroblastoma also.…”

There and back again: The journey of the estrogen-related receptors in the cancer realm

“…In contrast, expression of ERRg correlates with more favorable clinical outcomes. ERRg expression is linked to progression-free survival in both ovarian and breast cancer [18,23], and is downregulated in prostate cancer cell lines and in medulloblastoma [25,26], indicating that it may play a tumor-suppressing function in these cancers. Similarly, expression of ERRb is decreased in prostate cancer [27].…”