Our previous work found cancer-testis (CT) genes as a new source of epi-driver candidates of cancer. LIN28B was a CT gene, but the “driver” ability and the activation mechanism in lung adenocarcinoma (LUAD) remain unclear. We observed that LIN28B expression was restricted in testis. It was re-activated in LUAD patients without known genomic alterations in oncogenes and was related to poorer survival. In vitro and In vivo experiments confirmed that the activation of LIN28B could promote the proliferation and metastasis of LUAD cells and can influence cell cycle, DNA damage repair, and genome instability. In addition to the known let-7-LIN28B regulation loop, our results further revealed a let-7-independent Cis-regulator of LIN28B: LIN28B-AS1. LIN28B-AS1 is a CT long non-coding RNA (CT-lncRNA). It altered the messenger RNA stability of LIN28B by directly interacting with another CT protein IGF2BP1 but not with LIN28B and constituted a novel regulation network. In sum, we identify that LIN28B is an “epi-driver” of LUAD and clarify a new lncRNA-activated mechanism of LIN28B, which provide new candidate targets for precise anticancer therapy in the future.
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We thank the TCGA project for use of the multi-omics data of LUAD samples, and the Genotype-Tissue Expression (GTEx) project for use of the expression abundance of multiple normal tissues. This work was supported by Science Fund for Creative Research Groups of the National Natural Science Foundation of China (81521004), the State Key Program of National Natural Science of China (31530047), National Key Research and Development Program of China (2017YFC0907905), the Young Scientists Fund of the National Natural Science Foundation of China (81703295, 81702266), the National Key Basic Research Program Grant (2015CB943003), the Ten Thousand Talent Program, Jiangsu Specially-Appointed Professor project, Natural Science Foundation of Jiangsu Province (BK20160046), the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine), and Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (PPZY2015A067).
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The authors declare that they have no conflict of interest.
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