miRNA-21 is developmentally regulated in mouse brain and is co-expressed with SOX2 in glioma

Abstract

BackgroundMicroRNAs (miRNAs) and their role during tumor development have been studied in great detail during the last decade, albeit their expression pattern and regulation during normal development are however not so well established. Previous studies have shown that miRNAs are differentially expressed in solid human tumors. Platelet-derived growth factor (PDGF) signaling is known to be involved in normal development of the brain as well as in malignant primary brain tumors, gliomas, but the complete mechanism is still lacking. We decided to investigate the expression of the oncogenic miR-21 during normal mouse development and glioma, focusing on PDGF signaling as a potential regulator of miR-21.MethodsWe generated mouse glioma using the RCAS/tv-a system for driving PDGF-BB expression in a cell-specific manner. Expression of miR-21 in mouse cell cultures and mouse brain were assessed using Northern blot analysis and in situ hybridization. Immunohistochemistry and Western blot analysis were used to investigate SOX2 expression. LNA-modified siRNA was used for irreversible depletion of miR-21. For inhibition of PDGF signaling Gleevec (imatinib mesylate), Rapamycin and U0126, as well as siRNA were used. Statistical significance was calculated using double-sided unpaired Student´s t-test.ResultsWe identified miR-21 to be highly expressed during embryonic and newborn brain development followed by a gradual decrease until undetectable at postnatal day 7 (P7), this pattern correlated with SOX2 expression. Furthermore, miR-21 and SOX2 showed up-regulation and overlapping expression pattern in RCAS/tv-a generated mouse brain tumor specimens. Upon irreversible depletion of miR-21 the expression of SOX2 was strongly diminished in both mouse primary glioma cultures and human glioma cell lines. Interestingly, in normal fibroblasts the expression of miR-21 was induced by PDGF-BB, and inhibition of PDGF signaling in mouse glioma primary cultures resulted in suppression of miR-21 suggesting that miR-21 is indeed regulated by PDGF signaling.ConclusionsOur data show that miR-21 and SOX2 are tightly regulated already during embryogenesis and define a distinct population with putative tumor cell of origin characteristics. Furthermore, we believe that miR-21 is a mediator of PDGF-driven brain tumors, which suggests miR-21 as a promising target for treatment of glioma.

Associations between SOX2 and miR-200b expression with the clinicopathological characteristics and prognosis of patients with glioma

“…Following the irreversible depletion of miR-21, the expression of SOX2 was markedly reduced in mouse primary glioma cultures and human glioma cell lines. Therefore, miR-21 and SOX2 were concluded to be strongly regulated during embryogenesis, and define a distinct population of putative tumor cells (49). The results of the present study revealed higher miR-200b expression levels in the glioma tissues, as compared with the normal brain tissues.…”

“…In addition, SOX2 has been identified as a marker for undifferentiated and proliferating cells, with its expression upregulated in the most markedly anaplastic areas of glioblastomas and oligodendrogliomas (28). In mouse models (49), high expression of miR-21 has been observed during embryonic and newborn brain development, followed by a gradual reduction until undetectable at postnatal day 7, which correlates with SOX2 expression. miR-21 and SOX2 exhibited upregulation and an overlapping expression pattern in RCAS/tv-a generated mouse brain glioma specimens.…”

microRNA-21-induced dissociation of PDCD4 from rictor contributes to Akt-IKKβ-mTORC1 axis to regulate renal cancer cell invasion

“…miR-21 regulates self-renewal of mouse spermatogonial stem cells [83]. A recent study identified increased miR-21 expression to regulate stem cells during embryonic brain development [84]. This expression of miR-21 correlates with Sox2 expression.…”

Heregulin-1β Promotes the Synergistic Effect Between Allogenic Skin-Derived Precursor Differentiated Schwann Cells (SKP-SC) and Acellular Nerve Allograft (ANA) in Peripheral Nerve Regeneration Through Inhibiting Mir-21

“…Many previous studies demonstrated the direct interaction between miR-21 and SOX2. The induction of miR-21 strongly inhibited SOX2 expression andthe opposite effect was observed upon miR-21 inhibition strikingly (Polajeva et al, 2012;Singh et al, 2015;Trohatou et al, 2014;Yang and Rana, 2013). Previous studies in our lab found that heregulin-1β with SKP-SCs/ANA transplantation represented a powerful therapeutic approach, and facilitates the efficacy of acellular nerve allograft in peripheral nerve injury.…”

“…Silencing SOX2 expression in neural crest stem cells may reverse the inhibition of differentiation from neural crest stem cells to Schwann cells conducted by antagomir-21, which suggests that highly expressed miR-21 may promote this differentiation through inhibiting SOX2 protein expression (Ni et al, 2014). Other research shows that miR-21 might have specifically function by inhibiting the primarily level of SOX2 in human mesenchymal stem cells (MSCs) and might also act as a key molecule determining MSCs proliferation and differentiation (Trohatou et al, 2014;Yang and Rana, 2013).Also for other diseases such as glioma, miR-21 and SOX2 are revealed tightly regulated already during embryogenesis and define a distinct population with putative tumor cell of origin characteristics (Polajeva et al, 2012).…”