去泛素化酶USP16具有影响干细胞分化、造血干细胞生成等作用，但其在肿瘤发生发展中的作用却不清楚。我们的前期工作发现，Ras活化可诱导USP16表达；USP16缺失导致细胞增殖能力降低，并显著抑制K-Ras和SV40T共转化的MEFs的体内成瘤能力。利用USP16条件性敲除小鼠和K-RasG12D诱导的小鼠肺肿瘤模型，在肺组织中敲除USP16可抑制K-RasG12D驱动的肺肿瘤的生长。此外，USP16表达下调导致p38信号活化，抑制p38信号通路能逆转USP16下调对细胞生长的抑制作用；提示USP16可能通过抑制p38信号过度活化而促进K-Ras介导的肺肿瘤发生。因此，本项目将重点研究USP16在K-Ras驱动肺肿瘤中的作用，分析调控p38信号的分子机制，探讨USP16调控p38信号在人肺腺癌中的临床意义。本项目将进一步阐明K-Ras驱动肺肿瘤发生的分子机制，从而提供相关治疗新策略。

USP16 is a deubiquitinase that can regulate a variety of biological processes, including stem cell differentiation and hematogenesis. However, the function for USP16 in tumorigenesis is still unclear. Our preliminary data showed that Ras activation in cells significantly increased levels of USP16 protein. USP16 deficiency in K-Ras mutant human lung cancer cells and MEFs cells impaired cell proliferation. Moreover, the tumor formation capability of K-RasG12D/USP16-/-/SV40T-MEFs in nude mice was much lower than that of K-RasG12D/USP16+/+/SV40T-MEFs, as evidenced by delayed tumor onset and decreases in tumor size. In addition, by employing USP16 conditional knockout mice and K-RasG12D-driven mouse lung tumor model, we addressed the effects of USP16 on the development of lung tumor. The results revealed that USP16 deletion in lung tissue significantly suppressed lung tumor formation. Importantly, we found that downregulation of USP16 led to hyper-activation of p38 MAPK, and that suppression of the p38 signaling can attenuated the inhibitory effect of USP16 downregulation on cell growth, suggesting that USP16 may counterbalance p38 hyperactivation, which is a detriment event for K-Ras-driven lung tumorigenesis. Based on these results, we will further pursue the following specific aims: (1) to illustrate the role for USP16 in K-Ras-driven lung tumorigenesis; (2) to clarify the molecular details underlying the USP16-mediated regulation of p38 MAPK; (3) to explore the clinical relevance of USP16 regulation of p38 signaling in human lung cancer. The study will help us establish the notion that induction of USP16 in the context of K-Ras activation may be essential for the fitness of transformed cells, and improve our understanding of the mechanism underlying K-Ras-driven lung adenocarcinoma and the development of the therapeutic strategies for manipulating the patients.