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bioRxiv · 10.1101/2022.03.21.485231

Downregulation of Stem-loop binding protein by nicotine via α7-nicotinic acetylcholine receptor and its role in nicotine-induced cell transformation

Sun, Q.·Chen, D.·Raja, A.·Grunig, g.·Zelikoff, J.·Jin, C.
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Abstract

The use of electronic-cigarettes (e-cigs) has increased substantially in recent years, particularly among the younger generations. Liquid nicotine is the main component of e-cigs. Previous studies have shown that mice exposed to e-cig aerosols developed lung adenocarcinoma and bladder hyperplasia. These findings implicated a potential role for e-cig aerosols and nicotine in cancer development, although the underlying mechanisms are not fully understood. Here we report that exposure to liquid nicotine or nicotine aerosol generated from e-cig induces downregulation of Stem-loop binding protein (SLBP) and polyadenylation of canonical histone mRNAs in human bronchial epithelial cells and in mice lungs. Canonical histone mRNAs typically do not end in a poly(A) tail and the acquisition of such a tail via depletion of SLBP has been shown to causes chromosome instability. We show that nicotine-induced SLBP depletion is reversed by an inhibitor of 7-nAChR (nicotinic acetylcholine receptors) or siRNA specific for 7-nAChR, indicating a nAChR-dependent reduction of SLBP by nicotine. Moreover, not only CDK1 and CK2, two kinases well known for their function for SLBP phosphorylation and degradation, but also CDK2 and PI3K/AKT pathways are shown to be involved, 7-nAChR-dependently, in nicotine-induced SLBP depletion. Importantly, nicotine-induced anchorage-independent cell growth is attenuated by inhibition of 7-nAChR and is rescued by overexpression of SLBP. We propose that the SLBP depletion and polyadenylation of canonical histone mRNAs via activation of 7-nAChR and a series of downstream signal transduction pathways, are critical for nicotine-induced cell transformation and potential carcinogenesis.

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Sun, Q., Chen, D., Raja, A., Grunig, g., Zelikoff, J., Jin, C.. 2022-03-21. Downregulation of Stem-loop binding protein by nicotine via α7-nicotinic acetylcholine receptor and its role in nicotine-induced cell transformation. https://doi.org/10.1101/2022.03.21.485231

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