CCAT1 stimulation of the symmetric division of NSCLC stem cells through activation of the Wnt signalling cascade

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Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortalities worldwide, yet this condition remains a poorly understood malignancy, and the subgroup of cancer stem cells (CSCs) leading to therapeutic resistance and adverse prognosis have not been well studied. CSCs frequently undergo symmetric division, which facilitates expansion of the stem cell pool, contributing to long-term relapse and therapy failure. CCAT1 could act as a miRNA sponge to influence downstream genes; however, its roles in NSCLC stem cell are unclear. We first identified activation of Wnt signalling in NSCLC. Analysis of the clinical data from a public database showed a significant decrease of the Wnt signalling repressor Let-7c. Using biological and informatics analyses, we hypothesized that CCAT1 stimulated the main factors of the Wnt signalling pathway, of which the three most deregulated genes were further confirmed by western blotting. Axitinib, a Wnt signalling inhibitor, effectively stimulated asymmetric division, similar to Let-7c. CCAT1 inhibition decreased the ratio of symmetric division of stem cells, and both Let-7c and Axitinib significantly abolished CCAT1 induction of symmetric division by inhibiting Wnt signalling. Restoration of Let-7c blocked the CCAT1 effects, forming the CCAT1/Let-7c/Wnt regulatory axis to control the division of lung cancer stem cells. Stimulation of stem cells to divide asymmetrically by delivering Let-7c or suppressive Axitinib could represent prospective strategies for curing lung cancer patients.

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Acknowledgements

The authors acknowledge the Center for Translational Medicine of The First Affiliated Hospital of Xi’an Jiaotong University for technical assistance. The authors would like to thank Peijun Liu for assistance with experiments and technical guidance. The present study was financially supported through grants from the National Science Foundation for Young Scientists of China (grant No. 81602597) (Referred to Xin Sun). This work was also supported in part by Technical Research and Development Projects of Shaanxi Province (grant No. 2010K14-03) (Referred to Dapeng Liu), the National Natural Science Foundation of China (grant No. 81272418) (Referred to Hong Ren), and the Natural Science Foundation of Shaanxi Province (grant No. 2016JM8007) (Referred to Jing Zhang).

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Correspondence to H Ren or X Sun.

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All of the co-authors of the present study approved this article for publication. The authors declare that they have no conflicts of interest.

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Supplementary Information accompanies this paper on Gene Therapy website

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