Targeting of TGFβ signature and its essential component CTGF by miR-18 correlates with improved survival in glioblastoma

The miR-17 similar to 92 cluster is thought to be an oncogene, yet its expression is low in glioblastoma multiforme (GBM) cell lines. This could allow unfettered expression of miR-17 similar to 92 target genes such as connective tissue growth factor (CTGF; or CCN2), which is known to contribute to GBM pathogenesis. Indeed, microRNA-18a (but not other miR-17 similar to 92 members) has a functional site in the CTGF 3' UTR, and its forced reexpression sharply reduces CTGF protein and mRNA levels. Interestingly, it also reduces the levels of CTGF primary transcript. The unexpected effects of miR-18a on CTGF transcription are mediated in part by direct targeting of Smad3 and ensuing weakening of TGF beta signaling. Having defined the TGF beta signature in GBM cells, we demonstrate a significant anti-correlation between miR-18 and TGF beta signaling in primary GBM samples from The Cancer Genome Atlas. Most importantly, high levels of miR-18 combined with low levels of the TGF beta metagene correlate with prolonged patient survival. Thus, low expression of the miR-17 similar to 92 cluster, and specifically miR-18a, could significantly contribute to GBM pathogenesis.