Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Authors: Patel, Akash J.; Wan, Ying-Wooi; Al-Ouran, Rami; Revelli, Jean-Pierre; Cardenas, Maria F.; Oneissi, Mazen; Xi, Liu; Jalali, Ali; Magnotti, John F.; Muzny, Donna M.; Doddapaneni, HarshaVardhan; Sebastian, Sherly; Heck, Kent A.; Goodman, Clay; Gopinath, Shankar P.; Liu, Zhandong; Rao, Ganesh; Plon, Sharon E.; Yoshor, Daniel; Wheeler, David A.; Zoghbi, Huda Y.; Klisch, Tiemo J.
Abstract
Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all 3 World Health Organization (WHO) grades (I through III) using clinical, gene expression, and sequencing data. Unsupervised clustering analysis identified 3 molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which classifies more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell-cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.
FGF23 protects osteoblasts from dexamethasone-induced oxidative injury
AGING-US
Authors: Ji, Feng; Hu, Xiaohui; Hu, Wenhao; Hao, Yue-Dong
Abstract
Dexamethasone (DEX) can exert a cytotoxic effect on cultured osteoblasts. The current study explored the potential osteoblast cytoprotective effect of fibroblast growth factor 23 (FGF23). In OB-6 human osteoblastic cells and primary murine osteoblasts, FGF23 induced phosphorylation of the receptor FGFR1 and activated the downstream Akt-S6K1 signaling. FGF23-induced FGFR1-Akt-S6K phosphorylation was largely inhibited by FGFR1 shRNA, but augmented with ectopic FGFR1 expression in OB-6 cells. FGF23 attenuated DEX-induced death and apoptosis in OB-6 cells and murine osteoblasts. Its cytoprotective effects were abolished by FGFR1 shRNA, Akt inhibition or Akt1 knockout. Conversely, forced activation of Akt inhibited DEX-induced cytotoxicity in OB-6 cells. Furthermore, FGF23 activated Akt downstream nuclear-factor-E2-related factor 2 (Nrf2) signaling to alleviate DEX-induced oxidative injury. On the contrary, Nrf2 shRNA or knockout almost reversed FGF23-induced osteoblast cytoprotection against DEX. Collectively, FGF23 activates FGFR1-Akt and Nrf2 signaling cascades to protect osteoblasts from DEX-induced oxidative injury and cell death.
COA
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