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Downregulation of Cholinergic Receptor Alpha 5 (CHRNA5) in MCF7 breast cancer cells

ABSTRACT: Cholinergic Receptor Nicotinic Alpha 5 (CHRNA5), an important susceptibility locus for nicotine addiction and lung cancer, is not well studied in breast cancer. In our study, CHRNA5 was transiently depleted in MCF7 cells and transcriptomic changes were compared to siRNA controls. We for the first time showed by microarray analysis that silencing of CHRNA5 in MCF7 breast cancer cells, downregulated genes involved in the cell cycle and proliferation while resulting in reduced cell viability, DNA synthesis and G1 growth arrest. In addition, simultaneous treatment of CHRNA5 siRNA and topoisomerase inhibitors showed an important role of CHRNA5 in increased drug sensitivity. Phalloidin stained CHRNA5 siRNA treated cells on the other hand exhibited a distinct cellular morphotype with increased cellular extensions and a transcriptome characterized by mixed expression of epithelial-mesenchymal genes. Through bioinformatics analysis of the public transcriptome data we demonstrated a strong positive association of expression signature of CHRNA5 RNAi with that of a differentiated cell as well as hormone starvation. Hence, our study implicates CHRNA5 as an antiproliferative differentiation marker in breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE89333 | GEO | 2018/12/16

REPOSITORIES: GEO

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Project description:Epilepsy is a common neurological disease, manifested in unprovoked recurrent seizures. Epileptogenesis may develop due to genetic or pharmacological origins or following injury, but it remains unclear how the unaffected brain escapes this susceptibility to seizures. Here, we report that dynamic changes in forebrain microRNA (miR)-211 in the mouse brain shift the threshold for spontaneous and pharmacologically-induced seizures alongside changes in the cholinergic pathway genes, implicating this miR in the avoidance of seizures. We identified miR-211 as a putative attenuator of cholinergic-mediated seizures by intersecting forebrain miR profiles that were Ago-precipitated, synaptic vesicle target-enriched or differentially expressed under pilocarpine-induced seizures, and validated TGFBR2 and the nicotinic anti-inflammatory acetylcholine receptor nAChRa7 as murine and human miR-211 targets, respectively. To explore the link between miR-211 and epilepsy, we engineered dTg-211 mice with doxycycline-suppressible forebrain overexpression of miR-211. These mice reacted to doxycycline exposure by spontaneous electrocorticography-documented non-convulsive seizures, accompanied by forebrain accumulation of the convulsive seizures-mediating miR-134. RNA-sequencing demonstrated in doxycycline-treated dTg-211 cortices over-representation of synaptic activity, Ca2+ transmembrane transport, TGFβR-II signaling and cholinergic synapse pathways. Additionally, a cholinergic dis-regulated mouse model over-expressing a miR-refractory acetylcholinesterase-R splice variant showed a parallel propensity for convulsions, miR-211 decreases and miR-134 elevation. Our findings demonstrate that in mice, dynamic miR-211 decreases induce hyper-synchronization, non-convulsive and convulsive seizures, accompanied by expression changes in cholinergic and TGFBR2 pathways as well as in miR-134. Realizing the importance of miR-211 dynamics opens new venues for translational diagnosis of and interference with epilepsy.

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Downregulation of Cholinergic Receptor Alpha 5 (CHRNA5) in MCF7 breast cancer cells

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