Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo

Department of Pediatrics, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03755, USA.
Neuro-Oncology (Impact Factor: 5.56). 06/2011; 13(6):580-90. DOI: 10.1093/neuonc/nor033
Source: PubMed


MicroRNAs (miRNAs) are small, noncoding RNAs that play a critical role in developmental and physiological processes and are implicated in the pathogenesis of several human diseases, including cancer. They function by regulating target gene expression post-transcriptionally. In this study, we examined the role of oncogenic mir-21 in the pathogenesis of glioblastoma, the most aggressive form of primary brain tumor. We have previously reported that mir-21 is expressed at higher levels in primary glioblastoma-tissue and glioblastoma-derived cell lines than in normal brain tissue. We demonstrate that downregulation of mir-21 in glioblastoma-derived cell lines results in increased expression of its target, programmed cell death 4 (Pdcd4), a known tumor-suppressor gene. In addition, our data indicate that either downregulation of mir-21 or overexpression of its target, Pdcd4, in glioblastoma-derived cell lines leads to decreased proliferation, increased apoptosis, and decreased colony formation in soft agar. Using a glioblastoma xenograft model in immune-deficient nude mice, we observe that glioblastoma-derived cell lines in which mir-21 levels are downregulated or Pdcd4 is over-expressed exhibit decreased tumor formation and growth. Significantly, tumors grow when the glioblastoma-derived cell lines are transfected with anti-mir-21 and siRNA to Pdcd4, confirming that the tumor growth is specifically regulated by Pdcd4. These critical in vivo findings demonstrate an important functional linkage between mir-21 and Pdcd4 and further elucidate the molecular mechanisms by which the known high level of mir-21 expression in glioblastoma can attribute to tumorigenesis--namely, inhibition of Pdcd4 and its tumor-suppressive functions.

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    • "GBM-derived cell lines treated with anti-miR-21 had reduced proliferation and also exhibited enhanced apoptosis, compared with untreated controls. In addition, cell lines in which miR-21 levels were inhibited displayed decreased anchorage-independent growth, whereas GBM-derived cell lines expressing PDCD4 showed increased apoptosis and diminished anchorage-independent growth [43]. miR-21 seems to regulate drug resistance in various cancers, and therefore the use of miR- 21 inhibitors may function as an effective approach for reversing drug resistance in canmiRNA expression profiles in pediatric glioblastoma multiforme 240 Am J Cancer Res 2015;5(1):231-242 cer cells. "
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    • "It has been reported that miRNA-21 plays a vital role in keratinocyte migration and in re-epithelialization during wound healing, directly targeting TIMP3 in vitro and in vivo [25]. By down-regulating PDCD4, miRNA-21 contributes to glioblastoma proliferation while its inhibition induced apoptosis and decreased cell cycle progression, down-regulating EGFR, activated akt, cyclin D and bcl-2 in vitro and in vivo suggesting an important therapeutic potential of miRNA-21 [26], [27]. Thus, the fact that miRNA-21 is frequently elevated in most malignancies and its in vivo knockdown suppresses tumorous potential, suggests that its high levels are essential for promoting pathological cell growth. "
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    • "In a glioma mouse model important decrease in growth tumor was observed after inhibiting miR-10b by intratumoral antimiR injection [101]. Other animal studies also reported tumor reduction following inhibition of oncogenic miR-21 in GBM [116]. MiR-21 and miR-195 down regulation in GBM culture cells sensitize cells to treatment with 5-fluorouracil and temozolomide [117, 118]. "
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