Bone morphogenetic protein-9 promotes the proliferation of non-small cell lung cancer cells by activating PI3K/Akt and Smad1/5 pathways.

Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer other than small cell lung carcinoma (SCLC), which accounts for about 85% of all lung cancers. Bone morphogenetic protein (BMP)-9 in humans is encoded by the growth differentiation factor 2 gene, which belongs to the transforming growth factor-beta superfamily. In the present study, we explored the role of BMP-9 in A549 and NCI-H1650 cell proliferation and its possible molecular mechanisms. 25 NSCLC patients were recruited to evaluate mRNA expression of BMP-9 to determine its clinicopathologic significance. We found that recombinant protein BMP-9 and overexpression of BMP-9 promoted A549 and NCI-H1650 cell proliferation in vitro, which was abolished by phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002). Western blot results revealed that BMP-9 significantly activated the PI3K/Akt and Smad1/5 pathway signaling. In vivo, BMP-9 promoted tumor growth and PI3K/Akt and Smad1/5 signaling pathways in an A549 or NCI-H1650 cell line-derived xenograft model. Knockdown BMP-9 or BMP-9 receptor ALK1 inhibited A549 cell growth in vitro and in vivo, which was associated with regulating the PI3K/Akt and Smad1/5 signaling pathways. These results demonstrated that BMP-9 promoted A549 and NCI-H1650 cell proliferation via PI3K/Akt and Smad1/5 signaling pathways.

Disruption of neurogenesis and cortical development in transgenic mice misexpressing Olig2, a gene in the Down syndrome critical region.

The basic helix-loop-helix (bHLH) transcription factor Olig2 is crucial for mammalian central nervous system development. Human ortholog OLIG2 is located in the Down syndrome critical region in trisomy 21. To investigate the effect of Olig2 misexpression on brain development, we generated a developmentally regulated Olig2-overexpressing transgenic line with a Cre/loxP system. The transgenic mice with Olig2 misexpression in cortical neural stem/progenitor cells exhibited microcephaly, cortical dyslamination, hippocampus malformation, and profound motor deficits. Ectopic misexpression of Olig2 impaired cortical progenitor proliferation and caused precocious cell cycle exit. Massive neuronal cell death was detected in the developing cortex of Olig2-misexpressing mice. In addition, Olig2 misexpression led to a significant downregulation of neuronal specification factors including Ngn1, Ngn2 and Pax6, and a defect in cortical neurogenesis. Chromatin-immunoprecipitation and sequencing (ChIP-Seq) analysis indicates that Olig2 directly targets the promoter and/or enhancer regions of Nfatc4, Dscr1/Rcan1 and Dyrk1a, the critical neurogenic genes that contribute to Down syndrome phenotypes, and inhibits their expression. Together, our study suggests that Olig2 misexpression in neural stem cells elicits neurogenesis defects and neuronal cell death, which may contribute to developmental disorders including Down syndrome, where OLIG2 is triplicated on chromosomal 21.