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  • br In conclusion our study

    2022-05-22


    In conclusion, our study shows, both in vitro and in vivo, that overexpression of dupα7 in human NSCLC cell lines inhibits the onco-genic function of the tobacco-activated ancestral subunit that makes up α7-nAChR. Our finding is noteworthy, since to date few functions have been attributed to human-specific duplicate genes, even though these genes have been recognized as a primary source of evolutionary in-novation [44]. Eichler's group was one of the first to report a com-pendium of human-specific gene duplications identified [45]. Their study, which compiles 88 complete gene duplications that have oc-curred since the divergence of humans and chimpanzees, includes the CHRFAM7A gene. However, unlike other genes in the above study that provide genetic redundancy with respect to the parent gene, our data indicate that the CHRFAM7A gene acquires a function that differs from that of the ancestral gene (CHRNA7) and that negatively regulates its oncogenic activity. Interestingly, the new function of the CHRFAM7A gene, revealed here, is quite like the function recently attributed to another human-specific gene (SRGAP2C), the result of a partial dupli-cation of the ancestral gene (SRGAP2) expressed in LY 379268 [46]. Ac-cording to their study, the protein resulting from the duplicated gene would form a heterodimer with that of the ancestral gene, thereby se-questrating it and, thus, inhibiting its function. Inhibiting SRGAP2 function would have resulted in a greater density of dendritic spines and the consequent evolutionary advantage for the development of the neocortex in humans. Whether dupα7 naturally expressed in human primary tumors from NSCLC patients has a pathophysiological role does require further studies; in fact, we have recently reported that dupα7 gene expression is down-regulated whereas that of α7 is up-regulated in the above tumors compared to their paired healthy lung specimens [9]. Thus, there is a possibility that the deficient expression of the en-dogenous duplicated subunit along with the overexpression of the an-cestral subunit in the tumor would facilitate the oncogenic process promoted by tobacco smoking in NSCLC patients, suggesting that up-regulation of dupα7 expression in these tumors could offer a potential new therapeutic target in these patients. r> Conflicts of interest statement
    The authors declare that they have no conflicts of interests.
    Acknowledgements
    This study was supported by grants from the Ministry of Economy, Industry and Competitiveness, Government of Spain (SAF2014-56623-R and SAF2017-82689-R) and from the “Mutua Madrileña Investigación Biomédica” Foundation, Spain (FMM2011) to C. LY 379268 Montiel and F. Arnalich. J.L. Cedillo was recipient of a FPU fellowship (Ministry of Education, Culture and Sports, Government of Spain); A. Bordas and R. L. Arribas are recipients of a FPI fellowship (Autonomous University of Madrid); C. Martín-Sanchez was recipient of a FPI fellowship (Ministry of Economy, Industry and Competitiveness, Government of Spain).  Lung Cancer 128 (2019) 134–144
    Finally, M. Extremera and G. Atienza were hired with funds from the grants specified above. The authors thank Raquel Marcos-Hernández (Laboratory Technician) from Pathology Service, La Paz University Hospital, Madrid), for her help with the IHC experiments.
    References
    [3] C. Schaal, S. Chellappan, Nicotine-mediated regulation of nicotinic acetylcholine receptors in non-small cell lung adenocarcinoma by E2F1 and STAT1 transcription factors, PLoS One 11 (2016) e0156451.
    [16] D.P. Locke, N. Archidiacono, D. Misceo, et al., Refinement of a chimpanzee peri-centric inversion breakpoint to a segmental duplication cluster, Genome Biol. 4 (2003) R50.