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.

中文翻译：

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睾丸非编码RNA LIN28B-AS1通过与肺腺癌中的IGF2BP1相互作用激活驱动基因LIN28B。

我们以前的工作发现癌症-睾丸（CT）基因是新的epi-driver候选癌症来源。LIN28B是一个CT基因，但肺腺癌（LUAD）的“驱动”能力和激活机制尚不清楚。我们观察到LIN28B表达在睾丸中受到限制。在没有已知致癌基因基因组改变的LUAD患者中，它被重新激活，并且与较差的存活率有关。体外和体内实验证实，LIN28B的激活可以促进LUAD细胞的增殖和转移，并且可以影响细胞周期，DNA损伤修复和基因组不稳定。除了已知的let-7-LIN28B调节环外，我们的结果还揭示了LIN28B的let-7独立的顺式调节子：LIN28B-AS1。LIN28B-AS1是CT长的非编码RNA（CT-IncRNA）。它通过直接与另一种CT蛋白IGF2BP1相互作用但不与LIN28B相互作用而改变了LIN28B的信使RNA稳定性，并构成了一个新型的调控网络。总之，我们确定LIN28B是LUAD的“表象驱动器”，并阐明了LIN28B的新的lncRNA激活机制，这为将来的精确抗癌治疗提供了新的候选靶点。