JMJD3剔除促进Kras突变肺腺癌恶化的小鼠模型

Kras激活突变是造成肺腺癌的重要原因，但目前仍没有发现抑制Kras突变肺腺癌的治疗方法，因此，寻找Kras信号通路的调控分子，建立参与Kras突变肺腺癌发生发展的小鼠模型意义重大。动物模型研究发现，Kras激活突变肺腺癌发生的早期会有癌基因诱导的细胞衰老，而细胞实验发现JMJD3是Kras激活引起的细胞衰老的调控分子，提示JMJD3可能参与Kras激活突变肺腺癌的发生发展。因此，我们提出研究如下的假说：（1）Kras突变肺腺癌病人组织中，JMJD3水平下调；（2）剔除JMJD3可以加速Kras突变肺腺癌的发生发展；（3）JMJD3高表达可以抑制Kras突变肺腺癌的发生发展；（4）JMJD3调控的分子可能成为Kras突变肺腺癌的药物靶点。该研究对探索肺腺癌发生发展机理、发现肺腺癌药物新靶点具有重要的意义。

Thearpeutic targeting of Kras mutant lung adenocarcinoma represents a major goal in clinical oncology, but Kras is difficult to target and targeting its effector molecules are not effective for the disease. Kras mutant stimulates the expression of Jmjd3, which activates INK4a/ARF expression by demethylating H3K27me3, and provokes ARF mediated cellular senescence to suppress tumor formation and progression. These results suggest that JMJD3 regulates Kras mutant cell senescence and participates in Kras mutant lung adenocarcinoma developmend and progression. Therefore, we propose to study the hypothesis: (1) JMJD3 is downregulated in Kras mutant lung adenocarcinoma, (2) Jmjd3 loss can promote Kras mutant lung cancer development and progression, (3) Overexpression of JMJD3 will suppress Kras mutant lung cancer development and progression, (4) Jmjd3 regulated genes can be therapeutic targets for Kras mutant lung cancer. This study may provide a disease mechanism and therapeutic targets for Kras mutant lung adenocarcinoma.